%0 Journal Article %J J Alzheimers Dis %D 2024 %T African Ancestry Individuals with Higher Educational Attainment Are Resilient to Alzheimer's Disease Measured by pTau181. %A Rajabli, Farid %A Seixas, Azizi A %A Akgun, Bilcag %A Adams, Larry D %A Inciute, Jovita %A Hamilton, Kara L %A Whithead, Patrice G %A Konidari, Ioanna %A Gu, Tianjie %A Arvizu, Jamie %A Golightly, Charles G %A Starks, Takiyah D %A Laux, Renee %A Byrd, Goldie S %A Haines, Jonathan L %A Beecham, Gary W %A Griswold, Anthony J %A Vance, Jeffery M %A Cuccaro, Michael L %A Pericak-Vance, Margaret A %K Alzheimer Disease %K Apolipoprotein E4 %K Cognitive Dysfunction %K Educational Status %K Humans %K Resilience, Psychological %X

BACKGROUND: Cognitive and functional abilities in individuals with Alzheimer's disease (AD) pathology (ADP) are highly variable. Factors contributing to this variability are not well understood. Previous research indicates that higher educational attainment (EA) correlates with reduced cognitive impairments among those with ADP. While cognitive and functional impairments are correlated, they are distinguishable in their manifestations.

OBJECTIVE: To investigate whether levels of education are associated with functional impairments among those with ADP.

METHODS: This research involved 410 African American (AA) individuals (Institutional Review Boards 20070307, 01/27/2023) to ascertain whether EA correlates with functional resilience and if this effect varies between APOE ɛ4 carriers and non-carriers. Utilizing EA as a cognitive reserve proxy, CDR-FUNC as a functional difficulties measure, and blood pTau181 as an ADP proxy, the non-parametric Mann-Whitney U test assessed the relationship between EA and CDR-FUNC in individuals with advanced pTau181 levels.

RESULTS: The results showed that EA correlated with functional difficulties in AA individuals with high levels of pTau181, such that individuals with high EA are more likely to have better functional ability compared to those with lower EA (W = 730.5, p = 0.0007). Additionally, we found that the effect of high EA on functional resilience was stronger in ɛ4 non-carriers compared to ɛ4 carriers (W = 555.5, p = 0.022).

CONCLUSION: This study extends the role of cognitive reserve and EA to functional performance showing that cognitive reserve influences the association between ADP burden and functional difficulties. Interestingly, this protective effect seems less pronounced in carriers of the strong genetic risk allele ɛ4.

%B J Alzheimers Dis %V 98 %P 221-229 %8 2024 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/38393909?dopt=Abstract %R 10.3233/JAD-231116 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Alzheimer's Disease and Cognitive Decline in Patients with Cardiovascular Diseases Along the Heart-Brain Axis. %A Trieu, Calvin %A Van Harten, Argonde C %A Leeuwis, Anna E %A Exalto, Lieza G %A Hooghiemstra, Astrid M %A Verberk, Inge M W %A Allaart, Cor P %A Brunner-La Rocca, Hans-Peter %A Kappelle, L Jaap %A van Oostenbrugge, Robert J %A Biessels, Geert-Jan %A Teunissen, Charlotte E %A van der Flier, Wiesje M %X

BACKGROUND: We hypothesize that Alzheimer's disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases.

OBJECTIVE: To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline.

METHODS: From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-β42/40 (Aβ42/40), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models with terms for biomarker, time and biomarker*time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline.

RESULTS: Among patients, Aβ42/40 was not associated with cognitive performance at baseline. However, lower Aβ42/40 was associated with steeper decline in global cognition (β±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (-0.14±0.04) and memory (-0.31±0.09) and with steeper decline in global cognition (-0.07±0.02), memory (-0.09±0.04), attention (-0.05±0.02), and language (-0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (-0.22±0.05), memory (-0.43±0.10), attention (-0.14±0.06), language (-0.15±0.05), and executive functioning (-0.15±0.05) and steeper decline in global cognition (-0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (-0.16±0.04), memory (-0.28±0.09), attention (-0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found.

CONCLUSIONS: Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases.

%B J Alzheimers Dis %8 2024 Mar 12 %G eng %R 10.3233/JAD-231096 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Blood-Based mtDNA Quantification Indicates Population-Specific Differences Associated with Alzheimer's Disease-Related Risk. %A Gorham, Isabelle K %A Reid, Danielle Marie %A Sun, Jie %A Zhou, Zhengyang %A Barber, Robert C %A Phillips, Nicole R %X

BACKGROUND: Age is known to be the biggest risk factor for Alzheimer's disease (AD), and Mexican Americans (MAs), who are one of the fastest-aging populations in the United States, are at a uniquely elevated risk. Mitochondrial stress and dysfunction are key players in the progression of AD and are also known to be impacted by lifestyle and environmental exposures/stressors.

OBJECTIVE: This study aimed to identify population-specific differences in indicators of mitochondrial stress and dysfunction associated with AD risk that are detectable in the blood.

METHODS: Examining blood from both non-Hispanic white (NHW) and MA participants (N = 527, MA n = 284, NHW n = 243), mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) copy numbers were assessed through quantitative PCR. Data was stratified by population and sample type, and multiple linear regression analyses were performed to identify factors that may influence this phenotype of mitochondrial dysfunction.

RESULTS: In the MA cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and body mass index, CDR sum of boxes score, the APOEɛ2/ɛ3 genotype, and education. Further, there was a significant relationship between cell-free mtDNA copy number and both education and CDR sum score. In the NHW cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and both age and CDR sum score. Age was associated with cell-free mtDNA in the NHW cohort.

CONCLUSIONS: This evidence supports the existence of population-based differences in the factors that are predictive of this blood-based phenotype of mitochondrial dysfunction, which may be indicative of cognitive decline and AD risk.

%B J Alzheimers Dis %V 97 %P 1407-1419 %8 2024 Jan 30 %G eng %N 3 %R 10.3233/JAD-230880 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Comprehensive Analysis of Metabolites in Postmortem Brains of Patients with Alzheimer's Disease. %A Kurano, Makoto %A Saito, Yuko %A Yatomi, Yutaka %X

BACKGROUND: Disturbed metabolism has been proposed as being involved in the pathogenesis of Alzheimer's disease (AD), and more evidence from human AD brains is required.

OBJECTIVE: In this study, we attempted to identify or confirm modulations in the levels of metabolites associated with AD in postmortem AD brains.

METHODS: We performed metabolomics analyses using a gas chromatography mass spectrometry system in postmortem brains of patients with confirmed AD, patients with CERAD score B, and control subjects.

RESULTS: Impaired phosphorylation of glucose and elevation of several tricarboxylic acid (TCA) metabolites, except citrate, were observed and the degree of impaired phosphorylation and elevation in the levels of the TCA cycle metabolites were negatively and positively correlated, respectively, with the clinical phenotypes of AD. The levels of uronic acid pathway metabolites were modulated in AD and correlated positively with the amyloid-β content. The associations of nucleic acid synthesis and amino acid metabolites with AD depended on the kinds of metabolites; in particular, the contents of ribose 5-phosphate, serine and glycine were negatively correlated, while those of ureidosuccinic acid and indole-3-acetic acid were positively modulated in AD. Comprehensive statistical analyses suggested that alterations in the inositol pathway were most closely associated with AD.

CONCLUSIONS: The present study revealed many novel associations between metabolites and AD, suggesting that some of these might serve as novel potential therapeutic targets for AD.

%B J Alzheimers Dis %V 97 %P 1139-1159 %8 2024 Jan 30 %G eng %N 3 %R 10.3233/JAD-230942 %0 Journal Article %J J Alzheimers Dis %D 2024 %T A Continuous Extension of Gene Set Enrichment Analysis Using the Likelihood Ratio Test Statistics Identifies Vascular Endothelial Growth Factor as a Candidate Pathway for Alzheimer's Disease via ITGA5. %A Mahzarnia, Ali %A Lutz, Michael W %A Badea, Alexandra %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Biomarkers %K Cognitive Dysfunction %K Humans %K Likelihood Functions %K tau Proteins %K Vascular Endothelial Growth Factor A %X

BACKGROUND: Alzheimer's disease (AD) involves brain neuropathologies such as amyloid plaque and hyperphosphorylated tau tangles and is accompanied by cognitive decline. Identifying the biological mechanisms underlying disease onset and progression based on quantifiable phenotypes will help understand disease etiology and devise therapies.

OBJECTIVE: Our objective was to identify molecular pathways associated with hallmark AD biomarkers and cognitive status, accounting for variables such as age, sex, education, and APOE genotype.

METHODS: We introduce a pathway-based statistical approach, extending the gene set likelihood ratio test to continuous phenotypes. We first analyzed independently each of the three phenotypes (amyloid-β, tau, cognition) using continuous gene set likelihood ratio tests to account for covariates, including age, sex, education, and APOE genotype. The analysis involved 634 subjects with data available for all three phenotypes, allowing for the identification of common pathways.

RESULTS: We identified 14 pathways significantly associated with amyloid-β; 5 associated with tau; and 174 associated with cognition, which showed a larger number of pathways compared to biomarkers. A single pathway, vascular endothelial growth factor receptor binding (VEGF-RB), exhibited associations with all three phenotypes. Mediation analysis showed that among the VEGF-RB family genes, ITGA5 mediates the relationship between cognitive scores and pathological biomarkers.

CONCLUSIONS: We presented a new statistical approach linking continuous phenotypes, gene expression across pathways, and covariates like sex, age, and education. Our results reinforced VEGF RB2's role in AD cognition and demonstrated ITGA5's significant role in mediating the AD pathology-cognition connection.

%B J Alzheimers Dis %V 97 %P 635-648 %8 2024 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/38160360?dopt=Abstract %R 10.3233/JAD-230934 %0 Journal Article %J J Alzheimers Dis %D 2024 %T FACEmemory®, an Innovative Online Platform for Episodic Memory Pre-Screening: Findings from the First 3,000 Participants. %A Alegret, Montserrat %A García-Gutiérrez, Fernando %A Muñoz, Nathalia %A Espinosa, Ana %A Ortega, Gemma %A Lleonart, Núria %A Rodríguez, Isabel %A Rosende-Roca, Maitee %A Pytel, Vanesa %A Cantero-Fortiz, Yahveth %A Rentz, Dorene M %A Marquié, Marta %A Valero, Sergi %A Ruiz, Agustin %A Butler, Christopher %A Boada, Merce %X

BACKGROUND: The FACEmemory® online platform comprises a complex memory test and sociodemographic, medical, and family questions. This is the first study of a completely self-administered memory test with voice recognition, pre-tested in a memory clinic, sensitive to Alzheimer's disease, using information and communication technologies, and offered freely worldwide.

OBJECTIVE: To investigate the demographic and clinical variables associated with the total FACEmemory score, and to identify distinct patterns of memory performance on FACEmemory.

METHODS: Data from the first 3,000 subjects who completed the FACEmemory test were analyzed. Descriptive analyses were applied to demographic, FACEmemory, and medical and family variables; t-test and chi-square analyses were used to compare participants with preserved versus impaired performance on FACEmemory (cut-off = 32); multiple linear regression was used to identify variables that modulate FACEmemory performance; and machine learning techniques were applied to identify different memory patterns.

RESULTS: Participants had a mean age of 50.57 years and 13.65 years of schooling; 64.07% were women, and 82.10% reported memory complaints with worries. The group with impaired FACEmemory performance (20.40%) was older, had less schooling, and had a higher prevalence of hypertension, diabetes, dyslipidemia, and family history of neurodegenerative disease than the group with preserved performance. Age, schooling, sex, country, and completion of the medical and family history questionnaire were associated with the FACEmemory score. Finally, machine learning techniques identified four patterns of FACEmemory performance: normal, dysexecutive, storage, and completely impaired.

CONCLUSIONS: FACEmemory is a promising tool for assessing memory in people with subjective memory complaints and for raising awareness about cognitive decline in the community.

%B J Alzheimers Dis %V 97 %P 1173-1187 %8 2024 Jan 30 %G eng %N 3 %R 10.3233/JAD-230983 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Herpes Simplex Viral Infection Doubles the Risk of Dementia in a Contemporary Cohort of Older Adults: A Prospective Study. %A Vestin, Erika %A Boström, Gustaf %A Olsson, Jan %A Elgh, Fredrik %A Lind, Lars %A Kilander, Lena %A Lövheim, Hugo %A Weidung, Bodil %X

BACKGROUND: Evidence indicates that herpes simplex virus (HSV) participates in the pathogenesis of Alzheimer's disease (AD).

OBJECTIVE: We investigated AD and dementia risks according to the presence of herpesvirus antibodies in relation to anti-herpesvirus treatment and potential APOE ɛ4 carriership interaction.

METHODS: This study was conducted with 1002 dementia-free 70-year-olds living in Sweden in 2001-2005 who were followed for 15 years. Serum samples were analyzed to detect anti-HSV and anti-HSV-1 immunoglobulin (Ig) G, anti-cytomegalovirus (CMV) IgG, anti-HSV IgM, and anti-HSV and anti-CMV IgG levels. Diagnoses and drug prescriptions were collected from medical records. Cox proportional-hazards regression models were applied.

RESULTS: Cumulative AD and all-cause dementia incidences were 4% and 7%, respectively. Eighty-two percent of participants were anti-HSV IgG carriers, of whom 6% received anti-herpesvirus treatment. Anti-HSV IgG was associated with a more than doubled dementia risk (fully adjusted hazard ratio = 2.26, p = 0.031). No significant association was found with AD, but the hazard ratio was of the same magnitude as for dementia. Anti-HSV IgM and anti-CMV IgG prevalence, anti-herpesvirus treatment, and anti-HSV and -CMV IgG levels were not associated with AD or dementia, nor were interactions between anti-HSV IgG and APOE ɛ4 or anti-CMV IgG. Similar results were obtained for HSV-1.

CONCLUSIONS: HSV (but not CMV) infection may be indicative of doubled dementia risk. The low AD incidence in this cohort may have impaired the statistical power to detect associations with AD.

%B J Alzheimers Dis %V 97 %P 1841-1850 %8 2024 Feb 13 %G eng %N 4 %R 10.3233/JAD-230718 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Hypertension, Cognitive Decline, and Mild Cognitive Impairment Among Diverse Hispanics/Latinos: Study of Latinos-Investigation of Neurocognitive Aging Results (SOL-INCA). %A Márquez, Freddie %A Tarraf, Wassim %A Stickel, Ariana M %A Gonzalez, Kevin A %A Testai, Fernando D %A Cai, Jianwen %A Gallo, Linda C %A Talavera, Gregory A %A Daviglus, Martha L %A Wassertheil-Smoller, Sylvia %A DeCarli, Charles %A Schneiderman, Neil %A González, Hector M %X

BACKGROUND: Hypertension can have deleterious effects on cognitive function; however, few studies have examined its effects on cognition among Hispanics/Latinos.

OBJECTIVE: To assess associations between hypertension status with 1) change in cognitive performance, and 2) having mild cognitive impairment (MCI) among diverse Hispanics/Latinos.

METHODS: This population-based, prospective cohort, multisite study included Hispanic/Latino adults aged 45 to 72 years in enrolled in the Hispanic Community Health Study/Study of Latinos at Visit 1 (2008-2011; mean age of 63.40±8.24 years), and the Study of Latinos-Investigation of Neurocognitive Aging at Visit 2 (2016-2018), with a mean follow-up duration of 7 years (n = 6,173). Hypertension status was assessed at both visits: normotension (no hypertension), incident hypertension (only at Visit 2), and persistent hypertension (at both visits). We examined change in cognitive performance and having MCI (only assessed at Visit 2) relative to hypertension status and adjusted for demographics and cardiovascular disease risk factors.

RESULTS: Compared to normotension, persistent hypertension was associated with significantly increased decline in verbal fluency (β= -0.08; CI = [-0.16;-0.01]; p < 0.05), and processing speed (β= -0.11; CI = [-0.20;-0.02]; p < 0.05). Incident hypertension was not associated with significant change in cognitive performance. Both incident (OR = 1.70; CI = [1.16;2.50]; p < 0.01) and persistent hypertension (OR = 2.13; CI = [1.57;2.88]; p < 0.001) were associated with significantly higher odds ratios of having MCI.

CONCLUSIONS: These findings indicate that persistent hypertension is associated with clinical impairment and domain-specific cognitive decline in middle-aged and older Hispanics/Latinos. It underscores the importance of monitoring blood pressure in routine healthcare visits beginning at midlife in this population to reduce the burden of cognitive decline.

%B J Alzheimers Dis %V 97 %P 1449-1461 %8 2024 Jan 30 %G eng %N 3 %R 10.3233/JAD-230424 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Improving Healthcare Quality and Clinical Outcomes for Persons with Dementia in the Sub-Acute Hospital Through Person-Centered Care Practice. %A Chenoweth, Lynn %A Burley, Claire %A Cook, Jacquelene %A Cheah, Seong-Leang %A Reyes, Patricia %A Maiden, Genevieve %A McGuire, Jane %A McCade, Donna %A Brodaty, Henry %A Sukhapure, Mayouri %A Harrison, Fleur %A Williams, Anna %X

BACKGROUND: Person-centered care is considered beneficial for persons with dementia.

OBJECTIVE: To evaluate the impact of a person-centered knowledge translation intervention on the quality of healthcare and outcomes for persons with dementia.

METHODS: Over nine months, sub-acute hospital nursing, allied health, and medical staff (n = 90) participated in online and/or face-to-face person-centered education and were supported by senior nursing, allied health, and medical staff champions (n = 8) to implement person-centered healthcare. The quality of healthcare service, ward climate and care delivery were evaluated pre/post study intervention. In the week following hospital admission (Time 1) and week of discharge (Time 3), agitation incidence (co-primary outcome) was assessed in participants with dementia (n = 80). Participant delirium (co-primary outcome), accidents/injuries, psychotropic medicines, length of stay, readmission and discharge destination (secondary outcomes) were compared with a retrospective group (n = 77) matched on demographics, cognition and function in activities of daily living.

RESULTS: Improvements occurred post-intervention in service quality by 17.5% (p = 0.369, phi = 0.08), ward climate by 18.1% (p = 0.291, phi = 0.08), and care quality by 50% (p = 0.000, phi = 0.37). Participant agitation did not change from Time 1 to Time 3 (p = 0.223). Relative to the retrospective group, significant reductions occurred in participant delirium (p = 0.000, phi = 0.73), incidents/injuries (p = 0.000, phi = 0.99), psychotropic medicine use (p = 0.030, phi = 0.09), and hospital readmissions within 30 days (p = 0.002, phi = 0.25), but not in discharge to home (p = 0.171).

CONCLUSIONS: When person-centered healthcare knowledge is translated through staff education and practice support, persons with dementia can experience improved healthcare services and clinical outcomes, while healthcare services can benefit through reductions in unplanned service use.

%B J Alzheimers Dis %V 98 %P 619-628 %8 2024 Mar 19 %G eng %N 2 %R 10.3233/JAD-231056 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Interaction Between Arteriosclerosis and Amyloid-β on Cognitive Function. %A Frentz, Ingeborg %A van Arendonk, Joyce %A Leeuwis, Anna E %A Vernooij, Meike W %A van der Flier, Wiesje M %A Bos, Daniel %A De Deyn, Peter Paul %A Wolters, Frank J %A Ikram, M Arfan %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Arteriosclerosis %K Biomarkers %K Cognition %K Cognitive Dysfunction %K Female %K Humans %K Male %K tau Proteins %X

BACKGROUND: Dementia is a multifactorial disease, with Alzheimer's disease (AD) and vascular pathology often co-occurring in many individuals with dementia. Yet, the interplay between AD and vascular pathology in cognitive decline is largely undetermined.

OBJECTIVE: The aim of the present study was to examine the joint effect of arteriosclerosis and AD pathology on cognition in the general population without dementia.

METHODS: We determined the interaction between blood-based AD biomarkers and CT-defined arteriosclerosis on cognition in 2,229 dementia-free participants of the population-based Rotterdam Study (mean age: 68.9 years, 52% women) cross-sectionally.

RESULTS: Amyloid-β (Aβ)42 and arterial calcification were associated with cognitive performance. After further adjustment for confounders in a model that combined all biomarkers, only arterial calcification remained independently associated with cognition. There was a significant interaction between arterial calcification and Aβ42 and between arterial calcification and the ratio of Aβ42/40. Yet, estimates attenuated, and interactions were no longer statistically significant after adjustment for cardio metabolic risk factors.

CONCLUSIONS: Arteriosclerosis and AD display additive interaction-effects on cognition in the general population, that are due in part to cardio metabolic risk factors. These findings suggest that joint assessment of arteriosclerosis and AD pathology is important for understanding of disease etiology in individuals with cognitive impairment.

%B J Alzheimers Dis %V 97 %P 953-961 %8 2024 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/38217596?dopt=Abstract %R 10.3233/JAD-230604 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Loss of Adaptive DNA Breaks in Alzheimer's Disease Brains. %A Zhang, Xiaoyu %A Haeri, Mohammad %A Swerdlow, Russell H %A Wang, Ning %X

BACKGROUND: DNA breaks accumulate in Alzheimer's disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes. This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks.

OBJECTIVE: To characterize how AD impacts adaptive DNA breaks at nervous system genes.

METHODS: We leveraged the ability of DNA single- and double-strand breaks to activate poly(ADP-ribose) polymerases (PARPs) that conjugate poly(ADP-ribose) (PAR) to adjacent proteins. To characterize the genomic sites harboring DNA breaks in AD brains, nuclei extracted from 3 AD and 3 non-demented autopsy brains (frontal cortex, all male donors, age 78 to 91 years of age) were analyzed through CUT&RUN in which we targeted PAR with subsequent DNA sequencing.

RESULTS: Although the AD brains contained 19.9 times more PAR peaks than the non-demented brains, PAR peaks at nervous system genes were profoundly lost in AD brains, and the expression of these genes was downregulated. This result is consistent with our previous CUT&RUN targeting γH2AX, which marks DNA double-strand breaks. In addition, TOP2B expression was significantly decreased in the AD brains.

CONCLUSIONS: Although AD brains contain a net increase in DNA breaks, adaptive DNA breaks at nervous system genes are lost in AD brains. This could potentially reflect diminished TOP2B expression and contribute to impaired neuron function and cognition in AD patients.

%B J Alzheimers Dis %V 97 %P 1861-1875 %8 2024 Feb 13 %G eng %N 4 %R 10.3233/JAD-231303 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Mendelian Randomization of Blood Metabolites Suggests Circulating Glutamine Protects Against Late-Onset Alzheimer's Disease. %A Ramadan, Ferris A %A Arani, Gayatri %A Jafri, Ayan %A Thompson, Tingting %A Bland, Victoria L %A Renquist, Benjamin %A Raichlen, David A %A Alexander, Gene E %A Klimentidis, Yann C %X

BACKGROUND: Late-onset Alzheimer's disease (LOAD) represents a growing health burden. Previous studies suggest that blood metabolite levels influence risk of LOAD.

OBJECTIVE: We used a genetics-based study design which may overcome limitations of other epidemiological studies to assess the influence of metabolite levels on LOAD risk.

METHODS: We applied Mendelian randomization (MR) to evaluate bi-directional causal effects using summary statistics from the largest genome-wide association studies (GWAS) of 249 blood metabolites (n = 115,082) and GWAS of LOAD (ncase = 21,982, ncontrol = 41,944).

RESULTS: MR analysis of metabolites as exposures revealed a negative association of genetically-predicted glutamine levels with LOAD (Odds Ratio (OR) = 0.83, 95% CI = 0.73, 0.92) that was consistent in multiple sensitivity analyses. We also identified a positive association of genetically-predicted free cholesterol levels in small LDL (OR = 1.79, 95% CI = 1.36, 2.22) on LOAD. Using genetically-predicted LOAD as the exposure, we identified associations with phospholipids to total lipids ratio in large LDL (OR = 0.96, 95% CI = 0.94, 0.98), but not with glutamine, suggesting that the relationship between glutamine and LOAD is unidirectional.

CONCLUSIONS: Our findings support previous evidence that higher circulating levels of glutamine may be a target for protection against LOAD.

%B J Alzheimers Dis %8 2024 Mar 13 %G eng %R 10.3233/JAD-231063 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Odor Identification Across Time in Mutation Carriers and Non-Carriers in Autosomal-Dominant Alzheimer's Disease. %A Almkvist, Ove %A Larsson, Maria %A Graff, Caroline %K Alzheimer Disease %K Cognition %K Cognitive Dysfunction %K Humans %K Mutation %K Odorants %K Presenilin-1 %X

BACKGROUND: Impaired odor identification is a characteristic of sporadic Alzheimer'sdisease(AD), but its presence in autosomal-dominantAD (adAD) remains uncertain.

OBJECTIVE: To investigate odor identification ability in mutation carriers (MC) and non-carriers (NC) of adAD in relation to years to estimated clinical onset clinical onset (YECO) of disease.

METHODS: Participants from six families with autosomal-dominant mutations (APP Swedish, APP Arctic, and PSEN1 mutations) included 20 MC and 20 NC. The groups were comparable in age, gender, education, number of APOE ɛ4 alleles, and YECO, but differed in global cognition (Mini-Mental State Examination). The MC group included individuals in asymptomatic, symptomatic cognitively unimpaired, mild cognitive impairment, and dementia stages of disease, spanning approximately 40 years of the AD continuum. All NC were asymptomatic. Olfactory function was assessed by means of free and cued identification of common odors summarized as total identification.

RESULTS: MC performed poorer than NC in free and total identification. Four MC and none of the NC were anosmic. Olfactory functions in MC and NC were significantly and inversely related to time course (YECO) for both free and total identification. The decline in free identification began approximately 10 years prior to the estimated clinical onset of AD in MC. Odor identification proficiency was associated with episodic memory and executive function in MC and NC.

CONCLUSIONS: Impaired odor identification is present well before the clinical diagnosis of AD in MC and is associated with disease progression. Odor identification ability may be a useful early biomarker for adAD.

%B J Alzheimers Dis %V 97 %P 587-598 %8 2024 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/38160354?dopt=Abstract %R 10.3233/JAD-230618 %0 Journal Article %J J Alzheimers Dis %D 2024 %T RNA Analysis of Circulating Leukocytes in Patients with Alzheimer's Disease. %A Okinaka, Yuka %A Shinagawa, Yoshiyuki %A Claussen, Carsten %A Gul, Sheraz %A Matsui, Ikuko %A Matsui, Yutaka %A Taguchi, Akihiko %X

BACKGROUND: One of the key symptoms of Alzheimer's disease (AD) is the impairment of short-term memory. Hippocampal neurogenesis is essential for short-term memory and is known to decrease in patients with AD. Impaired short-term memory and impaired neurogenesis are observed in aged mice alongside changes in RNA expression of gap junction and metabolism-related genes in circulating leukocytes. Moreover, after penetrating the blood-brain barrier via the SDF1/CXCR4 axis, circulating leukocytes directly interact with hippocampal neuronal stem cells via gap junctions.

OBJECTIVE: Evaluation of RNA expression profiles in circulating leukocytes in patients with AD.

METHODS: Patients with AD (MMSE≧23, n = 10) and age-matched controls (MMSE≧28, n = 10) were enrolled into this study. RNA expression profiles of gap junction and metabolism-related genes in circulating leukocytes were compared between the groups (jRCT: 1050210166).

RESULTS: The ratios of gap junction and metabolism-related genes were significantly different between patients with AD and age-matched controls. However, due to large inter-individual variations, there were no statistically significant differences in the level of single RNA expression between these groups.

CONCLUSIONS: Our findings suggest a potential connection between the presence of circulating leukocytes and the process of hippocampal neurogenesis in individuals with AD. Analyzing RNA in circulating leukocytes holds promise as a means to offer novel insights into the pathology of AD, distinct from conventional markers.

%B J Alzheimers Dis %V 97 %P 1673-1683 %8 2024 Feb 13 %G eng %N 4 %R 10.3233/JAD-230874 %0 Journal Article %J J Alzheimers Dis %D 2024 %T The Role of Impaired Receptor Trafficking in Mediating the Pathological Effects of APOE4 in Alzheimer's Disease. %A Safieh, Mirna %A Liraz, Ori %A Ovadia, Maayan %A Michaelson, Danny %K Alzheimer Disease %K Animals %K Apolipoprotein E3 %K Apolipoprotein E4 %K Apolipoproteins E %K Mice %K Mice, Transgenic %X

BACKGROUND: Apolipoprotein E4 (APOE4) is the most prevalent genetic risk factor of Alzheimer's disease. Several studies suggest that APOE4 binding to its receptors is associated with their internalization and accumulation in intracellular compartments. Importantly, this phenomenon also occurs with other, non-ApoE receptors. Based on these observations, we hypothesized that APOE4 pathological effects are mediated by impairment in the life cycle of distinct receptors (APOER2, LRP1, IR, VEGFR).

OBJECTIVE: To examine the effects of APOE genotype on receptors protein levels and compartmentalization.

METHODS: Primary mouse neurons were prepared from APOE3 or APOE4 targeted replacement mice, or APOE-KO mice. Specific receptors protein levels were evaluated in these neurons, utilizing immunofluorescent staining. Additionally, surface membrane protein levels of those receptors were assessed by cell surface biotinylation assay and ELISA. Receptors' colocalization with intracellular compartments was assessed by double staining and confocal microscopy, followed by colocalization analysis. Finally, LRP1 or APOER2 were knocked-down with CRISPR/Cas9 system to examine their role in mediating APOE4 effects on the receptors.

RESULTS: Our results revealed lower receptors' levels in APOE4, specifically on the membrane surface. Additionally, APOE4 affects the compartmentation of these receptors in two patterns: the first was observed with LRP1 and was associated with decreased receptor levels in numerous intracellular compartments. The second was obtained with the other receptors and was associated with their accumulation in early endosomes and their decrease in the late endosomes.

CONCLUSIONS: These results provide a unifying mechanism, in which APOE4 drives the down regulation of various receptors, which plays important roles in distinct APOE4 related pathological processes.

%B J Alzheimers Dis %V 97 %P 753-775 %8 2024 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/38217595?dopt=Abstract %R 10.3233/JAD-230514 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Social Activity and Cognitive Decline in Older Residents of Long-Term Care Facilities: A Cohort Study. %A Angevaare, Milou J %A Pieters, Jack A %A Twisk, Jos W R %A Van Hout, Hein P J %X

BACKGROUND: Cognitive decline is a major reason for dependence and resource use in long-term care.

OBJECTIVE: We explored whether social activities may prevent cognitive decline of older residents of long-term care facilities.

METHODS: In a routine care cohort, 3,603 residents of long-term care facilities were assessed on average 4.4 times using the interRAI-Long-Term-Care-Facilities instrument which includes frequency of participation in social activities of long standing interest over the last 30 days and the Cognitive Performance Scale. Linear mixed models repeated measures analyses were performed corrected for age, sex, physical activity, Activities of Daily Living, mood, and health indicators.

RESULTS: Social activity was associated with cognitive preservation over time. This association was stronger in those with no or mild cognitive impairment at baseline, relative to those with moderate to severe impairment. Participation in specific social activities such as conversing and helping others showed a similar positive association. The relation between social activity and cognitive impairment appeared to be bi-directional.

CONCLUSIONS: The protective effects of social activity offer a window of opportunity to preserve cognitive functioning in long-term care residents.

%B J Alzheimers Dis %V 98 %P 433-443 %8 2024 Mar 19 %G eng %N 2 %R 10.3233/JAD-221053 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Socioeconomic Status and Dementia Risk Among Intensive Care Unit Survivors: Using National Health Insurance Cohort in Korea. %A Park, Yu Shin %A Joo, Hye Jin %A Jang, Yun Seo %A Jeon, Hajae %A Park, Eun-Cheol %A Shin, Jaeyong %K Aged %K Dementia %K Humans %K Intensive Care Units %K National Health Programs %K Republic of Korea %K Retrospective Studies %K Social Class %K Survivors %X

BACKGROUND: In aging populations, more elderly patients are going to the intensive care unit (ICU) and surviving. However, the specific factors influencing the occurrence of post-intensive care syndrome in the elderly remain uncertain.

OBJECTIVE: To investigate the association between socioeconomic status (SES) and risk of developing dementia within two years following critical care.

METHODS: This study included participants from the Korean National Health Insurance Service Cohort Database who had not been diagnosed with dementia and had been hospitalized in the ICU from 2003 to 2019. Dementia was determined using specific diagnostic codes (G30, G31) and prescription of certain medications (rivastigmine, galantamine, memantine, or donepezil). SES was categorized into low (medical aid beneficiaries) and non-low (National Health Insurance) groups. Through a 1:3 propensity score matching based on sex, age, Charlson comorbidity index, and primary diagnosis, the study included 16,780 patients. We used Cox proportional hazard models to estimate adjusted hazard ratios (HR) of dementia.

RESULTS: Patients with low SES were higher risk of developing dementia within 2 years after receiving critical care than those who were in non-low SES (HR: 1.23, 95% CI: 1.04-1.46). Specifically, patients with low SES and those in the high-income group exhibited the highest incidence rates of developing dementia within two years after receiving critical care, with rates of 3.61 (95% CI: 3.13-4.17) for low SES and 2.58 (95% CI: 2.20-3.03) for high income, respectively.

CONCLUSIONS: After discharge from critical care, compared to the non-low SES group, the low SES group was associated with an increased risk of developing dementia.

%B J Alzheimers Dis %V 97 %P 273-281 %8 2024 Jan 02 %G eng %N 1 %R 10.3233/JAD-230715 %0 Journal Article %J J Alzheimers Dis %D 2023 %T A 19-Year-Old Adolescent with Probable Alzheimer's Disease. %A Jia, Jianping %A Zhang, Yue %A Shi, Yuqing %A Yin, Xuping %A Wang, Shiyuan %A Li, Yan %A Zhao, Tan %A Liu, Wenying %A Zhou, Aihong %A Jia, Longfei %K Adolescent %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Fluorodeoxyglucose F18 %K Humans %K Magnetic Resonance Imaging %K Male %K Positron-Emission Tomography %X

Alzheimer's disease (AD) primarily affects older adults. In this report, we present the case of a 19-year-old male with gradual memory decline for 2 years and World Health Organization-University of California Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT) results also showing memory impairment. Positron emission tomography-magnetic resonance imaging with 18F fluorodeoxyglucose revealed atrophy of the bilateral hippocampus and hypometabolism in the bilateral temporal lobe. Examination of the patient's cerebrospinal fluid showed an increased concentration of p-tau181 and a decreased amyloid-β 42/40 ratio. However, through whole-genome sequencing, no known gene mutations were identified. Considering the above, the patient was diagnosed with probable AD.

%B J Alzheimers Dis %V 91 %P 915-922 %8 2023 %G eng %N 3 %R 10.3233/JAD-221065 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer's Disease. %A Lilek, Jaclyn %A Ajroud, Kaouther %A Feldman, Alexander Z %A Krishnamachari, Sesha %A Ghourchian, Shadi %A Gefen, Tamar %A Spencer, Callen L %A Kawles, Allegra %A Mao, Qinwen %A Tranovich, Jessica F %A Jack, Clifford R %A Mesulam, M-Marsel %A Reichard, R Ross %A Zhang, Hui %A Murray, Melissa E %A Knopman, David %A Dickson, Dennis W %A Petersen, Ronald C %A Smith, Benjamin %A Ashe, Karen H %A Mielke, Michelle M %A Nelson, Kathryn M %A Flanagan, Margaret E %B J Alzheimers Dis %V 92 %P 241-260 %8 2023 Mar 07 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/36744338?dopt=Abstract %R 10.3233/JAD-220848 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Activation of TNF Receptor 2 Improves Synaptic Plasticity and Enhances Amyloid-β Clearance in an Alzheimer's Disease Mouse Model with Humanized TNF Receptor 2. %A Ortí-Casañ, Natalia %A Wajant, Harald %A Kuiperij, H Bea %A Hooijsma, Annelien %A Tromp, Leon %A Poortman, Isabelle L %A Tadema, Norick %A de Lange, Julia H E %A Verbeek, Marcel M %A De Deyn, Peter P %A Naudé, Petrus J W %A Eisel, Ulrich L M %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Humans %K Mice %K Mice, Transgenic %K Neuronal Plasticity %K Receptors, Tumor Necrosis Factor, Type II %K Tumor Necrosis Factor-alpha %X

BACKGROUND: Tumor necrosis factor-alpha (TNF-α) is a master cytokine involved in a variety of inflammatory and neurological diseases, including Alzheimer's disease (AD). Therapies that block TNF-α proved ineffective as therapeutic for neurodegenerative diseases, which might be explained by the opposing functions of the two receptors of TNF (TNFRs): while TNFR1 stimulation mediates inflammatory and apoptotic pathways, activation of TNFR2 is related to neuroprotection. Despite the success of targeting TNFR2 in a transgenic AD mouse model, research that better mimics the human context is lacking.

OBJECTIVE: The aim of this study is to investigate whether stimulation of TNFR2 with a TNFR2 agonist is effective in activating human TNFR2 and attenuating AD neuropathology in the J20xhuTNFR2-k/i mouse model.

METHODS: Transgenic amyloid-β (Aβ)-overexpressing mice containing a human extracellular TNFR2 domain (J20xhuTNFR2-k/i) were treated with a TNFR2 agonist (NewStar2). After treatment, different behavioral tests and immunohistochemical analysis were performed to assess different parameters, such as cognitive functions, plaque deposition, synaptic plasticity, or microglial phagocytosis.

RESULTS: Treatment with NewStar2 in J20xhuTNFR2-k/i mice resulted in a drastic decrease in plaque load and beta-secretase 1 (BACE-1) compared to controls. Moreover, TNFR2 stimulation increased microglial phagocytic activity, leading to enhanced Aβ clearance. Finally, activation of TNFR2 rescued cognitive impairments and improved synaptic plasticity.

CONCLUSION: Our findings demonstrate that activation of human TNFR2 ameliorates neuropathology and improves cognitive functions in an AD mouse model. Moreover, our study confirms that the J20xhuTNFR2-k/i mouse model is suitable for testing human TNFR2-specific compounds.

%B J Alzheimers Dis %V 94 %P 977-991 %8 2023 %G eng %N 3 %R 10.3233/JAD-221230 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Advanced Alzheimer's Disease Patients Show Safe, Significant, and Persistent Benefit in 6-Month Bryostatin Trial. %A Alkon, Daniel L %A Sun, Miao-Kun %A Tuchman, Alan J %A Thompson, Richard E %K Alzheimer Disease %K Bryostatins %K Cognition Disorders %K Double-Blind Method %K Humans %K Treatment Outcome %X

BACKGROUND: In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies.

OBJECTIVE: To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing.

METHODS: In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints. Patient randomization was stratified by baseline SIB to insure balance in baseline cognitive ability between treatment arms.

RESULTS: With no safety events noted by the data safety and monitoring board, the Moderately Severe (MMSE 10-14) Bryostatin-treated patients were significantly improved above the placebo patients for Weeks #13 through Week #42. After two cycles of 7 x i.v. Bryostatin doses over a 26-week period, the 10-14 Cohort Severe Impairment Battery (SIB), measured every 2 weeks, showed significant benefit using a Mixed Model Repeated Measures model (MMRM, 2-tailed, p < 0.05) for Weeks #13 through #42, even 16 weeks after dosing completion by Week #26. Placebo 10-14 patients showed no benefit, declining to negative 12.8 points by Week #42. Trend analyses confirmed the MMRM data for this Cohort, with a significant downward slope (equivalent to Cognitive Decline) for the placebo group, p < 0.001, 2-tailed, but no significant decline for the Bryostatin-treated group (p = 0.409, NS), treatment versus placebo p < 0.007. The Moderate Cohort patients showed no significant benefit.

CONCLUSIONS: The Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial, versus placebo patients' decline of -12.8 SIB points.

%B J Alzheimers Dis %V 96 %P 759-766 %8 2023 %G eng %N 2 %R 10.3233/JAD-230868 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Age-Related Association Between APOE ɛ4 and Cognitive Progression in de novo Parkinson's Disease. %A Liu, Jia-Yao %A Ma, Ling-Zhi %A Wang, Jun %A Cui, Xin-Jing %A Sheng, Ze-Hu %A Fu, Yan %A Li, Meng %A Ou, Ya-Nan %A Yu, Jin-Tai %A Tan, Lan %A Lian, Yan %K Aged %K Apolipoprotein E4 %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Genotype %K Heterozygote %K Humans %K Parkinson Disease %X

BACKGROUND: APOE ɛ4 genotype was correlated with exacerbation of pathology and higher risk of dementia in Parkinson's disease (PD). Meanwhile, the differential influence of APOE ɛ4 on cognition in young and old individuals interpreted as antagonistic pleiotropy.

OBJECTIVE: To examine whether the effect of APOE ɛ4 on cognitive progression in de novo PD is age dependent.

METHODS: In this study, 613 de novo PD patients were recruited from Parkinson's Progression Markers Initiative (PPMI). To examine the age-dependent relationship between APOE ɛ4 and cognitive changes, we added 3-way interaction of APOE ɛ4*baseline age*time to the linear mixed-effect (LME) models and evaluated the specific roles of APOE ɛ4 in the middle age group and elderly group separately. Cox regression was utilized to examine the progression of cognition in age-stratified PD participants.

RESULTS: Age significantly modified relationship between APOE ɛ4 and cognitive changes in most cognitive domains (pinteraction <0.05). In the elderly group, APOE ɛ4 carriers showed steeper decline in global cognition (p = 0.001) as well as in most cognitive domains, and they had a greater risk of cognitive progression (adjusted HR 1.625, 95% CI 1.143-2.310, p = 0.007), compared with non-carriers. However, in the middle age group, no significant relationships between APOE ɛ4 and cognitive decline can be detected.

CONCLUSION: Our results indicated that the APOE ɛ4 allele has an age-dependent effect on cognitive decline in PD patients. The underlying mechanisms need to be investigated in the future.

%B J Alzheimers Dis %V 91 %P 1121-1132 %8 2023 %G eng %N 3 %R 10.3233/JAD-220976 %0 Journal Article %J J Alzheimers Dis %D 2023 %T An Alternative View of Familial Alzheimer's Disease Genetics. %A Lardelli, Michael %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Humans %K Iron %K Mutation %K Presenilin-1 %X

Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin's amyloid cascade hypothesis is valid but is commonly interpreted too narrowly to support, incorrectly, the primacy of the amyloid-β peptide (Aβ) in driving Alzheimer's disease pathogenesis. Instead, increased activity of the βCTF (C99) fragment of AβPP is the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5' iron responsive element. Similar arguments support that the pathological effects of familial Alzheimer's disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes in AβPP cleavage to produce different ratios of Aβ length. Rather, these mutations likely act through effects on presenilin holoprotein conformation and function, and possibly the formation and stability of multimers of presenilin holoprotein and/or of the γ-secretase complex. All fAD mutations in APP, PSEN1, and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of "pseudo-hypoxia" being of central importance. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease.

%B J Alzheimers Dis %V 96 %P 13-39 %8 2023 %G eng %N 1 %R 10.3233/JAD-230313 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Alzheimer's Disease: A Systems View Provides a Unifying Explanation of Its Development. %A Grobler, Corlia %A van Tongeren, Marvi %A Gettemans, Jan %A Kell, Douglas B %A Pretorius, Etheresia %K Alzheimer Disease %K Amyloid beta-Peptides %K Humans %K Neurofibrillary Tangles %K Plaque, Amyloid %K tau Proteins %X

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder affecting 50 million people globally. It is characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles, consisting of amyloid-β and hyperphosphorylated tau proteins, respectively. Despite global research efforts, there is currently no cure available, due in part to an incomplete understanding of the disease pathogenesis. Numerous possible mechanisms, or hypotheses, explaining the origins of sporadic or late-onset AD have been proposed, including the amyloid-β, inflammatory, vascular, and infectious hypotheses. However, despite ample evidence, the failure of multiple trial drugs at the clinical stage illuminates the possible pitfalls of these hypotheses. Systems biology is a strategy which aims to elucidate the interactions between parts of a whole. Using this approach, the current paper shows how the four previously mentioned hypotheses of AD pathogenesis can be intricately connected. This approach allows for seemingly contradictory evidence to be unified in a system-focused explanation of sporadic AD development. Within this view, it is seen that infectious agents, such as P. gingivalis, may play a central role. The data presented here shows that when present, P. gingivalis or its virulence factors, such as gingipains, may induce or exacerbate pathologies underlying sporadic AD. This evidence supports the view that infectious agents, and specifically P. gingivalis, may be suitable treatment targets in AD.

%B J Alzheimers Dis %V 91 %P 43-70 %8 2023 %G eng %N 1 %R 10.3233/JAD-220720 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Alzheimer's Disease and Neurosyphilis: Meaningful Commonalities and Differences of Clinical Phenotype and Pathophysiological Biomarkers. %A Milano, Chiara %A Hoxhaj, Domeniko %A Del Chicca, Marta %A Pascazio, Alessia %A Paoli, Davide %A Tommasini, Luca %A Vergallo, Andrea %A Pizzanelli, Chiara %A Tognoni, Gloria %A Nuti, Angelo %A Ceravolo, Roberto %A Siciliano, Gabriele %A Hampel, Harald %A Baldacci, Filippo %X

BACKGROUND: Neurosyphilis-associated cognitive and behavioral impairment- historically coined as "general paralysis of the insane"- share clinical and neuroradiological features with the neurodegenerative disease spectrum, in particular Alzheimer's disease (AD). Anatomopathological similarities have been extensively documented, i.e., neuronal loss, fibrillary alterations, and local amyloid-β deposition. Consequently, accurate classification and timely differential diagnosis may be challenging.

OBJECTIVE: To describe clinical, bio-humoral, brain MRI, FDG-PET, and amyloid-PET features in cases of neurosyphilis with an AD-like phenotypical presentation, as well as clinical outcome in terms of response to antibiotic therapy.

METHODS: We selected the studies comparing patients with AD and with neurosyphilis associated cognitive impairment, to investigate candidate biomarkers classifying the two neurological diseases.

RESULTS: The neuropsychological phenotype of general paralysis, characterized by episodic memory impairment and executive disfunction, substantially mimics clinical AD features. Neuroimaging often shows diffuse or medial temporal cortical atrophy, thus contributing to a high rate of misdiagnosis. Cerebrospinal fluid (CSF)-based analysis may provide supportive diagnostic value, since increased proteins or cells are often found in neurosyphilis, while published data on pathophysiological AD candidate biomarkers are controversial. Finally, psychometric testing using cross-domain cognitive tests, may highlight a wider range of compromised functions in neurosyphilis, involving language, attention, executive function, and spatial ability, which are atypical for AD.

CONCLUSION: Neurosyphilis should be considered a potential etiological differential diagnosis of cognitive impairment whenever imaging, neuropsychological or CSF features are atypical for AD, in order to promptly start antibiotic therapy and delay or halt cognitive decline and disease progression.

%B J Alzheimers Dis %V 94 %P 611-625 %8 2023 Jul 18 %G eng %N 2 %R 10.3233/JAD-230170 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Alzheimer's Disease Mitochondrial Cascade Hypothesis: A Current Overview. %A Swerdlow, Russell H %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Humans %K Mitochondria %K Signal Transduction %X

Viable Alzheimer's disease (AD) hypotheses must account for its age-dependence; commonality; association with amyloid precursor protein, tau, and apolipoprotein E biology; connection with vascular, inflammation, and insulin signaling changes; and systemic features. Mitochondria and parameters influenced by mitochondria could link these diverse characteristics. Mitochondrial biology can initiate changes in pathways tied to AD and mediate the dysfunction that produces the clinical phenotype. For these reasons, conceptualizing a mitochondrial cascade hypothesis is a straightforward process and data accumulating over decades argue the validity of its principles. Alternative AD hypotheses may yet account for its mitochondria-related phenomena, but absent this happening a primary mitochondrial cascade hypothesis will continue to evolve and attract interest.

%B J Alzheimers Dis %V 92 %P 751-768 %8 2023 %G eng %N 3 %R 10.3233/JAD-221286 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Alzheimer's Disease Pathology Outside of the Cerebrum Is Related to a Higher Odds of Dementia. %A Buchman, Aron S %A Leurgans, Sue E %A Kim, Namhee %A Agrawal, Sonal %A Oveisgharan, Shahram %A Zammit, Andrea R %A VanderHorst, Veronique %A Nag, Sukrit %A Bennett, David A %X

BACKGROUND: Assessments of Alzheimer's disease pathology do not routinely include lower brainstem, olfactory bulb, and spinal cord.

OBJECTIVE: Test if amyloid-β (Aβ) and paired helical filament (PHF) tau-tangles outside the cerebrum are associated with the odds of dementia.

METHODS: Autopsies were obtained in decedents with cognitive testing (n = 300). Aβ plaques and PHF tau-tangles were assessed in 24 sites: cerebrum (n = 14), brainstem (n = 5), olfactory bulb, and four spinal cord levels. Since spinal Aβ were absent in the first 165 cases, it was not assessed in the remaining cases.

RESULTS: Age at death was 91 years old. About 90% had Aβ in cerebrum and of these, half had Aβ in the brainstem. Of the latter, 85% showed Aβ in the olfactory bulb. All but one participant had tau-tangles in the cerebrum and 86% had brainstem tau-tangles. Of the latter, 80% had tau-tangles in olfactory bulb and 36% tau-tangles in one or more spinal cord levels. About 90% of adults with tau-tangles also had Aβ in one or more regions. In a logistic model controlling for demographics, Aβ and tau-tangles within the cerebrum, the presence of Aβ in olfactory bulb [OR, 1.74(1.00, 3.05)]; tau-tangles in brainstem [OR, 4.00(1.1.57,10.21)]; and spinal cord [OR, 1.87 (1.21,3.11)] were independently associated with higher odds of dementia.

CONCLUSION: Regional differences in Aβ and tau-tangle accumulation extend beyond cerebrum to spinal cord and their presence outside the cerebrum are associated with a higher odds of dementia. Further studies are needed to clarify the extent, burden, and consequences of AD pathology outside of cerebrum.

%B J Alzheimers Dis %V 96 %P 563-578 %8 2023 Nov 07 %G eng %N 2 %R 10.3233/JAD-230223 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Anti-Amyloid Monoclonal Antibody Lecanemab: 16 Cautionary Notes. %A Kepp, Kasper P %A Sensi, Stefano L %A Johnsen, Kasper B %A Barrio, Jorge R %A Høilund-Carlsen, Poul F %A Neve, Rachael L %A Alavi, Abass %A Herrup, Karl %A Perry, George %A Robakis, Nikolaos K %A Vissel, Bryce %A Espay, Alberto J %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloidogenic Proteins %K Antibodies, Monoclonal %K Humans %K United States %X

After the CLARITY-AD clinical trial results of lecanemab were interpreted as positive, and supporting the amyloid hypothesis, the drug received accelerated Food and Drug Administration approval. However, we argue that benefits of lecanemab treatment are uncertain and may yield net harm for some patients, and that the data do not support the amyloid hypothesis. We note potential biases from inclusion, unblinding, dropouts, and other issues. Given substantial adverse effects and subgroup heterogeneity, we conclude that lecanemab's efficacy is not clinically meaningful, consistent with numerous analyses suggesting that amyloid-β and its derivatives are not the main causative agents of Alzheimer's disease dementia.

%B J Alzheimers Dis %V 94 %P 497-507 %8 2023 %G eng %N 2 %R 10.3233/JAD-230099 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Apathy as a Predictor of Conversion from Mild Cognitive Impairment to Alzheimer's Disease: A Texas Alzheimer's Research and Care Consortium (TARCC) Cohort-Based Analysis. %A Salem, Haitham %A Suchting, Robert %A Gonzales, Mitzi M %A Seshadri, Sudha %A Teixeira, Antônio L %X

BACKGROUND: Apathy is among the neuropsychiatric symptoms frequently observed in people with cognitive impairment. It has been postulated to be a potential predictor of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD).

OBJECTIVE: To detect conversion rates from MCI to AD, and to determine the effect of apathy on the progression to AD in patients with MCI enrolled in the Texas Alzheimer's Research and Care Consortium (TARCC) cohort.

METHODS: Apathy was determined by a positive response to the respective item in the Neuropsychiatric Inventory -Questionnaire (NPI-Q) completed by family members or caregivers. The final dataset included 2,897 observations from 1,092 individuals with MCI at the baseline. Kaplan-Meier survival curves were estimated to provide indices of the probability of conversion to AD over time across all individuals as well as between those with and without apathy. Cox proportional hazards regression measured the hazard associated with apathy and several other predictors of interest.

RESULTS: Over a period of 8.21 years, 17.3% of individuals had conversion from MCI to AD (n = 190 of 1,092 total individuals) across observations. The median time-to-conversion across all participants was 6.41 years. Comparing individuals with apathy (n = 158) versus without apathy (n = 934), 36.1% and 14.2% had conversion to AD, respectively. The median time-to-conversion was 3.79 years for individuals with apathy and 6.83 years for individuals without apathy. Cox proportional hazards regression found significant effects of several predictors, including apathy, on time-to-conversion. Age and cognitive performance were found to moderate the relationship between apathy and time-to-conversion.

CONCLUSIONS: Apathy is associated with progression from MCI to AD, suggesting that it might improve risk prediction and aid targeted intervention delivery.

%B J Alzheimers Dis %V 92 %P 129-139 %8 2023 Mar 07 %G eng %N 1 %R 10.3233/JAD-220826 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Apolipoprotein ɛ4-Associated Protection Against Pediatric Enteric Infections is a Survival Advantage in Pre-Industrial Populations. %A Smith, Carr J %A Ashford, J Wesson %X

Until 300,000 years ago, ancestors of modern humans ubiquitously carried the apolipoprotein E (APOE) ɛ4/ɛ4 genotype, when the ɛ3 allele mutated from the ancestral ɛ4, which elevates the risk of Alzheimer's disease. Modern humans living today predominantly carry the ɛ3 allele, which provides protection against heart disease and dementia in long-lived populations. The ancestral ɛ4 allele has been highly preserved in isolated populations in tropical and Arctic regions with high pathogen burdens, e.g., helminths. Early humans experienced serious enteric infections that exerted evolutionary selection pressure, and factors that mitigate infant and childhood mortality from enteric infections also exert selection pressure. Some bacteria can exploit the host's defensive inflammatory response to colonize and invade the host. Pathogen-induced inflammation associated with infant and childhood diarrhea can damage the gut wall long after the invading organisms are no longer present. Inflammation not only resides in the mucosal wall, but also induces systemic inflammation. Baseline systemic inflammation is lower in ɛ4 carriers, yet ɛ4 carriers display a stronger host inflammatory response that reduces pathogen burdens, increasing infant and early childhood survival. Evolutionary selection of the ɛ3 allele likely occurred after humans moved into temperate zones with lower pathogen burdens, unrelated to protection from Alzheimer's disease.

%B J Alzheimers Dis %V 93 %P 907-918 %8 2023 May 30 %G eng %N 3 %R 10.3233/JAD-221218 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Aspirin Use and Risk of Alzheimer's Disease: A 2-Sample Mendelian Randomization Study. %A Ding, Pingjian %A Gorenflo, Maria P %A Zhu, Xiaofeng %A Xu, Rong %X

BACKGROUND: Observational studies have shown inconsistent findings of the relationships between aspirin use and the risk of Alzheimer's disease (AD).

OBJECTIVE: Since residual confounding and reverse causality were challenging issues inherent in observational studies, we conducted a 2-sample Mendelian randomization analysis (MR) to investigate whether aspirin use was causally associated with the risk of AD.

METHODS: We conducted 2-sample MR analyses utilizing summary genetic association statistics to estimate the potential causal relationship between aspirin use and AD. Single-nucleotide variants associated with aspirin use in a genome-wide association study (GWAS) of UK Biobank were considered as genetic proxies for aspirin use. The GWAS summary-level data of AD were derived from a meta-analysis of GWAS data from the International Genomics of Alzheimer's Project (IGAP) stage I.

RESULTS: Univariable MR analysis based on these two large GWAS data sources showed that genetically proxied aspirin use was associated with a decreased risk of AD (Odds Ratio (OR): 0.87; 95%CI: 0.77-0.99). In multivariate MR analyses, the causal estimates remained significant after adjusting for chronic pain, inflammation, heart failure (OR = 0.88, 95%CI = 0.78-0.98), or stroke (OR = 0.87, 95%CI = 0.77-0.99), but was attenuated when adjusting for coronary heart disease, blood pressure, and blood lipids.

CONCLUSION: Findings from this MR analysis suggest a genetic protective effect of aspirin use on AD, possibly influenced by coronary heart disease, blood pressure, and lipid levels.

%B J Alzheimers Dis %V 92 %P 989-1000 %8 2023 Apr 04 %G eng %N 3 %R 10.3233/JAD-220787 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Association Between Oral Bacteria and Alzheimer's Disease: A Systematic Review and Meta-Analysis. %A Liu, Sixin %A Dashper, Stuart G %A Zhao, Rui %K Alzheimer Disease %K Cognitive Dysfunction %K Humans %K Microbiota %K Porphyromonas gingivalis %K Risk Factors %X

BACKGROUND: Pre-clinical evidence implicates oral bacteria in the pathogenesis of Alzheimer's disease (AD), while clinical studies show diverse results.

OBJECTIVE: To comprehensively assess the association between oral bacteria and AD with clinical evidence.

METHODS: Studies investigating the association between oral bacteria and AD were identified through a systematic search of six databases PubMed, Embase, Cochrane Central Library, Scopus, ScienceDirect, and Web of Science. Methodological quality ratings of the included studies were performed. A best evidence synthesis was employed to integrate the results. When applicable, a meta-analysis was conducted using a random-effect model.

RESULTS: Of the 16 studies included, ten investigated periodontal pathobionts and six were microbiome-wide association studies. Samples from the brain, serum, and oral cavity were tested. We found over a ten-fold and six-fold increased risk of AD when there were oral bacteria (OR = 10.68 95% CI: 4.48-25.43; p < 0.00001, I2 = 0%) and Porphyromonas gingivalis (OR = 6.84 95% CI: 2.70-17.31; p < 0.0001, I2 = 0%) respectively in the brain. While AD patients exhibited lower alpha diversity of oral microbiota than healthy controls, the findings of bacterial communities were inconsistent among studies. The best evidence synthesis suggested a moderate level of evidence for an overall association between oral bacteria and AD and for oral bacteria being a risk factor for AD.

CONCLUSION: Current evidence moderately supports the association between oral bacteria and AD, while the association was strong when oral bacteria were detectable in the brain. Further evidence is needed to clarify the interrelationship between both individual species and bacterial communities and the development of AD.

%B J Alzheimers Dis %V 91 %P 129-150 %8 2023 %G eng %N 1 %R 10.3233/JAD-220627 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Association of Age-Related Spontaneous Internal Jugular Vein Reflux with Cognitive Impairment and Incident Dementia. %A Adachi, Utako %A Toi, Sono %A Hosoya, Megumi %A Hoshino, Takao %A Seki, Misa %A Yoshizawa, Hiroshi %A Tsutsumi, Yukiko %A Maruyama, Kenji %A Kitagawa, Kazuo %X

BACKGROUND: It remains unclear whether changes in the venous circulation contribute to cognitive decline.

OBJECTIVE: This study aimed to clarify whether the spontaneous jugular vein reflux (JVR) is associated with cognitive impairment and incident dementia.

METHODS: Patients with any evidence of cerebral vessel disease on magnetic resonance imaging (MRI) were consecutively enrolled between October 2015 to July 2019. We employed carotid duplex sonography to measure the internal jugular vein (IJV). The subjects were classified into two groups based on the degree of JVR on either side: none, mild (JVR(-) group) and moderate, severe (JVR (+) group) JVR. They underwent both the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment-Japanese (MoCA-J) global tests. Their cognitive status was prospectively assessed until March 2023.

RESULTS: 302 patients with an MMSE score ≥24 underwent duplex sonography of the IJV. Among them, 91 had spontaneous JVR on either side. Both MMSE and MoCA-J were significantly lower in patients with JVR (+) group than in the JVR (-) group. After the adjustment for risk factors and MRI findings, intergroup differences in MoCA-J remained significant. Among the cognitive subdomains, median executive function and memory scores were significantly lower in the JVR (+) group than in the JVR (-) group. During the median 5.2-year follow-up, 11 patients with incident dementia were diagnosed. Patients with severe JVR were significantly more likely to be diagnosed with dementia (log-rank test, p = 0.031).

CONCLUSIONS: Spontaneous IJV reflux especially severe JVR, was associated with global cognitive function, and potentially with incident dementia.

%B J Alzheimers Dis %V 96 %P 1221-1230 %8 2023 Nov 21 %G eng %N 3 %R 10.3233/JAD-230771 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Association of Alcohol Consumption with Cognition in Older Population: The A4 Study. %A Nallapu, Bhargav T %A Petersen, Kellen K %A Lipton, Richard B %A Grober, Ellen %A Sperling, Reisa A %A Ezzati, Ali %X

BACKGROUND: Alcohol use disorders have been categorized as a 'strongly modifiable' risk factor for dementia.

OBJECTIVE: To investigate the cross-sectional association between alcohol consumption and cognition in older adults and if it is different across sexes or depends on amyloid-β (Aβ) accumulation in the brain.

METHODS: Cognitively unimpaired older adults (N = 4387) with objective and subjective cognitive assessments and amyloid positron emission tomography (PET) imaging were classified into four categories based on their average daily alcohol use. Multivariable linear regression was then used to test the main effects and interactions with sex and Aβ levels.

RESULTS: Individuals who reported no alcohol consumption had lower scores on the Preclinical Alzheimer Cognitive Composite (PACC) compared to those consuming one or two drinks/day. In sex-stratified analysis, the association between alcohol consumption and cognition was more prominent in females. Female participants who consumed two drinks/day had better performance on PACC and Cognitive Function Index (CFI) than those who reported no alcohol consumption. In an Aβ-stratified sample, the association between alcohol consumption and cognition was present only in the Aβ- subgroup. The interaction between Aβ status and alcohol consumption on cognition was not significant.

CONCLUSION: Low or moderate consumption of alcohol was associated with better objective cognitive performance and better subjective report of daily functioning in cognitively unimpaired individuals. The association was present only in Aβ- individuals, suggesting that the pathophysiologic mechanism underlying the effect of alcohol on cognition is independent of Aβ pathology. Further investigation is required with larger samples consuming three or more drinks/day.

%B J Alzheimers Dis %V 93 %P 1381-1393 %8 2023 Jun 13 %G eng %N 4 %R 10.3233/JAD-221079 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Association of Influenza Vaccination and Dementia Risk: A Meta-Analysis of Cohort Studies. %A Sun, Huimin %A Liu, Min %A Liu, Jue %K Aged %K Aged, 80 and over %K Cohort Studies %K Dementia %K Humans %K Influenza, Human %K Vaccination %X

BACKGROUND: Dementia is a critical global public health problem. Previous cohort studies have found that influenza vaccination can decrease the risk of dementia.

OBJECTIVE: This meta-analysis aimed to systematically examine the relationship between influenza vaccination and dementia risk.

METHODS: We searched PubMed, Embase, Web of Science, ScienceDirect, medRxiv, and bioRxiv for studies investigating dementia risk based on influenza vaccination status, up to September 14, 2022. Relative risks (RRs) and 95% confidence intervals (95% CIs) were pooled in the meta-analysis. Subgroup analyses and sensitivity analyses were conducted as well.

RESULTS: Of the 4,087 articles initially reviewed, 6 cohort studies were included in the final meta-analysis, and all eligible studies were at low risk of bias. There were 2,087,195 participants without dementia at baseline (mean age: 61.8-75.5 years, 57.05% males), and 149,804 (7.18%) cases of dementia occurred during 4.00-13.00 years of follow-up. Pooled analysis of adjusted RRs found that influenza vaccination could reduce dementia risk by 31% (RR = 0.69, 95% CI: 0.57-0.83). Subgroup analyses showed that in the study with a mean age of 75-80 years or 75%-100% males, the association was generally weakened compared with studies with a mean age of 60-75 years or 25%-50% males. The results were stable in the sensitivity analyses, and no publication bias was observed.

CONCLUSION: Influenza vaccination in older adults was markedly associated with a decreased risk of dementia. More mechanistic studies and epidemiological studies are needed to clarify the association between influenza vaccination and decreased dementia risk.

%B J Alzheimers Dis %V 92 %P 667-678 %8 2023 %G eng %N 2 %R 10.3233/JAD-221036 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Association of Interleukin-6 and Interleukin-8 with Cognitive Decline in an Asian Memory Clinic Population. %A Teoh, Nicole Shu Ning %A Gyanwali, Bibek %A Lai, Mitchell K P %A Chai, Yuek Ling %A Chong, Joyce R %A Chong, Eddie Jun Yi %A Chen, Christopher %A Tan, Chuen Seng %A Hilal, Saima %K Aged %K Biomarkers %K Canada %K Cognition %K Cognitive Dysfunction %K Female %K Humans %K Interleukin-6 %K Interleukin-8 %K Male %K Neuroinflammatory Diseases %K Neuropsychological Tests %X

BACKGROUND: Neuroinflammation has been postulated to play an important role in cognitive impairment, cognitive decline, and dementia. Inflammatory biomarkers such as interleukin-6 (IL-6) and IL-8 are found to be associated with the neuro-inflammatory process and worse cognitive function. However, it is unknown whether these interleukins are associated with long-term cognitive function.

OBJECTIVE: To investigate the association of baseline IL-6 and IL-8 with cognitive function at baseline as well as its association with cognitive decline over five-year follow-up.

METHODS: 387 patients were recruited from an ongoing memory clinic-based study who underwent comprehensive physical, medical, neuropsychological and blood assessments together with brain MRI. IL-6 and IL-8 were measured using LUMINEX assays. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network neuropsychological battery was used to assess cognitive decline across multiple domains.

RESULTS: Among the 387 (mean age = 72.9 years and 53.7% males) participants, 322 had at least two follow-up assessments and were included in the longitudinal analysis. Negative linear trend associations were found between tertiles of IL-8 with baseline global cognition (p-trend< 0.001), attention (p-trend = 0.005), executive function (p-trend< 0.001), and visuospatial function (p-trend = 0.002) domains. No association was found between baseline IL-8 and cognitive decline. IL-6 was not associated with both baseline and follow-up cognition.

CONCLUSION: IL-8 was associated with worse cognition especially in attention, executive function, and visuospatial function, suggesting the role of neuroinflammation in cognitive impairment. Hence, blood inflammatory biomarkers may be useful indicators in identifying patients at risk of cognitive impairment and warrant consideration for inclusion in treatment trials.

%B J Alzheimers Dis %V 92 %P 445-455 %8 2023 %G eng %N 2 %R 10.3233/JAD-220971 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Association of Sarcopenia and Its Defining Components with the Degree of Cognitive Impairment in a Memory Clinic Population. %A Larsson, LE %A Wang, Rui %A Cederholm, Tommy %A Wiggenraad, Fleur %A Rydén, Marie %A Hagman, Göran %A Hellénius, Mai-Lis %A Kivipelto, Miia %A Thunborg, Charlotta %X

BACKGROUND: Sarcopenia and cognitive impairment are two leading causes of disabilities.

OBJECTIVE: The objective was to examine the prevalence of sarcopenia and investigate the association between sarcopenia diagnostic components (muscle strength, muscle mass, and physical performance) and cognitive impairment in memory clinic patients.

METHODS: 368 patients were included (age 59.0±7.25 years, women: 58.7%), displaying three clinical phenotypes of cognitive impairments, i.e., subjective cognitive impairment (SCI, 57%), mild cognitive impairment (MCI, 26%), and Alzheimer's disease (AD, 17%). Sarcopenia was defined according to diagnostic algorithm recommended by the European Working Group on Sarcopenia in Older People. Components of sarcopenia were grip strength, bioelectrical impedance analysis, and gait speed. They were further aggregated into a score (0-3 points) by counting the numbers of limited components. Multi-nominal logistic regression was applied.

RESULTS: Probable sarcopenia (i.e., reduced grip strength) was observed in 9.6% of the patients, and 3.5% were diagnosed with sarcopenia. Patients with faster gait speed showed less likelihood of MCI (odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.06-0.90) and AD (OR: 0.12, 95% CI: 0.03-0.60). One or more limited sarcopenia components was associated with worse cognitive function. After adjusting for potential confounders, the association remained significant only for AD (OR 4.29, 95% CI 1.45-11.92).

CONCLUSION: The results indicate a connection between the sarcopenia components and cognitive impairments. Limitations in the sarcopenia measures, especially slow walking speed, were related to poorer cognitive outcomes. More investigationsare required to further verify the causal relationship between sarcopenia and cognitive outcomes.

%B J Alzheimers Dis %V 96 %P 777-788 %8 2023 Nov 07 %G eng %N 2 %R 10.3233/JAD-221186 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Associations Between Ambient Air Pollution and Cognitive Abilities from Midlife to Early Old Age: Modification by APOE Genotype. %A Franz, Carol E %A Gustavson, Daniel E %A Elman, Jeremy A %A Fennema-Notestine, Christine %A Hagler, Donald J %A Baraff, Aaron %A Tu, Xin M %A Wu, Tsung-Chin %A De Anda, Jaden %A Beck, Asad %A Kaufman, Joel D %A Whitsel, Nathan %A Finch, Caleb E %A Chen, Jiu-Chiuan %A Lyons, Michael J %A Kremen, William S %X

BACKGROUND: Fine particulate matter (PM2.5) and nitrogen dioxide (NO2) measures of ambient air pollution are associated with accelerated age-related cognitive impairment, and Alzheimer's disease and related dementias (ADRD).

OBJECTIVE: We examined associations between air pollution, four cognitive factors, and the moderating role of apolipoprotein E (APOE) genotype in the understudied period of midlife.

METHODS: Participants were ∼1,100 men in the Vietnam Era Twin Study of Aging. Baseline cognitive assessments were from 2003 to 2007. Measures included past (1993-1999) and recent (3 years prior to baseline assessment) PM2.5 and NO2 exposure, in-person assessment of episodic memory, executive function, verbal fluency, and processing speed, and APOE genotype. Average baseline age was 56 years with a 12-year follow-up. Analyses adjusted for health and lifestyle covariates.

RESULTS: Performance in all cognitive domains declined from age 56 to 68. Higher PM2.5 exposures were associated with worse general verbal fluency. We found significant exposure-by-APOE genotype interactions for specific cognitive domains: PM2.5 with executive function and NO2 with episodic memory. Higher PM2.5 exposure was related to worse executive function in APOE ɛ4 carriers, but not in non-carriers. There were no associations with processing speed.

CONCLUSION: These results indicate negative effects of ambient air pollution exposure on fluency alongside intriguing differential modifications of cognitive performance by APOE genotype. APOE ɛ4 carriers appeared more sensitive to environmental differences. The process by which air pollution and its interaction with genetic risk for ADRD affects risk for later life cognitive decline or progression to dementia may begin in midlife.

%B J Alzheimers Dis %V 93 %P 193-209 %8 2023 May 02 %G eng %N 1 %R 10.3233/JAD-221054 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Associations Between Local Area Deprivation and Physical Activity Participation in People with Cognitive Impairment in the North East of England. %A Mc Ardle, Ríona %A Hamilton, Calum %A Del Din, Silvia %A Kingston, Andrew %A Robinson, Louise %A Galna, Brook %A Thomas, Alan J %A Rochester, Lynn %X

BACKGROUND: Promoting physical activity, such as habitual walking behaviors, in people with cognitive impairment may support their ability to remain independent with a good quality of life for longer. However, people with cognitive impairment participate in less physical activity compared to cognitively unimpaired older adults. The local area in which people live may significantly impact abilities to participate in physical activity. For example, people who live in more deprived areas may have less safe and walkable routes.

OBJECTIVE: To examine this further, this study aimed to explore associations between local area deprivation and physical activity in people with cognitive impairment and cognitively unimpaired older adults (controls).

METHODS: 87 participants with cognitive impairment (mild cognitive impairment or dementia) and 27 older adult controls from the North East of England were included in this analysis. Participants wore a tri-axial wearable accelerometer (AX3, Axivity) on their lower backs continuously for seven days. The primary physical activity outcome was daily step count. Individuals' neighborhoods were linked to UK government area deprivation statistics. Hierarchical Bayesian models assessed the association between local area deprivation and daily step count in people with cognitive impairment and controls.

RESULTS: Key findings indicated that there was no association between local area deprivation and daily step count in people with cognitive impairment, but higher deprivation was associated with lower daily steps for controls.

CONCLUSION: These findings suggest that cognitive impairment may be associated with lower participation in physical activity which supersedes the influence of local area deprivation observed in normal aging.

%B J Alzheimers Dis %V 95 %P 265-273 %8 2023 Aug 29 %G eng %N 1 %R 10.3233/JAD-230358 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Associations of Midlife Lifestyle and Health Factors with Long-Term Changes in Blood-Based Biomarkers of Alzheimer's Disease and Neurodegeneration. %A Merten, Natascha %A Pinto, A Alex %A Paulsen, Adam J %A Chen, Yanjun %A Engelman, Corinne D %A Hancock, Laura M %A Johnson, Sterling C %A Schubert, Carla R %X

BACKGROUND: Pathological biomarkers of Alzheimer's disease (AD) and other dementias can change decades before clinical symptoms. Lifestyle and health factors might be relevant modifiable risk factors for dementia. Many previous studies have been focusing on associations of lifestyle and health-related factors with clinical outcomes later in life.

OBJECTIVE: We aimed to determine to what extent midlife factors of lifestyle, inflammation, vascular, and metabolic health were associated with long-term changes in blood-based biomarkers of AD (amyloid beta (Aβ)) and neurodegeneration (neurofilament light chain (NfL); total tau(TTau)).

METHODS: In 1,529 Beaver Dam Offspring Study (BOSS) participants (mean age 49 years, standard deviation (SD) = 9;54% were women), we applied mixed-effects models with baseline risk factors as determinants and 10-year serum biomarker change as outcomes.

RESULTS: We found that education and inflammatory markers were associated with levels and/or change over time across all three markers of AD and neurodegeneration in the blood. There were baseline associations of measures of cardiovascular health with lower Aβ42/Aβ40. TTau changed little over time and was higher in individuals with diabetes. Individuals with lower risk in a number of cardiovascular and metabolic risk factors, including diabetes, hypertension, and atherosclerosis had slower accumulation of neurodegeneration over time, as determined by NfL levels.

CONCLUSION: Various lifestyle and health factors, including education and inflammation, were associated with longitudinal changes of neurodegenerative and AD biomarker levels in midlife. If confirmed, these findings could have important implications for developing early lifestyle and health interventions that could potentially slow processes of neurodegeneration and AD.

%B J Alzheimers Dis %V 94 %P 1381-1395 %8 2023 Aug 15 %G eng %N 4 %R 10.3233/JAD-221287 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Associations of the Harvard Automated Phone Task and Alzheimer's Disease Pathology in Cognitively Normal Older Adults: Preliminary Findings. %A Gonzalez, Christopher %A Mimmack, Kayden J %A Amariglio, Rebecca E %A Becker, J Alex %A Chhatwal, Jasmeer P %A Fitzpatrick, Colleen D %A Gatchel, Jennifer R %A Johnson, Keith A %A Katz, Zoe S %A Kuppe, Madeline K %A Locascio, Joseph J %A Udeogu, Onyinye J %A Papp, Kathryn V %A Premnath, Pranitha %A Properzi, Michael J %A Rentz, Dorene M %A Schultz, Aaron P %A Sperling, Reisa A %A Vannini, Patrizia %A Wang, Sharon %A Marshall, Gad A %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Amyloid %K Amyloid beta-Peptides %K Amyloidogenic Proteins %K Cognitive Dysfunction %K Entorhinal Cortex %K Humans %K Positron-Emission Tomography %K tau Proteins %X

BACKGROUND: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer's disease (AD) is critical.

OBJECTIVE: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults.

METHODS: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid.

RESULTS: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone.

CONCLUSION: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.

%B J Alzheimers Dis %V 94 %P 217-226 %8 2023 %G eng %N 1 %R 10.3233/JAD-220885 %0 Journal Article %J J Alzheimers Dis %D 2023 %T BACE2: A Promising Neuroprotective Candidate for Alzheimer's Disease. %A Yeap, Yee Jie %A Kandiah, Nagaendran %A Nizetic, Dean %A Lim, Kah-Leong %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Aspartic Acid Endopeptidases %K Humans %X

Alzheimer's disease (AD) is the most common cause of dementia that affects millions of predominantly elderly individuals worldwide. Despite intensive research over several decades, controversies still surround the etiology of AD and the disease remains incurable. Meanwhile, new molecular players of the central amyloid cascade hypothesis have emerged and among these is a protease known as β-site APP cleavage enzyme 2 (BACE2). Unlike BACE1, BACE2 cleaves the amyloid-β protein precursor within the Aβ domain that accordingly prevents the generation of Aβ42 peptides, the aggregation of which is commonly regarded as the toxic entity that drives neurodegeneration in AD. Given this non-amyloidogenic role of BACE2, it is attractive to position BACE2 as a therapeutic target for AD. Indeed, several groups including ours have demonstrated a neuroprotective role for BACE2 in AD. In this review, we discuss emerging evidence supporting the ability of BACE2 in mitigating AD-associated pathology in various experimental systems including human pluripotent stem cell-derived cerebral organoid disease models. Alongside this, we also provide an update on the identification of single nucleotide polymorphisms occurring in the BACE2 gene that are linked to increased risk and earlier disease onset in the general population. In particular, we highlight a recently identified point mutation on BACE2 that apparently leads to sporadic early-onset AD. We believe that a better understanding of the role of BACE2 in AD would provide new insights for the development of viable therapeutic strategies for individuals with dementia.

%B J Alzheimers Dis %V 94 %P S159-S171 %8 2023 %G eng %N s1 %R 10.3233/JAD-220867 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Best Medicine for Dementia: The Life-Long Defense of the Brain. %A Andersson, Marcus J %A Stone, Jonathan %K Aging %K Alzheimer Disease %K Brain %K Cognitive Dysfunction %K Dementia %K Humans %X

This review deals with an unwelcome reality about several forms of dementia, including Alzheimer's disease- that these dementias are caused, in part or whole, by the aging of the vasculature. Since the vasculature ages in us all, dementia is our fate, sealed by the realit!ies of the circulation; it is not a disease with a cure pending. Empirically, cognitive impairment before our 7th decade is uncommon and considered early, while a diagnosis in our 11th decade is late but common in that cohort (>40%). Projections from earlier ages suggest that the prevalence of dementia in people surviving into their 12th decade exceeds 80%. We address the question why so few of many interventions known to delay dementia are recognized as therapy; and we try to resolve this few-and-many paradox, identifying opportunities for better treatment, especially pre-diagnosis. The idea of dementia as a fate is resisted, we argue, because it negates the hope of a cure. But the price of that hope is lost opportunity. An approach more in line with the evidence, and more likely to limit suffering, is to understand the damage that accumulates with age in the cerebral vasculature and therefore in the brain, and which eventually gives rise to cognitive symptoms in late life, too often leading to dementia. We argue that hope should be redirected to delaying that damage and with it the onset of cognitive loss; and, for each individual, it should be redirected to a life-long defense of their brain.

%B J Alzheimers Dis %V 94 %P 51-66 %8 2023 %G eng %N 1 %R 10.3233/JAD-230429 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Can Traditional Board Games Prevent or Slow Down Cognitive Impairment? A Systematic Review and Meta-Analysis. %A Pozzi, Federico Emanuele %A Appollonio, Ildebrando %A Ferrarese, Carlo %A Tremolizzo, Lucio %K Aged %K Alzheimer Disease %K Cognition %K Cognitive Dysfunction %K Executive Function %K Humans %K Quality of Life %X

BACKGROUND: Traditional board games can entail significant skills encompassing several cognitive functions across different domains. Therefore, they may potentially represent effective cognitive interventions in the aging population with or without Alzheimer's disease or other types of dementia.

OBJECTIVE: We aimed at verifying the hypothesis that traditional board games can prevent or slow down cognitive decline, through a systematic review on traditional board games and dementia.

METHODS: We searched five databases with tailored search strings. We included studies assessing the impact of board games on elderly subjects at risk of or suffering from cognitive impairment, or subjects with cognitive impairment irrespective of age. Studies where the effect of board games was not separated by cards or other games were excluded. A meta-analysis was performed for specific cognitive and non-cognitive outcomes.

RESULTS: Board games improved mental function, as measured by Montreal Cognitive Assessment (p = 0.003) and Mini-Mental State Examination (p = 0.02). Ska and Go improved Trail Making Test -A, while Mahjong improved executive functions. There was no consistent effect across different games on Digit Span or Categorical Fluency. Chess improved quality of life measured with the WHO-QoL-OLD scale (p < 0.00001). Mahjong temporarily improved depressive symptoms. Go increased BDNF levels and left middle temporal gyrus and bilateral putamen metabolism.

CONCLUSIONS: Traditional board games may slow global cognitive decline and improve the quality of life in elderly subjects. Different games have varying impacts on specific cognitive domains, possibly mediated by functional and biological factors.

%B J Alzheimers Dis %V 95 %P 829-845 %8 2023 %G eng %N 3 %R 10.3233/JAD-230473 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cardiorespiratory Fitness Attenuates the Deleterious Effects of Sleep Apnea on Cerebral Structure and Perfusion in the Wisconsin Sleep Cohort Study. %A Edmunds, Kyle J %A Driscoll, Ira %A Hagen, Erika W %A Barnet, Jodi H %A Ravelo, Laurel A %A Plante, David T %A Gaitán, Julian M %A Lose, Sarah R %A Motovylyak, Alice %A Bendlin, Barbara B %A Okonkwo, Ozioma C %A Peppard, Paul E %X

BACKGROUND: Emerging evidence suggests that age-related changes in cerebral health may be sensitive to vascular risk modifiers, such as physical activity and sleep.

OBJECTIVE: We examine whether cardiorespiratory fitness modifies the association of obstructive sleep apnea (OSA) severity with MRI-assessed measures of cerebral structure and perfusion.

METHODS: Using data from a cross-sectional sample of participants (n = 129, 51% female, age range 49.6-85.3 years) in the Wisconsin Sleep Cohort study, we estimated linear models of MRI-assessed total and regional gray matter (GM) and white matter (WM) volumes, WM hyperintensity (WMH:ICV ratio), total lesion volume, and arterial spin labeling (ASL) cerebral blood flow (CBF), using an estimated measure of cardiorespiratory fitness (CRF) and OSA severity as predictors. Participants' sleep was assessed using overnight in-laboratory polysomnography, and OSA severity was measured using the apnea-hypopnea index (AHI), or the mean number of recorded apnea and hypopnea events per hour of sleep. The mean±SD time difference between PSG data collection and MRI data collection was 1.7±1.5 years (range: [0, 4.9 years]).

RESULTS: OSA severity was associated with reduced total GM volume (β=-0.064; SE = 0.023; p = 0.007), greater total WM lesion volume (interaction p = 0.023), and greater WMHs (interaction p = 0.017) in less-fit subjects. Perfusion models revealed significant differences in the association of AHI and regional CBF between fitness groups (interaction ps <  0.05).

CONCLUSION: This work provides new evidence for the protective role of cardiorespiratory fitness against the deleterious effects of OSA on brain aging in late-middle age to older adults.

%B J Alzheimers Dis %V 95 %P 427-435 %8 2023 Sep 12 %G eng %N 2 %R 10.3233/JAD-220910 %0 Journal Article %J J Alzheimers Dis %D 2023 %T CERAD (Consortium to Establish a Registry for Alzheimer's Disease) Neuropsychology Assessment Battery: 35 Years and Counting. %A Fillenbaum, Gerda G %A Mohs, Richard %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cross-Sectional Studies %K Humans %K Neuropsychological Tests %K Neuropsychology %K Psychometrics %K Registries %X

BACKGROUND: In 1986, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) was mandated to develop a brief neuropsychological assessment battery (CERAD-NAB) for AD, for uniform neuropsychological assessment, and information aggregation. Initially used across the National Institutes of Aging-funded Alzheimer's Disease Research Centers, it has become widely adopted wherever information is desired on cognitive status and change therein, particularly in older populations.

OBJECTIVE: Our purpose is to provide information on the multiple uses of the CERAD-NAB since its inception, and possible further developments.

METHODS: Since searching on "CERAD neuropsychological assessment battery" or similar terms missed important information, "CERAD" alone was entered into PubMed and SCOPUS, and CERAD-NAB use identified from the resulting studies. Use was sorted into major categories, e.g., psychometric information, norms, dementia/differential dementia diagnosis, epidemiology, intervention evaluation, genetics, etc., also translations, country of use, and alternative data gathering approaches.

RESULTS: CERAD-NAB is available in ∼20 languages. In addition to its initial purpose assessing AD severity, CERAD-NAB can identify mild cognitive impairment, facilitate differential dementia diagnosis, determine cognitive effects of naturally occurring and experimental interventions (e.g., air pollution, selenium in soil, exercise), has helped to clarify cognition/brain physiology-neuroanatomy, and assess cognitive status in dementia-risk conditions. Surveys of primary and tertiary care patients, and of population-based samples in multiple countries have provided information on prevalent and incident dementia, and cross-sectional and longitudinal norms for ages 35-100 years.

CONCLUSION: CERAD-NAB has fulfilled its original mandate, while its uses have expanded, keeping up with advances in the area of dementia.

%B J Alzheimers Dis %V 93 %P 1-27 %8 2023 %G eng %N 1 %R 10.3233/JAD-230026 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cerebral Gray and White Matter Monogalactosyl Diglyceride Levels Rise with the Progression of Alzheimer's Disease. %A Blusztajn, Jan Krzysztof %A Aytan, Nurgul %A Rajendiran, Thekkelnaycke %A Mellott, Tiffany J %A Soni, Tanu %A Burant, Charles F %A Serrano, Geidy E %A Beach, Thomas G %A Lin, Honghuang %A Stein, Thor D %X

BACKGROUND: Multiple studies have reported brain lipidomic abnormalities in Alzheimer's disease (AD) that affect glycerophospholipids, sphingolipids, and fatty acids. However, there is no consensus regarding the nature of these abnormalities, and it is unclear if they relate to disease progression.

OBJECTIVE: Monogalactosyl diglycerides (MGDGs) are a class of lipids which have been recently detected in the human brain. We sought to measure their levels in postmortem human brain and determine if these levels correlate with the progression of the AD-related traits.

METHODS: We measured MGDGs by ultrahigh performance liquid chromatography tandem mass spectrometry in postmortem dorsolateral prefrontal cortex gray matter and subcortical corona radiata white matter samples derived from three cohorts of participants: the Framingham Heart Study, the Boston University Alzheimer's Disease Research Center, and the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (total n = 288).

RESULTS: We detected 40 molecular species of MGDGs (including diacyl and alkyl/acyl compounds) and found that the levels of 29 of them, as well as total MGDG levels, are positively associated with AD-related traits including pathologically confirmed AD diagnosis, clinical dementia rating, Braak and Braak stage, neuritic plaque score, phospho-Tau AT8 immunostaining density, levels of phospho-Tau396 and levels of Aβ40. Increased MGDG levels were present in both gray and white matter, indicating that they are widespread and likely associated with myelin-producing oligodendrocytes-the principal cell type of white matter.

CONCLUSIONS: Our data implicate the MGDG metabolic defect as a central correlate of clinical and pathological progression in AD.

%B J Alzheimers Dis %V 95 %P 1623-1634 %8 2023 Oct 10 %G eng %N 4 %R 10.3233/JAD-230543 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cerebrospinal Fluid Panel of Synaptic Proteins in Cerebral Amyloid Angiopathy and Alzheimer's Disease. %A van den Berg, Emma %A Nilsson, Johanna %A Kersten, Iris %A Brinkmalm, Gunnar %A de Kort, Anna M %A Klijn, Catharina J M %A Schreuder, Floris H B M %A Jäkel, Lieke %A Gobom, Johan %A Portelius, Erik %A Zetterberg, Henrik %A Brinkmalm, Ann %A Blennow, Kaj %A Kuiperij, H Bea %A Verbeek, Marcel M %X

BACKGROUND: Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) share pathogenic pathways related to amyloid-β deposition. Whereas AD is known to affect synaptic function, such an association for CAA remains yet unknown.

OBJECTIVE: We therefore aimed to investigate synaptic dysfunction in CAA.

METHODS: Multiple reaction monitoring mass spectrometry was used to quantify cerebrospinal fluid (CSF) concentrations of 15 synaptic proteins in CAA and AD patients, and age- and sex-matched cognitively unimpaired controls.

RESULTS: We included 25 patients with CAA, 49 patients with AD, and 25 controls. Only neuronal pentraxin-2 levels were decreased in the CSF of CAA patients compared with controls (p = 0.04). CSF concentrations of 12 other synaptic proteins were all increased in AD compared with CAA or controls (all p≤0.01) and were unchanged between CAA and controls. Synaptic protein concentrations in the subgroup of CAA patients positive for AD biomarkers (CAA/ATN+; n = 6) were similar to AD patients, while levels in CAA/ATN- (n = 19) were comparable with those in controls. A regression model including all synaptic proteins differentiated CAA from AD at high accuracy levels (area under the curve 0.987).

CONCLUSION: In contrast to AD, synaptic CSF biomarkers were found to be largely unchanged in CAA. Moreover, concomitant AD pathology in CAA is associated with abnormal synaptic protein levels. Impaired synaptic function in AD was confirmed in this independent cohort. Our findings support an apparent differential involvement of synaptic dysfunction in CAA and AD and may reflect distinct pathological mechanisms.

%B J Alzheimers Dis %V 92 %P 467-475 %8 2023 Mar 21 %G eng %N 2 %R 10.3233/JAD-220977 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cerebrospinal Fluid sTREM-2, GFAP, and β-S100 in Symptomatic Sporadic Alzheimer's Disease: Microglial, Astrocytic, and APOE Contributions Along the Alzheimer's Disease Continuum. %A Bonomi, Chiara Giuseppina %A Assogna, Martina %A Di Donna, Martina Gaia %A Bernocchi, Francesca %A De Lucia, Vincenzo %A Nuccetelli, Marzia %A Fiorelli, Denise %A Loizzo, Stefano %A Mercuri, Nicola Biagio %A Koch, Giacomo %A Martorana, Alessandro %A Motta, Caterina %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Astrocytes %K Biomarkers %K Humans %K Microglia %K Peptide Fragments %K tau Proteins %X

BACKGROUND: Many transversal mechanisms act synergistically at different time-points in the cascade of Alzheimer's disease (AD), since amyloid-β (Aβ) deposition, tau pathology, and neuroinflammation influence each other.

OBJECTIVE: We explored the contributions of microglia and astrocytes in patients with symptomatic sporadic AD stratified according to AT(N) system and APOE genotype.

METHODS: We compared the cerebrospinal fluid (CSF) levels of sTREM-2 and markers of astrocytic activation (GFAP; β-S100) from 71 patients with AD (23 A+T-,48 A+T+; 38 APOEɛ3, 33 APOEɛ4) and 30 healthy controls (HC). With multivariate analyses we investigated associations between glial biomarkers, Aβ42, and p-tau in all subgroups.

RESULTS: CSF sTREM-2 was higher in A+T+ [1.437 (0.264)] and A+T- [1.355 (0.213)] than in HC [1.042 (0.198); both p < 0.001]; GFAP and β-S100 were comparable across groups. Considering all patients, sTREM-2 positively associated with Aβ42 (p = 0.04) and p-tau (=0.016), with the first being present only in the A+T- subgroup (p = 0.023). GFAP positively associated with Aβ42 in all patients (p = 0.020) and in the A+T+ subgroup (p = 0.04). Stratifying by APOE, a positive association of sTREM-2 and p-tau was confirmed selectively in carriers of ɛ4 (p = 0.018). Finally, sTREM-2 positively correlated with β-S100 in all subgroups, and with GFAP in A+T+ (p = 0.042).

CONCLUSION: Our results confirm the increase of CSF sTREM-2 in AD, which associates with reduced amyloidopathy in A+T- patients. Moreover, microglial activation seems to increase CSF tau levels in carriers of APOEɛ4, is associated with astrocytic reactivity (GFAP) in A+T+, and likely leads the acquisition of a more neurotoxic astrocytic phenotype (β-S100).

%B J Alzheimers Dis %V 92 %P 1385-1397 %8 2023 %G eng %N 4 %R 10.3233/JAD-221010 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Characterizing Limbic-Predominant Age-Related TDP-43 Encephalopathy Without Alzheimer's Disease and Lewy Body Dementia in the Oldest Old: A Case Series. %A Leiby, Anne-Marie C %A Scambray, Kiana A %A Nguyen, Hannah L %A Basith, Farheen %A Fakhraee, Shahrzad %A Melikyan, Zarui A %A Bukhari, Syed A %A Montine, Thomas J %A Corrada, Maria M %A Kawas, Claudia H %A Sajjadi, S Ahmad %K Aged %K Aged, 80 and over %K Alzheimer Disease %K DNA-Binding Proteins %K Humans %K Lewy Body Disease %K Syncope %K Tauopathies %K TDP-43 Proteinopathies %X

BACKGROUND: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a clinicopathological construct proposed to facilitate studying TDP-43 pathology in older individuals.

OBJECTIVE: Our aim was to describe clinical and cognitive characteristics of LATE-NC without Alzheimer's disease neuropathologic change (ADNC) and Lewy body (LB) and to compare this with ADNC and primary age related tauopathy (PART).

METHODS: In 364 autopsies of the oldest old of The 90+ Study, we identified those with LATE-NC without ADNC and LB. Control groups were participants with ADNC and PART.

RESULTS: Of 31% of participants who had LATE-NC, only 5 (1.4%) had LATE-NC without ADNC and LB, all of whom had tau. These participants had a gradual and progressive cognitive decline. Four (80%) had dementia at death, a rate that was higher than ADNC (50%) and PART (21.7%). Mean duration of cognitive impairment was twice as long in LATE-NC without ADNC and LB (6.2 years) compared to ADNC (2.9 years) and PART (3 years). LATE-NC without ADNC and LB group had a higher prevalence of syncope, depression, and extrapyramidal signs than the ADNC and PART groups.

CONCLUSIONS: Despite the high prevalence of LATE-NC, LATE-NC without ADNC and LB was rare in this large oldest-old cohort, highlighting the very high prevalence of multiple pathologic changes in the oldest old. Slowly progressive cognitive decline, ubiquitous memory impairment, history of syncope and depression, and extrapyramidal signs were prominent features among our LATE-NC without ADNC and LB group.

%B J Alzheimers Dis %V 96 %P 113-124 %8 2023 %G eng %N 1 %R 10.3233/JAD-230238 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Characterizing Performance Gaps of a Code-Based Dementia Algorithm in a Population-Based Cohort of Cognitive Aging. %A Vassilaki, Maria %A Fu, Sunyang %A Christenson, Luke R %A Garg, Muskan %A Petersen, Ronald C %A St Sauver, Jennifer %A Sohn, Sunghwan %K Alzheimer Disease %K Cognitive Aging %K Cognitive Dysfunction %K Dementia %K Disease Progression %K Female %K Humans %K Male %X

BACKGROUND: Multiple algorithms with variable performance have been developed to identify dementia using combinations of billing codes and medication data that are widely available from electronic health records (EHR). If the characteristics of misclassified patients are clearly identified, modifying existing algorithms to improve performance may be possible.

OBJECTIVE: To examine the performance of a code-based algorithm to identify dementia cases in the population-based Mayo Clinic Study of Aging (MCSA) where dementia diagnosis (i.e., reference standard) is actively assessed through routine follow-up and describe the characteristics of persons incorrectly categorized.

METHODS: There were 5,316 participants (age at baseline (mean (SD)): 73.3 (9.68) years; 50.7% male) without dementia at baseline and available EHR data. ICD-9/10 codes and prescription medications for dementia were extracted between baseline and one year after an MCSA dementia diagnosis or last follow-up. Fisher's exact or Kruskal-Wallis tests were used to compare characteristics between groups.

RESULTS: Algorithm sensitivity and specificity were 0.70 (95% CI: 0.67, 0.74) and 0.95 (95% CI: 0.95, 0.96). False positives (i.e., participants falsely diagnosed with dementia by the algorithm) were older, with higher Charlson comorbidity index, more likely to have mild cognitive impairment (MCI), and longer follow-up (versus true negatives). False negatives (versus true positives) were older, more likely to have MCI, or have more functional limitations.

CONCLUSIONS: We observed a moderate-high performance of the code-based diagnosis method against the population-based MCSA reference standard dementia diagnosis. Older participants and those with MCI at baseline were more likely to be misclassified.

%B J Alzheimers Dis %V 95 %P 931-940 %8 2023 %G eng %N 3 %R 10.3233/JAD-230344 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Chiral Amino Acid Profiling in Serum Reveals Potential Biomarkers for Alzheimer's Disease. %A Liu, Mingxia %A Li, Mo %A He, Jing %A He, Yi %A Yang, Jian %A Sun, Zuoli %K Alzheimer Disease %K Amino Acids %K Aspartic Acid %K Biomarkers %K D-Aspartic Acid %K Humans %K Neurodegenerative Diseases %K Phenylalanine %K Proline %K Tandem Mass Spectrometry %X

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disease, and increasing evidence has linked dysregulation of amino acids to AD pathogenesis. However, the existing studies often ignore the chirality of amino acids, and some results are inconsistent and controversial. The changes of amino acid profiles in AD from the perspective of enantiomers remain elusive.

OBJECTIVE: The purpose of this study is to investigate whether the levels of amino acids, especially D-amino acids, are deregulated in the peripheral serum of AD patients, with the ultimate goal of discovering novel biomarkers for AD.

METHODS: The chiral amino acid profiles were determined by HPLC-MS/MS with a pre-column derivatization method. Experimental data obtained from 37 AD patients and 34 healthy controls (HC) were statistically analyzed.

RESULTS: Among the 35 amino acids detected, D-proline, D/total-proline ratio, D-aspartate, and D/total-aspartate ratio were decreased, while D-phenylalanine was elevated in AD compared to HC. Significant age-dependent increases in D-proline, D/total-proline ratio, and D-phenylalanine were observed in HC, but not in AD. Receiver operator characteristic analyses of the combination of D-proline, D-aspartate, D-phenylalanine, and age for discriminating AD from HC provided satisfactory area under the curve (0.87), specificity (97.0%), and sensitivity (83.8%). Furthermore, the D-aspartate level was significantly decreased with the progression of AD, as assessed by the Clinical Dementia Rating Scale and Mini-Mental State Examination.

CONCLUSION: The panels of D-proline, D-phenylalanine, and D-aspartate in peripheral serum may serve as novel biomarker candidates for AD. The latter parameter is further associated with the severity of AD.

%B J Alzheimers Dis %V 94 %P 291-301 %8 2023 %G eng %N 1 %R 10.3233/JAD-230142 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Chronic Sleep Disturbances Alters Sleep Structure and Tau Phosphorylation in AβPP/PS1 AD Mice and Their Wild-Type Littermates. %A Zhang, Feng %A Niu, Long %A Zhong, Rujia %A Li, Song %A Le, Weidong %X

BACKGROUND: Emerging evidence indicates that sleep disorders are the common non-cognitive symptoms of Alzheimer's disease (AD), and they may contribute to the pathogenesis of this disease.

OBJECTIVE: In this study, we aim to investigate the effect of chronic sleep deprivation (CSD) on AD-related pathologies with a focus on tau phosphorylation and the underlying DNA methylation regulation.

METHODS: AβPPswe/PS1ΔE9 AD mice and their wild-type (WT) littermates were subjected to a two-month CSD followed by electroencephalography and electromyography recording. The mice were examined for learning and memory evaluation, then pathological, biochemical, and epigenetic assessments including western blotting, immunofluorescence, dot blotting, and bisulfite sequencing.

RESULTS: The results show that CSD caused sleep disorders shown as sleep pattern change, poor sleep maintenance, and increased sleep fragmentation. CSD increased tau phosphorylation at different sites and increased the level of tau kinases in AD and WT mice. The increased expression of cyclin-dependent kinase 5 (CDK5) may result from decreased DNA methylation of CpG sites in the promoter region of CDK5 gene, which might be associated with the downregulation of DNA methyltransferase 3A and 3B.

CONCLUSION: CSD altered AD-related tau phosphorylation through epigenetic modification of tau kinase gene. The findings in this study may give insights into the mechanisms underlying the effects of sleep disorders on AD pathology and provide new therapeutic targets for the treatment of this disease.

%B J Alzheimers Dis %V 92 %P 1341-1355 %8 2023 Apr 18 %G eng %N 4 %R 10.3233/JAD-221048 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Circulating Omega-3 and Omega-6 Fatty Acids, Cognitive Decline, and Dementia in Older Adults. %A de Oliveira Otto, Marcia C %A Wu, Jason H Y %A Thacker, Evan L %A Lai, Heidi Tsz Mung %A Lemaitre, Rozenn N %A Padhye, Nikhil %A Song, Xiaoling %A King, Irena B %A Lopez, Oscar %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Arachidonic Acid %K Cognitive Dysfunction %K Dementia %K Fatty Acids %K Fatty Acids, Omega-3 %K Fatty Acids, Omega-6 %K Fatty Acids, Unsaturated %K Humans %X

BACKGROUND: Comprising nearly 35% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown.

OBJECTIVE: We investigated prospective associations of plasma phospholipid omega-3 (ALA [18 : 3], EPA [20 : 5], DPA [22 : 5], DHA [22 : 6]) and omega-6 (LA [18 : 2], AA [20 : 4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged≥65 years in the Cardiovascular Health Study.

METHODS: Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes.

RESULTS: Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA.

CONCLUSION: Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life.

%B J Alzheimers Dis %V 95 %P 965-979 %8 2023 %G eng %N 3 %R 10.3233/JAD-230083 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cleveland Clinic Cognitive Battery (C3B): Normative, Reliability, and Validation Studies of a Self-Administered Computerized Tool for Screening Cognitive Dysfunction in Primary Care. %A Rao, Stephen M %A Galioto, Rachel %A Sokolowski, Megan %A Pierce, Madelyn %A Penn, Lisa %A Sturtevant, Anna %A Skugor, Blazenka %A Anstead, Brent %A Leverenz, James B %A Schindler, David %A Blum, David %A Alberts, Jay L %A Posk, Lori %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Cognition %K Cognitive Dysfunction %K Humans %K Middle Aged %K Neuropsychological Tests %K Primary Health Care %K Reproducibility of Results %K Young Adult %X

BACKGROUND: The self-administered iPad-based Cleveland Clinic Cognitive Battery (C3B) was designed specifically for the efficient screening of cognitive functioning of older adults in a primary care setting.

OBJECTIVE: 1) Generate regression-based norms from healthy participants to enable demographic corrections to facilitate clinical interpretation; 2) estimate test-retest reliability and practice effects; 3) examine ability to discriminate mild cognitive impairment (MCI) from healthy aging; 4) d etermine validity of screening in a distracting clinical environment; and 5) determine completion rates and patient satisfaction in a primary care setting.

METHODS: Study 1 (S1) recruited a stratified sample of 428 healthy adults, ages 18-89, to generate regression-based equations. S2 assessed 2-week test-retest reliability and practice effects in 30 healthy elders. S3 recruited 30 MCI patients and 30 demographically-matched healthy controls. In S4, 30 healthy elders self-administered the C3B in a distracting environment and in a quiet private room in counterbalanced order. In a demonstration project, 470 consecutive primary care patients were administered the C3B as part of routine clinical care (S5).

RESULTS: C3B performance was primarily influenced by age, education, and race (S1), had acceptably high test-retest reliability and minimal practice effects (S2), discriminated MCI from healthy controls (S3), was not negatively impacted by a distracting clinical environment (S4), had high completion rates (>92%) and positive ratings from primary care patients (S5).

CONCLUSION: The C3B is a computerized cognitive screening tool that is reliable, validated, self-administered, and is conducive to integration into a busy primary care clinical workflow for detecting MCI, early Alzheimer's disease, and other related dementias.

%B J Alzheimers Dis %V 92 %P 1051-1066 %8 2023 %G eng %N 3 %R 10.3233/JAD-220929 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Coexistence of Amyotrophic Lateral Sclerosis and Alzheimer's Disease: Case Report and Review of the Literature. %A Verde, Federico %A Aiello, Edoardo Nicolò %A Adobbati, Laura %A Poletti, Barbara %A Solca, Federica %A Tiloca, Cinzia %A Sangalli, Davide %A Maranzano, Alessio %A Muscio, Cristina %A Ratti, Antonia %A Zago, Stefano %A Ticozzi, Nicola %A Frisoni, Giovanni Battista %A Silani, Vincenzo %K Alzheimer Disease %K Amyotrophic Lateral Sclerosis %K Brain %K Cognitive Dysfunction %K Female %K Frontotemporal Dementia %K Humans %K Male %X

We describe a case of amyotrophic lateral sclerosis (ALS) associated with Alzheimer's disease (AD) and review the literature about the coexistence of the two entities, highlighting the following: mean age at onset is 63.8 years, with slight female predominance; ALS tends to manifest after cognitive impairment and often begins in the bulbar region; average disease duration is 3 years; cognitive phenotype is mostly amnestic; the pattern of brain involvement is, in most cases, consistent with AD. Our case and the reviewed ones suggest that patients with ALS and dementia lacking unequivocal features of FTD should undergo additional examinations in order to recognize AD.

%B J Alzheimers Dis %V 95 %P 1383-1399 %8 2023 %G eng %N 4 %R 10.3233/JAD-230562 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cognition and Cognitive Changes in a Low-Income Sub-Saharan African Aging Population. %A Kohler, Iliana V %A Kämpfen, Fabrice %A Bandawe, Chiwoza %A Kohler, Hans-Peter %X

BACKGROUND: Cognition and its age-related changes remain vastly understudied in low-income countries (LICs), despite evidence suggesting that cognitive decline among aging low-income populations is a rapidly increasing disease burden often occurring at younger ages as compared to high-income countries (HICs).

OBJECTIVE: We examine patterns of cognition among men and women, 45 + years old, living in rural Malawi. We analyze how key socioeconomic characteristics predict levels of cognition and its changes as individuals get older.

METHODS: Utilizing the Mature Adults Cohort of the Malawi Longitudinal Study of Families and Health (MLSFH-MAC) collected during 2012-2017, we estimate standard regression models to analyze predictors of the age- and sex-specific levels and longitudinal changes in cognition. Cognition is assessed with a screening instrument that is adapted to this low-literacy context and measures different domains such as language, attention, or executive functioning.

RESULTS: Women have lower levels of cognition than men, a pattern in stark contrast to findings in HICs. Schooling and socioeconomic status increase the probability of having consistently high performance during the cognitive assessment. Cognitive decline accelerates with age and is detectable already at mid-adult ages (45-55 years). Despite lower levels of cognitive function observed among women, the pace of decline with age is similar for both genders.

CONCLUSION: Women are particularly affected by poor cognition in this context. The study emphasizes the importance of prioritizing cognitive health and research on cognition among older individuals in sub-Saharan Africa LICs, to which relatively little health care resources continue to be allocated.

%B J Alzheimers Dis %V 95 %P 195-212 %8 2023 Aug 29 %G eng %N 1 %R 10.3233/JAD-230271 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cognitive and Neuropsychological Profiles in Alzheimer's Disease and Primary Age-Related Tauopathy and the Influence of Comorbid Neuropathologies. %A Walker, Jamie M %A Gonzales, Mitzi M %A Goette, William %A Farrell, Kurt %A White Iii, Charles L %A Crary, John F %A Richardson, Timothy E %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Cognition %K Executive Function %K Humans %K Tauopathies %X

BACKGROUND: Alzheimer's disease neuropathologic change (ADNC) is defined by the progression of both hyperphosphorylated-tau (p-tau) and amyloid-β (Aβ) and is the most common underlying cause of dementia worldwide. Primary age-related tauopathy (PART), an Aβ-negative tauopathy largely confined to the medial temporal lobe, is increasingly being recognized as an entity separate from ADNC with diverging clinical, genetic, neuroanatomic, and radiologic profiles.

OBJECTIVE: The specific clinical correlates of PART are largely unknown; we aimed to identify cognitive and neuropsychological differences between PART, ADNC, and subjects with no tauopathy (NT).

METHODS: We compared 2,884 subjects with autopsy-confirmed intermediate-high stage ADNC to 208 subjects with definite PART (Braak stage I-IV, Thal phase 0, CERAD NP score "absent") and 178 NT subjects from the National Alzheimer's Coordinating Center dataset.

RESULTS: PART subjects were older than either ADNC or NT patients. The ADNC cohort had more frequent neuropathological comorbidities as well as APOE ɛ4 alleles than the PART or NT cohort, and less frequent APOE ɛ2 alleles than either group. Clinically, ADNC patients performed significantly worse than NT or PART subjects across cognitive measures, but PART subjects had selective deficits in measures of processing speed, executive function, and visuospatial function, although additional cognitive measures were further impaired in the presence of neuropathologic comorbidities. In isolated cases of PART with Braak stage III-IV, there are additional deficits in measures of language.

CONCLUSION: Overall, these findings demonstrate underlying cognitive features specifically associated with PART, and reinforce the concept that PART is a distinct entity from ADNC.

%B J Alzheimers Dis %V 92 %P 1037-1049 %8 2023 %G eng %N 3 %R 10.3233/JAD-230022 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Complexity of Nutritional Problems in Persons with Dementia: Expanding a Theoretical Model. %A van Buuren, Cornelia Pieternella %A van der Steen, Jenny Theodora %A Olthof-Nefkens, Maria %A Bakker, Christian %A Koopmans, Raymond Theodorus Catherina Maria %A Perry, Marieke %A Kalf, Johanna Gezina %K Attitude of Health Personnel %K Dementia %K Focus Groups %K Health Personnel %K Humans %K Nursing Homes %X

BACKGROUND: Persons with dementia are at risk of developing nutritional problems. Theoretical models on nutritional problems have been developed, but have not been evaluated with healthcare professionals.

OBJECTIVE: This study aimed to explore the comprehensiveness and applicability of a theoretical model of nutritional problems in persons with dementia for daily nursing home practice.

METHODS: A qualitative design employing a combined deductive and inductive approach was used. Healthcare professionals were eligible to participate if they 1) had expert knowledge of and experience with nutritional problems related to dementia, and 2) worked in a nursing home affiliated with an academic network covering the east and south of the Netherlands. Three focus group interviews with 20 healthcare professionals from seven professions were held. We conducted thematic analysis and we compared themes with existing theoretical models from the literature.

RESULTS: We identified six themes, four of which corresponded with the existing models (observing and analysing nutritional problems; consequences of nutritional problems; functioning of the person with dementia; environmental factors). Interprofessional collaboration and ethical factors were identified as new themes. The analyses indicated interactions within each theme, between themes, and a bidirectional connection between themes.

CONCLUSIONS: This study demonstrated the relevance of interprofessional collaboration and ethical considerations in nutritional problems related to dementia. It uncovered complex bidirectional relations within and between factors regarding nutritional problems. All aspects should be taken into account to minimize the consequences of nutritional problems for persons with dementia.

%B J Alzheimers Dis %V 96 %P 183-192 %8 2023 %G eng %N 1 %R 10.3233/JAD-230135 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Computational Evaluation of Azadirachta indica-Derived Bioactive Compounds as Potential Inhibitors of NLRP3 in the Treatment of Alzheimer's Disease. %A Ishabiyi, Felix Oluwasegun %A Ogidi, James Okwudirichukwu %A Olukade, Baliqis Adejoke %A Amorha, Chizoba Christabel %A El-Sharkawy, Lina Y %A Okolo, Chukwuemeka Calistus %A Adeniyi, Titilope Mary %A Atasie, Nkechi Hope %A Ibrahim, Abdulwasiu %A Balogun, Toheeb Adewale %K Alzheimer Disease %K Azadirachta %K Humans %K Molecular Docking Simulation %K NLR Family, Pyrin Domain-Containing 3 Protein %X

BACKGROUND: The development of therapeutic agents against Alzheimer's disease (AD) has stalled recently. Drug candidates targeting amyloid-β (Aβ) deposition have often failed clinical trials at different stages, prompting the search for novel targets for AD therapy. The NLRP3 inflammasome is an integral part of innate immunity, contributing to neuroinflammation and AD pathophysiology. Thus, it has become a promising new target for AD therapy.

OBJECTIVE: The study sought to investigate the potential of bioactive compounds derived from Azadirachta-indica to inhibit the NLRP3 protein implicated in the pathophysiology of AD.

METHODS: Structural bioinformatics via molecular docking and density functional theory (DFT) analysis was utilized for the identification of novel NLRP3 inhibitors from A. indica bioactive compounds. The compounds were further subjected to pharmacokinetic and drug-likeness analysis. Results obtained from the compounds were compared against that of oridonin, a known NLRP3 inhibitor.

RESULTS: The studied compounds optimally saturated the binding site of the NLRP3 NACHT domain, forming principal interactions with the different amino acids at its binding site. The studied compounds also demonstrated better bioactivity and chemical reactivity as ascertained by DFT analysis and all the compounds except 7-desacetyl-7-benzoylazadiradione, which had two violations, conformed to Lipinski's rule of five.

CONCLUSION: In silico studies show that A. indica derived compounds have better inhibitory potential against NLRP3 and better pharmacokinetic profiles when compared with the reference ligand (oridonin). These compounds are thus proposed as novel NLRP3 inhibitors for the treatment of AD. Further wet-lab studies are needed to confirm the potency of the studied compounds.

%B J Alzheimers Dis %V 94 %P S67-S85 %8 2023 %G eng %N s1 %R 10.3233/JAD-221020 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Costs During the Last Five Years of Life for Patients with Clinical and Pathological Confirmed Diagnosis of Lewy Body Dementia and Alzheimer's Disease. %A Zhu, Carolyn W %A Gu, Yian %A Kociolek, Anton J %A Fernandez, Kayri K %A Cosentino, Stephanie %A Stern, Yaakov %X

BACKGROUND: Little is known regarding healthcare expenditures for patients with dementia with Lewy bodies (DLB) during the end of life.

OBJECTIVE: This study estimated Medicare expenditures during the last 5 years of life in a decedent sample of patients who were clinically diagnosed with Alzheimer's disease (AD) or DLB and had autopsy confirmed diagnosis.

METHODS: The study included 58 participants clinically diagnosed with mild dementia at study entry (AD: n = 44, DLB: n = 14) and also had autopsy-confirmed diagnoses of pure AD (n = 32), mixed AD+Lewy body (LB) (n = 5), or pure LB (n = 11). Total Medicare expenditures were compared by clinical and pathology confirmed diagnosis, adjusting for sex, age at death, and patient's cognition, function, comorbidities, and psychiatric and extrapyramidal symptoms.

RESULTS: When pathology diagnoses were not considered, predicted annualized total Medicare expenditures during the last 5 years of life were similar between clinically diagnosed AD ($7,465±1,098) and DLB ($7,783±1,803). When clinical diagnoses were not considered, predicted expenditures were substantially higher in patients with pathology confirmed mixed AD+LB ($12,005±2,455) than either pure AD ($6,173±941) or pure LB ($4,629±1,968) cases. Considering clinical and pathology diagnosis together, expenditures for patients with clinical DLB and pathology mixed AD+LB ($23,592±3,679) dwarfed other groups.

CONCLUSION: Medicare expenditures during the last 5 years of life were substantially higher in patients with mixed AD+LB pathology compared to those with pure-AD and pure-DLB pathologies, particularly in those clinically diagnosed with DLB. Results highlight the importance of having both clinical and pathology diagnoses in examining healthcare costs.

%B J Alzheimers Dis %V 92 %P 457-466 %8 2023 Mar 21 %G eng %N 2 %R 10.3233/JAD-221021 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Costs of Dementia in Low- And Middle-Income Countries: A Systematic Review. %A Kenne Malaha, Angeladine %A Thébaut, Clémence %A Achille, Dayna %A Preux, Pierre-Marie %A Guerchet, Maëlenn %K Cost of Illness %K Dementia %K Developing Countries %K Health Care Costs %K Health Expenditures %K Humans %X

BACKGROUND: The proportion of people living with dementia in low- and middle-income countries (LMICs) is expected to reach 71% by 2050. Appraising the economic burden of the disease may contribute to strategic policy planning.

OBJECTIVE: To review studies conducted on the costs of dementia in LMICs, describe their methodology and summarize available costs estimates.

METHODS: Systematic review, including a search of health, economics, and social science bibliographic databases. No date or language restrictions were applied. All studies with a direct measure of the costs of dementia care were included.

RESULTS: Of the 6,843 publications reviewed, 17 studies from 11 LMICs were included. Costs of dementia tended to increase with the severity of the disease. Medical costs were greater in the mild stage, while social and informal care costs were highest in the moderate and severe stages. Annual cost estimates per patient ranged from PPP$131.0 to PPP$31,188.8 for medical costs; from PPP$16.1 to PPP$10,581.7 for social care services and from PPP$140.0 to PPP$25,798 for informal care. Overall, dementia care can cost from PPP$479.0 to PPP$66,143.6 per year for a single patient.

CONCLUSION: Few studies have been conducted on the costs of dementia in LMICs, and none so far in Africa. There seems to be a need to provide accurate data on the burden of disease in these countries to guide public health policies in the coming decades.

%B J Alzheimers Dis %V 91 %P 115-128 %8 2023 %G eng %N 1 %R 10.3233/JAD-220239 %0 Journal Article %J J Alzheimers Dis %D 2023 %T COVID-19 as a Risk Factor for Alzheimer's Disease. %A Golzari-Sorkheh, Mahdieh %A Weaver, Donald F %A Reed, Mark A %K Alzheimer Disease %K COVID-19 %K Humans %K Nervous System Diseases %K Neuroinflammatory Diseases %K Risk Factors %K SARS-CoV-2 %X

Severe acute respiratory disease coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although a primarily respiratory disease, recent reports indicate that it also affects the central nervous system (CNS). Over 25% of COVID-19 patients report neurological symptoms such as memory loss, anosmia, hyposmia, confusion, and headaches. The neurological outcomes may be a result of viral entry into the CNS and/or resulting neuroinflammation, both of which underlie an elevated risk for Alzheimer's disease (AD). Herein, we ask: Is COVID-19 a risk factor for AD? To answer, we identify the literature and review mechanisms by which COVID-19-mediated neuroinflammation can contribute to the development of AD, evaluate the effects of acute versus chronic phases of infection, and lastly, discuss potential therapeutics to address the rising rates of COVID-19 neurological sequelae.

%B J Alzheimers Dis %V 91 %P 1-23 %8 2023 %G eng %N 1 %R 10.3233/JAD-220800 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cross-Sectional Analysis of Periodontal Disease and Cognitive Impairment Conducted in a Memory Clinic: The Pearl Study. %A Saji, Naoki %A Ishihara, Yuichi %A Murotani, Kenta %A Uchiyama, Akira %A Takeda, Akinori %A Sakurai, Takashi %A Matsushita, Kenji %X

BACKGROUND: Periodontal disease (PeD) is a risk factor of Alzheimer's disease and is associated with cognitive decline in older adults. However, the relationships between subitems of neuropsychological tests and PeD have not been fully clarified.

OBJECTIVE: To evaluate associations between PeD and subitems of neuropsychological tests.

METHODS: We performed a cross-sectional analysis of data of 183 participants (women: 50% , mean age: 79 years) from a clinical study. We enrolled patients who visited our memory clinic and assessed demographics, dementia-related risk factors, neuropsychological tests, brain magnetic resonance images, and a dental screening check. We evaluated the relationships between cognitive function and PeD using multivariable logistic regression analyses.

RESULTS: Participants with dementia were less likely to make periodical visits to the dentist, had fewer teeth, had less frequent tooth brushing habits, and were more likely to have PeD. Impaired cognitive function was significantly associated with an increasing degree of PeD. In multivariable logistic regression analyses, impaired visuospatial function and attention were associated with twice the risk of moderate or severe PeD compared with individuals with preserved visuospatial function and attention (odds ratio: 2.11, 95% confidence interval: 1.04-4.29, p = 0.037). Impaired word recall and recognition and following commands were associated with increased risk of PeD (odds ratio: 2.80, 95% confidence interval: 1.41-5.32, p = 0.003).

CONCLUSIONS: Cognitive decline, such as impaired visuospatial function, attention, word recall and recognition, and inability to follow commands were independently and strongly associated with PeD. These items can be assessed easily on a daily basis.

%B J Alzheimers Dis %V 96 %P 369-380 %8 2023 Oct 24 %G eng %N 1 %R 10.3233/JAD-230742 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Deep Reinforcement Learning-Based Retinal Imaging in Alzheimer's Disease: Potential and Perspectives. %A Hui, Herbert Y H %A Ran, An Ran %A Dai, Jia Jia %A Cheung, Carol Y %K Alzheimer Disease %K Artificial Intelligence %K Humans %K Machine Learning %K Magnetic Resonance Imaging %K Retina %X

Alzheimer's disease (AD) remains a global health challenge in the 21st century due to its increasing prevalence as the major cause of dementia. State-of-the-art artificial intelligence (AI)-based tests could potentially improve population-based strategies to detect and manage AD. Current retinal imaging demonstrates immense potential as a non-invasive screening measure for AD, by studying qualitative and quantitative changes in the neuronal and vascular structures of the retina that are often associated with degenerative changes in the brain. On the other hand, the tremendous success of AI, especially deep learning, in recent years has encouraged its incorporation with retinal imaging for predicting systemic diseases. Further development in deep reinforcement learning (DRL), defined as a subfield of machine learning that combines deep learning and reinforcement learning, also prompts the question of how it can work hand in hand with retinal imaging as a viable tool for automated prediction of AD. This review aims to discuss potential applications of DRL in using retinal imaging to study AD, and their synergistic application to unlock other possibilities, such as AD detection and prediction of AD progression. Challenges and future directions, such as the use of inverse DRL in defining reward function, lack of standardization in retinal imaging, and data availability, will also be addressed to bridge gaps for its transition into clinical use.

%B J Alzheimers Dis %V 94 %P 39-50 %8 2023 %G eng %N 1 %R 10.3233/JAD-230055 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Is Dementia Associated with COVID-19 Mortality? A Multicenter Retrospective Cohort Study Conducted in 50 Hospitals in Germany. %A Kostev, Karel %A Gessler, Nele %A Wohlmuth, Peter %A Arnold, Dirk %A Bein, Berthold %A Bohlken, Jens %A Herrlinger, Klaus %A Jacob, Louis %A Koyanagi, Ai %A Nowak, Lorenz %A Smith, Lee %A Wesseler, Claas %A Sheikhzadeh, Sara %A Wollmer, Marc Axel %K COVID-19 %K COVID-19 Testing %K Dementia %K Germany %K Hospitalization %K Hospitals %K Humans %K Mortality %K Retrospective Studies %X

BACKGROUND: Dementia has been identified as a major predictor of mortality associated with COVID-19.

OBJECTIVE: The objective of this study was to investigate the association between dementia and mortality in COVID-19 inpatients in Germany across a longer interval during the pandemic.

METHODS: This retrospective study was based on anonymized data from 50 hospitals in Germany and included patients with a confirmed COVID-19 diagnosis hospitalized between March 11, 2020 and July, 20, 2022. The main outcome of the study was the association of mortality during inpatient stays with dementia diagnosis, which was studied using multivariable logistic regression adjusted for age, sex, and comorbidities as well as univariate logistic regression for matched pairs.

RESULTS: Of 28,311 patients diagnosed with COVID-19, 11.3% had a diagnosis of dementia. Prior to matching, 26.5% of dementia patients and 11.5% of non-dementia patients died; the difference decreased to 26.5% of dementia versus 21.7% of non-dementia patients within the matched pairs (n = 3,317). This corresponded to an increase in the risk of death associated with dementia (OR = 1.33; 95% CI: 1.16-1.46) in the univariate regression conducted for matched pairs.

CONCLUSION: Although dementia was associated with COVID-19 mortality, the association was weaker than in previously published studies. Further studies are needed to better understand whether and how pre-existing neuropsychiatric conditions such as dementia may impact the course and outcome of COVID-19.

%B J Alzheimers Dis %V 91 %P 719-726 %8 2023 %G eng %N 2 %R 10.3233/JAD-220918 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Detecting Anosognosia from the Prodromal Stage of Alzheimer's Disease. %A Guieysse, Thomas %A Lamothe, Roxane %A Houot, Marion %A Razafimahatratra, Solofo %A Medani, Takfarinas %A Lejeune, François-Xavier %A Dreyfus, Gérard %A Klarsfeld, André %A Pantazis, Dimitrios %A Koechlin, Etienne %A Andrade, Katia %K Agnosia %K Alzheimer Disease %K Brain %K Caregivers %K Humans %K Neuropsychological Tests %K Prodromal Symptoms %X

BACKGROUND: Though not originally developed for this purpose, the Healthy Aging Brain Care Monitor (HABC-M) seems a valuable instrument for assessing anosognosia in Alzheimer's disease (AD).

OBJECTIVES: Our study aimed at 1) investigating the validity of the HABC-M (31 items), and its cognitive, psychological, and functional subscales, in discriminating AD patients from controls; 2) exploring whether the HABC-M discrepancy scores between the self-reports of patients/controls in these different domains and the respective ratings provided by their caregivers/informants correlate with an online measure of self-awareness; 3) determining whether the caregiver burden level, also derived from the HABC-M, could add additional support for detecting anosognosia.

METHODS: The HABC-M was administered to 30 AD patients and 30 healthy controls, and to their caregivers/informants. A measure of online awareness was established from subjects' estimation of their performances in a computerized experiment.

RESULTS: The HABC-M discrepancy scores distinguished AD patients from controls. The cognitive subscale discriminated the two groups from the prodromal AD stage, with an AUC of 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden level raised it to 0.94 [0.86;0.99]. Significant correlations between the HABC-M and online discrepancy scores were observed in the patients group, providing convergent validity of these methods.

CONCLUSIONS: The cognitive HABC-M (six items) can detect anosognosia across the AD spectrum. The caregiver burden (four items) may corroborate the suspicion of anosognosia. The short-hybrid scale, built from these 10 items instead of the usual 31, showed the highest sensitivity for detecting anosognosia from the prodromal AD stage, which may further help with timely diagnosis.

%B J Alzheimers Dis %V 95 %P 1723-1733 %8 2023 %G eng %N 4 %R 10.3233/JAD-230552 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Diagnostic Performance of Cerebrospinal Fluid Neurofilament Light Chain and Soluble Amyloid-β Protein Precursor β in the Subcortical Small Vessel Type of Dementia. %A Axelsson Andrén, Elin %A Kettunen, Petronella %A Bjerke, Maria %A Rolstad, Sindre %A Zetterberg, Henrik %A Blennow, Kaj %A Wallin, Anders %A Svensson, Johan %X

BACKGROUND: The subcortical small vessel type of dementia (SSVD) is a common subtype of vascular dementia, but there is a lack of disease-specific cerebrospinal fluid (CSF) biomarkers.

OBJECTIVE: We investigated whether CSF concentrations of neurofilament light chain (NFL), soluble amyloid-β protein precursor α (sAβPPα), sAβPPβ, and CSF/serum albumin ratio could separate SSVD from healthy controls, Alzheimer's disease (AD), and mixed dementia (combined AD and SSVD).

METHODS: This was a mono-center study of patients with SSVD (n = 38), AD (n = 121), mixed dementia (n = 62), and controls (n = 96). The CSF biomarkers were measured using immunoassays, and their independent contribution to the separation between groups were evaluated using the Wald test. Then, the area under the receiver operating characteristics curve (AUROC) and 95% confidence intervals (CIs) were calculated.

RESULTS: Elevated neurofilament light chain (NFL) and decreased sAβPPβ independently separated SSVD from controls, and sAβPPβ also distinguished SSVD from AD and mixed dementia. The combination of NFL and sAβPPβ discriminated SSVD from controls with high accuracy (AUROC 0.903, 95% CI: 0.834-0.972). Additionally, sAβPPβ combined with the core AD biomarkers (amyloid-β42, total tau, and phosphorylated tau181) had a high ability to separate SSVD from AD (AUROC 0.886, 95% CI: 0.830-0.942) and mixed dementia (AUROC 0.903, 95% CI: 0.838-0.968).

CONCLUSIONS: The high accuracy of NFL and sAβPPβ to separate SSVD from controls supports that SSVD is a specific diagnostic entity. Moreover, SSVD was distinguished from AD and mixed dementia using sAβPPβ in combination with the core AD biomarkers.

%B J Alzheimers Dis %V 96 %P 1515-1528 %8 2023 Dec 05 %G eng %N 4 %R 10.3233/JAD-230680 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Diet's Role in Modifying Risk of Alzheimer's Disease: History and Present Understanding. %A Grant, William B %A Blake, Steven M %K Alzheimer Disease %K Cross-Sectional Studies %K Diet %K Humans %K Prospective Studies %K Risk Factors %X

Diet is an important nonpharmacological risk-modifying factor for Alzheimer's disease (AD). The approaches used here to assess diet's role in the risk of AD include multi-country ecological studies, prospective and cross-sectional observational studies, and laboratory studies. Ecological studies have identified fat, meat, and obesity from high-energy diets as important risk factors for AD and reported that AD rates peak about 15-20 years after national dietary changes. Observational studies have compared the Western dietary pattern with those of the Dietary Approaches to Stop Hypertension (DASH), Mediterranean (MedDi), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets. Those studies identified AD risk factors including higher consumption of saturated and total fats, meat, and ultraprocessed foods and a lower risk of AD with higher consumption of fruits, legumes, nuts, omega-3 fatty acids, vegetables, and whole grains. Diet-induced factors associated with a significant risk of AD include inflammation, insulin resistance, oxidative stress, elevated homocysteine, dietary advanced glycation end products, and trimethylamine N-oxide. The molecular mechanisms by which dietary bioactive components and specific foods affect risk of AD are discussed. Given most countries' entrenched food supply systems, the upward trends of AD rates would be hard to reverse. However, for people willing and able, a low-animal product diet with plenty of anti-inflammatory, low-glycemic load foods may be helpful.

%B J Alzheimers Dis %V 96 %P 1353-1382 %8 2023 %G eng %N 4 %R 10.3233/JAD-230418 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Different Trajectories of Apathy and Depression Among Subjective Cognitive Impairment Individuals with or without Conversion to Dementia: Results from the Memento Cohort in France. %A Bogdan, Anamaria %A Fabre, Roxane %A Desmidt, Thomas %A Golebiowski, Jérôme %A Topin, Jérémie %A Bethus, Ingrid %A Hanon, Olivier %A Boutoleau-Bretonnière, Claire %A Wagemann, Nathalie %A Annweiler, Cedric %A Ousset, Pierre-Jean %A Godefroy, Olivier %A Rouch, Isabelle %A Paccalin, Marc %A Sukhorukova, Maryana %A Gabelle, Audrey %A Robert, Gabriel %A David, Renaud %X

BACKGROUND: Apathy and depression are two early behavioral symptoms in Alzheimer's disease (AD) and related disorders that often occur prior to the onset of cognitive decline and memory disturbances. Both have been associated with an increased risk of conversion to dementia, with a distinct neuropathology.

OBJECTIVE: The assessment of the trajectories of apathy and depression and their independent impact on dementia conversion.

METHODS: Apathy and Depression were measured using the Neuropsychiatric Inventory for caregiver (NPI) and clinician (NPI-C), among the nondemented individuals reporting subjective cognitive decline (SCD) at baseline. They were followed up over a 60-month period. Some converted to dementia, according to the methodology carried out by the French Memento Cohort.

RESULTS: Among individuals with SCD (n = 2,323), the levels of apathy and depression were low and did not evolve significantly over the 60-month period, despite a trend in apathy increasing as of month 24. Regarding SCD individuals who converted to dementia within the 60-month period (n = 27), the prevalence of depression remained globally steady, while the levels of apathy increased over time.

CONCLUSION: Apathy and depression have different trajectories among individuals with SCD and apathy alone is more likely-compared to depression-to be associated with conversion to dementia.

%B J Alzheimers Dis %V 95 %P 415-426 %8 2023 Sep 12 %G eng %N 2 %R 10.3233/JAD-230162 %0 Journal Article %J bioRxiv %D 2023 %T Disrupted excitation-inhibition balance in cognitively normal individuals at risk of Alzheimer's disease. %A Fortel, Igor %A Zhan, Liang %A Ajilore, Olusola %A Wu, Yichao %A Mackin, Scott %A Leow, Alex %X

BACKGROUND: Sex differences impact Alzheimer's disease (AD) neuropathology, but cell-to-network level dysfunctions in the prodromal phase are unclear. Alterations in hippocampal excitation-inhibition balance (EIB) have recently been linked to early AD pathology.

OBJECTIVE: Examine how AD risk factors (age, APOE-ɛ4, amyloid-β) relate to hippocampal EIB in cognitively normal males and females using connectome-level measures.

METHODS: Individuals from the OASIS-3 cohort (age 42-95) were studied (N = 437), with a subset aged 65+ undergoing neuropsychological testing (N = 231).

RESULTS: In absence of AD risk factors (APOE-ɛ4/Aβ+), whole-brain EIB decreases with age more significantly in males than females (p = 0.021, β = -0.007). Regression modeling including APOE-ɛ4 allele carriers (Aβ-) yielded a significant positive AGE-by-APOE interaction in the right hippocampus for females only (p = 0.013, β = 0.014), persisting with inclusion of Aβ+ individuals (p = 0.012, β = 0.014). Partial correlation analyses of neuropsychological testing showed significant associations with EIB in females: positive correlations between right hippocampal EIB with categorical fluency and whole-brain EIB with the trail-making test (p < 0.05).

CONCLUSION: Sex differences in EIB emerge during normal aging and progresses differently with AD risk. Results suggest APOE-ɛ4 disrupts hippocampal balance more than amyloid in females. Increased excitation correlates positively with neuropsychological performance in the female group, suggesting a duality in terms of potential beneficial effects prior to cognitive impairment. This underscores the translational relevance of APOE-ɛ4 related hyperexcitation in females, potentially informing therapeutic targets or early interventions to mitigate AD progression in this vulnerable population.

%B bioRxiv %8 2023 Aug 22 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/37662359?dopt=Abstract %R 10.1101/2023.08.21.554061 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Early Amnestic Mild Cognitive Impairment Is Associated with Reduced Total Cerebral Blood Flow with no Brain Tissue Loss. %A Liu, Che %A Lee, Sang H %A Loewenstein, David A %A Galvin, James E %A Levin, Bonnie E %A McKinney, Alexander %A Alperin, Noam %X

BACKGROUND: Lower cerebral blood flow (CBF) and brain atrophy are linked to Alzheimer's disease (AD). It is still undetermined whether reduced CBF precedes or follows brain tissue loss.

OBJECTIVE: We compared total CBF (tCBF), global cerebral perfusion (GCP), and volumes of AD-prone regions between cognitively normal (CN) and early amnestic mild cognitive impairment (aMCI) and tested their associations with cognitive performance to assess their predictive value for differentiation between CN and early aMCI.

METHODS: A total of 74 participants (mean age 69.9±6.2 years, 47 females) were classified into two groups: 50 CN and 24 aMCI, of whom 88% were early aMCI. tCBF, GCP, and global and regional brain volumetry were measured using phase-contrast and T1-weighted MRI. Neuropsychological tests tapping global cognition and four cognitive domains (memory, executive function, language, and visuospatial) were administered. Comparisons and associations were investigated using analyses of covariance (ANCOVA) and linear regression analyses, respectively.

RESULTS: Women had significantly higher GCP than men. Both, tCBF and GCP were significantly reduced in aMCI compared with CN, while volume differences in volumes of cerebral gray matter, white matter, and AD-prone regions were not significant. tCBF and GCP were significantly associated with global cognition (standardized beta (stβ) = 0.324 and stβ= 0.326) and with memory scores (stβ≥0.297 and stβ≥0.264) across all participants. Associations of tCBF and GCP with memory scores were also significant in CN (stβ= 0.327 and stβ= 0.284) and in aMCI (stβ= 0.627 and stβ= 0.485).

CONCLUSION: Reduced tCBF and GCP are sensitive biomarkers of early aMCI that likely precede brain tissue loss.

%B J Alzheimers Dis %V 91 %P 1313-1322 %8 2023 Feb 14 %G eng %N 4 %R 10.3233/JAD-220734 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Early Depressive Symptoms Predict Faster Dementia Progression in Autosomal-Dominant AD %A Acosta-Baena, Natalia %A Lopera-Gómez, Carlos M %A Jaramillo-Elorza, Mario C %A Velilla-Jiménez, Lina %A Villegas-Lanau, Carlos Andrés %A Sepúlveda-Falla, Diego %A Arcos-Burgos, Mauricio %A Lopera, Francisco %X

BACKGROUND: Depression is associated with Alzheimer's disease (AD).

OBJECTIVE: To evaluate the association between depressive symptoms and age of onset of cognitive decline in autosomal dominant AD, and to determine possible factors associated to early depressive symptoms in this population.

METHODS: We conducted a retrospective study to identify depressive symptoms among 190 presenilin 1 (PSEN1) E280A mutation carriers, subjected to comprehensive clinical evaluations in up to a 20-year longitudinal follow-up. We controlled for the following potential confounders: APOE, sex, hypothyroidism, education, marital status, residence, tobacco, alcohol, and drug abuse.

RESULTS: PSEN1 E280A carriers with depressive symptoms before mild cognitive impairment (MCI) develop dementia faster than E280A carriers without depressive symptoms (Hazard Ratio, HR = 1.95; 95% CI, 1.15-3.31). Not having a stable partner accelerated the onset of MCI (HR = 1.60; 95 % CI, 1.03-2.47) and dementia (HR = 1.68; 95 % CI, 1.09-2.60). E280A carriers with controlled hypothyroidism had later age of onset of depressive symptoms (HR = 0.48; 95 % CI, 0.25-0.92), dementia (HR = 0.43; 95 % CI, 0.21-0.84), and death (HR = 0.35; 95 % CI, 0.13-0.95). APOEɛ2 significantly affected AD progression in all stages. APOE polymorphisms were not associate to depressive symptoms. Women had a higher frequency and developed earlier depressive symptoms than men throughout the illness (HR = 1.63; 95 % CI, 1.14-2.32).

CONCLUSION: Depressive symptoms accelerated progress and faster cognitive decline of autosomal dominant AD. Not having a stable partner and factors associated with early depressive symptoms (e.g., in females and individuals with untreated hypothyroidism), could impact prognosis, burden, and costs.

%B J Alzheimers Dis %V 92 %P 911-923 %8 2023 Apr 04 %G eng %N 3 %R 10.3233/JAD-221294 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Early Diagnosis of Mild Cognitive Impairment due to Alzheimer's Disease Using a Composite of MemTrax and Blood Biomarkers. %A Chen, Weineng %A Lin, Cha %A Su, Fengjuan %A Fang, Yingying %A Liu, Ganqiang %A Chen, Yu-Chian %A Zhou, Xianbo %A Yao, Xiaoli %A Ashford, Curtis B %A Li, Feng %A Ashford, J Wesson %A Fu, Qingling %A Pei, Zhong %X

BACKGROUND: Accessible measurements for the early detection of mild cognitive impairment (MCI) due to Alzheimer's disease (AD) are urgently needed to address the increasing prevalence of AD.

OBJECTIVE: To determine the benefits of a composite MemTrax Memory Test and AD-related blood biomarker assessment for the early detection of MCI-AD in non-specialty clinics.

METHODS: The MemTrax Memory Test and Montreal Cognitive Assessment were administered to 99 healthy seniors with normal cognitive function and 101 patients with MCI-AD; clinical manifestation and peripheral blood samples were collected. We evaluated correlations between the MemTrax Memory Test and blood biomarkers using Spearman's rank correlation analyses and then built discrimination models using various machine learning approaches that combined the MemTrax Memory Test and blood biomarker results. The models' performances were assessed according to the areas under the receiver operating characteristic curve.

RESULTS: The MemTrax Memory Test and Montreal Cognitive Assessment areas under the curve for differentiating patients with MCI-AD from the healthy controls were similar. The MemTrax Memory Test strongly correlated with phosphorylated tau 181 and amyloid-β 42/40. The area under the curve for the best composite MemTrax Memory Test and blood biomarker model was 0.975 (95% confidence interval: 0.950-0.999).

CONCLUSION: Combining MemTrax Memory Test and blood biomarker results is a promising new technique for the early detection of MCI-AD.

%B J Alzheimers Dis %V 94 %P 1093-1103 %8 2023 Aug 01 %G eng %N 3 %R 10.3233/JAD-230182 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Early Life Stress Enhances Cognitive Decline and Alters Synapse Function and Interneuron Numbers in Young Male APP/PS1 Mice. %A Brosens, Niek %A Samouil, Dimitris %A Stolker, Sabine %A Katsika, Efthymia Vasilina %A Weggen, Sascha %A Lucassen, Paul J %A Krugers, Harm J %K Adverse Childhood Experiences %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Cognitive Dysfunction %K Disease Models, Animal %K Interneurons %K Male %K Mice %K Mice, Transgenic %K Plaque, Amyloid %K Presenilin-1 %K Synapses %X

BACKGROUND: Exposure to stress early in life increases the susceptibility to Alzheimer's disease (AD) pathology in aged AD mouse models. So far, the underlying mechanisms have remained elusive.

OBJECTIVE: To investigate 1) effects of early life stress (ELS) on early functional signs that precede the advanced neuropathological changes, and 2) correlate synaptosomal protein content with cognition to identify neural correlates of AD.

METHODS: APPswe/PS1dE9 mice and littermates were subjected to ELS by housing dams and pups with limited bedding and nesting material from postnatal days 2-9. At 3 months of age, an age where no cognitive loss or amyloid-β (Aβ) pathology is typically reported in this model, we assessed hippocampal Aβ pathology, synaptic strength and synapse composition and interneuron populations. Moreover, cognitive flexibility was assessed and correlated with synaptosomal protein content.

RESULTS: While ELS did not affect Aβ pathology, it increased synaptic strength and decreased the number of calretinin+ interneurons in the hippocampal dentate gyrus. Both genotype and condition further affected the level of postsynaptic glutamatergic protein content. Finally, APP/PS1 mice were significantly impaired in cognitive flexibility at 3 months of age, and ELS exacerbated this impairment, but only at relatively high learning criteria.

CONCLUSIONS: ELS reduced cognitive flexibility in young APP/PS1 mice and altered markers for synapse and network function. These findings at an early disease stage provide novel insights in AD etiology and in how ELS could increase AD susceptibility.

%B J Alzheimers Dis %V 96 %P 1097-1113 %8 2023 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/37980670?dopt=Abstract %R 10.3233/JAD-230727 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Effect of Exercise on Falls in People Living with Dementia: A Systematic Review. %A Jehu, Deborah A %A Davis, Jennifer C %A Gill, Jessica %A Oke, Olabamibo %A Liu-Ambrose, Teresa %K Dementia %K Exercise %K Female %K Humans %K Independent Living %X

BACKGROUND: People living with dementia (PWD) are at a heightened risk for falls. However, the effects of exercise on falls in PWD are unclear.

OBJECTIVE: To conduct a systematic review of randomized controlled trials (RCTs) examining the efficacy of exercise to reduce falls, recurrent falls, and injurious falls relative to usual care among PWD.

METHODS: We included peer-reviewed RCTs evaluating any exercise mode on falls and related injuries among medically diagnosed PWD aged ≥55years (international prospective register of systematic reviews (PROSPERO) ID:CRD42021254637). We excluded studies that did not solely involve PWD and were not the primary publication examining falls. We searched the Cochrane Dementia and Cognitive Improvement Group's Specialized Register and grey literature on 08/19/2020 and 04/11/2022; topical categories included dementia, exercise, RCTs, and falls. We evaluated the risk of bias (ROB) using the Cochrane ROB Tool-2 and study quality using the Consolidated Standards of Reporting Trials.

RESULTS: Twelve studies were included (n = 1,827; age = 81.3±7.0 years; female = 59.3%; Mini-Mental State Examination = 20.1±4.3 points; intervention duration = 27.8±18.5 weeks; adherence = 75.5±16.2%; attrition = 21.0±12.4%). Exercise reduced falls in two studies [Incidence Rate Ratio (IRR) range = 0.16 to 0.66; fall rate range: intervention = 1.35-3.76 falls/year, control = 3.07-12.21 falls/year]; all other studies (n = 10) reported null findings. Exercise did not reduce recurrent falls (n = 0/2) or injurious falls (n = 0/5). The RoB assessment ranged from some concerns (n = 9) to high RoB (n = 3); no studies were powered for falls. The quality of reporting was good (78.8±11.4%).

CONCLUSION: There was insufficient evidence to suggest that exercise reduces falls, recurrent falls, or injurious falls among PWD. Well-designed studies powered for falls are needed.

%B J Alzheimers Dis %V 92 %P 1199-1217 %8 2023 %G eng %N 4 %R 10.3233/JAD-221038 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Effect of Lecanemab in Early Alzheimer's Disease: Mechanistic Interpretation in the Amyloid Cascade Hypothesis 2.0 Perspective. %A Volloch, Vladimir %A Rits-Volloch, Sophia %K Alzheimer Disease %K Amyloid %K Amyloid beta-Peptides %K Amyloidogenic Proteins %K Humans %X

In clinical trials, lecanemab and donanemab showed statistically significant yet marginal slowdown of Alzheimer's disease (AD)-associated cognitive decline. This could be due to their sub-optimal design and/or deployment; alternatively, their limited efficiency could be intrinsic. Distinguishing between the two is of great importance considering the acute need of efficient AD therapy and tremendous resources being invested in its pursuit. The present study analyzes the mode of operation of lecanemab and donanemab within the framework of recently proposed Amyloid Cascade Hypothesis 2.0 and concludes that the second possibility is correct. It suggests that substantial improvement of the efficiency of these drugs in symptomatic AD is unlikely and proposes the alternative therapeutic strategy.

%B J Alzheimers Dis %V 93 %P 1277-1284 %8 2023 %G eng %N 4 %R 10.3233/JAD-230164 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Effect of Metabolic Syndrome Risk Factors on Processing Speed and Executive Function in Three Racialized Groups. %A Bouges, Shenikqua %A Fischer, Barbara %A Norton, Derek L %A Wyman, Mary F %A Lambrou, Nickolas %A Zuelsdorff, Megan %A Van Hulle, Carol A %A Ennis, Gilda E %A James, Taryn T %A Johnson, Adrienne L %A Chin, Nathaniel %A Carlsson, Cynthia M %A Gleason, Carey E %X

BACKGROUND: Metabolic syndrome (MetS) has been associated with increased risk for Alzheimer's disease and related dementias (ADRD). Understanding the association of MetS risk factors to processing speed and executive function in the pre-clinical stages of ADRD in under-represented groups would offer insight on potential mechanisms through which MetS associates with ADRD risk.

OBJECTIVE: Examine association of MetS features and processing speed and executive function across three racial groups.

METHODS: Cognitively unimpaired adults from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Disease Prevention completed blood-draws and neuropsychological testing. Six cognitive outcomes were assessed in association to MetS risk factors: Trailmaking Tests A and B, Animal Fluency, Digit Symbol, and composite scores for Processing Speed and Executive Function. Linear mixed effect models were used to assess the relationship between MetS risk factor count and longitudinal cognitive performance across three racialized groups.

RESULTS: Participant sample sizes varied by outcome analyzed (N = 714-1,088). African American and Native American groups exhibited higher rates of MetS than non-Hispanic Whites. MetS was associated with processing speed and executive function across all racialized groups. Three-way interaction by racialized group was limited to one cognitive outcome: Trailmaking Test A.

CONCLUSION: Metabolic dysfunction incrementally affects cognitive trajectory, with generally similar associations across racial groups. Since racialized groups exhibit higher levels of both MetS and ADRD, MetS may represent a driving factor for increased ADRD risk experience by racialized group and an important and modifiable target through which to reduce risk of ADRD.

%B J Alzheimers Dis %V 92 %P 285-294 %8 2023 Mar 07 %G eng %N 1 %R 10.3233/JAD-220920 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Effect of Pathway-Specific Polygenic Risk Scores for Alzheimer's Disease (AD) on Rate of Change in Cognitive Function and AD-Related Biomarkers Among Asymptomatic Individuals. %A Xu, Yuexuan %A Vasiljevic, Eva %A Deming, Yuetiva K %A Jonaitis, Erin M %A Koscik, Rebecca L %A Van Hulle, Carol A %A Lu, Qiongshi %A Carboni, Margherita %A Kollmorgen, Gwendlyn %A Wild, Norbert %A Carlsson, Cynthia M %A Johnson, Sterling C %A Zetterberg, Henrik %A Blennow, Kaj %A Engelman, Corinne D %X

BACKGROUND: Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan.

OBJECTIVE: In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways.

METHODS: PRS and p-PRSs with and without APOE were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample.

RESULTS: We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-β, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded.

CONCLUSION: In addition to APOE, the p-PRSs can predict age-dependent changes in amyloid-β, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-β and tau, long before the onset of clinical symptoms.

%B J Alzheimers Dis %V 94 %P 1587-1605 %8 2023 Aug 15 %G eng %N 4 %R 10.3233/JAD-230097 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Effects of a Physical Activity Program that Incorporates Exercises Targeting Balance, Strength, and Proprioception on Cognitive Functions and Physical Performance in Old Adults with Mild Cognitive Impairment. %A Boulares, Ayoub %A Fabre, Claudine %A Cherni, Ala %A Jdidi, Hela %A Gaied Chortane, Sabri %A Trompetto, Carlo %A Puce, Luca %A Bragazzi, Nicola Luigi %K Accidental Falls %K Aged %K Aged, 80 and over %K Cognition %K Cognitive Dysfunction %K Exercise %K Exercise Therapy %K Humans %K Physical Functional Performance %K Postural Balance %K Proprioception %K Time and Motion Studies %X

BACKGROUND: Aging often leads to cognitive function decline, sensory structure deterioration, and musculoskeletal system weakening. This impacts postural control during static and dynamic activities like walking, increasing the fall risk among the elderly. Older adults with mild cognitive impairment (MCI) face an elevated fall risk and cognitive decline, magnifying the public health concern.

OBJECTIVE: This study aimed to explore solutions by investigating the effects of a multi-component physical activity program on cognitive and motor functions in MCI patients.

METHODS: Twenty-three participants were enrolled in the study and assigned into two groups: an intervention group (n = 13; age = 85.7±5.5 years) and a control group (n = 9; age = 85±6.7 years). The study spanned two months, with participants engaging in three 60-minute weekly physical exercise sessions. The intervention focused on improving proprioception, muscle strength, and balance.

RESULTS: Results demonstrated significant enhancements in physical performance, fall risk reduction, and balance (p < 0.05). Various tests, including the timed up and go test, Unipedal Stance test, Tinetti test, Short Physical Performance Battery, and 6-minute walking test, indicated these improvements. Cognitive function was evaluated with the Mini-Mental State Examination, revealing non-significant progress (p > 0.05). Predictive models for outcomes were developed using linear regression analysis during the follow-up stage.

CONCLUSIONS: This study underscores the effectiveness of a multi-component physical activity program encompassing balance, proprioception, and muscle-strengthening exercises as a non-pharmaceutical approach in improving balance skills and playing a key role in mitigating the risk of falls among old adults with MCI.

%B J Alzheimers Dis %V 96 %P 245-260 %8 2023 %G eng %N 1 %R 10.3233/JAD-230305 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Effects of Brain Pathologies on Spatiotemporal Gait Parameters in Patients with Mild Cognitive Impairment. %A Lindh-Rengifo, Magnus %A Jonasson, Stina B %A Ullén, Susann %A Palmqvist, Sebastian %A van Westen, Danielle %A Stomrud, Erik %A Mattsson-Carlgren, Niklas %A Nilsson, Maria H %A Hansson, Oskar %X

BACKGROUND: Impaired gait can precede dementia. The associations between gait parameters and brain pathologies are therefore of interest.

OBJECTIVE: To explore how different brain pathologies (i.e., vascular and Alzheimer's) are associated with specific gait parameters from various gait components in persons with mild cognitive impairment (MCI), who have an increased risk of developing dementia.

METHODS: This cross-sectional study included 96 patients with MCI (mean 72, ±7.5 years; 52% women). Gait was evaluated by using an electronic walkway, GAITRite®. Four gait parameters (step velocity variability; step length; step time; stance time asymmetry) were used as dependent variables in multivariable linear regression analyses. Independent variables included Alzheimer's disease pathologies (amyloid-β and tau) by using PET imaging and white matter hyperintensities (WMH) by using MRI. Covariates included age, sex, comorbidities (and intracranial volume in analyses that includedWMH).

RESULTS: Increased tau-PET (Braak I-IV region of interest [ROI]) was associated with step velocity variability (standardized regression coefficient, β= 0.383, p < 0.001) and step length (β= 0.336, p < 0.001), which remained significant when using different Braak ROIs (I-II, III-IV, V-VI). The associations remained significant when adjusting for WMH (p < 0.001). When also controlling for gait speed, tau was no longer significantly (p = 0.168) associated with an increased step length. No significant associations between gait and Aβ-PET load or WMH were identified.

CONCLUSIONS: The results indicate that one should pay specific attention to assess step velocity variability when targeting single task gait in patients with MCI. Future studies should address additional gait variability measures and dual tasking in larger cohorts.

%B J Alzheimers Dis %V 96 %P 161-171 %8 2023 Oct 24 %G eng %N 1 %R 10.3233/JAD-221303 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Effects of Remote Expressive Arts Program in Older Adults with Mild Cognitive Impairment: A Randomized Controlled Trial. %A Luo, Yuting %A Lin, Rong %A Yan, Yuanjiao %A Su, Jiawei %A Lin, Shengmei %A Ma, Mingping %A Li, Hong %K Activities of Daily Living %K Aged %K Brain %K Cognition %K Cognitive Dysfunction %K Humans %K Magnetic Resonance Imaging %X

BACKGROUND: Mild cognitive impairment (MCI) is a stage of cognitive ability loss with intact activities of daily living and an increased risk for the development of dementia.

OBJECTIVE: This study evaluated the intervention effect of remote expressive arts program (rEAP) on cognitive function in older adults with MCI and investigated the underlying neurobiological mechanisms.

METHODS: We assigned 73 older MCI patients to receive rEAP or health education (HE), who underwent neuropsychological evaluation and resting-state functional magnetic resonance imaging before and after treatment. Neuropsychological scores were analyzed using SPSS software, and regional homogeneity (ReHo) values and seed-based functional connectivity (FC) were analyzed using Matlab software.

RESULTS: The rEAP group showed more significant improvements in cognitive function than the HE group. rEAP affected spontaneous brain activity and brain networks. The ReHo values in the right anterior cingulate/paracingulate cortex and the left dorsolateral superior frontal gyrus significantly increased and decreased, respectively, in the rEAP and HE groups. Further, ReHo value changes were significantly associated with the corresponding neuropsychological test score changes in the rEAP group. Moreover, the rEAP group showed decreased FC between the posterior cingulate cortex and the right middle temporal gyrus and increased FC between the ventromedial prefrontal cortex and left angular gyrus.

CONCLUSION: The 12-week rEAP improved cognitive function in MCI patients. Additionally, the alterations of spontaneous brain network connections and activity helped improve and maintain cognitive function in MCI patients.

%B J Alzheimers Dis %V 91 %P 815-831 %8 2023 %G eng %N 2 %R 10.3233/JAD-215685 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Effects of Striatal Amyloidosis on the Dopaminergic System and Behavior: A Comparative Study in Male and Female 5XFAD Mice. %A Lansdell, Theresa A %A Xu, Hui %A Galligan, James J %A Dorrance, Anne M %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloidosis %K Animals %K Disease Models, Animal %K Dopamine %K Female %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Plaque, Amyloid %X

BACKGROUND: Nearly two-thirds of patients diagnosed with Alzheimer's disease (AD) are female. In addition, female patients with AD have more significant cognitive impairment than males at the same disease stage. This disparity suggests there are sex differences in AD progression. While females appear to be more affected by AD, most published behavioral studies utilize male mice. In humans, there is an association between antecedent attention-deficit/hyperactivity disorder and increased risk of dementia. Functional connectivity studies indicate that dysfunctional cortico-striatal networks contribute to hyperactivity in attention deficit hyperactivity disorder. Higher plaque density in the striatum accurately predicts the presence of clinical AD pathology. In addition, there is a link between AD-related memory dysfunction and dysfunctional dopamine signaling.

OBJECTIVE: With the need to consider sex as a biological variable, we investigated the influence of sex on striatal plaque burden, dopaminergic signaling, and behavior in prodromal 5XFAD mice.

METHODS: Six-month-old male and female 5XFAD and C57BL/6J mice were evaluated for striatal amyloid plaque burden, locomotive behavior, and changes in dopaminergic machinery in the striatum.

RESULTS: 5XFAD female mice had a higher striatal amyloid plaque burden than male 5XFAD mice. 5XFAD females, but not males, were hyperactive. Hyperactivity in female 5XFAD mice was associated with increased striatal plaque burden and changes in dopamine signaling in the dorsal striatum.

CONCLUSION: Our results indicate that the progression of amyloidosis involves the striatum in females to a greater extent than in males. These studies have significant implications for using male-only cohorts in the study of AD progression.

%B J Alzheimers Dis %V 94 %P 1361-1375 %8 2023 %G eng %N 4 %R 10.3233/JAD-220905 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Efficacy and Safety of Physiotherapy in People with Dementia: A Systematic Review. %A Saúde, Alexandra %A Bouça-Machado, Raquel %A Leitão, Mariana %A Benedetti, Andrea %A Ferreira, Joaquim J %K Cognitive Dysfunction %K Dementia %K Humans %K Physical Therapy Modalities %K Resistance Training %X

BACKGROUND: Physiotherapy has become increasingly relevant as a new therapeutic intervention for dementia. However, it is unclear which interventions are the most suitable.

OBJECTIVE: This study sought to summarize and critically appraise the evidence on physiotherapy interventions in dementia.

METHODS: A systematic review conducted using CENTRAL, MEDLINE, and PEDro databases, from their inception to July 2022, identified all experimental studies of dementia that included physiotherapy interventions.

RESULTS: Of 194 articles included, the most frequently used interventions were aerobic training (n = 82, 42%), strength training (n = 79, 41%), balance training (n = 48, 25%), and stretching (n = 22, 11%). These were associated with a positive effect on several motor and cognitive outcomes. A total number of 1,119 adverse events were reported.

CONCLUSION: Physiotherapy has several motor and cognitive benefits in dementia. Future research should focus on establishing a physiotherapy prescription protocol for people with mild cognitive impairment and for each stage of dementia.

%B J Alzheimers Dis %V 94 %P 909-917 %8 2023 %G eng %N 3 %R 10.3233/JAD-230463 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Efficacy of Souvenaid® Combined with Acetylcholinesterase Inhibitors in the Treatment of Mild Alzheimer's Disease. %A García-Alberca, José María %A Gris, Esther %A de la Guía, Paz %A Mendoza, Silvia %A de la Rica, María López %X

BACKGROUND: Souvenaid® is a medical food that contains nutrients that can help synapse synthesis in Alzheimer's disease (AD). The potential effectiveness of combination therapy of Souvenaid with cholinesterase inhibitors (AChEI) is currently not well-known.

OBJECTIVE: To look into the effect of combination therapy with Souvenaid plus AChEI in people with mild AD in the real-world.

METHODS: We carried out a retrospective analysis in mild AD patients attending a memory clinic. Three groups were studied according to the treatment they received: Souvenaid alone (n = 66), AChEI alone (n = 84), and Souvenaid+AChEI (n = 70). Treatment effects were evaluated at baseline, 6 and 12 months. Cognitive functioning was assessed by Mini-Mental State Examination (MMSE), Rey Auditory Verbal Learning Test (RAVLT), Symbol Digit Modalities Test (SDMT), Boston Naming Test (BNT), Trail Making Test (TMT/A-B), Phonemic and Semantic Verbal Fluency Test (PVFT/SVFT); neuropsychiatric symptoms were evaluated by the Neuropsychiatric Inventory (NPI); functional capacity was assessed by the Bayer Activities Daily Living Scale (BAYER-S). A Mixed Model for Repeated Measures analysis was carried out to evaluate changes in outcome scores.

RESULTS: After 12 months Souvenaid+AChEI showed significant improvement in MMSE (p < 0.001), RAVLT (p < 0.0001), SVFT (p = 0.002), PVFT (p = 0.007), TMTA (p = 0.039), TMTB (p = 0.001), and NPI (p < 0.0001) compared to AChEI alone.

CONCLUSION: Souvenaid showed cognitive and behavioral benefits in mild AD patients. These effects increased when Souvenaid and AChEI were used in combination. This study can serve as a model for the design of prospective controlled trials that help to support the combined use of Souvenaid and antidementia drugs in AD.

%B J Alzheimers Dis %V 91 %P 1459-1469 %8 2023 Feb 14 %G eng %N 4 %R 10.3233/JAD-221003 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Elevated Pure Tone Thresholds Are Associated with Altered Microstructure in Cortical Areas Related to Auditory Processing and Attentional Allocation. %A McEvoy, Linda K %A Bergstrom, Jaclyn %A Hagler, Donald J %A Wing, David %A Reas, Emilie T %X

BACKGROUND: Hearing loss is associated with cognitive decline and increased risk for Alzheimer's disease, but the basis of this association is not understood.

OBJECTIVE: To determine whether hearing impairment is associated with advanced brain aging or altered microstructure in areas involved with auditory and cognitive processing.

METHODS: 130 participants, (mean 76.4±7.3 years; 65% women) of the Rancho Bernardo Study of Healthy Aging had a screening audiogram in 2003-2005 and brain magnetic resonance imaging in 2014-2016. Hearing ability was defined as the average pure tone threshold (PTA) at 500, 1000, 2000, and 4000 Hz in the better-hearing ear. Brain-predicted age difference (Brain-pad) was calculated as the difference between brain-predicted age based on a validated structural imaging biomarker of brain age, and chronological age. Regional diffusion metrics in temporal and frontal cortex regions were obtained from diffusion-weighted MRIs. Linear regression analyses adjusted for age, gender, education, and health-related measures.

RESULTS: PTAs were not associated with brain-PAD (β= 0.09; 95% CI: -0.084 to 0.243; p = 0.34). PTAs were associated with reduced restricted diffusion and increased free water diffusion primarily in right hemisphere temporal and frontal areas (restricted diffusion: βs = -0.21 to -0.30; 95% CIs from -0.48 to -0.02; ps <  0.03; free water: βs = 0.18 to 0.26; 95% CIs 0.01 to 0.438; ps <  0.04).

CONCLUSIONS: Hearing impairment is not associated with advanced brain aging but is associated with differences in brain regions involved with auditory processing and attentional control. It is thus possible that increased dementia risk associated with hearing impairment arises, in part, from compensatory brain changes that may decrease resilience.

%B J Alzheimers Dis %V 96 %P 1163-1172 %8 2023 Nov 21 %G eng %N 3 %R 10.3233/JAD-230767 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Emerging Roles of Meningeal Lymphatic Vessels in Alzheimer's Disease. %A Guo, Xiaodi %A Zhang, Guoxin %A Peng, Qinyu %A Huang, Liqin %A Zhang, Zhaohui %A Zhang, Zhentao %K Alzheimer Disease %K Apolipoprotein E4 %K Glymphatic System %K Humans %K Lymphatic System %K Lymphatic Vessels %X

Meningeal lymphatic vessels (mLVs), the functional lymphatic system present in the meninges, are the key drainage route responsible for the clearance of molecules, immune cells, and cellular debris from the cerebrospinal fluid and interstitial fluid into deep cervical lymph nodes. Aging and ApoE4, the two most important risk factors for Alzheimer's disease (AD), induce mLV dysfunction, decrease cerebrospinal fluid influx and outflux, and exacerbate amyloid pathology and cognitive dysfunction. Dysfunction of mLVs results in the deposition of metabolic products, accelerates neuroinflammation, and promotes the release of pro-inflammatory cytokines in the brain. Thus, mLVs represent a novel therapeutic target for treating neurodegenerative and neuroinflammatory diseases. This review aims to summarize the structure and function of mLVs and to discuss the potential effect of aging and ApoE4 on mLV dysfunction, as well as their roles in the pathogenesis of AD.

%B J Alzheimers Dis %V 94 %P S355-S366 %8 2023 %G eng %N s1 %R 10.3233/JAD-221016 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Emotional Dysregulation in Mild Behavioral Impairment Is Associated with Reduced Cortical Thickness in the Right Supramarginal Gyrus. %A Imai, Ayu %A Matsuoka, Teruyuki %A Narumoto, Jin %K Alzheimer Disease %K Attention %K Cognitive Dysfunction %K Dementia %K Humans %K Neuropsychological Tests %K Parietal Lobe %K Retrospective Studies %X

BACKGROUND: Mild behavioral impairment (MBI) has attracted attention as a possible precursor symptom of dementia, but its neural basis has not been fully investigated.

OBJECTIVE: We aimed to investigate the relationship between MBI and surface area, cortical thickness, and volume in the temporal and parietal lobes, which are strongly associated with dementia and emotional disorders.

METHODS: This retrospective study evaluated 123 participants: 90 with mild cognitive impairment (MCI), 13 with subjective cognitive decline (SCD), and 20 cognitively healthy (CH). Using analysis of covariance (ANCOVA) with sex, age, and MMSE score as covariates, cortical thickness, surface area, and volume in 10 regions were compared between groups with and without MBI. Groups with MBI emotional dysregulation were also compared with groups without MBI.

RESULTS: ANCOVA revealed significantly smaller cortical thickness in the MBI group's right parahippocampal (p = 0.01) and supramarginal gyri (p = 0.002). After multiple comparison correction, only the right supramarginal gyrus was significantly smaller (p = 0.02). When considering only MBI emotional dysregulation, the right parahippocampal and supramarginal gyrus' cortical thicknesses were significantly smaller in this MBI group (p = 0.03, 0.01). However, multiple comparison correction identified no significant differences (p = 0.14, 0.11).

CONCLUSION: Overall MBI and the emotional dysregulation domains were associated with reduced cortical thickness in the right parahippocampal and supramarginal gyri. Since neurodegeneration in the medial temporal and parietal lobe precedes early Alzheimer's disease (AD), MBI, particularly emotion dysregulation, may predict early AD below the diagnostic threshold.

%B J Alzheimers Dis %V 93 %P 521-532 %8 2023 %G eng %N 2 %R 10.3233/JAD-220948 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Epileptic Prodromal Alzheimer's Disease Treated with Antiseizure Medications: Medium-Term Outcome of Seizures and Cognition. %A Hautecloque-Raysz, Geoffroy %A Sellal, François %A Bousiges, Olivier %A Phillipi, Nathalie %A Blanc, Frédéric %A Cretin, Benjamin %X

BACKGROUND: The medium term outcome (over more than one year) of epileptic prodromal AD (epAD) patients treated with antiseizure medications (ASMs) is unknown in terms of seizure response, treatment tolerability, and cognitive and functional progression.

OBJECTIVE: To describe such medium term outcome over a mean of 5.1±2.1 years.

METHODS: We retrospectively compared 19 epAD patients with 16 non-epileptic prodromal AD (nepAD) patients: 1) at baseline for demographics, medical history, cognitive fluctuations (CFs), psychotropic medications, MMSE scores, visually rated hippocampal atrophy, CSF neurodegenerative biomarkers, and standard EEG recordings; 2) during follow-up (FU) for psychotropic medications, MMSE progression, and conversion to dementia. In the epAD group, we analyzed baseline and FU types of seizures as well as each line of ASM with the corresponding efficacy and tolerability.

RESULTS: At baseline, the epAD group had more CFs than the nepAD group (58% versus 20%, p = 0.03); focal impaired awareness seizures were the most common type (n = 12, 63.1%), occurring at a monthly to quarterly frequency (89.5%), and were well controlled with monotherapy in 89.5% of cases (including 63.1% seizure-free individuals). During FU, treated epAD patients did not differ significantly from nepAD patients in MMSE progression or in conversion to dementia.

CONCLUSION: Epilepsy is commonly controlled with ASMs over the medium term in epAD patients, with similar functional and cognitive outcomes to nepAD patients. Pathophysiologically, epilepsy is likely to be an ASM-modifiable cognitive aggravating factor at this stage of AD.

%B J Alzheimers Dis %V 94 %P 1057-1074 %8 2023 Aug 01 %G eng %N 3 %R 10.3233/JAD-221197 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Etiology and Clinical Significance of Network Hyperexcitability in Alzheimer's Disease: Unanswered Questions and Next Steps. %A Samudra, Niyatee %A Ranasinghe, Kamalini %A Kirsch, Heidi %A Rankin, Katherine %A Miller, Bruce %K Alzheimer Disease %K Causality %K Clinical Relevance %K Electroencephalography %K Humans %K Levetiracetam %K Seizures %X

Cortical network hyperexcitability related to synaptic dysfunction in Alzheimer's disease (AD) is a potential target for therapeutic intervention. In recent years, there has been increased interest in the prevalence of silent seizures and interictal epileptiform discharges (IEDs, or seizure tendency), with both entities collectively termed "subclinical epileptiform activity" (SEA), on neurophysiologic studies in AD patients. SEA has been demonstrated to be common in AD, with prevalence estimates ranging between 22-54%. Converging lines of basic and clinical evidence imply that modifying a hyperexcitable state results in an improvement in cognition. In particular, though these results require further confirmation, post-hoc findings from a recent phase II clinical trial suggest a therapeutic effect with levetiracetam administration in patients with AD and IEDs. Here, we review key unanswered questions as well as potential clinical trial avenues. Specifically, we discuss postulated mechanisms and treatment of hyperexcitability in patients with AD, which are of interest in designing future disease-modifying therapies. Criteria to prompt screening and optimal screening methodology for hyperexcitability have yet to be defined, as does timing and personalization of therapeutic intervention.

%B J Alzheimers Dis %V 92 %P 13-27 %8 2023 %G eng %N 1 %R 10.3233/JAD-220983 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Evaluation of Blood-Based Plasma Biomarkers as Potential Markers of Amyloid Burden in Preclinical Alzheimer's Disease. %A Winston, Charisse N %A Langford, Oliver %A Levin, Natalie %A Raman, Rema %A Yarasheski, Kevin %A West, Tim %A Abdel-Latif, Sara %A Donohue, Michael %A Nakamura, Akinori %A Toba, Kenji %A Masters, Colin L %A Doecke, James %A Sperling, Reisa A %A Aisen, Paul S %A Rissman, Robert A %K Alzheimer Disease %K Amyloid %K Amyloid beta-Peptides %K Amyloidogenic Proteins %K Biomarkers %K Cross-Sectional Studies %K Humans %K Peptide Fragments %K Positron-Emission Tomography %X

BACKGROUND: Participant eligibility for the A4 Study was determined by amyloid PET imaging. Given the disadvantages of amyloid PET imaging in accessibility and cost, blood-based biomarkers may serve as a sufficient biomarker and more cost-effective screening tool for patient enrollment into preclinical AD trials.

OBJECTIVE: To determine if a blood-based screening test can adequately identify amyloid burden in participants screened into a preclinical AD trial.

METHODS: In this cross-sectional study, 224 participants from the A4 Study received an amyloid PET scan (18Florbetapir) within 90 days of blood sample collection. Blood samples from all study participants were processed within 2 h after phlebotomy. Plasma amyloid measures were quantified by Shimazdu and C2 N Diagnostics using mass spectrometry-based platforms. A corresponding subset of blood samples (n = 100) was processed within 24 h after phlebotomy and analyzed by C2 N.

RESULTS: Plasma Aβ42/Aβ40 demonstrated the highest association for Aβ accumulation in the brain with an AUC 0.76 (95%CI = 0.69, 0.82) at C2 N and 0.80 (95%CI = 0.75, 0.86) at Shimadzu. Blood samples processed to plasma within 2 h after phlebotomy provided a better prediction of amyloid PET status than blood samples processed within 24 h (AUC 0.80 versus 0.64; p < 0.001). Age, sex, and APOE ɛ4 carrier status did not the diagnostic performance of plasma Aβ42/Aβ40 to predict amyloid PET positivity in A4 Study participants.

CONCLUSION: Plasma Aβ42/Aβ40 may serve as a potential biomarker for predicting elevated amyloid in the brain. Utilizing blood testing over PET imaging may improve screening efficiency into clinical trials.

%B J Alzheimers Dis %V 92 %P 95-107 %8 2023 %G eng %N 1 %R 10.3233/JAD-221118 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Excessive Sedentary Time Is Associated with Cognitive Decline in Older Patients with Minor Ischemic Stroke. %A Liang, Hongtao %A Yin, Xiang %A Chen, Tian %A Zhang, Yan %A Zhang, Qin %A Lin, Jie %A Yin, Huan %A Tang, Jinghua %A He, Yingyi %A Xia, Ping %A Zhu, Yongping %A Li, Haihua %A Mo, Yongbiao %A Li, Yongyong %A Wang, Ying %A Yang, Xiao %A Hu, Zicheng %X

BACKGROUND: Cognitive impairment is commonly seen after acute ischemic stroke (AIS). Sedentary behaviors increase the risk of dementia among community dwelling population.

OBJECTIVE: This study aims to investigate the association of sedentary behaviors with poststroke cognitive impairment among older adults of minor AIS.

METHODS: This cohort study recruited 594 older subjects with minor AIS from three hospitals in China during February 1, 2016, and December 31, 2018. Participants were followed up for two years and the sedentary time per day was self-reported at the endpoint of follow-up. Cognitive functions were assessed by Mini-Mental State Examination (MMSE). Participants were categorized into the high and low sedentary time group according to the median sedentary time of the participants.

RESULTS: At two years of follow-up, the long sedentary time group had significantly lower MMSE scores than the short sedentary time group [median, (95% CI): 21 (18 to 25) versus 22 (18 to 25), p = 0.368]. The long sedentary time group had a higher speed of cognitive decline than the short sedentary time group. Excessive sedentary time was associated with a higher risk of longitudinal cognitive decline (OR: 2.267, 95% CI: 1.594 to 3.225), adjusting for age, sex, education, body mass index, APOE genotype, comorbidities, symptoms of depression, anxiety, and insomnia, baseline MMSE scores and National Institute of Health Stroke Scale scores, cognitive therapy, and TOAST ischemic stroke subtypes.

CONCLUSIONS: This study identified a possible link between sedentary behaviors and longitudinal cognitive decline among older patients with minor AIS, suggesting that reducing sedentary time might be helpful for preventing poststroke dementia.

%B J Alzheimers Dis %V 96 %P 173-181 %8 2023 Oct 24 %G eng %N 1 %R 10.3233/JAD-230008 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Exercise-Related Physical Activity Relates to Brain Volumes in 10,125 Individuals. %A Raji, Cyrus A %A Meysami, Somayeh %A Hashemi, Sam %A Garg, Saurabh %A Akbari, Nasrin %A Ahmed, Gouda %A Chodakiewitz, Yosef Gavriel %A Nguyen, Thanh Duc %A Niotis, Kellyann %A Merrill, David A %A Attariwala, Rajpaul %X

BACKGROUND: The potential neuroprotective effects of regular physical activity on brain structure are unclear, despite links between activity and reduced dementia risk.

OBJECTIVE: To investigate the relationships between regular moderate to vigorous physical activity and quantified brain volumes on magnetic resonance neuroimaging.

METHODS: A total of 10,125 healthy participants underwent whole-body MRI scans, with brain sequences including isotropic MP-RAGE. Three deep learning models analyzed axial, sagittal, and coronal views from the scans. Moderate to vigorous physical activity, defined by activities increasing respiration and pulse rate for at least 10 continuous minutes, was modeled with brain volumes via partial correlations. Analyses adjusted for age, sex, and total intracranial volume, and a 5% Benjamini-Hochberg False Discovery Rate addressed multiple comparisons.

RESULTS: Participant average age was 52.98±13.04 years (range 18-97) and 52.3% were biologically male. Of these, 7,606 (75.1%) reported engaging in moderate or vigorous physical activity approximately 4.05±3.43 days per week. Those with vigorous activity were slightly younger (p < 0.00001), and fewer women compared to men engaged in such activities (p = 3.76e-15). Adjusting for age, sex, body mass index, and multiple comparisons, increased days of moderate to vigorous activity correlated with larger normalized brain volumes in multiple regions including: total gray matter (Partial R = 0.05, p = 1.22e-7), white matter (Partial R = 0.06, p = 9.34e-11), hippocampus (Partial R = 0.05, p = 5.96e-7), and frontal, parietal, and occipital lobes (Partial R = 0.04, p≤1.06e-5).

CONCLUSIONS: Exercise-related physical activity is associated with increased brain volumes, indicating potential neuroprotective effects.

%B J Alzheimers Dis %V 97 %P 829-839 %8 2024 Jan 16 %G eng %N 2 %R 10.3233/JAD-230740 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Exploring Reasons for Differential Vulnerability and Alzheimer's Disease Risk in Racial and Ethnic Minorities. %A Daniel, E Valerie %A Kleiman, Michael J %A Galvin, James E %K Aged %K Alzheimer Disease %K Cross-Sectional Studies %K Ethnic and Racial Minorities %K Ethnicity %K Humans %K White People %X

BACKGROUND: African American and Hispanic older adults are reported to have up to a 2-fold higher risk of Alzheimer's disease and related disorders (ADRD), but the reasons for this increased vulnerability have not been fully explored. The Vulnerability Index (VI) was designed to identify individuals who are at risk of developing cognitive impairment in the future, capturing 12 sociodemographic variables and modifiable medical comorbidities associated with higher ADRD risk. However, a prior limitation of the VI was that the original study cohort had limited diversity. We examined the association of the VI within and between non-Hispanic White, African American, and Hispanic older adults with and without cognitive impairment and different socioeconomic strata enrolled in a community-based dementia screening study.

OBJECTIVE: To explore reasons for reported higher ADRD vulnerability in African Americans and Hispanics.

METHODS: In a cross-sectional study of 300 non-Hispanic White, African American, and Hispanic older adults with and without cognitive impairment, we studied the association between cognitive status, the VI, and socioeconomic status (SES).

RESULTS: When considering race/ethnicity, the presence of more vascular comorbidities drove greater vulnerability. When considering SES, vascular comorbidities played a less prominent role suggesting resources and access to care drives risk. The VI had differential effects on cognitive performance with the greatest effect in the earlier stages of impairment.

CONCLUSION: Findings from this study provide a deeper understanding of the differential risk of ADRD in multicultural older adults captured by the VI and how barriers to healthcare access may increase vulnerability in racial/ethnic minorities.

%B J Alzheimers Dis %V 91 %P 495-506 %8 2023 %G eng %N 1 %R 10.3233/JAD-220959 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Exposure to World Trade Center Dust Exacerbates Cognitive Impairment and Evokes a Central and Peripheral Pro-Inflammatory Transcriptional Profile in an Animal Model of Alzheimer's Disease. %A Iban-Arias, Ruth %A Trageser, Kyle J %A Yang, Eun-Jeong %A Griggs, Elizabeth %A Radu, Aurelian %A Naughton, Sean %A Al Rahim, Md %A Tatsunori, Oguchi %A Raval, Urdhva %A Palmieri, Joshua %A Huang, Zerlina %A Chen, Lung-Chi %A Pasinetti, Giulio Maria %K Alzheimer Disease %K Animals %K Cognitive Dysfunction %K Dust %K Mice %K Models, Animal %K September 11 Terrorist Attacks %X

BACKGROUND: The terrorist attacks on September 11, 2001, on the World Trade Center (WTC) led to intense fires and a massive dense cloud of toxic gases and suspended pulverized debris. In the subsequent years, following the attack and cleanup efforts, a cluster of chronic health conditions emerged among First Responders (FR) who were at Ground Zero for prolonged periods and were repeatedly exposed to high levels of WTC particulate matter (WTCPM). Among those are neurological complications which may increase the risk for the development of Alzheimer's disease (AD) later in life.

OBJECTIVE: We hypothesize that WTCPM dust exposure affects the immune cross-talking between the periphery and central nervous systems that may induce brain permeability ultimately promoting AD-type phenotype.

METHODS: 5XFAD and wild-type mice were intranasally administered with WTCPM dust collected at Ground Zero within 72 h after the attacks. Y-maze assay and novel object recognition behavioral tests were performed for working memory deficits and learning and recognition memory, respectively. Transcriptomic analysis in the blood and hippocampus was performed and confirmed by RT qPCR.

RESULTS: Mice exposed to WTCPM dust exhibited a significant impairment in spatial and recognition short and long-term memory. Furthermore, the transcriptomic analysis in the hippocampal formation and blood revealed significant changes in genes related to immune-inflammatory responses, and blood-brain barrier disruption.

CONCLUSION: These studies suggest a putative peripheral-brain immune inflammatory cross-talking that may potentiate cognitive decline, identifying for the first time key steps which may be therapeutically targetable in future studies in WTC FR.

%B J Alzheimers Dis %V 91 %P 779-794 %8 2023 %G eng %N 2 %R 10.3233/JAD-221046 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Extracellular Tau Oligomers Damage the Axon Initial Segment. %A Best, Merci N %A Lim, Yunu %A Ferenc, Nina N %A Kim, Nayoung %A Min, Lia %A Wang, Dora Bigler %A Sharifi, Kamyar %A Wasserman, Anna E %A McTavish, Sloane A %A Siller, Karsten H %A Jones, Marieke K %A Jenkins, Paul M %A Mandell, James W %A Bloom, George S %X

BACKGROUND: In Alzheimer's disease (AD) brain, neuronal polarity and synaptic connectivity are compromised. A key structure for regulating polarity and functions of neurons is the axon initial segment (AIS), which segregates somatodendritic from axonal proteins and initiates action potentials. Toxic tau species, including extracellular oligomers (xcTauOs), spread tau pathology from neuron to neuron by a prion-like process, but few other cell biological effects of xcTauOs have been described.

OBJECTIVE: Test the hypothesis that AIS structure is sensitive to xcTauOs.

METHODS: Cultured wild type (WT) and tau knockout (KO) mouse cortical neurons were exposed to xcTauOs, and quantitative western blotting and immunofluorescence microscopy with anti-TRIM46 monitored effects on the AIS. The same methods were used to compare TRIM46 and two other resident AIS proteins in human hippocampal tissue obtained from AD and age-matched non-AD donors.

RESULTS: Without affecting total TRIM46 levels, xcTauOs reduce the concentration of TRIM46 within the AIS and cause AIS shortening in cultured WT, but not TKO neurons. Lentiviral-driven tau expression in tau KO neurons rescues AIS length sensitivity to xcTauOs. In human AD hippocampus, the overall protein levels of multiple resident AIS proteins are unchanged compared to non-AD brain, but TRIM46 concentration within the AIS and AIS length are reduced in neurons containing neurofibrillary tangles.

CONCLUSION: xcTauOs cause partial AIS damage in cultured neurons by a mechanism dependent on intracellular tau, thereby raising the possibility that the observed AIS reduction in AD neurons in vivo is caused by xcTauOs working in concert with endogenous neuronal tau.

%B J Alzheimers Dis %V 93 %P 1425-1441 %8 2023 Jun 13 %G eng %N 4 %R 10.3233/JAD-221284 %0 Journal Article %J J Alzheimers Dis %D 2023 %T From Association to Intervention: The Alzheimer's Disease-Associated Processes and Targets (ADAPT) Ontology. %A Daly, Timothy %A Henry, Vincent %A Bourdenx, Mathieu %K Alzheimer Disease %K Biomarkers %K Biomedical Research %K Humans %X

BACKGROUND: Many putative causes and risk factors have been associated with outcomes in Alzheimer's disease (AD) but all attempts at disease-modifying treatment have failed to be clinically significant. Efforts to address this "association-intervention" mismatch have tended to focus on the novel design of interventions.

OBJECTIVE: Here, we instead deal with the notion of association in depth. We introduce the concept of disease-associated process (DAP) as a flexible concept that can unite different areas of study of AD from genetics to epidemiology to identify disease-modifying targets.

METHODS: We sort DAPs using three properties: specificity for AD, frequency in patients, and pathogenic intensity for dementia before using a literature review to apply these properties in three ways. Firstly, we describe and visualize known DAPs. Secondly, we exemplify qualitative specificity analysis with the DAPs of tau protein pathology and autophagy to reveal their differential implication in AD. Finally, we use DAP properties to define the terms "risk factor," "cause," and "biomarker."

RESULTS: We show how DAPs fit into our collaborative disease ontology, the Alzheimer's Disease-Associated Processes and Targets (ADAPT) ontology. We argue that our theoretical system can serve as a democratic research forum, offering a more biologically adequate view of dementia than reductionist models.

CONCLUSION: The ADAPT ontology is a tool that could help to ground debates around priority setting using objective criteria for the identifying of targets in AD. Further efforts are needed to address issues of how biomedical research into AD is prioritized and funded.

%B J Alzheimers Dis %V 94 %P S87-S96 %8 2023 %G eng %N s1 %R 10.3233/JAD-221004 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Genome-Wide Mapping Implicates 5-Hydroxymethylcytosines in Diabetes Mellitus and Alzheimer's Disease. %A Beadell, Alana V %A Zhang, Zhou %A Capuano, Ana W %A Bennett, David A %A He, Chuan %A Zhang, Wei %A Arvanitakis, Zoe %X

BACKGROUND: Diabetes mellitus (DM) is a recognized risk factor for dementia. Because DM is a potentially modifiable condition, greater understanding of the mechanisms linking DM to the clinical expression of Alzheimer's disease dementia may provide insights into much needed dementia therapeutics.

OBJECTIVE: In this feasibility study, we investigated DM as a dementia risk factor by examining genome-wide distributions of the epigenetic DNA modification 5-hydroxymethylcytosine (5hmC).

METHODS: We obtained clinical samples from the Rush Memory and Aging Project and used the highly sensitive 5hmC-Seal technique to perform genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) from antemortem serum samples and in genomic DNA from postmortem prefrontal cortex brain tissue from 80 individuals across four groups: Alzheimer's disease neuropathologically defined (AD), DM clinically defined, AD with DM, and individuals with neither disease (controls).

RESULTS: Distinct 5hmC signatures and biological pathways were enriched in persons with both AD and DM versus AD alone, DM alone, or controls, including genes inhibited by EGFR signaling in oligodendroglia and those activated by constitutive RHOA. We also demonstrate the potential diagnostic value of 5hmC profiling in circulating cfDNA. Specifically, an 11-gene weighted model distinguished AD from non-AD/non-DM controls (AUC = 91.8% ; 95% CI, 82.9-100.0%), while a 4-gene model distinguished DM-associated AD from AD alone (AUC = 87.9% ; 95% CI, 77.5-98.3%).

CONCLUSION: We demonstrate in this small sample the feasibility of detecting and characterizing 5hmC in DM-associated AD and of using 5hmC information contained in circulating cfDNA to detect AD in high-risk individuals, such as those with diabetes.

%B J Alzheimers Dis %V 93 %P 1135-1151 %8 2023 May 30 %G eng %N 3 %R 10.3233/JAD-221113 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Helicobacter pylori Infection Is Associated with Long-Term Cognitive Decline in Older Adults: A Two-Year Follow-Up Study. %A Wang, Jian %A Yu, Neng-Wei %A Wang, Duo-Zi %A Guo, Lei %A Yang, Shu %A Zheng, Bo %A Guo, Fu-Qiang %A Wang, Jian-Hong %X

BACKGROUND: Previous cross-sectional studies have identified a possible link between Helicobacter pylori (H. pylori) infection and dementia. However, the association of H. pylori infection with longitudinal cognitive decline has rarely been investigated.

OBJECTIVE: This cohort study aims to demonstrate the effects of H. pylori infection on longitudinal cognitive decline.

METHODS: This cohort study recruited 268 subjects with memory complaints. Among these subjects, 72 had a history of H. pylori infection, and the rest 196 subjects had no H. pylori infection. These subjects were followed up for 24 months and received cognitive assessment in fixed intervals of 12 months.

RESULTS: At baseline, H. pylori infected, and uninfected participants had no difference in MMSE scores. At 2 years of follow-up, H. pylori infected participants had lower MMSE scores than uninfected participants. H. pylori infection was associated with an increased risk of longitudinal cognitive decline, as defined by a decrease of MMSE of 3 points or more during follow-up, adjusting for age, sex, education, APOEɛ4 genotype, hypertension, diabetes, hyperlipidemia, and smoking history (HR: 2.701; 95% CI: 1.392 to 5.242). H. pylori infection was associated with larger cognitive decline during follow-up, adjusting for the above covariates (standardized coefficient: 0.282, p < 0.001). Furthermore, H. pylori infected subjects had significantly higher speed of cognitive decline than uninfected subjects during follow-up, adjusting for the above covariates.

CONCLUSION: H. pylori infection increases the risk of longitudinal cognitive decline in older subjects with memory complaints. This study is helpful for further understanding the association between infection and dementia.

%B J Alzheimers Dis %V 91 %P 1351-1358 %8 2023 Feb 14 %G eng %N 4 %R 10.3233/JAD-221112 %0 Journal Article %J J Alzheimers Dis %D 2023 %T High-Quality Sleep Mitigates ABCA7-Related Generalization Deficits in Healthy Older African Americans. %A Sinha, Neha %A Fausto, Bernadette A %A Mander, Bryce %A Gluck, Mark A %X

BACKGROUND: Both sleep deficiencies and Alzheimer's disease (AD) disproportionately affect older African Americans. Genetic susceptibility to AD further compounds risk for cognitive decline in this population. Aside from APOE ɛ4, ABCA7 rs115550680 is the strongest genetic locus associated with late-onset AD in African Americans. While sleep and ABCA7 rs115550680 independently influence late-life cognitive outcomes, we know too little about the interplay between these two factors on cognitive function.

OBJECTIVE: We investigated the interaction between sleep and ABCA7 rs115550680 on hippocampal-dependent cognitive function in older African Americans.

METHODS: One-hundred fourteen cognitively healthy older African Americans were genotyped for ABCA7 risk (n = 57 carriers of risk "G" allele; n = 57 non-carriers), responded to lifestyle questionnaires, and completed a cognitive battery. Sleep was assessed via a self-reported rating of sleep quality (poor, average, good). Covariates included age and years of education.

RESULTS: Using ANCOVA, we found that carriers of the risk genotype who reported poor or average sleep quality demonstrated significantly poorer generalization of prior learning¾a cognitive marker of AD¾compared to their non-risk counterparts. Conversely, there was no genotype-related difference in generalization performance in individuals who reported good sleep quality.

CONCLUSION: These results indicate that sleep quality may be neuroprotective against genetic risk for AD. Future studies employing more rigorous methodology should investigate the mechanistic role of sleep neurophysiology in the pathogenesis and progression of AD associated with ABCA7. There is also need for the continued development of non-invasive sleep interventions tailored to racial groups with specific AD genetic risk profiles.

%B J Alzheimers Dis %V 94 %P 281-290 %8 2023 Jun 27 %G eng %N 1 %R 10.3233/JAD-230043 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Hippocampal Volume and Episodic Associative Memory Identify Memory Risk in Subjective Cognitive Decline Individuals in the CIMA-Q Cohort, Regardless of Cognitive Reserve Level and APOE4 Status. %A Caillaud, Marie %A Maltezos, Samantha %A Hudon, Carol %A Mellah, Samira %A Belleville, Sylvie %X

BACKGROUND: Subjective cognitive decline (SCD) was proposed to identify older adults who complain about their memory but perform within a normal range on standard neuropsychological tests. Persons with SCD are at increased risk of dementia meaning that some SCD individuals experience subthreshold memory decline due to an underlying progression of Alzheimer's disease (AD).

OBJECTIVE: Our main goal was to determine whether hippocampal volume and APOE4, which represent typical AD markers, predict inter-individual differences in memory performance among SCD individuals and can be used to identify a meaningful clinical subgroup.

METHODS: Neuropsychological assessment, structural MRI, and genetic testing for APOE4 were administered to one hundred and twenty-five older adults over the age of 65 from the CIMAQ cohort: 66 SCD, 29 individuals with mild cognitive impairment (MCI), and 30 cognitively intact controls (CTRLS). Multiple regression models were first used to identify which factor (hippocampal volume, APOE4 allele, or cognitive reserve) best predicted inter-individual differences in a Face-name association memory task within the SCD group.

RESULTS: Hippocampal volume was found to be the only and best predictor of memory performance. We then compared the demographic, clinical and cognitive characteristics of two SCD subgroups, one with small hippocampal volume (SCD/SH) and another with normal hippocampal volume (SCD/NH), with MCI and CTRLS. SCD/SH were comparable to MCI on neuropsychological tasks evaluating memory (i.e., test of delayed word recall), whereas SCD/NH were comparable to CTRLS.

CONCLUSION: Thus, using hippocampal volume allows identification of an SCD subgroup with a cognitive profile consistent with a higher risk of conversion to AD.

%B J Alzheimers Dis %V 94 %P 1047-1056 %8 2023 Aug 01 %G eng %N 3 %R 10.3233/JAD-230131 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Hypermethylation at CREBBP Is Associated with Cognitive Impairment in a Mexican American Cohort. %A Abraham Daniel, Ann %A Silzer, Talisa %A Sun, Jie %A Zhou, Zhengyang %A Hall, Courtney %A Phillips, Nicole %A Barber, Robert %X

BACKGROUND: The aging Mexican American (MA) population is the fastest growing ethnic minority group in the US. MAs have a unique metabolic-related risk for Alzheimer's disease (AD) and mild cognitive impairment (MCI), compared to non-Hispanic whites (NHW). This risk for cognitive impairment (CI) is multifactorial involving genetics, environmental, and lifestyle factors. Changes in environment and lifestyle can alter patterns and even possibly reverse derangement of DNA methylation (a form of epigenetic regulation).

OBJECTIVE: We sought to identify ethnicity-specific DNA methylation profiles that may be associated with CI in MAs and NHWs.

METHODS: DNA obtained from peripheral blood of 551 participants from the Texas Alzheimer's Research and Care Consortium was typed on the Illumina Infinium® MethylationEPIC chip array, which assesses over 850K CpG genomic sites. Within each ethnic group (N = 299 MAs, N = 252 NHWs), participants were stratified by cognitive status (control versus CI). Beta values, representing relative degree of methylation, were normalized using the Beta MIxture Quantile dilation method and assessed for differential methylation using the Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages in R.

RESULTS: Two differentially methylated sites were significant: cg13135255 (MAs) and cg27002303 (NHWs) based on an FDR p < 0.05. Three suggestive sites obtained were cg01887506 (MAs) and cg10607142 and cg13529380 (NHWs). Most methylation sites were hypermethylated in CI compared to controls, except cg13529380 which was hypomethylated.

CONCLUSION: The strongest association with CI was at cg13135255 (FDR-adjusted p = 0.029 in MAs), within the CREBBP gene. Moving forward, identifying additional ethnicity-specific methylation sites may be useful to discern CI risk in MAs.

%B J Alzheimers Dis %V 92 %P 1229-1239 %8 2023 Apr 18 %G eng %N 4 %R 10.3233/JAD-221031 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Impact of Computerized Cognitive Training on Default Mode Network Connectivity in Subjects at Risk for Alzheimer's Disease: A 78-week Randomized Controlled Trial. %A Petrella, Jeffrey R %A Michael, Andrew M %A Qian, Min %A Nwosu, Adaora %A Sneed, Joel %A Goldberg, Terry E %A Devanand, Davangere P %A Doraiswamy, P Murali %K Alzheimer Disease %K Brain %K Cognitive Dysfunction %K Cognitive Training %K Default Mode Network %K Humans %K Magnetic Resonance Imaging %K Nerve Net %X

BACKGROUND: Mild cognitive impairment (MCI) represents a high risk group for Alzheimer's disease (AD). Computerized Cognitive Games Training (CCT) is an investigational strategy to improve targeted functions in MCI through the modulation of cognitive networks.

OBJECTIVE: The goal of this study was to examine the effect of CCT versus a non-targeted active brain exercise on functional cognitive networks.

METHODS: 107 patients with MCI were randomized to CCT or web-based crossword puzzles. Resting-state functional MRI (fMRI) was obtained at baseline and 18 months to evaluate differences in fMRI measured within- and between-network functional connectivity (FC) of the default mode network (DMN) and other large-scale brain networks: the executive control, salience, and sensorimotor networks.

RESULTS: There were no differences between crosswords and games in the primary outcome, within-network DMN FC across all subjects. However, secondary analyses suggest differential effects on between-network connectivity involving the DMN and SLN, and within-network connectivity of the DMN in subjects with late MCI. Paradoxically, in both cases, there was a decrease in FC for games and an increase for the crosswords control (p < 0.05), accompanied by lesser cognitive decline in the crosswords group.

CONCLUSION: Results do not support a differential impact on within-network DMN FC between games and crossword puzzle interventions. However, crossword puzzles might result in cognitively beneficial remodeling between the DMN and other networks in more severely impaired MCI subjects, parallel to the observed clinical benefits.

%B J Alzheimers Dis %V 91 %P 483-494 %8 2023 %G eng %N 1 %R 10.3233/JAD-220946 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Impact of Hearing Aids on Progression of Cognitive Decline, Depression, and Quality of Life Among People with Cognitive Impairment and Dementia. %A Atef, Roaa Zayed %A Michalowsky, Bernhard %A Raedke, Anika %A Platen, Moritz %A Mohr, Wiebke %A Mühlichen, Franka %A Thyrian, Jochen René %A Hoffmann, Wolfgang %K Aged %K Cognitive Dysfunction %K Deafness %K Dementia %K Depression %K Hearing Aids %K Humans %K Presbycusis %K Quality of Life %X

BACKGROUND: Hearing loss is common in people with dementia (PwD) and a modifiable risk factor for cognitive decline. Recent studies revealed that hearing loss could cause social isolation and depression, which is associated with health-related quality of life (HRQoL). However, there is a lack of knowledge about the impact of the utilization of hearing aids on these outcomes.

OBJECTIVE: To assess whether hearing aids use might be positively associated with the progression of cognitive function, depression, and HRQoL among PwD.

METHODS: We analyzed two-year follow-up data from 258 PwD (≥70 years, living at home). Cognitive decline was measured with Mini-Mental Status Examination (MMSE), depression using Geriatric Depression Scale (GDS), and HRQoL with Quality of Life in Alzheimer's Disease Scale (QoL-AD). The impact of hearing aid utilization on the progression of outcomes was assessed using multivariate regression models.

RESULTS: 123 patients had hearing loss (47.7%), from which n = 54 (43.9%) used hearing aids. Patients with hearing loss were older and had a lower HRQoL than those without hearing loss. Use of hearing aids in patients with hearing loss was associated with a lower increase in depressive symptoms (b = -0.74, CI95 -1.48 --0.01, p = 0.047) over time as compared to those not using hearing aids. There was no effect on PwD's cognition, and the association with higher HRQoL was significant after one, but not consistently over two years.

CONCLUSION: Early detection and intervention of presbycusis using hearing aids might improve mental health and HRQoL in dementia.

%B J Alzheimers Dis %V 92 %P 629-638 %8 2023 %G eng %N 2 %R 10.3233/JAD-220938 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Impact of Routine Vaccinations on Alzheimer's Disease Risk in Persons 65 Years and Older: A Claims-Based Cohort Study using Propensity Score Matching. %A Harris, Kristofer %A Ling, Yaobin %A Bukhbinder, Avram S %A Chen, Luyao %A Phelps, Kamal N %A Cruz, Gabriela %A Thomas, Jenna %A Kim, Yejin %A Jiang, Xiaoqian %A Schulz, Paul E %X

BACKGROUND: Accumulating evidence suggests that adult vaccinations can reduce the risk of developing Alzheimer's disease (AD) and Alzheimer's disease related dementias.

OBJECTIVE: To compare the risk for developing AD between adults with and without prior vaccination against tetanus and diphtheria, with or without pertussis (Tdap/Td); herpes zoster (HZ); or pneumococcus.

METHODS: A retrospective cohort study was performed using Optum's de-identified Clinformatics® Data Mart Database. Included patients were free of dementia during a 2-year look-back period and were≥65 years old by the start of the 8-year follow-up period. We compared two similar cohorts identified using propensity score matching (PSM), one vaccinated and another unvaccinated, with Tdap/Td, HZ, or pneumococcal vaccines. We calculated the relative risk (RR) and absolute risk reduction (ARR) for developing AD.

RESULTS: For the Tdap/Td vaccine, 7.2% (n = 8,370) vaccinated patients and 10.2% (n = 11,857) unvaccinated patients developed AD during follow-up; the RR was 0.70 (95% CI, 0.68-0.72) and ARR was 0.03 (95% CI, 0.02-0.03). For the HZ vaccine, 8.1% (n = 16,106) vaccinated patients and 10.7% (n = 21,273) unvaccinated patients developed AD during follow-up; the RR was 0.75 (95% CI, 0.73-0.76) and ARR was 0.02 (95% CI, 0.02-0.02). For the pneumococcal vaccine, 7.92% (n = 20,583) vaccinated patients and 10.9% (n = 28,558) unvaccinated patients developed AD during follow-up; the RR was 0.73 (95% CI, 0.71-0.74) and ARR was 0.02 (95% CI, 0.02-0.03).

CONCLUSION: Several vaccinations, including Tdap/Td, HZ, and pneumococcal, are associated with a reduced risk for developing AD.

%B J Alzheimers Dis %V 95 %P 703-718 %8 2023 Sep 12 %G eng %N 2 %R 10.3233/JAD-221231 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Impact of the MIND Diet on Cognition in Individuals with Dementia. %A Healy, Elizabeth %K Alzheimer Disease %K Cognition %K Cognition Disorders %K Cognitive Dysfunction %K Diet, Mediterranean %K Humans %X

BACKGROUND: Alzheimer's disease (AD) plagues 6.5 million Americans 65+, yet treatments are lacking. The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet has been developed to address the expansive impact of dementias on the general public. This systematic review evaluated the impact of the MIND diet on cognition in those with pathologies across the dementia spectrum.

OBJECTIVE: To evaluate the application of the MIND diet for prevention and/or treatment of dementia.

METHODS: PubMed was used to conduct a search using the MIND diet and terms related to cognition. Articles were excluded if they were published prior to 2018, studied a population without dementia or significant risk factors, or did not include those 65 + . The overall quality of each source was analyzed based on the cognitive test(s) used, the selection of subjects, and the sample size.

RESULTS: The search generated 33 papers, which yielded 11 articles after screening. Of these studies, one was conducted on those with mild cognitive impairment, one with AD, two with general dementia, and seven with at-risk individuals. All the studies found a positive correlation between adherence and some form of cognitive functioning, but results were mixed for specific cognitive domains.

CONCLUSIONS: These findings suggest that the MIND diet may be a useful long-term treatment option for those with various dementia pathologies. However, more research is needed on subjects with onset dementias. Additionally, there is a need for more research into the mechanisms behind the common comorbidities.

%B J Alzheimers Dis %V 96 %P 967-977 %8 2023 %G eng %N 3 %R 10.3233/JAD-230651 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Impact of Yoga Versus Memory Enhancement Training on Hippocampal Connectivity in Older Women at Risk for Alzheimer's Disease. %A Kilpatrick, Lisa A %A Siddarth, Prabha %A Krause-Sorio, Beatrix %A Milillo, Michaela M %A Aguilar-Faustino, Yesenia %A Ercoli, Linda %A Narr, Katherine L %A Khalsa, Dharma S %A Lavretsky, Helen %X

BACKGROUND: Yoga may be an ideal early intervention for those with modifiable risk factors for Alzheimer's disease (AD) development.

OBJECTIVE: To examine the effects of Kundalini yoga (KY) training versus memory enhancement training (MET) on the resting-state connectivity of hippocampal subregions in women with subjective memory decline and cardiovascular risk factors for AD.

METHODS: Participants comprised women with subjective memory decline and cardiovascular risk factors who participated in a parent randomized controlled trial (NCT03503669) of 12-weeks of KY versus MET and completed pre- and post-intervention resting-state magnetic resonance imaging scans (yoga: n = 11, age = 61.45±6.58 years; MET: n = 11, age = 64.55±6.41 years). Group differences in parcellated (Cole-anticevic atlas) hippocampal connectivity changes (post- minus pre-intervention) were evaluated by partial least squares analysis, controlling for age. Correlations between hippocampal connectivity and perceived stress and frequency of forgetting (assessed by questionnaires) were also evaluated.

RESULTS: A left anterior hippocampal subregion assigned to the default mode network (DMN) in the Cole-anticevic atlas showed greater increases in connectivity with largely ventral visual stream regions with KY than with MET (p < 0.001), which showed associations with lower stress (p < 0.05). Several posterior hippocampal subregions assigned to sensory-based networks in the Cole-anticevic atlas showed greater increases in connectivity with regions largely in the DMN and frontoparietal network with MET than with KY (p < 0.001), which showed associations with lower frequency of forgetting (p < 0.05).

CONCLUSION: KY training may better target stress-related hippocampal connectivity, whereas MET may better target hippocampal sensory-integration supporting better memory reliability, in women with subjective memory decline and cardiovascular risk factors.

%B J Alzheimers Dis %V 95 %P 149-159 %8 2023 Aug 29 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/37482992?dopt=Abstract %R 10.3233/JAD-221159 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Impaired Early Insulin Response to Glucose Load Predicts Episodic Memory Decline: A 10-Year Population-Based Cohort Follow-Up of 45-74-Year-Old Men and Women. %A Toppala, Sini %A Ekblad, Laura L %A Viitanen, Matti %A Rinne, Juha O %A Jula, Antti %X

BACKGROUND: Diabetes increases the risk for cognitive decline, but the mechanisms behind this association remain unknown. Impaired early insulin secretion in elderly men and insulin resistance, both of which are pathophysiological features of type 2 diabetes, have previously been linked to Alzheimer's disease.

OBJECTIVE: To examine if the early insulin response to oral glucose load predicts cognitive performance after 10 years in men and women aged 45-74 years.

METHODS: This study was based on a subpopulation of the Health 2000 Survey, a Finnish nationwide, population-based health examination study, and its follow-up, the Health 2011 Study. In total, 961 45-74-year-old individuals (mean age at baseline 55.6 years, 55.8% women) were examined. An oral glucose tolerance test was performed in 2001-2002, and early insulin response was defined as the ratio of the 30-min increment in insulin concentration to that of glucose concentration. Cognitive function was evaluated at baseline and follow-up with categorical verbal fluency, word-list learning, and word-list delayed recall. Statistical analyses were performed using multivariable linear models adjusted for age, sex, education, APOE&z.epsi;4 genotype, vascular risk factors including diabetes, and depressive symptoms.

RESULTS: A lower early insulin response to glucose load predicted lower performance (β: 0.21, p = 0.03) and greater decline (β: 0.19, p = 0.03) in the word-list delayed recall test. Baseline early insulin response did not predict verbal fluency or word-list learning (all p-values≥0.13).

CONCLUSION: Our results suggest that decreased early insulin secretion predicts episodic memory decline in middle-aged to elderly men and women.

%B J Alzheimers Dis %V 92 %P 349-359 %8 2023 Mar 07 %G eng %N 1 %R 10.3233/JAD-220894 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Implication of Circulating Extracellular Vesicles-Bound Amyloid-β42 Oligomers in the Progression of Alzheimer's Disease. %A M.R. BenKhedher %A Haddad, Mohamed %A Fülöp, Tamás %A Laurin, Danielle %A Ramassamy, Charles %X

BACKGROUND: The perplex interrelation between circulating extracellular vesicles (cEVs) and amyloid-β (Aβ) deposits in the context of Alzheimer's disease (AD) is poorly understood.

OBJECTIVE: This study aims to 1) analyze the possible cross-linkage of the neurotoxic amyloid-β oligomers (oAβ) to the human cEVs, 2) identify cEVs corona proteins associated with oAβ binding, and 3) analyze the distribution and expression of targeted cEVs proteins in preclinical participants converted to AD 5 years later (Pre-AD).

METHODS: cEVs were isolated from 15 Pre-AD participants and 15 healthy controls selected from the Canadian Study of Health and Aging. Biochemical, clinical, lipid, and inflammatory profiles were measured. oAβ and cEVs interaction was determined by nanoparticle tracking analysis and proteinase K digestion. cEVs bound proteins were determined by ELISA.

RESULTS: oAβ were trapped by cEVs and were topologically bound to their external surface. We identified surface-exposed proteins functionally able to conjugate oAβ including apolipoprotein J (apoJ), apoE and RAGE, with apoJ being 30- to 130-fold higher than RAGE and apoE, respectively. The expression of cEVs apoJ was significantly lower in Pre-AD up to 5 years before AD onset.

CONCLUSION: Our findings suggest that cEVs might participate in oAβ clearance and that early dysregulation of cEVs could increase the risk of conversion to AD.

%B J Alzheimers Dis %V 96 %P 813-825 %8 2023 Nov 07 %G eng %N 2 %R 10.3233/JAD-230823 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Insights into the Pathophysiology of Alzheimer's Disease and Potential Therapeutic Targets: A Current Perspective. %A Rajah Kumaran, Kesevan %A Yunusa, Suleiman %A Perimal, Enoch %A Wahab, Habibah %A Müller, Christian P %A Hassan, Zurina %K Aged %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Humans %K Neurofibrillary Tangles %K Oxidative Stress %K Plaque, Amyloid %K tau Proteins %X

The aging population increases steadily because of a healthy lifestyle and medical advancements in healthcare. However, Alzheimer's disease (AD) is becoming more common and problematic among older adults. AD-related cases show an increasing trend annually, and the younger age population may also be at risk of developing this disorder. AD constitutes a primary form of dementia, an irreversible and progressive brain disorder that steadily damages cognitive functions and the ability to perform daily tasks. Later in life, AD leads to death as a result of the degeneration of specific brain areas. Currently, the cause of AD is poorly understood, and there is no safe and effective therapeutic agent to cure or slow down its progression. The condition is entirely preventable, and no study has yet demonstrated encouraging findings in terms of treatment. Identifying this disease's pathophysiology can help researchers develop safe and efficient therapeutic strategies to treat this ailment. This review outlines and discusses the pathophysiology that resulted in the development of AD including amyloid-β plaques, tau neurofibrillary tangles, neuroinflammation, oxidative stress, cholinergic dysfunction, glutamate excitotoxicity, and changes in neurotrophins level may sound better based on the literature search from Scopus, PubMed, ScienceDirect, and Google Scholar. Potential therapeutic strategies are discussed to provide more insights into AD mechanisms by developing some possible pharmacological agents for its treatment.

%B J Alzheimers Dis %V 91 %P 507-530 %8 2023 %G eng %N 2 %R 10.3233/JAD-220666 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Intracellular Amyloid-β in the Normal Rat Brain and Human Subjects and Its relevance for Alzheimer's Disease. %A Kobro-Flatmoen, Asgeir %A Hormann, Thea Meier %A Gouras, Gunnar %X

BACKGROUND: Amyloid-β (Aβ) is a normal product of neuronal activity, including that of the aggregation-prone Aβ42 variant that is thought to cause Alzheimer's disease (AD). Much knowledge about AD comes from studies of transgenic rodents expressing mutated human amyloid-β protein precursor (AβPP) to increase Aβ production or the Aβ42/40 ratio. Yet, little is known about the normal expression of Aβ42 in rodent brains.

OBJECTIVE: To characterize the brain-wide expression of Aβ42 throughout the life span of outbred Wistar rats, and to relate these findings to brains of human subjects without neurological disease.

METHODS: Aβ42 immunolabeling of 12 Wistar rat brains (3-18 months of age) and brain sections from six human subjects aged 20-88 years.

RESULTS: In healthy Wistar rats, we find intracellular Aβ42 (iAβ42) in neurons throughout the brain at all ages, but levels vary greatly between brain regions. The highest levels are in neurons of entorhinal cortex layer II, alongside hippocampal neurons at the CA1/subiculum border. Concerning entorhinal cortex layer II, we find similarly high levels of iAβ42 in the human subjects.

CONCLUSION: Expression of iAβ42 in healthy Wistar rats predominates in the same structures where iAβ accumulates and Aβ plaques initially form in the much used, Wistar based McGill-R-Thy1-APP rat model for AD. The difference between wild-type Wistar rats and these AD model rats, with respect to Aβ42, is therefore quantitative rather that qualitative. This, taken together with our human results, indicate that the McGill rat model in fact models the underlying wild-type neuronal population-specific vulnerability to Aβ42 accumulation.

%B J Alzheimers Dis %V 95 %P 719-733 %8 2023 Sep 12 %G eng %N 2 %R 10.3233/JAD-230349 %0 Journal Article %J J Alzheimers Dis %D 2023 %T JAD: A Forum for Philosophy in Science. %A Daly, Timothy %K Alzheimer Disease %K Humans %K Philosophy %X

The Journal of Alzheimer's Disease (JAD) is already an established forum for cutting-edge science as well as ethical reflection. But I argue that beyond science and ethics, JAD is also a forum for philosophy in science, and that interdisciplinary researchers asking innovative questions about AD should publish their reflections and findings in JAD.

%B J Alzheimers Dis %V 95 %P 411-413 %8 2023 %G eng %N 2 %R 10.3233/JAD-230407 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Ketogenic Diet as a Promising Non-Drug Intervention for Alzheimer's Disease: Mechanisms and Clinical Implications. %A Xu, Yunlong %A Zheng, Fuxiang %A Zhong, Qi %A Zhu, Yingjie %K Alzheimer Disease %K Brain %K Diet, Ketogenic %K Humans %K Ketone Bodies %K Neuroinflammatory Diseases %X

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is mainly characterized by cognitive deficits. Although many studies have been devoted to developing disease-modifying therapies, there has been no effective therapy until now. However, dietary interventions may be a potential strategy to treat AD. The ketogenic diet (KD) is a high-fat and low-carbohydrate diet with adequate protein. KD increases the levels of ketone bodies, providing an alternative energy source when there is not sufficient energy supply because of impaired glucose metabolism. Accumulating preclinical and clinical studies have shown that a KD is beneficial to AD. The potential underlying mechanisms include improved mitochondrial function, optimization of gut microbiota composition, and reduced neuroinflammation and oxidative stress. The review provides an update on clinical and preclinical research on the effects of KD or medium-chain triglyceride supplementation on symptoms and pathophysiology in AD. We also detail the potential mechanisms of KD, involving amyloid and tau proteins, neuroinflammation, gut microbiota, oxidative stress, and brain metabolism. We aimed to determine the function of the KD in AD and outline important aspects of the mechanism, providing a reference for the implementation of the KD as a potential therapeutic strategy for AD.

%B J Alzheimers Dis %V 92 %P 1173-1198 %8 2023 %G eng %N 4 %R 10.3233/JAD-230002 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Klotho Gene Expression Is Decreased in Peripheral Blood Mononuclear Cells in Patients with Alzheimer's Disease and Frontotemporal Dementia. %A Sorrentino, Federica %A Fenoglio, Chiara %A Sacchi, Luca %A Serpente, Maria %A Arighi, Andrea %A Carandini, Tiziana %A Arosio, Beatrice %A Ferri, Evelyn %A Arcaro, Marina %A Visconte, Caterina %A Rotondo, Emanuela %A Scarpini, Elio %A Galimberti, Daniela %X

BACKGROUND: The longevity gene Klotho (KL) was recently associated with neurodegenerative diseases including Alzheimer's disease (AD). Its role in the brain has not been completely elucidated, although evidence suggests that KL-VS heterozygosity is associated with a reduced risk of AD in Apolipoprotein E ɛ4 carriers. Conversely, no data about genetic association with frontotemporal dementia (FTD) are available so far.

OBJECTIVE: To investigate the involvement of KL in AD and FTD by the determination of the genetic frequency of KL-VS variant and the expression analysis of KL gene.

METHODS: A population consisting of 438 patients and 240 age-matched controls was enrolled for the study. KL-VS and APOE genotypes were assessed by allelic discrimination through a QuantStudio 12K system. KL gene expression analysis was performed in a restricted cohort of patients consisting of 43 AD patients, 41 FTD patients and 19 controls. KL gene expression was assessed in peripheral blood mononuclear cells with specific TaqMan assay. Statistical analysis was performed using GraphPad 9 Prims software.

RESULTS: KL-VS frequency was comparable to the ones found in literature and no differences were found in both allelic and genotypic frequencies between patients and controls were found. Conversely, KL expression levels were significantly lower in AD and FTD patients compared with controls (mean fold regulation - 4.286 and - 6.561 versus controls in AD and FTD, respectively, p = 0.0037).

CONCLUSION: This is the first study investigating KL in FTD. We showed a decreased expression of the gene in AD and FTD, independent of the genotype, suggesting a role of Klotho in common steps during neurodegeneration.

%B J Alzheimers Dis %V 94 %P 1225-1231 %8 2023 Aug 01 %G eng %N 3 %R 10.3233/JAD-230322 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Landscape of Double-Stranded DNA Breaks in Postmortem Brains from Alzheimer's Disease and Non-Demented Individuals. %A Zhang, Xiaoyu %A Liu, Yan %A Huang, Ming %A Gunewardena, Sumedha %A Haeri, Mohammad %A Swerdlow, Russell H %A Wang, Ning %X

BACKGROUND: Alzheimer's disease (AD) brains accumulate DNA double-strand breaks (DSBs), which could contribute to neurodegeneration and dysfunction. The genomic distribution of AD brain DSBs is unclear.

OBJECTIVE: To map genome-wide DSB distributions in AD and age-matched control brains.

METHODS: We obtained autopsy brain tissue from 3 AD and 3 age-matched control individuals. The donors were men between the ages of 78 to 91. Nuclei extracted from frontal cortex tissue were subjected to Cleavage Under Targets & Release Using Nuclease (CUT&RUN) assay with an antibody against γH2AX, a marker of DSB formation. γH2AX-enriched chromatins were purified and analyzed via high-throughput genomic sequencing.

RESULTS: The AD brains contained 18 times more DSBs than the control brains and the pattern of AD DSBs differed from the control brain pattern. In conjunction with published genome, epigenome, and transcriptome analyses, our data revealed aberrant DSB formation correlates with AD-associated single-nucleotide polymorphisms, increased chromatin accessibility, and upregulated gene expression.

CONCLUSION: To our knowledge, this study is the first to characterize the AD brain DSB landscape. Our data suggest in AD, an accumulation of DSBs at ectopic genomic loci could contribute to an aberrant upregulation of gene expression.

%B J Alzheimers Dis %V 94 %P 519-535 %8 2023 Jul 18 %G eng %N 2 %R 10.3233/JAD-230316 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Linking Air Pollution Exposure to Blood-Based Metabolic Features in a Community-Based Aging Cohort with and without Dementia. %A Kalia, Vrinda %A Kulick, Erin R %A Vardarajan, Badri %A Gu, Yian %A Manly, Jennifer J %A Elkind, Mitchell S V %A Kaufman, Joel D %A Jones, Dean P %A Baccarelli, Andrea A %A Mayeux, Richard %A Kioumourtzoglou, Marianthi-Anna %A Miller, Gary W %K Aged %K Aging %K Air Pollutants %K Air Pollution %K Dementia %K Environmental Exposure %K Humans %K Nitrogen Dioxide %K Particulate Matter %X

BACKGROUND: Long-term exposure to air pollution has been associated with changes in levels of metabolites measured in the peripheral blood. However, most research has been conducted in ethnically homogenous, young or middle-aged populations.

OBJECTIVE: To study the relationship between the plasma metabolome and long-term exposure to three air pollutants: particulate matter (PM) less than 2.5μm in aerodynamic diameter (PM2.5), PM less than 10μm in aerodynamic diameter (PM10), and nitrogen dioxide (NO2) in an ethnically diverse, older population.

METHODS: Plasma metabolomic profiles of 107 participants of the Washington Heights and Inwood Community Aging Project in New York City, collected from 1995-2015, including non-Hispanic white, Caribbean Hispanic, and non-Hispanic Black older adults were used. We estimated the association between each metabolic feature and predicted annual mean exposure to the air pollutants using three approaches: 1) A metabolome wide association study framework; 2) Feature selection using elastic net regression; and 3) A multivariate approach using partial-least squares discriminant analysis.

RESULTS: 79 features associated with exposure to PM2.5 but none associated with PM10 or NO2. PM2.5 exposure was associated with altered amino acid metabolism, energy production, and oxidative stress response, pathways also associated with Alzheimer's disease. Three metabolites were associated with PM2.5 exposure through all three approaches: cysteinylglycine disulfide, a diglyceride, and a dicarboxylic acid. The relationship between several features and PM2.5 exposure was modified by diet and metabolic diseases.

CONCLUSIONS: These relationships uncover the mechanisms through which PM2.5 exposure can lead to altered metabolic outcomes in an older population.

%B J Alzheimers Dis %V 96 %P 1025-1040 %8 2023 Nov 21 %G eng %N 3 %R 10.3233/JAD-230122 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Lipid Invasion Model: Growing Evidence for This New Explanation of Alzheimer's Disease. %A Rudge, Jonathan D'Arcy %K Alzheimer Disease %K Amyloid beta-Peptides %K Blood-Brain Barrier %K Brain %K Cholesterol %K Humans %X

The Lipid Invasion Model (LIM) is a new hypothesis for Alzheimer's disease (AD) which argues that AD is a result of external lipid invasion to the brain, following damage to the blood-brain barrier (BBB). The LIM provides a comprehensive explanation of the observed neuropathologies associated with the disease, including the lipid irregularities first described by Alois Alzheimer himself, and accounts for the wide range of risk factors now identified with AD, all of which are also associated with damage to the BBB. This article summarizes the main arguments of the LIM, and new evidence and arguments in support of it. The LIM incorporates and extends the amyloid hypothesis, the current main explanation of the disease, but argues that the greatest cause of late-onset AD is not amyloid-β (Aβ) but bad cholesterol and free fatty acids, let into the brain by a damaged BBB. It suggests that the focus on Aβ is the reason why we have made so little progress in treating the disease in the last 30 years. As well as offering new perspectives for further research into the diagnosis, prevention, and treatment of AD, based on protecting and repairing the BBB, the LIM provides potential new insights into other neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis/motor neuron disease.

%B J Alzheimers Dis %V 94 %P 457-470 %8 2023 %G eng %N 2 %R 10.3233/JAD-221175 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Lithium Provides Broad Therapeutic Benefits in an Alzheimer's Disease Mouse Model. %A Wiseman, Alyssa L %A Briggs, Clark A %A Peritt, Ariel %A Kapecki, Nicolas %A Peterson, Daniel A %A Shim, Seong S %A Stutzmann, Grace E %K Alzheimer Disease %K Animals %K Calcium %K Disease Models, Animal %K Hippocampus %K Lithium %K Mice %K Mice, Transgenic %K Nitric Oxide Synthase Type I %K tau Proteins %X

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder with a progressive loss of cognitive function. Currently, no effective treatment regimen is available. Lithium, a mood stabilizer for bipolar disorder, exerts broad neuroprotective and neurotrophic actions and improves cognitive function.

OBJECTIVE: The study investigated if lithium stabilizes Ca2+ signaling abnormalities in hippocampal neurons and subsequently normalize downstream effects on AD neuropathology and synaptic plasticity in young AD mice.

METHODS: Four-month-old 3xTg-AD mice were treated with a LiCl diet chow for 30 days. At the end of the lithium treatment, a combination of two-photon Ca2+ imaging, electrophysiology, and immunohistochemistry assays were used to assess the effects of the LiCl treatment on inositol trisphosphate receptor (IP3R)-dependent endoplasmic reticulum (ER) Ca2+ and voltage-gated Ca2+ channel (VGCC)-mediated Ca2+ signaling in CA1 neurons, neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels and synaptic plasticity in the hippocampus and overlying cortex from 3xTg-ADmice.

RESULTS: Thirty-day LiCl treatment reduced aberrant IP3R-dependent ER Ca2+ and VGCC-mediated Ca2+ signaling in CA1 pyramidal neurons from 3xTg-AD mice and restored neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels to control levels in the hippocampal subfields and overlying cortex. The LiCl treatment enhanced post-tetanic potentiation (PTP), a form of short-term plasticity in the hippocampus.

CONCLUSION: The study found that lithium exerts therapeutic effects across several AD-associated early neuronal signaling abnormalities including aberrant Ca2+ signaling, nNOS, and p-tau formation and enhances short-term synaptic plasticity. Lithium could serve as an effective treatment or co-therapeutic for AD.

%B J Alzheimers Dis %V 91 %P 273-290 %8 2023 %G eng %N 1 %R 10.3233/JAD-220758 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Longitudinal Effects of Herpesviruses on Multiple Cognitive Outcomes in Healthy Elderly Adults. %A Weidung, Bodil %A Josefsson, Maria %A Lyttkens, Peter %A Olsson, Jan %A Elgh, Fredrik %A Lind, Lars %A Kilander, Lena %A Lövheim, Hugo %X

BACKGROUND: Herpesviruses have been proposed to be involved in Alzheimer's disease development as potentially modifiable pathology triggers.

OBJECTIVE: To investigate associations of serum antibodies for herpes simplex virus (HSV)-1 and cytomegalovirus (CMV) and anti-herpesvirus treatment with cognitive outcomes in relation to interactions with APOE ɛ4.

METHODS: The study included 849 participants in the population-based Prospective Investigation of the Vasculature in Uppsala Seniors study. Cognitive performance at the ages of 75 and 80 years was assessed using the Mini-Mental State Examination (MMSE), trail-making test (TMT) A and B, and 7-minute screening test (7MS).

RESULTS: Anti- HSV-1 IgG positivity was associated cross-sectionally with worse performance on the MMSE, TMT-A, TMT-B, 7MS, enhanced free recall, and verbal fluency tests (p = 0.016, p = 0.016, p <  0.001, p = 0.001, p = 0.033, and p <  0.001, respectively), but not orientation or clock drawing. Cognitive scores did not decline over time and longitudinal changes did not differ according to HSV-1 positivity. Anti- CMV IgG positivity was not associated cross-sectionally with cognition, but TMT-B scores declined more in anti- CMV IgG carriers. Anti- HSV-1 IgG interacted with APOE ɛ4 in association with worse TMT-A and better enhanced cued recall. Anti- HSV IgM interacted with APOE ɛ4 and anti-herpesvirus treatment in association with worse TMT-A and clock drawing, respectively.

CONCLUSION: These findings indicate that HSV-1 is linked to poorer cognition in cognitively healthy elderly adults, including impairments in executive function, memory, and expressive language. Cognitive performance did not decline over time, nor was longitudinal decline associated with HSV-1.

%B J Alzheimers Dis %V 94 %P 751-762 %8 2023 Jul 18 %G eng %N 2 %R 10.3233/JAD-221116 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer's Disease. %A Chwa, Won Jong %A Raji, Cyrus A %A Toups, Kat %A Hathaway, Ann %A Gordon, Deborah %A Chung, Henrianna %A Boyd, Alan %A Hill, Benjamin D %A Hausman-Cohen, Sharon %A Attarha, Mouna %A Jarrett, Michael %A Bredesen, Dale E %K Alzheimer Disease %K Atrophy %K Brain %K Cognitive Dysfunction %K Gray Matter %K Humans %K Magnetic Resonance Imaging %K Precision Medicine %K White Matter %X

BACKGROUND: Alzheimer's disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized.

OBJECTIVE: Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI).

METHODS: Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios.

RESULTS: Montreal Cognitive Assessment scores (p < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons.

%B J Alzheimers Dis %V 96 %P 1051-1058 %8 2023 %G eng %N 3 %R 10.3233/JAD-230481 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Machine Learning Selection of Most Predictive Brain Proteins Suggests Role of Sugar Metabolism in Alzheimer's Disease. %A Tandon, Raghav %A Levey, Allan I %A Lah, James J %A Seyfried, Nicholas T %A Mitchell, Cassie S %X

BACKGROUND: The complex and not yet fully understood etiology of Alzheimer's disease (AD) shows important proteopathic signs which are unlikely to be linked to a single protein. However, protein subsets from deep proteomic datasets can be useful in stratifying patient risk, identifying stage dependent disease markers, and suggesting possible disease mechanisms.

OBJECTIVE: The objective was to identify protein subsets that best classify subjects into control, asymptomatic Alzheimer's disease (AsymAD), and AD.

METHODS: Data comprised 6 cohorts; 620 subjects; 3,334 proteins. Brain tissue-derived predictive protein subsets for classifying AD, AsymAD, or control were identified and validated with label-free quantification and machine learning.

RESULTS: A 29-protein subset accurately classified AD (AUC = 0.94). However, an 88-protein subset best predicted AsymAD (AUC = 0.85) or Control (AUC = 0.89) from AD (AUC = 0.96). AD versus Control: APP, DHX15, NRXN1, PBXIP1, RABEP1, STOM, and VGF. AD versus AsymAD: ALDH1A1, BDH2, C4A, FABP7, GABBR2, GNAI3, PBXIP1, and PKAR1B. AsymAD versus Control: APP, C4A, DMXL1, EXOC2, PITPNB, REBEP1, and VGF. Additional predictors: DNAJA3, PTBP2, SLC30A9, VAT1L, CROCC, PNP, SNCB, PRKAR1B, ENPP6, HAPLN2, PSMD4, and CMAS.

CONCLUSION: Biomarkers were dynamically separable across disease stages. Predictive proteins were significantly enriched to sugar metabolism.

%B J Alzheimers Dis %V 92 %P 411-424 %8 2023 Mar 21 %G eng %N 2 %R 10.3233/JAD-220683 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Malignant Brain Aging: The Formidable Link Between Dysregulated Signaling Through Mechanistic Target of Rapamycin Pathways and Alzheimer's Disease (Type 3 Diabetes). %A de la Monte, Suzanne M %K Alzheimer Disease %K Brain %K Diabetes Mellitus %K Humans %K Insulin %K Sirolimus %K TOR Serine-Threonine Kinases %X

Malignant brain aging corresponds to accelerated age-related declines in brain functions eventually derailing the self-sustaining forces that govern independent vitality. Malignant brain aging establishes the path toward dementing neurodegeneration, including Alzheimer's disease (AD). The full spectrum of AD includes progressive dysfunction of neurons, oligodendrocytes, astrocytes, microglia, and the microvascular systems, and is mechanistically driven by insulin and insulin-like growth factor (IGF) deficiencies and resistances with accompanying deficits in energy balance, increased cellular stress, inflammation, and impaired perfusion, mimicking the core features of diabetes mellitus. The underlying pathophysiological derangements result in mitochondrial dysfunction, abnormal protein aggregation, increased oxidative and endoplasmic reticulum stress, aberrant autophagy, and abnormal post-translational modification of proteins, all of which are signature features of both AD and dysregulated insulin/IGF-1-mechanistic target of rapamycin (mTOR) signaling. This article connects the dots from benign to malignant aging to neurodegeneration by reviewing the salient pathologies associated with initially adaptive and later dysfunctional mTOR signaling in the brain. Effective therapeutic and preventive measures must be two-pronged and designed to 1) address complex and shifting impairments in mTOR signaling through the re-purpose of effective anti-diabetes therapeutics that target the brain, and 2) minimize the impact of extrinsic mediators of benign to malignant aging transitions, e.g., inflammatory states, obesity, systemic insulin resistance diseases, and repeated bouts of general anesthesia, by minimizing exposures or implementing neuroprotective measures.

%B J Alzheimers Dis %V 95 %P 1301-1337 %8 2023 %G eng %N 4 %R 10.3233/JAD-230555 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Medial Temporal Lobe Atrophy in Predementia Alzheimer's Disease: A Longitudinal Multi-Site Study Comparing Staging and A/T/N in a Clinical Research Cohort. %A Jarholm, Jonas Alexander %A Bjørnerud, Atle %A Dalaker, Turi Olene %A Akhavi, Mehdi Sadat %A Kirsebom, Bjørn Eivind %A Pålhaugen, Lene %A Nordengen, Kaja %A Grøntvedt, Gøril Rolfseng %A Nakling, Arne %A Kalheim, Lisa F %A Almdahl, Ina S %A Tecelao, Sandra %A Fladby, Tormod %A Selnes, Per %K Alzheimer Disease %K Atrophy %K Cognitive Dysfunction %K Entorhinal Cortex %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Temporal Lobe %X

BACKGROUND: Atrophy of the medial temporal lobe (MTL) is a biological characteristic of Alzheimer's disease (AD) and can be measured by segmentation of magnetic resonance images (MRI).

OBJECTIVE: To assess the clinical utility of automated volumetry in a cognitively well-defined and biomarker-classified multi-center longitudinal predementia cohort.

METHODS: We used Automatic Segmentation of Hippocampal Subfields (ASHS) to determine MTL morphometry from MRI. We harmonized scanner effects using the recently developed longitudinal ComBat. Subjects were classified according to the A/T/N system, and as normal controls (NC), subjective cognitive decline (SCD), or mild cognitive impairment (MCI). Positive or negative values of A, T, and N were determined by cerebrospinal fluid measurements of the Aβ42/40 ratio, phosphorylated and total tau. From 406 included subjects, longitudinal data was available for 206 subjects by stage, and 212 subjects by A/T/N.

RESULTS: Compared to A-/T-/N- at baseline, the entorhinal cortex, anterior and posterior hippocampus were smaller in A+/T+orN+. Compared to NC A- at baseline, these subregions were also smaller in MCI A+. Longitudinally, SCD A+ and MCI A+, and A+/T-/N- and A+/T+orN+, had significantly greater atrophy compared to controls in both anterior and posterior hippocampus. In the entorhinal and parahippocampal cortices, longitudinal atrophy was observed only in MCI A+ compared to NC A-, and in A+/T-/N- and A+/T+orN+ compared to A-/T-/N-.

CONCLUSION: We found MTL neurodegeneration largely consistent with existing models, suggesting that harmonized MRI volumetry may be used under conditions that are common in clinical multi-center cohorts.

%B J Alzheimers Dis %V 94 %P 259-279 %8 2023 %G eng %N 1 %R 10.3233/JAD-221274 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Mediation Effect of Brain Volume on the Relationship Between Peripheral Inflammation and Cognitive Decline. %A Zhuo, Bingting %A Zheng, Dashan %A Cai, Miao %A Wang, Chongjian %A Zhang, Shiyu %A Zhang, Zilong %A Tian, Fei %A Wang, Xiaojie %A Lin, Hualiang %K Atrophy %K Brain %K Cognition %K Cognitive Dysfunction %K Cohort Studies %K Encephalitis %K Humans %K Inflammation %K Magnetic Resonance Imaging %X

BACKGROUND: Studies have reported the associations between inflammation, brain volume, and cognition separately. It is reasonable to assume peripheral inflammation may contribute to cognitive decline through brain volume atrophy.

OBJECTIVE: To examine the associations between peripheral inflammation, brain volume, and cognition among adults, and to investigate whether brain volume atrophy mediates the inflammation-cognition relationshipMethods:We retrieved 20,381 participants with available data on peripheral inflammation, brain volume, and cognition from the UK Biobank cohort. Cognitive function was assessed by performance on cognitive tasks probing various cognitive domains. Brain volumes were measured by magnetic resonance imaging (MRI). Multivariable linear models were used to investigate the associations between three peripheral inflammatory indexes (C-reactive protein, systemic immune-inflammatory index, neutrophil-to-lymphocyte ratio), brain volume, and cognition. Mediation analyses were conducted to assess the potential mediating effect of brain volume atrophy. All results were corrected for multiple comparisons using the false-discovery rate (FDR).

RESULTS: Peripheral inflammation was inversely associated with grey matter volume (GMV), white matter volume (WMV), and cognition after adjusting for potential covariates. For instance, CRP was associated with the GMV of left parahippocampal gyrus (β= -0.05, 95% confidence interval [CI]: -0.06 to -0.04, pFDR =1.07×10-16) and general cognitive factor (β= -0.03, 95% CI: -0. -0.04 to -0.01, pFDR = 0.001). Brain volume atrophy mediated the inflammation-cognitive decline relationship, accounting for 15-29% of the overall impact.

CONCLUSION: In this cohort study, peripheral inflammation was associated with brain volume atrophy and cognitive decline. Brain atrophy may mediate the inflammation-cognitive decline relationship.

%B J Alzheimers Dis %V 95 %P 523-533 %8 2023 %G eng %N 2 %R 10.3233/JAD-230253 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Mediation of Reduced Hippocampal Volume by Cerebral Amyloid Angiopathy in Pathologically Confirmed Patients with Alzheimer's Disease. %A Nagaraja, Nandakumar %A Wang, Wei-En %A Duara, Ranjan %A DeKosky, Steven T %A Vaillancourt, David %X

BACKGROUND: Hippocampal atrophy in cerebral amyloid angiopathy (CAA) has been reported to be similar to that in Alzheimer's disease (AD).

OBJECTIVE: To evaluate if CAA pathology partly mediates reduced hippocampal volume in patients with AD.

METHODS: Patients with a clinical diagnosis of AD and neuropathological confirmation of AD+/-CAA in the National Alzheimer's Coordinating Center database were included in the study. The volumes of temporal lobe structures were calculated on T1-weighted imaging (T1-MRI) using automated FreeSurfer software, from images acquired on average 5 years prior to death. Multivariate regression analysis was performed to compare brain volumes in four CAA groups. The hippocampal volume on T1-MRI was correlated with Clinical Dementia Rating sum of boxes (CDRsb) score, apolipoprotein E (APOE) genotype, and hippocampal atrophy at autopsy.

RESULTS: The study included 231 patients with no (n = 45), mild (n = 70), moderate (n = 67), and severe (n = 49) CAA. Among the four CAA groups, patients with severe CAA had a smaller mean left hippocampal volume (p = 0.023) but this was not significant when adjusted for APOE ɛ4 (p = 0.07). The left hippocampal volume on MRI correlated significantly with the hippocampal atrophy grading on neuropathology (p = 0.0003). Among patients with severe CAA, the left hippocampal volume on T1-MRI: (a) decreased with an increase in the number of APOE ɛ4 alleles (p = 0.04); but (b) had no evidence of correlation with CDRsb score (p = 0.57).

CONCLUSION: Severe CAA was associated with smaller left hippocampal volume on T1-MRI up to five years prior to death among patients with neuropathologically confirmed AD. This relationship was dependent on APOE ɛ4 genotype.

%B J Alzheimers Dis %V 93 %P 495-507 %8 2023 May 16 %G eng %N 2 %R 10.3233/JAD-220624 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Microglia-Astrocyte Communication in Alzheimer's Disease. %A Wu, Yingying %A Eisel, Ulrich L M %K Alzheimer Disease %K Astrocytes %K Central Nervous System %K Communication %K Humans %K Microglia %X

Microglia and astrocytes are regarded as active participants in the central nervous system under various neuropathological conditions, including Alzheimer's disease (AD). Both microglia and astrocyte activation have been reported to occur with a spatially and temporarily distinct pattern. Acting as a double-edged sword, glia-mediated neuroinflammation may be both detrimental and beneficial to the brain. In a variety of neuropathologies, microglia are activated before astrocytes, which facilitates astrocyte activation. Yet reactive astrocytes can also prevent the activation of adjacent microglia in addition to helping them become activated. Studies describe changes in the genetic profile as well as cellular and molecular responses of these two types of glial cells that contribute to dysfunctional immune crosstalk in AD. In this paper, we construct current knowledge of microglia-astrocyte communication, highlighting the multifaceted functions of microglia and astrocytes and their role in AD. A thorough comprehension of microglia-astrocyte communication could hasten the creation of novel AD treatment approaches.

%B J Alzheimers Dis %V 95 %P 785-803 %8 2023 %G eng %N 3 %R 10.3233/JAD-230199 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Microglial Imaging in Alzheimer's Disease and Its Relationship to Brain Amyloid: A Human 18F-GE180 PET Study. %A Yang, Zhengshi %A Banks, Sarah J %A Ritter, Aaron R %A Cummings, Jeffrey L %A Sreenivasan, Karthik %A Kinney, Jefferson W %A Caldwell, Jessica K %A Wong, Christina G %A Miller, Justin B %A Cordes, Dietmar %X

BACKGROUND: Emerging evidence suggests a potential causal role of neuroinflammation in Alzheimer's disease (AD). Using positron emission tomography (PET) to image overexpressed 18 kDA translocator protein (TSPO) by activated microglia has gained increasing interest. The uptake of 18F-GE180 TSPO PET was observed to co-localize with inflammatory markers and have a two-stage association with amyloid PET in mice. Very few studies evaluated the diagnostic power of 18F-GE180 PET in AD population and its interpretation in human remains controversial about whether it is a marker of microglial activation or merely reflects disrupted blood-brain barrier integrity in humans.

OBJECTIVE: The goal of this study was to study human GE180 from the perspective of the previous animal observations.

METHODS: With data from twenty-four participants having 18F-GE180 and 18F-AV45 PET scans, we evaluated the group differences of 18F-GE180 uptake between participants with and without cognitive impairment. An association analysis of 18F-GE180 and 18F-AV45 was then conducted to test if the relationship in humans is consistent with the two-stage association in AD mouse model.

RESULTS: Elevated 18F-GE180 was observed in participants with cognitive impairment compared to those with normal cognition. No regions showed reduced 18F-GE180 uptake. Consistent with mouse model, a two-stage association between 18F-GE180 and 18F-AV45 was observed.

CONCLUSIONS: 18F-GE180 PET imaging showed promising utility in detecting pathological alterations in a symptomatic AD population. Consistent two-stage association between 18F-GE180 and amyloid PET in human and mouse suggested that 18F-GE180 uptake in human might be considerably influenced by microglial activation.

%B J Alzheimers Dis %V 96 %P 1505-1514 %8 2023 Dec 05 %G eng %N 4 %R 10.3233/JAD-230631 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Microglia-Mediated Neurovascular Unit Dysfunction in Alzheimer's Disease. %A Huang, Wenhao %A Xia, Qing %A Zheng, Feifei %A Zhao, Xue %A Ge, Fangliang %A Xiao, Jiaying %A Liu, Zijie %A Shen, Yingying %A Ye, Ke %A Wang, Dayong %A Li, Yanze %K Alzheimer Disease %K Astrocytes %K Blood-Brain Barrier %K Humans %K Microglia %K Neurons %X

The neurovascular unit (NVU) is involved in the pathological changes in Alzheimer's disease (AD). The NVU is a structural and functional complex that maintains microenvironmental homeostasis and metabolic balance in the central nervous system. As one of the most important components of the NVU, microglia not only induce blood-brain barrier breakdown by promoting neuroinflammation, the infiltration of peripheral white blood cells and oxidative stress but also mediate neurovascular uncoupling by inducing mitochondrial dysfunction in neurons, abnormal contraction of cerebral vessels, and pericyte loss in AD. In addition, microglia-mediated dysfunction of cellular components in the NVU, such as astrocytes and pericytes, can destroy the integrity of the NVU and lead to NVU impairment. Therefore, we review the mechanisms of microglia-mediated NVU dysfunction in AD. Furthermore, existing therapeutic advancements aimed at restoring the function of microglia and the NVU in AD are discussed. Finally, we predict the role of pericytes in microglia-mediated NVU dysfunction in AD is the hotspot in the future.

%B J Alzheimers Dis %V 94 %P S335-S354 %8 2023 %G eng %N s1 %R 10.3233/JAD-221064 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Midlife Neuropsychological Profiles and Associated Vascular Risk: The Bogalusa Heart Study. %A De Anda-Duran, Ileana %A Kolachalama, Vijaya B %A Carmichael, Owen T %A Hwang, Phillip H %A Fernandez, Camilo %A Au, Rhoda %A Bazzano, Lydia A %A Libon, David J %X

BACKGROUND: Individuals with Alzheimer's disease (AD) often present with coexisting vascular pathology that is expressed to different degrees and can lead to clinical heterogeneity.

OBJECTIVE: To examine the utility of unsupervised statistical clustering approaches in identifying neuropsychological (NP) test performance subtypes that closely correlate with carotid intima-media thickness (cIMT) in midlife.

METHODS: A hierarchical agglomerative and k-means clustering analysis based on NP scores (standardized for age, sex, and race) was conducted among 1,203 participants (age 48±5.3 years) from the Bogalusa Heart Study. Regression models assessed the association between cIMT ≥50th percentile and NP profiles, and global cognitive score (GCS) tertiles for sensitivity analysis.

RESULTS: Three NP profiles were identified: Mixed-low performance [16%, n = 192], scores ≥1 SD below the mean on immediate, delayed free recall, recognition verbal memory, and information processing; Average [59%, n = 704]; and Optimal [26%, n = 307] NP performance. Participants with greater cIMT were more likely to have a Mixed-low profile [OR = 3.10, 95% CI (2.13, 4.53), p < 0.001] compared to Optimal. After adjusting for education and cardiovascular (CV) risks, results remained. The association with GCS tertiles was more attenuated [lowest (34%, n = 407) versus highest (33%, n = 403) tertile: adjusted OR = 1.66, 95% CI (1.07, 2.60), p = 0.024].

CONCLUSION: As early as midlife, individuals with higher subclinical atherosclerosis were more likely to be in the Mixed-low profile, underscoring the potential malignancy of CV risk as related to NP test performance, suggesting that classification approaches may aid in identifying those at risk for AD/vascular dementia spectrum illness.

%B J Alzheimers Dis %V 94 %P 101-113 %8 2023 Jun 27 %G eng %N 1 %R 10.3233/JAD-220931 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Mild Cognitive Impairment is Associated with Poorer Everyday Decision Making. %A Fenton, Laura %A Han, S Duke %A DiGuiseppi, Carolyn G %A Fowler, Nicole R %A Hill, Linda %A Johnson, Rachel L %A Peterson, Ryan A %A Knoepke, Christopher E %A Matlock, Daniel D %A Moran, Ryan %A Karlawish, Jason %A Betz, Marian E %K Aged %K Cognitive Dysfunction %K Decision Making %K Delivery of Health Care %K Educational Status %K Female %K Humans %K Independent Living %K Male %X

BACKGROUND: Older adults are faced with many unique and highly consequential decisions such as those related to finances, healthcare, and everyday functioning (e.g., driving cessation). Given the significant impact of these decisions on independence, wellbeing, and safety, an understanding of how cognitive impairment may impact decision making in older age is important.

OBJECTIVE: To examine the impact of mild cognitive impairment (MCI) on responses to a modified version of the Short Portable Assessment of Capacity for Everyday Decision making (SPACED).

METHODS: Participants were community-dwelling, actively driving older adults (N = 301; M age = 77.1 years, SD = 5.1; 69.4% with a college degree or higher; 51.2% female; 95.3% White) enrolled in the Advancing Understanding of Transportation Options (AUTO) study. A generalized linear model adjusted for age, education, sex, randomization group, cognitive assessment method, and study site was used to examine the relationship between MCI status and decision making.

RESULTS: MCI status was associated with poorer decision making; participants with MCI missed an average of 2.17 times more points on the SPACED than those without MCI (adjusted mean ratio: 2.17, 95% CI: 1.02, 4.61, p = 0.044).

CONCLUSION: This finding supports the idea that older adults with MCI exhibit poorer decision-making abilities than cognitively normal older adults. It also suggests that older adults with MCI may exhibit poorer decision making across a wide range of decision contexts.

%B J Alzheimers Dis %V 94 %P 1607-1615 %8 2023 %G eng %N 4 %R 10.3233/JAD-230222 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Mindfulness Prevents Depression and Psychopathology in Elderly People with Mild to Moderate Alzheimer's Disease: A Randomized Clinical Trial. %A Quintana-Hernández, Domingo J %A Rojas-Hernández, Jaime %A Santana-Del Pino, Angelo %A Céspedes Suárez, Carmen %A Pellejero Silva, Mónica %A Miró-Barrachina, María Teresa %A Ibáñez Fernández, Ignacio %A Estupiñán López, José Antonio %A Borkel, Lucas F %K Aged %K Alzheimer Disease %K Depression %K Donepezil %K Humans %K Longitudinal Studies %K Mindfulness %X

BACKGROUND: This longitudinal study addressed whether mindfulness practice prevents psychological and behavioral symptoms, especially mood disorders, in Alzheimer's disease (AD).

OBJECTIVE: To assess the incidence of depression in the course of AD and to determine which non-pharmacological treatment (NPT) is most effective in preventing psychopathological symptoms.

METHODS: We conducted a longitudinal, non-inferiority and equivalence randomized clinical trial, repeated-measures design, with a control group and three experimental treatments: mindfulness, cognitive stimulation, and relaxation. Each experimental group performed three weekly sessions for two years. The pharmacological treatment of all participants was donepezil (10 mg). Participants were patients with probable AD without diagnosed depression from the public neurology services of the Canary Health Service, Spain. Psychological evaluation was performed using the Geriatric Depression Scale (GDS), Hamilton Depression Rating Scale (HDRS), and Neuropsychiatric Inventory (NPI-Q). The statistical analysis included only patients who attended at least 75% of the sessions. A nonparametric, repeated-measures analysis was performed with Kruskal-Wallis H test and between-group differences with Mann-Whitney U test with Bonferroni correction (p < 0.008). Effect size was calculated with partial eta-squared.

RESULTS: The results showed significant differences with large effect sizes (η2p>0.14) between mindfulness and the rest of the experimental groups as well as the control in the GDS, HDRS, and NPI-Q scales.

CONCLUSION: Compared to the other experimental groups, only mindfulness prevented the onset of depression and other psychopathologies in early-stage AD. Based on its effectiveness in maintaining cognitive functions and preventing psychopathology, we recommend mindfulness as the first-choice NPT for mild to moderate AD.

%B J Alzheimers Dis %V 91 %P 471-481 %8 2023 %G eng %N 1 %R 10.3233/JAD-220889 %0 Journal Article %J J Alzheimers Dis %D 2023 %T miRNAs and Stem Cells as Promising Diagnostic and Therapeutic Targets for Alzheimer's Disease. %A Elzayat, Emad M %A Shahien, Sherif A %A El-Sherif, Ahmed A %A Hosney, Mohamed %K Acitretin %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Disease Susceptibility %K Humans %K MicroRNAs %K Stem Cell Transplantation %K Stem Cells %X

Alzheimer's disease (AD) is a cumulative progressive neurodegenerative disease characterized mainly by impairment in cognitive functions accompanied by memory loss, disturbance in behavior and personality, and difficulties in learning. Although the main causes of AD pathogenesis are not fully understood yet, amyloid-β peptides and tau proteins are supposed to be responsible for AD onset and pathogenesis. Various demographic, genetic, and environmental risk factors are involved in AD onset and pathogenesis such as age, gender, several genes, lipids, malnutrition, and poor diet. Significant changes were observed in microRNA (miRNA) levels between normal and AD cases giving hope for a diagnostic procedure for AD through a simple blood test. As yet, only two classes of AD therapeutic drugs are approved by FDA. They are classified as acetylcholinesterase inhibitors and N-methyl-D-aspartate antagonists (NMDA). Unfortunately, they can only treat the symptoms but cannot cure AD or stop its progression. New therapeutic approaches were developed for AD treatment including acitretin due to its ability to cross blood-brain barrier in the brain of rats and mice and induce the expression of ADAM 10 gene, the α-secretase of human amyloid-β protein precursor, stimulating the non-amyloidogenic pathway for amyloid-β protein precursor processing resulting in amyloid-β reduction. Also stem cells may have a crucial role in AD treatment as they can improve cognitive functions and memory in AD rats through regeneration of damaged neurons. This review spotlights on promising diagnostic techniques such as miRNAs and therapeutic approaches such as acitretin and/or stem cells keeping in consideration AD pathogenesis, stages, symptoms, and risk factors.

%B J Alzheimers Dis %V 94 %P S203-S225 %8 2023 %G eng %N s1 %R 10.3233/JAD-221298 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Mitochondria Profoundly Influence Apolipoprotein E Biology. %A Gabrielli, Alexander P %A Weidling, Ian %A Ranjan, Amol %A Wang, Xiaowan %A Novikova, Lesya %A Chowdhury, Subir Roy %A Menta, Blaise %A Berkowicz, Alexandra %A Wilkins, Heather M %A Peterson, Kenneth R %A Swerdlow, Russell H %K Alzheimer Disease %K Apolipoproteins E %K Biology %K Cell Line, Tumor %K DNA, Mitochondrial %K Humans %K Mitochondria %K Neuroblastoma %K RNA, Messenger %K Transcription Factors %X

BACKGROUND: Mitochondria can trigger Alzheimer's disease (AD)-associated molecular phenomena, but how mitochondria impact apolipoprotein E (APOE; apoE) is not well known.

OBJECTIVE: Consider whether and how mitochondrial biology influences APOE and apoE biology.

METHODS: We measured APOE expression in human SH-SY5Y neuronal cells with different forms of mitochondrial dysfunction including total, chronic mitochondrial DNA (mtDNA) depletion (ρ0 cells); acute, partial mtDNA depletion; and toxin-induced mitochondrial dysfunction. We further assessed intracellular and secreted apoE protein levels in the ρ0 cells and interrogated the impact of transcription factors and stress signaling pathways known to influence APOE expression.

RESULTS: SH-SY5Y ρ0 cells exhibited a 65-fold increase in APOE mRNA, an 8-fold increase in secreted apoE protein, and increased intracellular apoE protein. Other models of primary mitochondrial dysfunction including partial mtDNA-depletion, toxin-induced respiratory chain inhibition, and chemical-induced manipulations of the mitochondrial membrane potential similarly increased SH-SY5Y cell APOE mRNA. We explored potential mediators and found in the ρ0 cells knock-down of the C/EBPα and NFE2L2 (Nrf2) transcription factors reduced APOE mRNA. The activity of two mitogen-activated protein kinases, JNK and ERK, also strongly influenced ρ0 cell APOE mRNA levels.

CONCLUSION: Primary mitochondrial dysfunction either directly or indirectly activates APOE expression in a neuronal cell model by altering transcription factors and stress signaling pathways. These studies demonstrate mitochondrial biology can influence the biology of the APOE gene and apoE protein, which are implicated in AD.

%B J Alzheimers Dis %V 92 %P 591-604 %8 2023 %G eng %N 2 %R 10.3233/JAD-221177 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Montreal Cognitive Assessment in Mild Cognitive Impairment: Relationship with Cerebrospinal Fluid Biomarkers and Conversion to Dementia. %A Bernardes, Catarina %A Lima, Marisa %A Duro, Diana %A Silva-Spínola, Anuschka %A Durães, João %A Tábuas-Pereira, Miguel %A Baldeiras, Ines %A Freitas, Sandra %A Santana, Isabel %X

BACKGROUND: Mild cognitive impairment (MCI) is considered a prodromal state of dementia. Abnormal values of cerebrospinal fluid Alzheimer's disease biomarkers (CSF-AD-b) have been associated with a higher risk of conversion to dementia (due to Alzheimer's disease), but studies evaluating the ability of Montreal Cognitive Assessment (MoCA) in this task are lacking.

OBJECTIVE: This study aims to investigate the relationship between MoCA and CSF-AD-b, as well as the ability of those tools to predict conversion to dementia.

METHODS: Taking advantage of our MCI cohort with biological characterization on longitudinal follow-up (180 patients followed for 62.6 months during which 41.3% converted), we computed MoCA and MMSE z-scores, using Portuguese normative data. The performance in MoCA z-score was correlated with CSF-AD-b and the relative time to conversion and risk according to baseline characteristics were analyzed using Kaplan-Meier analysis and Cox regression models.

RESULTS: MoCA z-scores were correlated with Aβ42 (p = 0.026), t-tau (p = 0.033), and p-tau (p = 0.01). Impaired MMSE (p < 0.001) and MoCA z-scores (p = 0.019), decreased Aβ42 (p < 0.001) and increased t-tau (p < 0.001) and p-tau (p < 0.001) were associated with shorter estimated time of conversion. Aβ42 (p < 0.001) and MMSE z-scores (p = 0.029) were independent predictors of conversion. For those with at least 9 years of education, MoCA z-score (p = 0.004) (but not MMSE) was an independent predictor of conversion as well as Aβ42.

CONCLUSIONS: This study confirms the role of CSF-AD-b, namely Aβ42, in predicting conversion from MCI to dementia and suggests the utility of MoCA in predicting conversion in highly educated subjects, supporting its use in the evaluation of MCI patients.

%B J Alzheimers Dis %V 96 %P 1173-1182 %8 2023 Nov 21 %G eng %N 3 %R 10.3233/JAD-230916 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Moral Emotions and Their Brain Structural Correlates Across Neurodegenerative Disorders. %A Baez, Sandra %A Trujillo-Llano, Catalina %A de Souza, Leonardo Cruz %A Lillo, Patricia %A Forno, Gonzalo %A Santamaría-García, Hernando %A Okuma, Cecilia %A Alegria, Patricio %A Huepe, David %A Ibáñez, Agustín %A Decety, Jean %A Slachevsky, Andrea %K Alzheimer Disease %K Brain %K Emotions %K Frontotemporal Dementia %K Humans %K Magnetic Resonance Imaging %K Morals %K Neuropsychological Tests %X

BACKGROUND: Although social cognition is compromised in patients with neurodegenerative disorders such as behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD), research on moral emotions and their neural correlates in these populations is scarce. No previous study has explored the utility of moral emotions, compared to and in combination with classical general cognitive state tools, to discriminate bvFTD from AD patients.

OBJECTIVE: To examine self-conscious (guilt and embarrassment) and other-oriented (pity and indignation) moral emotions, their subjective experience, and their structural brain underpinnings in bvFTD (n = 31) and AD (n = 30) patients, compared to healthy controls (n = 37). We also explored the potential utility of moral emotions measures to discriminate bvFTD from AD.

METHODS: We used a modified version of the Moral Sentiment Task measuring the participants' accuracy scores and their emotional subjective experiences.

RESULTS: bvFTD patients exhibited greater impairments in self-conscious and other-oriented moral emotions as compared with AD patients and healthy controls. Moral emotions combined with general cognitive state tools emerged as useful measures to discriminate bvFTD from AD patients. In bvFTD patients, lower moral emotions scores were associated with lower gray matter volumes in caudate nucleus and inferior and middle temporal gyri. In AD, these scores were associated with lower gray matter volumes in superior and middle frontal gyri, middle temporal gyrus, inferior parietal lobule and supramarginal gyrus.

CONCLUSION: These findings contribute to a better understanding of moral emotion deficits across neurodegenerative disorders, highlighting the potential benefits of integrating this domain into the clinical assessment.

%B J Alzheimers Dis %V 92 %P 153-169 %8 2023 %G eng %N 1 %R 10.3233/JAD-221131 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Mortality Risks and Causes of Death by Dementia Types in a Japanese Cohort with Dementia: NCGG-STORIES. %A Ono, Rei %A Sakurai, Takashi %A Sugimoto, Taiki %A Uchida, Kazuaki %A Nakagawa, Takeshi %A Noguchi, Taiji %A Komatsu, Ayane %A Arai, Hidenori %A Saito, Tami %K Aged %K Alzheimer Disease %K Cause of Death %K Cognitive Dysfunction %K Dementia %K East Asian People %K Female %K Humans %K Lewy Body Disease %K Male %X

BACKGROUND: Prognosis-related information regarding dementia needs to be updated, as changes in medical and long-term care environments for patients with dementia in recent decades may be improving the prognosis of the disease.

OBJECTIVE: We aimed to investigate the mortality, cause of death, and prognostic factors by types of dementia in a Japanese clinic-based cohort.

METHODS: The National Center for Geriatrics and Gerontology-Life Stories of People with Dementia consists of clinical records and prognostic data of patients who visited the Memory Clinic in Japan. Patients who attended the clinic between July 2010 and September 2018, or their close relatives, were asked about death information via a postal survey. A cohort of 3,229 patients (mean age, 76.9; female, 1,953) was classified into six groups: normal cognition (NC), mild cognitive impairment (MCI), Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration. A Cox proportional hazards model was employed to compare the mortality of each type of dementia, MCI, and NC.

RESULTS: Patients with all types of dementia and MCI had higher mortality rates than those with NC (hazard risks: 2.61-5.20). The most common cause of death was pneumonia, followed by cancer. In the MCI, AD, and DLB groups, older age, male sex, and low cognitive function were common prognostic factors but not presence of apolipoprotein E ɛ4 allele.

CONCLUSION: Our findings suggest important differences in the mortality risk and cause of death among patients with dementia, which will be useful in advanced care planning and policymaking.

%B J Alzheimers Dis %V 92 %P 487-498 %8 2023 %G eng %N 2 %R 10.3233/JAD-221290 %0 Journal Article %J J Alzheimers Dis %D 2023 %T MRI Visible Perivascular Spaces and the Risk of Incident Mild Cognitive Impairment in a Community Sample. %A Pase, Matthew P %A Pinheiro, Adlin %A Rowsthorn, Ella %A Demissie, Serkalem %A Hurmez, Saoresho %A Aparicio, Hugo %A Rodriguez-Lara, Frances %A Gonzales, Mitzi M %A Beiser, Alexa %A DeCarli, Charles %A Seshadri, Sudha %A Romero, Jose Rafael %X

BACKGROUND: Magnetic resonance imaging (MRI) visible perivascular spaces (PVS) are associated with the risk of incident dementia but their association with the early stages of cognitive impairment remains equivocal.

OBJECTIVE: We examined the association between MRI visible PVS and the risk of incident mild cognitive impairment (MCI) in the community-based Framingham Heart Study (FHS).

METHODS: FHS participants aged at least 50 years free of stroke, cognitive impairment, and dementia at the time of MRI were included. PVS were rated according to severity in the basal ganglia and centrum semiovale (CSO) using established criteria. Cox regression analyses were used to relate PVS to incident MCI adjusted for demographic and cardiovascular variables.

RESULTS: The mean age of the sample (1,314 participants) at MRI was 68 years (SD, 9; 54% women). There were 263 cases of incident MCI over a median 7.4 years follow-up (max, 19.8 years). MCI risk increased with higher PVS severity in the CSO. Relative to persons with the lowest severity rating, persons with the highest severity rating in the CSO had a higher risk of incident MCI (hazard ratio [HR] = 2.55; 95% confidence interval [CI], 1.48-4.37; p = 0.0007). In secondary analysis, this association seemed stronger in women. Risk of incident MCI was nominally higher for participants with the highest severity grade of PVS in the basal ganglia, though not statistically significant relative to the lowest grade (HR = 2.19; 95% CI, 0.78-6.14; p = 0.14).

CONCLUSIONS: PVS burden in the CSO may be a risk marker for early cognitive impairment.

%B J Alzheimers Dis %V 96 %P 103-112 %8 2023 Oct 24 %G eng %N 1 %R 10.3233/JAD-230445 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol. %A Bahrani, Ahmed A %A Abner, Erin L %A DeCarli, Charles S %A Barber, Justin M %A Sutton, Abigail C %A Maillard, Pauline %A Sandoval, Francisco %A Arfanakis, Konstantinos %A Yang, Yung-Chuan %A Evia, Arnold M %A Schneider, Julie A %A Habes, Mohamad %A Franklin, Crystal G %A Seshadri, Sudha %A Satizabal, Claudia L %A Caprihan, Arvind %A Thompson, Jeffrey F %A Rosenberg, Gary A %A Wang, Danny J J %A Jann, Kay B %A Zhao, Chenyang %A Lu, Hanzhang %A Rosenberg, Paul B %A Albert, Marilyn S %A Ali, Doaa G %A Singh, Herpreet %A Schwab, Kristin %A Greenberg, Steven M %A Helmer, Karl G %A Powel, David K %A Gold, Brian T %A Goldstein, Larry B %A Wilcock, Donna M %A Jicha, Gregory A %X

BACKGROUND: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease.

OBJECTIVE: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol.

METHODS: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity.

RESULTS: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression.

CONCLUSIONS: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

%B J Alzheimers Dis %V 96 %P 683-693 %8 2023 Nov 07 %G eng %N 2 %R 10.3233/JAD-230629 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Necroptosis and Alzheimer's Disease: Pathogenic Mechanisms and Therapeutic Opportunities. %A Zhang, Ruxin %A Song, Yanrong %A Su, Xuefeng %K Alzheimer Disease %K Amyloid beta-Peptides %K Apoptosis %K Humans %K Necrosis %K Neurodegenerative Diseases %X

Alzheimer's disease (AD) is considered to be the most common neurodegenerative disease, with clinical symptoms encompassing progressive memory loss and cognitive impairment. Necroptosis is a form of programmed necrosis that promotes cell death and neuroinflammation, which further mediates the pathogenesis of several neurodegenerative diseases, especially AD. Current evidence has strongly suggested that necroptosis is activated in AD brains, resulting in neuronal death and cognitive impairment. We searched the PubMed database, screening all articles published before September 28, 2022 related to necroptosis in the context of AD pathology. The keywords in the search included: "necroptosis", "Alzheimer's disease", "signaling pathways", "Aβ", Aβo", "Tau", "p-Tau", "neuronal death", "BBB damage", "neuroinflammation", "microglia", "mitochondrial dysfunction", "granulovacuolar degeneration", "synaptic loss", "axonal degeneration", "Nec-1", "Nec-1s", "GSK872", "NSA", "OGA", "RIPK1", "RIPK3", and "MLKL". Results show that necroptosis has been involved in multiple pathological processes of AD, including amyloid-β aggregation, Tau accumulation, neuronal death, and blood-brain barrier damage, etc. More importantly, existing research on AD necroptosis interventions, including drug intervention and potential gene targets, as well as its current clinical development status, was discussed. Finally, the issues pertaining to necroptosis in AD were presented. Accordingly, this review may provide further insight into clinical perspectives and challenges for the future treatment of AD by targeting the necroptosis pathway.

%B J Alzheimers Dis %V 94 %P S367-S386 %8 2023 %G eng %N s1 %R 10.3233/JAD-220809 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Neural Stem Cells in the Treatment of Alzheimer's Disease: Current Status, Challenges, and Future Prospects. %A Chen, Xiaokun %A Jiang, Shenzhong %A Wang, Renzhi %A Bao, Xinjie %A Li, Yongning %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Cholinergic Neurons %K Disease Models, Animal %K Humans %K Neural Stem Cells %X

Alzheimer's disease (AD), a progressive dementia, is one of the world's most dangerous and debilitating diseases. Clinical trial results of amyloid-β (Aβ) and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing. There are currently no effective strategies for slowing the progression of AD. Further understanding of the mechanisms underlying AD and the development of novel therapeutic options are critical. Neurogenesis is impaired in AD, which contributes to memory deficits. Transplanted neural stem cells (NSCs) can regenerate degraded cholinergic neurons, and new neurons derived from NSCs can form synaptic connections with neighboring neurons. In theory, employing NSCs to replace and restore damaged cholinergic neurons and brain connections may offer new treatment options for AD. However there remain barriers to surmount before NSC-based therapy can be used clinically. The objective of this article is to describe recent advances in the treatment of AD models and clinical trials involving NSCs. In addition, we discuss the challenges and prospects associated with cell transplant therapy for AD.

%B J Alzheimers Dis %V 94 %P S173-S186 %8 2023 %G eng %N s1 %R 10.3233/JAD-220721 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Neuroinflammation: A Common Pathway in Alzheimer's Disease and Epilepsy. %A Liew, Yee %A Retinasamy, Thaarvena %A Arulsamy, Alina %A Ali, Idrish %A Jones, Nigel C %A O'Brien, Terence J %A Shaikh, Mohd Farooq %K Alzheimer Disease %K Biomarkers %K Brain %K Epilepsy %K Humans %K Neuroinflammatory Diseases %X

BACKGROUND: Neuroinflammation is an innate immunological response of the central nervous system that may be induced by a brain insult and chronic neurodegenerative conditions. Recent research has shown that neuroinflammation may contribute to the initiation of Alzheimer's disease (AD) pathogenesis and associated epileptogenesis.

OBJECTIVE: This systematic review aimed to investigate the available literature on the shared molecular mechanisms of neuroinflammation in AD and epilepsy.

METHODS: The search included in this systematic review was obtained from 5 established databases. A total of 2,760 articles were screened according to inclusion criteria. Articles related to the modulation of the inflammatory biomarkers commonly associated with the progression of AD and epilepsy in all populations were included in this review.

RESULTS: Only 7 articles met these criteria and were chosen for further analysis. Selected studies include both in vitro and in vivo research conducted on rodents. Several neuroinflammatory biomarkers were reported to be involved in the cross-talk between AD and epilepsy.

CONCLUSION: Neuroinflammation was directly associated with the advancement of AD and epilepsy in populations compared to those with either AD or epilepsy. However, more studies focusing on common inflammatory biomarkers are required to develop standardized monitoring guidelines to prevent the manifestation of epilepsy and delay the progression of AD in patients.

%B J Alzheimers Dis %V 94 %P S253-S265 %8 2023 %G eng %N s1 %R 10.3233/JAD-230059 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Neuropathologic Changes of Alzheimer's Disease and Related Dementias: Relevance to Future Prevention. %A White, Lon R %A Corrada, Maria M %A Kawas, Claudia H %A Cholerton, Brenna A %A Edland, Steve E %A Flanagan, Margaret E %A Montine, Thomas J %X

BACKGROUND: Decedents with late-life dementia are often found at autopsy to have vascular pathology, cortical Lewy bodies, hippocampal sclerosis, and/or TDP-43 encephalopathy alone or with concurrent Alzheimer's disease (AD) lesions. Nonetheless, it is commonly believed that AD neuropathologic changes (NC) are the dominant or exclusive drivers of late-life dementia.

OBJECTIVE: Assess associations of end-of-life cognitive impairment with any one or any combination of five distinct NC. Assess impairment prevalence among subjects having natural resistance to each type of NC.

METHODS: Brains from 1,040 autopsied participants of the Honolulu-Asia Study, the Nun Study, and the 90 + Study were examined for NC of AD, Lewy body dementia, microvascular brain injury, hippocampal sclerosis, and limbic predominate TDP-43 encephalopathy. Associations with impairment were assessed for each NC and for NC polymorbidity (variable combinations of 2-5 concurrent NC).

RESULTS: Among 387 autopsied decedents with severe cognitive impairment, 20.4% had only AD lesions (ADNC), 25.3% had ADNC plus 1 other NC, 11.1% had ADNC plus 2 or more other NC, 28.7% had no ADNC but 1-4 other NC, and 14.5% had no/negligible NC. Combinations of any two, three, or four NC were highly frequent among the impaired. Natural resistance to ADNC or any other single NC had a modest impact on overall cohort impairment levels.

CONCLUSION: Polymorbidity involving 1-5 types of concurrent NC is a dominant neuropathologic feature of AD and related dementias. This represents a daunting challenge to future prevention and could explain failures of prior preventive intervention trials and of efforts to identify risk factors.

%B J Alzheimers Dis %V 95 %P 307-316 %8 2023 Aug 29 %G eng %N 1 %R 10.3233/JAD-230331 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Neuropathology of Anti-Amyloid-β Immunotherapy: A Case Report. %A Castellani, Rudolph J %A Shanes, Elisheva %A McCord, Matthew %A Reish, Nicholas J %A Flanagan, Margaret E %A Mesulam, M-Marsel %A Jamshidi, Pouya %X

Host responses to anti-amyloid-β (Aβ) antibody therapy are evident in neuroimaging changes and clinical symptoms in a subset of clinical trial subjects receiving such therapy. The pathological basis for the imaging changes and clinical symptoms is not known, nor is the precise mechanism of Aβ clearing. We report the autopsy findings in a 65-year-old woman who received three open label infusions of the experimental anti-Aβ drug lecanemab over about one month. Four days after the last infusion, she was treated with tissue plasminogen activator for acute stroke symptoms and died several days later with multifocal hemorrhage. Neuropathological examination demonstrated histiocytic vasculitis involving blood vessels with cerebral amyloid angiopathy. Fragmentation and phagocytosis of vascular Aβ were present throughout the cerebral cortex. Phagocytosis of parenchymal Aβ plaques was noted. Changes suggestive of Aβ and phosphorylated tau "clearing" were also noted. The findings overall suggest that anti-Aβ treatment stimulated a host response to Aβ, i.e., target engagement. The findings also provide evidence that amyloid-related imaging abnormalities might be indicative of an Aβ phagocytic syndrome within cerebral vasculature and parenchymal brain tissue in some cases.

%B J Alzheimers Dis %V 93 %P 803-813 %8 2023 May 16 %G eng %N 2 %R 10.3233/JAD-221305 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Neuroprotective Effect of Phloretin in Rotenone-Induced Mice Model of Parkinson's Disease: Modulating mTOR-NRF2-p62 Mediated Autophagy-Oxidative Stress Crosstalk. %A Shirgadwar, Shubhendu M %A Kumar, Rahul %A Preeti, Kumari %A Khatri, Dharmendra Kumar %A Singh, Shashi Bala %K Animals %K Antioxidants %K Autophagy %K Humans %K Kelch-Like ECH-Associated Protein 1 %K Mice %K Mice, Inbred C57BL %K Neuroblastoma %K Neurodegenerative Diseases %K Neuroprotective Agents %K NF-E2-Related Factor 2 %K Oxidative Stress %K Parkinson Disease %K Phloretin %K Prospective Studies %K Rotenone %K TOR Serine-Threonine Kinases %X

BACKGROUND: Parkinson's disease (PD) is an age-related progressive multifactorial, neurodegenerative disease. The autophagy and Keap1-Nrf2 axis system are both implicated in the oxidative-stress response, metabolic stress, and innate immunity, and their dysregulation is associated with pathogenic processes in PD. Phloretin (PLT) is a phenolic compound reported possessing anti-inflammatory and antioxidant activities.

OBJECTIVE: To evaluate the neuroprotective potential of PLT in PD via modulating the autophagy-antioxidant axisMethods:The neuroprotective effect of PLT was evaluated in vitro using rotenone (ROT) exposed SH-SY5Y cell line and in vivo using ROT administered C57BL/6 mice. Mice were administered with PLT (50 and 100 mg/kg, p.o.) concomitantly with ROT (1 mg/kg, i.p) for 3 weeks. Locomotive activity and anxiety behaviors were assessed using rotarod and open field tests respectively. Further apoptosis (Cytochrome-C, Bax), α-Synuclein (α-SYN), tyrosine hydroxylase (TH), antioxidant proteins (nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1) and autophagic (mTOR, Atg5,7, p62, Beclin,LC3B-I/II) protein activity were evaluated both in in vitro and in vivo.

RESULTS: PLT improved locomotive activity and anxiety-like behavior in mice. Further PLT diminished apoptotic cell death, α-SYN expression and improved the expression of TH, antioxidant, and autophagic regulating protein.

CONCLUSION: Taken together, present data deciphers that the PLT effectively improves motor and non-motor symptoms via modulating the mTOR/NRF2/p62 pathway-mediated feedback loop. Hence, PLT could emerge as a prospective disease-modifying drug for PD management.

%B J Alzheimers Dis %V 94 %P S109-S124 %8 2023 %G eng %N s1 %R 10.3233/JAD-220793 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Neuroprotective Mechanisms of Amylin Receptor Activation, Not Antagonism, in the APP/PS1 Mouse Model of Alzheimer's Disease. %A Corrigan, Rachel R %A Labrador, Luis %A Grizzanti, John %A Mey, Megan %A Piontkivska, Helen %A Casadesus-Smith, Gemma %X

BACKGROUND: Amylin, a pancreatic amyloid peptide involved in energy homeostasis, is increasingly studied in the context of Alzheimer's disease (AD) etiology. To date, conflicting pathogenic and neuroprotective roles for this peptide and its analogs for AD pathogenesis have been described.

OBJECTIVE: Whether the benefits of amylin are associated with peripheral improvement of metabolic tone/function or directly through the activation of central amylin receptors is also unknown and downstream signaling mechanisms of amylin receptors are major objectives of this study.

METHODS: To address these questions more directly we delivered the amylin analog pramlintide systemically (IP), at previously identified therapeutic doses, while centrally (ICV) inhibiting the receptor using an amylin receptor antagonist (AC187), at doses known to impact CNS function.

RESULTS: Here we show that pramlintide improved cognitive function independently of CNS receptor activation and provide transcriptomic data that highlights potential mechanisms. Furthermore, we show than inhibition of the amylin receptor increased amyloid-beta pathology in female APP/PS1 mice, an effect than was mitigated by peripheral delivery of pramlintide. Through transcriptomic analysis of pramlintide therapy in AD-modeled mice we found sexual dimorphic modulation of neuroprotective mechanisms: oxidative stress protection in females and membrane stability and reduced neuronal excitability markers in males.

CONCLUSION: These data suggest an uncoupling of functional and pathology-related events and highlighting a more complex receptor system and pharmacological relationship that must be carefully studied to clarify the role of amylin in CNS function and AD.

%B J Alzheimers Dis %V 91 %P 1495-1514 %8 2023 Feb 14 %G eng %N 4 %R 10.3233/JAD-221057 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Neuroprotective Properties of Eudesmin on a Cellular Model of Amyloid-β Peptide Toxicity. %A Castillo, Carolina %A Bravo-Arrepol, Gastón %A Wendt, Aline %A Saez-Orellana, Francisco %A Millar, Camila %A Burgos, Carlos F %A Gavilán, Javiera %A Pacheco, Carla %A Ahumada-Rudolph, Ramón %A Napiórkowska, Mariola %A Pérez, Claudia %A Becerra, José %A Fuentealba, Jorge %A Cabrera-Pardo, Jaime R %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Lignans %K Mice %K Neuroprotective Agents %K PC12 Cells %K Rats %X

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. One of the hallmarks in AD is amyloid-β peptide (Aβ) accumulation, where the soluble oligomers of Aβ (AβOs) are the most toxic species, deteriorating the synaptic function, membrane integrity, and neuronal structures, which ultimately lead to apoptosis. Currently, there are no drugs to arrest AD progression, and current scientific efforts are focused on searching for novel leads to control this disease. Lignans are compounds extracted from conifers and have several medicinal properties. Eudesmin (Eu) is an extractable lignan from the wood of Araucaria araucana, a native tree from Chile. This metabolite has shown a range of biological properties, including the ability to control inflammation and antibacterial effects.

OBJECTIVE: In this study, the neuroprotective abilities of Eu on synaptic failure induced by AβOs were analyzed.

METHODS: Using neuronal models, PC12 cells, and in silico simulations we evaluated the neuroprotective effect of Eu (30 nM) against the toxicity induced by AβOs.

RESULTS: In primary cultures from mouse hippocampus, Eu preserved the synaptic structure against AβOs toxicity, maintaining stable levels of the presynaptic protein SV2 at the same concentration. Eu also averted synapsis failure from the AβOs toxicity by sustaining the frequencies of cytosolic Ca2+ transients. Finally, we found that Eu (30 nM) interacts with the Aβ aggregation process inducing a decrease in AβOs toxicity, suggesting an alternative mechanism to explain the neuroprotective activity of Eu.

CONCLUSION: We believe that Eu represents a novel lead that reduces the Aβ toxicity, opening new research venues for lignans as neuroprotective agents.

%B J Alzheimers Dis %V 94 %P S97-S108 %8 2023 %G eng %N s1 %R 10.3233/JAD-220935 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Noninvasive Gamma Sensory Stimulation May Reduce White Matter and Myelin Loss in Alzheimer's Disease. %A Da, Xiao %A Hempel, Evan %A Ou, Yangming %A Rowe, Olivia Elizabeth %A Malchano, Zach %A Hajós, Mihály %A Kern, Ralph %A Megerian, Jonathan Thomas %A Cimenser, Aylin %X

BACKGROUND: Patients with Alzheimer's disease (AD) demonstrate progressive white matter atrophy and myelin loss. Restoring myelin content or preventing demyelination has been suggested as a therapeutic approach for AD.

OBJECTIVE: Herein, we investigate the effects of non-invasive, combined visual and auditory gamma-sensory stimulation on white matter atrophy and myelin content loss in patients with AD.

METHODS: In this study, we used the magnetic resonance imaging (MRI) data from the OVERTURE study (NCT03556280), a randomized, controlled, clinical trial in which active treatment participants received daily, non-invasive, combined visual and auditory, 40 Hz stimulation for six months. A subset of OVERTURE participants who meet the inclusion criteria for detailed white matter (N = 38) and myelin content (N = 36) assessments are included in the analysis. White matter volume assessments were performed using T1-weighted MRI, and myelin content assessments were performed using T1-weighted/T2-weighted MRI. Treatment effects on white matter atrophy and myelin content loss were assessed.

RESULTS: Combined visual and auditory gamma-sensory stimulation treatment is associated with reduced total and regional white matter atrophy and myelin content loss in active treatment participants compared to sham treatment participants. Across white matter structures evaluated, the most significant changes were observed in the entorhinal region.

CONCLUSIONS: The study results suggest that combined visual and auditory gamma-sensory stimulation may modulate neuronal network function in AD in part by reducing white matter atrophy and myelin content loss. Furthermore, the entorhinal region MRI outcomes may have significant implications for early disease intervention, considering the crucial afferent connections to the hippocampus and entorhinal cortex.

%B J Alzheimers Dis %V 97 %P 359-372 %8 2024 Jan 02 %G eng %N 1 %R 10.3233/JAD-230506 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Non-Pharmacological Interventions for Feeding and Eating Disorders in Persons with Dementia: Systematic Review and Evidence Summary. %A Chen, Hong-Li %A Li, Cheng %A Wang, Jing %A Fei, Yang %A Min, Min %A Zhao, Yue %A Shan, En-Fang %A Yin, Yue-Heng %A Liu, Chong-Yuan %A Li, Xian-Wen %K Caregivers %K Dementia %K Feeding and Eating Disorders %K Health Status %K Humans %K Nutritional Status %X

BACKGROUND: Feeding and eating disorders related to cognitive and psycho-behavioral symptoms are strongly associated with health status in persons with dementia (PWD). Non-pharmacological interventions have been the priority selection to address this significant issue. However, the direct targets of non-pharmacological interventions are unclear and there is no consistent evidence of recommendations on the intervention of different dementia stages and the settings of intervention practice.

OBJECTIVE: To provide caregivers with a set of self-help non-pharmacological interventions for feeding and eating disorders in PWD.

METHODS: Based on the process of evidence summary, a systematic literature search was performed on dementia websites and seven databases. Two researchers screened the studies independently and appraise the quality. The evidence was graded by Joanna Briggs Institute Grades of Recommendation.

RESULTS: Twenty-eight articles were included. Twenty-three non-pharmacological intervention recommendations were categorized into six themes containing oral nutritional supplementation, assistance with eating and drinking, person-centered mealtime care, environmental modification, education or training, and multi-component intervention. These interventions corresponded to three direct targets including improving engagement, making up for loss ability, and increasing food intake directly. They were applied to different stages of dementia and most interventions were targeted at PWD in long-term care institutions.

CONCLUSION: This article summarized the direct targets and the specific implementation of recommendations at different stages of dementia to provide caregivers with self-help non-pharmacological interventions. The practice of recommendations was more applicable to institutionalized PWD. When applied to PWD at home, caregivers need to identify the specific feeding and eating conditions at different stages and adopted the interventions in conjunction with the wishes of the PWD and professional advice.

%B J Alzheimers Dis %V 94 %P 67-88 %8 2023 %G eng %N 1 %R 10.3233/JAD-221032 %0 Journal Article %J J Alzheimers Dis %D 2023 %T A Novel Strategy for Alzheimer's Disease Based on the Regulatory Effect of Amyloid-β on Gut Flora. %A Huang, Li %A Lu, Zhaogang %A Zhang, Hexin %A Wen, Hongyong %A Li, Zongji %A Liu, Qibing %A Wang, Rui %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloidogenic Proteins %K Brain %K Gastrointestinal Microbiome %K Humans %X

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases worldwide. The accumulation of amyloid-β (Aβ) protein and plaque formation in the brain are two major causes of AD. Interestingly, growing evidence demonstrates that the gut flora can alleviate AD by affecting amyloid production and metabolism. However, the underlying mechanism remains largely unknown. This review will discuss the possible association between the gut flora and Aβ in an attempt to provide novel therapeutic directions for AD treatment based on the regulatory effect of Aβ on the gut flora.

%B J Alzheimers Dis %V 94 %P S227-S239 %8 2023 %G eng %N s1 %R 10.3233/JAD-220651 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Observed Improvement in Cognition During a Personalized Lifestyle Intervention in People with Cognitive Decline. %A Sandison, Heather %A Callan, Nini G L %A Rao, Rammohan V %A Phipps, John %A Bradley, Ryan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K California %K Cognition %K Cognitive Dysfunction %K Diet, Healthy %K Dietary Supplements %K Disease Progression %K Exercise %K Feasibility Studies %K Female %K Healthy Lifestyle %K Humans %K Infections %K Male %K Memory %K Middle Aged %K Nutritional Status %K Pragmatic Clinical Trials as Topic %K Reproducibility of Results %K Stress, Psychological %K Time Factors %K Treatment Outcome %K Verbal Behavior %X

BACKGROUND: Alzheimer's disease (AD) is a chronic condition marked by progressive objective cognitive impairment (OCI). No monotherapy has substantially altered disease progression, suggesting the disease is multifactorial and may require a multimodal therapeutic approach.

OBJECTIVE: We sought to determine if cognitive function in a sample with OCI would change in response to a multimodal, individualized care plan based on potential contributors to cognitive decline (e.g., nutritional status, infection, etc.).

METHODS: Participants (n = 34) were recruited from the San Diego, CA area. The multimodal intervention included lifestyle changes (i.e., movement, diet, and stress management), nutraceutical support, and medications. It was delivered pragmatically over four clinical visits, and outcome measures were gathered at four study visits, occurring at baseline, one, three, and six months (primary endpoint). Study participants received weekly phone calls for nutrition support throughout study participation. Outcome measures included the Cambridge Brain Sciences (CBS) battery, and the Montreal Cognitive Assessment (MoCA).

RESULTS: At 6 months, mean MoCA scores improved from 19.6±3.1 to 21.7±6.2 (p = 0.013). Significant improvement was observed in mean scores of the CBS memory domain [25.2 (SD 23.3) to 35.8 (SD 26.9); p < 0.01] and CBS overall composite cognition score [24.5 (SD 16.1) to 29.7 (SD 20.5); p = 0.02]. All CBS domains improved.

CONCLUSION: Multiple measures of cognitive function improved after six months of intervention. Our results support the feasibility and impact of a multimodal, individualized treatment approach to OCI, warranting further research.

%B J Alzheimers Dis %V 94 %P 993-1004 %8 2023 %G eng %N 3 %R 10.3233/JAD-230004 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Odor Discrimination as a Marker of Early Alzheimer's Disease. %A Audronyte, Egle %A Pakulaite-Kazliene, Gyte %A Sutnikiene, Vaiva %A Kaubrys, Gintaras %K Alzheimer Disease %K Cognitive Dysfunction %K Humans %K Neuropsychological Tests %K Odorants %K Olfaction Disorders %K Smell %X

BACKGROUND: Olfactory dysfunction is an early symptom of Alzheimer's disease (AD). However, olfactory tests are rarely performed in clinical practice because their diagnostic efficacy in detecting early AD is unclear.

OBJECTIVE: To investigate odor discrimination in patients with early AD and the efficacy of olfactory discrimination tests in differentiating these patients from subjects with normal cognition (CN).

METHODS: Thirty patients each with mild dementia due to AD (MD-AD) and mild cognitive impairment due to AD (MCI-AD) and 30 older subjects with CN were enrolled. All participants underwent cognitive examinations (CDR, MMSE, ADAS-Cog 13, and verbal fluency) and odor discrimination tests (Sniffin' Sticks test, Burghart®, Germany).

RESULTS: The MD-AD group achieved significantly worse scores on the olfactory discrimination test than the MCI-AD group, and the MCI-AD group achieved significantly worse results than the CN group (p < 0.05). A cut-off score of≤10 had a diagnostic accuracy of 94.44% (95% CI, 87.51-98.17%) in differentiating patients with MCI-AD/MD-AD from subjects with CN and of 91.67% (95% CI, 81.61-97.24%) in differentiating those with MCI-AD from subjects with CN. Our multinomial logistic regression model with demographic data and ADAS-Cog 13 scores as predictor variables correctly classified 82.2% of the cases (CN, 93.3%; MC-AD, 70%; MD-AD, 83.3%); on adding the olfactory discrimination score to the model, the percentage increased to 92.2% (CN, 96.7%; MCI-AD, 86.7%; MD-AD, 93.3%).

CONCLUSION: Odor discrimination is impaired in cases of early AD and continues to deteriorate as the disease progresses. The olfactory discrimination test showed good diagnostic efficacy in detecting early AD.

%B J Alzheimers Dis %V 94 %P 1169-1178 %8 2023 %G eng %N 3 %R 10.3233/JAD-230077 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Pathogenesis, Animal Models, and Drug Discovery of Alzheimer's Disease. %A Xia, Zhao-Di %A Ma, Ruo-Xin %A Wen, Jin-Feng %A Zhai, Yu-Fei %A Wang, Yu-Qi %A Wang, Feng-Yun %A Liu, Dan %A Zhao, Xiao-Long %A Sun, Bao %A Jia, Pu %A Zheng, Xiao-Hui %K Alzheimer Disease %K Animals %K Drug Discovery %K Models, Animal %K Neurodegenerative Diseases %K Quality of Life %X

Alzheimer's disease (AD), the most common cause of dementia, is a chronic neurodegenerative disease induced by multiple factors. The high incidence and the aging of the global population make it a growing global health concern with huge implications for individuals and society. The clinical manifestations are progressive cognitive dysfunction and lack of behavioral ability, which not only seriously affect the health and quality of life of the elderly, but also bring a heavy burden to the family and society. Unfortunately, almost all the drugs targeting the classical pathogenesis have not achieved satisfactory clinical effects in the past two decades. Therefore, the present review provides more novel ideas on the complex pathophysiological mechanisms of AD, including classical pathogenesis and a variety of possible pathogenesis that have been proposed in recent years. It will be helpful to find out the key target and the effect pathway of potential drugs and mechanisms for the prevention and treatment of AD. In addition, the common animal models in AD research are outlined and we examine their prospect for the future. Finally, Phase I, II, III, and IV randomized clinical trials or on the market of drugs for AD treatment were searched in online databases (Drug Bank Online 5.0, the U.S. National Library of Medicine, and Alzforum). Therefore, this review may also provide useful information in the research and development of new AD-based drugs.

%B J Alzheimers Dis %V 94 %P 1265-1301 %8 2023 %G eng %N 4 %R 10.3233/JAD-230326 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Pathogenomic Signature and Aberrant Neurogenic Events in Experimental Cerebral Ischemic Stroke: A Neurotranscriptomic-Based Implication for Dementia. %A Roshan, Syed Aasish %A Elangovan, Gayathri %A Gunaseelan, Dharani %A Jayachandran, Swaminathan K %A Kandasamy, Mahesh %A Anusuyadevi, Muthuswamy %K Animals %K Brain %K Dementia %K Humans %K Infarction, Middle Cerebral Artery %K Ischemic Stroke %K Neurogenesis %K Rats %K Stroke %X

BACKGROUND: Cerebral ischemic stroke is caused due to neurovascular damage or thrombosis, leading to neuronal dysfunction, neuroinflammation, neurodegeneration, and regenerative failure responsible for neurological deficits and dementia. The valid therapeutic targets against cerebral stroke remain obscure. Thus, insight into neuropathomechanisms resulting from the aberrant expression of genes appears to be crucial.

OBJECTIVE: In this study, we have elucidated how neurogenesis-related genes are altered in experimental stroke brains from the available transcriptome profiles in correlation with transcriptome profiles of human postmortem stroke brain tissues.

METHODS: The transcriptome datasets available on the middle cerebral artery occlusion (MCAo) rat brains were obtained from the Gene Expression Omnibus, National Center for Biotechnology Information. Of the available datasets, 97 samples were subjected to the meta-analysis using the network analyst tool followed by Cytoscape-based enrichment mapping analysis. The key differentially expressed genes (DEGs) were validated and compared with transcriptome profiling of human stroke brains.

RESULTS: Results revealed 939 genes are differently expressed in the brains of the MCAo rat model of stroke, in which 30 genes are key markers of neural stem cells, and regulators of neurogenic processes. Its convergence with DEGs from human stroke brains has revealed common targets.

CONCLUSION: This study has established a panel of highly important DEGs to signify the potential therapeutic targets for neuroregenerative strategy against pathogenic events associated with cerebral stroke. The outcome of the findings can be translated to mitigate neuroregeneration failure seen in various neurological and metabolic disease manifestations with neurocognitive impairments.

%B J Alzheimers Dis %V 94 %P S289-S308 %8 2023 %G eng %N s1 %R 10.3233/JAD-220831 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Pathological and Therapeutic Advances in Parkinson's Disease: Mitochondria in the Interplay. %A Naren, Padmashri %A Cholkar, Anjali %A Kamble, Suchita %A Khan, Sabiya Samim %A Srivastava, Saurabh %A Madan, Jitender %A Mehra, Neelesh %A Tiwari, Vinod %A Singh, Shashi Bala %A Khatri, Dharmendra Kumar %K Aged %K alpha-Synuclein %K Humans %K Mitochondria %K Oxidative Stress %K Parkinson Disease %X

Parkinson's disease (PD) is the second most common neurodegenerative illness majorly affecting the population between the ages of 55 to 65 years. Progressive dopaminergic neuronal loss and the collective assemblage of misfolded alpha-synuclein in the substantia nigra, remain notable neuro-pathological hallmarks of the disease. Multitudes of mechanistic pathways have been proposed in attempts to unravel the pathogenesis of PD but still, it remains elusive. The convergence of PD pathology is found in organelle dysfunction where mitochondria remain a major contributor. Mitochondrial processes like bioenergetics, mitochondrial dynamics, and mitophagy are under strict regulation by the mitochondrial genome and nuclear genome. These processes aggravate neurodegenerative activities upon alteration through neuroinflammation, oxidative damage, apoptosis, and proteostatic stress. Therefore, the mitochondria have grabbed a central position in the patho-mechanistic exploration of neurodegenerative diseases like PD. The management of PD remains a challenge to physicians to date, due to the variable therapeutic response of patients and the limitation of conventional chemical agents which only offer symptomatic relief with minimal to no disease-modifying effect. This review describes the patho-mechanistic pathways involved in PD not only limited to protein dyshomeostasis and oxidative stress, but explicit attention has been drawn to exploring mechanisms like organelle dysfunction, primarily mitochondria and mitochondrial genome influence, while delineating the newer exploratory targets such as GBA1, GLP, LRRK2, and miRNAs and therapeutic agents targeting them.

%B J Alzheimers Dis %V 94 %P S399-S428 %8 2023 %G eng %N s1 %R 10.3233/JAD-220682 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Patterns of Aging Changes in Bodyweight May Predict Alzheimer's Disease. %A Ukraintseva, Svetlana %A Duan, Hongzhe %A Holmes, Rachel %A Bagley, Olivia %A Wu, Deqing %A Yashkin, Arseniy %A Kulminski, Alexander %A Akushevich, Igor %A Whitson, Heather %A Stallard, Eric %A Yashin, Anatoliy %A Arbeev, Konstantin %X

Relationships between patterns of aging-changes in bodyweight and AD are not fully understood. We compared mean age-trajectories of weight between those who did and did not develop late-onset-AD, and evaluated impact of age at maximum weight (AgeMax), and slope of decline in weight, on AD risk. Women with late-onset-AD had lower weight three or more decades before AD onset, and ∼10 years younger AgeMax, compared to AD-free women. APOE4 carriers had younger AgeMax and steeper slope. Older AgeMax and flatter slope predicted lower AD risk. Premature decline in weight could be a sign of accelerated physical aging contributing to AD.

%B J Alzheimers Dis %V 97 %P 163-170 %8 2024 Jan 02 %G eng %N 1 %R 10.3233/JAD-220998 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Phonological and Semantic Fluency in Alzheimer's Disease: A Systematic Review and Meta-Analysis. %A Olmos-Villaseñor, Rocio %A Sepulveda-Silva, Consuelo %A Julio-Ramos, Teresa %A Fuentes-Lopez, Eduardo %A Toloza-Ramirez, David %A Santibañez, Rodrigo A %A Copland, David A %A Mendez-Orellana, Carolina %K Alzheimer Disease %K Humans %K Linguistics %K Neuropsychological Tests %K Semantics %K Verbal Behavior %X

BACKGROUND: Semantic and Phonological fluency (SF and PF) are routinely evaluated in patients with Alzheimer's disease (AD). There are disagreements in the literature regarding which fluency task is more affected while developing AD. Most studies focus on SF assessment, given its connection with the temporoparietal amnesic system. PF is less reported, it is related to working memory, which is also impaired in probable and diagnosed AD. Differentiating between performance on these tasks might be informative in early AD diagnosis, providing an accurate linguistic profile.

OBJECTIVE: Compare SF and PF performance in healthy volunteers, volunteers with probable AD, and patients with AD diagnosis, considering the heterogeneity of age, gender, and educational level variables.

METHODS: A total of 8 studies were included for meta-analysis, reaching a sample size of 1,270 individuals (568 patients diagnosed with AD, 340 with probable AD diagnosis, and 362 healthy volunteers).

RESULTS: The three groups consistently performed better on SF than PF. When progressing to a diagnosis of AD, we observed a significant difference in SF and PF performance across our 3 groups of interest (p = 0.04). The age variable explained a proportion of this difference in task performance across the groups, and as age increases, both tasks equally worsen.

CONCLUSION: The performance of SF and PF might play a differential role in early AD diagnosis. These tasks rely on partially different neural bases of language processing. They are thus worth exploring independently in diagnosing normal aging and its transition to pathological stages, including probable and diagnosed AD.

%B J Alzheimers Dis %V 95 %P 1-12 %8 2023 %G eng %N 1 %R 10.3233/JAD-221272 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Physical Activity for Cognitive Health: A Model for Intervention Design for People Experiencing Cognitive Concerns and Symptoms of Depression or Anxiety. %A Curran, Eleanor %A Palmer, Victoria J %A Ellis, Kathryn A %A Chong, Terence W H %A Rego, Thomas %A Cox, Kay L %A Anstey, Kaarin J %A Westphal, Alissa %A Moorhead, Rebecca %A Southam, Jenny %A Lai, Rhoda %A You, Emily %A Lautenschlager, Nicola T %X

BACKGROUND: People experiencing cognitive concerns and symptoms of depression or anxiety are at risk for Alzheimer's disease and dementia. We know physical activity can benefit cognition but understanding how to best support engagement is an ongoing challenge. Evidence-based conceptual models of factors underpinning physical activity engagement in target populations can inform intervention tailoring to address this challenge.

OBJECTIVE: This study (part of a pragmatic physical activity implementation trial) aimed to develop a specified model of physical activity engagement in people experiencing depressive or anxiety symptoms and cognitive concerns, to enable optimized dementia risk reduction intervention tailoring.

METHODS: We employed a qualitative design, triangulating data from three sources: semi-structured individual interviews with people experiencing cognitive concerns and mild to moderate depressive or anxiety symptoms; review of published evidence; and the Capability, Opportunity and Motivation system of behavior, an existing behavioral science model. Findings were integrated to develop a contextualized model of mechanisms of action for optimizing engagement.

RESULTS: Twenty-one participants were interviewed, and 24 relevant papers included. Convergent and complementary themes extended understanding of intervention needs. Findings highlighted emotional regulation, capacities to enact intentions despite barriers, and confidence in existing skills as areas of population-specific need that have not previously been emphasized. The final model provides specificity, directionality, and linked approaches for intervention tailoring.

CONCLUSION: This study demonstrated that people experiencing cognitive concerns and symptoms of depression or anxiety require different interventions to improve physical activity engagement. The novel model can enable more precise intervention tailoring, and, ultimately, benefits for a key at-risk population.

%B J Alzheimers Dis %V 94 %P 781-799 %8 2023 Jul 18 %G eng %N 2 %R 10.3233/JAD-221216 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The PI3K/AKT Signaling Pathway and Caspase-3 in Alzheimer's Disease: Which One Is the Beginner? %A Khezri, Mohammad Rafi %A Ghasemnejad-Berenji, Morteza %A Moloodsouri, Donya %K Alzheimer Disease %K Apoptosis %K Caspase 3 %K Humans %K Phosphatidylinositol 3-Kinases %K Proto-Oncogene Proteins c-akt %K Signal Transduction %X

One of the main players in apoptosis during Alzheimer's disease progression are different members of caspase family of proteases. The most well-known member of this family is caspase-3, in which alterations of its levels have been detected in samples from Alzheimer's disease patients. There are numerous intracellular factors involved in regulation of cellular apoptosis through regulation of caspase-3 activity, the most important of which is the PI3K/AKT signaling pathway. This commentary tries to highlight the probable relations between PI3K/AKT signaling pathway and caspase-3 in Alzheimer's disease.

%B J Alzheimers Dis %V 92 %P 391-393 %8 2023 %G eng %N 2 %R 10.3233/JAD-221157 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Plasma Amyloid-β Homeostasis Is Associated with Body Mass Index and Weight Loss in People with Overweight and Obesity. %A Brook, Emily S %A D'Alonzo, Zachary J %A Lam, Virginie %A Chan, Dick %A Dhaliwal, Satvinder Singh %A Watts, Geraldb F %A Mamo, John C L %A Takechi, Ryusuke %X

BACKGROUND: Obesity is linked to a higher incidence of Alzheimer's disease (AD). Studies show that plasma amyloid-β (Aβ) dyshomeostasis, particularly low 42/40 ratio indicates a heightened risk for developing AD. However, the relationship between body mass index (BMI) and circulating plasma Aβ has not been extensively studied.

OBJECTIVE: We hypothesized that people with a high BMI have altered plasma Aβ homeostasis compared with people with a lower BMI. We also tested whether reducing BMI by calorie-restriction could normalize plasma concentrations of Aβ.

METHODS: Plasma concentrations of Aβ 40, Aβ 42, and Aβ 42/40 ratio were measured in 106 participants with BMIs classified as lean, overweight, or obese. From this cohort, twelve participants with overweight or obese BMIs entered a 12-week calorie-restriction weight loss program. We then tested whether decreasing BMI affected plasma Aβ concentrations.

RESULTS: Plasma Aβ 42/40 ratio was 17.54% lower in participants with an obese BMI compared to lean participants (p <  0.0001), and 11.76% lower compared to participants with an overweight BMI (p <  0.0001). The weight loss regimen decreased BMI by an average of 4.02% (p = 0.0005) and was associated with a 6.5% decrease in plasma Aβ 40 (p = 0.0425). However, weight loss showed negligible correlations with plasma Aβ 40, Aβ 42, and Aβ 42/40 ratio.

CONCLUSION: Obesity is associated with aberrant plasma Aβ homeostasis which may be associated with an increased risk for AD. Weight loss appears to lower Aβ 40, but large-scale longitudinal studies in addition to molecular studies are required to elucidate the underlying mechanisms of how obesity and weight loss influence plasma Aβ homeostasis.

%B J Alzheimers Dis %V 93 %P 653-664 %8 2023 May 16 %G eng %N 2 %R 10.3233/JAD-220529 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Plasma ApoE4 Levels Are Lower than ApoE2 and ApoE3 Levels, and Not Associated with Plasma Aβ 40/42 Ratio as a Biomarker of Amyloid-β Amyloidosis in Alzheimer's Disease. %A Nakamura, Takumi %A Kawarabayashi, Takeshi %A Ueda, Tetsuya %A Shimomura, Sachiko %A Hoshino, Masaki %A Itoh, Ken %A Ihara, Kazushige %A Nakaji, Shigeyuki %A Takatama, Masamitsu %A Ikeda, Yoshio %A Shoji, Mikio %X

BACKGROUND: APOE4 is the strongest risk factor for Alzheimer's disease (AD). However, limited information is currently available on APOE4 and the pathological role of plasma apolipoprotein E (ApoE) 4 remains unclear.

OBJECTIVE: The aims of the present study were to measure plasma levels of total ApoE (tE), ApoE2, ApoE3, and ApoE4 using mass spectrometry and elucidate the relationships between plasma ApoE and blood test items.

METHODS: We herein examined plasma levels of tE, ApoE2, ApoE3, and ApoE4 in 498 subjects using liquid chromatograph-mass spectrometry (LC-MS/MS).

RESULTS: Among 498 subjects, mean age was 60 years and 309 were female. tE levels were distributed as ApoE2/E3 = ApoE2/E4 >ApoE3/E3 = ApoE3/E4 >ApoE4/E4. In the heterozygous group, ApoE isoform levels were distributed as ApoE2 >ApoE3 >ApoE4. ApoE levels were not associated with aging, the plasma amyloid-β (Aβ) 40/42 ratio, or the clinical diagnosis of AD. Total cholesterol levels correlated with the level of each ApoE isoform. ApoE2 levels were associated with renal function, ApoE3 levels with low-density lipoprotein cholesterol and liver function, and ApoE4 levels with triglycerides, high-density lipoprotein cholesterol, body weight, erythropoiesis, and insulin metabolism.

CONCLUSION: The present results suggest the potential of LC-MS/MS for the phenotyping and quantitation of plasma ApoE. Plasma ApoE levels are regulated in the order of ApoE2 >ApoE3 >ApoE4 and are associated with lipids and multiple metabolic pathways, but not directly with aging or AD biomarkers. The present results provide insights into the multiple pathways by which peripheral ApoE4 influences the progression of AD and atherosclerosis.

%B J Alzheimers Dis %V 93 %P 333-348 %8 2023 May 02 %G eng %N 1 %R 10.3233/JAD-220996 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte Reactivity Biomarkers for Alzheimer's Disease. %A Chatterjee, Pratishtha %A Doré, Vincent %A Pedrini, Steve %A Krishnadas, Natasha %A Thota, Rohith %A Bourgeat, Pierrick %A Ikonomovic, Milos D %A Rainey-Smith, Stephanie R %A Burnham, Samantha C %A Fowler, Christopher %A Taddei, Kevin %A Mulligan, Rachel %A Ames, David %A Masters, Colin L %A Fripp, Jurgen %A Rowe, Christopher C %A Martins, Ralph N %A Villemagne, Victor L %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Astrocytes %K Biomarkers %K Brain %K Cognitive Dysfunction %K Glial Fibrillary Acidic Protein %K Humans %K Positron-Emission Tomography %K tau Proteins %X

BACKGROUND: Astrocyte reactivity is an early event along the Alzheimer's disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD.

OBJECTIVE: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers.

METHODS: Plasma GFAP and Aβ were measured using the Simoa® platform in participants who underwent brain 18F-SMBT-1 and Aβ-PET imaging, comprising 54 healthy control (13 Aβ-PET+ and 41 Aβ-PET-), 11 mild cognitively impaired (3 Aβ-PET+ and 8 Aβ-PET-) and 6 probable AD (5 Aβ-PET+ and 1 Aβ-PET-) individuals. Linear regressions were used to assess associations of interest.

RESULTS: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aβ deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aβ (plasma Aβ42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aβ (Aβ-PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG.

CONCLUSION: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aβ load.

%B J Alzheimers Dis %V 92 %P 615-628 %8 2023 %G eng %N 2 %R 10.3233/JAD-220908 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Plasma Soluble ST2 Levels Are Higher in Neurodegenerative Disorders and Associated with Poorer Cognition. %A Tan, Yi Jayne %A Siow, Isabel %A Saffari, Seyed Ehsan %A Ting, Simon K S %A Li, Zeng %A Kandiah, Nagaendran %A Tan, Louis C S %A Tan, Eng King %A Ng, Adeline S L %K Alzheimer Disease %K Biomarkers %K Cognition %K Cross-Sectional Studies %K Frontotemporal Dementia %K Humans %K Interleukin-1 Receptor-Like 1 Protein %K Interleukin-33 %K Parkinson Disease %X

BACKGROUND: Suppressor of tumorgenicity 2 (ST2) is highly expressed in brain tissue and is a receptor for interleukin 33 (IL-33). ST2 exists in two forms, a transmembrane receptor (ST2L) and a soluble decoy receptor (sST2). IL-33 binds to ST2L, triggering downstream signaling pathways involved in amyloid plaque clearance. Conversely, sST2 binds competitively to IL-33, attenuating its neuroprotective effects. High sST2 levels have been reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD), suggesting that the IL-33/ST2 signaling pathway may be implicated in neurodegenerative diseases.

OBJECTIVE: To investigate plasma sST2 levels in controls and patients with MCI, AD, frontotemporal dementia (FTD), and Parkinson's disease (PD).

METHODS: Plasma sST2 levels were measured using ELISA in 397 subjects (91 HC, 46 MCI, 38 AD, 28 FTD, and 194 PD). Cerebrospinal fluid (CSF) levels of sST2 were measured in 22 subjects. Relationship between sST2 and clinical outcomes were analyzed.

RESULTS: Plasma sST2 levels were increased across all disease groups compared to controls, with highest levels seen in FTD followed by AD and PD. Dementia patients with higher sST2 had lower cross-sectional cognitive scores in Frontal Assessment Battery and Digit Span Backward. At baseline, PD-MCI patients had higher sST2, associated with worse attention. In the longitudinal PD cohort, higher sST2 significantly associated with decline in global cognition and visuospatial domains. Plasma sST2 levels correlated with CSF sST2 levels.

CONCLUSION: Plasma sST2 is raised across neurodegenerative diseases and is associated with poorer cognition. Higher baseline sST2 is a potential biomarker of disease severity in neurodegeneration.

%B J Alzheimers Dis %V 92 %P 573-580 %8 2023 %G eng %N 2 %R 10.3233/JAD-221072 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Playing Russian Roulette with Alzheimer's Disease Patients: Do the Cognitive Benefits of Lecanemab Outweigh the Risk of Edema, Stroke and Encephalitis? %A Atwood, Craig S %A Perry, George %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognition %K Edema %K Encephalitis %K Humans %K Russia %K Stroke %X

The questionable approval of aducanumab and the recent approval of lecanemab (Leqembi; Eisai and Biogen) by the FDA has raised the issue of safety (stroke, meningitis, and encephalitis) over efficacy (slowing of cognitive decline). This communication recounts the important physiological functions of amyloid-β as a barrier protein with unique sealant and anti-pathogenic activities important for maintaining vascular integrity coupled with innate immune functions that prevent encephalitis and meningitis. The approval of a drug that obviates both of these purposive functions increases the risk of hemorrhage, edema and downstream pathogenic outcomes and should be clearly outlined to patients.

%B J Alzheimers Dis %V 92 %P 799-801 %8 2023 %G eng %N 3 %R 10.3233/JAD-230040 %0 Journal Article %J J Alzheimers Dis %D 2023 %T PM2.5 and Dementia in a Low Exposure Setting: The Influence of Odor Identification Ability and APOE. %A Andersson, John %A Sundström, Anna %A Nordin, Maria %A Segersson, David %A Forsberg, Bertil %A Adolfsson, Rolf %A Oudin, Anna %K Air Pollutants %K Air Pollution %K Apolipoproteins E %K Cohort Studies %K Dementia %K Environmental Exposure %K Humans %K Longitudinal Studies %K Odorants %K Particulate Matter %X

BACKGROUND: Growing evidence show that long term exposure to air pollution increases the risk of dementia.

OBJECTIVE: The aim of this study was to investigate associations between PM2.5 exposure and dementia in a low exposure area, and to investigate the role of olfaction and the APOE ɛ4 allele in these associations.

METHODS: Data were drawn from the Betula project, a longitudinal study on aging, memory, and dementia in Sweden. Odor identification ability was assessed using the Scandinavian Odor Identification Test (SOIT). Annual mean PM2.5 concentrations were obtained from a dispersion-model and matched at the participants' residential address. Proportional hazard regression was used to calculate hazard ratios.

RESULTS: Of 1,846 participants, 348 developed dementia during the 21-year follow-up period. The average annual mean PM2.5 exposure at baseline was 6.77μg/m3, which is 1.77μg/m3 above the WHO definition of clean air. In a fully adjusted model (adjusted for age, sex, APOE, SOIT, cardiovascular diseases and risk factors, and education) each 1μg/m3 difference in annual mean PM2.5-concentration was associated with a hazard ratio of 1.23 for dementia (95% CI: 1.01-1.50). Analyses stratified by APOE status (ɛ4 carriers versus non-carriers), and odor identification ability (high versus low), showed associations only for ɛ4 carriers, and for low performance on odor identification ability.

CONCLUSION: PM2.5 was associated with an increased risk of dementia in this low pollution setting. The associations between PM2.5 and dementia seemed stronger in APOE carriers and those with below average odor identification ability.

%B J Alzheimers Dis %V 92 %P 679-689 %8 2023 %G eng %N 2 %R 10.3233/JAD-220469 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Poor Oral Health as a Risk Factor for Dementia in a Swedish Population: A Cohort Study with 40 Years of Follow-Up. %A He, Fei %A Luo, Huizi %A Yin, Li %A Roosaar, Ann %A Axéll, Tony %A Zhao, Hongwei %A Ye, Weimin %K Aged, 80 and over %K Cohort Studies %K Dementia %K Follow-Up Studies %K Humans %K Oral Health %K Risk Factors %K Sweden %K Tooth Loss %X

BACKGROUND: Whether poor oral health is associated with dementia risk remains unclear.

OBJECTIVE: We conducted a cohort study of 14,439 participants who were followed up for up to 40 years in Uppsala County, central Sweden, aiming to explore the association between poor oral health, namely the number of tooth loss, dental plaque status, and oral mucosal lesions, and the risk of dementia.

METHODS: We used Cox proportional hazards regression model to derive cause-specific hazard ratios (HR) and corresponding 95% confidence intervals (CI), while adjusting for baseline potential confounders as well as a time-varying covariate, Charlson's Comorbidity Index score.

RESULTS: Dementia risk was substantially higher among those with a higher number of tooth loss; compared to the group with tooth loss 0-10, the HRs were 1.21 (95% CI: 1.02, 1.42), 1.17 (95% CI: 0.97, 1.40), and 1.30 (95% CI: 1.09, 1.54) respectively for groups with increasing number of tooth loss. There was some evidence of dose-risk association in this study, with a HR of 1.10 (1.04, 1.18) comparing adjacent groups (ptrend = 0.001). In a stratified analysis by attained age, tooth loss was more pronouncedly associated with the risk of dementia onset before age 80 (those with 21-32 versus 0-10 lost teeth, HR = 1.82, (95% CI: 1.32, 2.51); HR = 1.22 (95% CI: 1.10, 1.35) comparing adjacent groups, ptrend < 0.001).

CONCLUSION: In summary, there are some indications that poor oral health, as indicated by more tooth loss, is positively associated with an increased risk of dementia, especially for dementia onset before age 80.

%B J Alzheimers Dis %V 92 %P 171-181 %8 2023 %G eng %N 1 %R 10.3233/JAD-215177 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Post-Translational Chemical Modifications of Amyloid-β Peptides by 4-Hydroxy-2-Nonenal. %A Kikuchi, Hiroyuki %A Takahashi, Miki %A Komatsu, Hiroaki %A Axelsen, Paul H %X

BACKGROUND: The extraction and quantification of amyloid-β (Aβ) peptides in brain tissue commonly uses formic acid (FA) to disaggregate Aβ fibrils. However, it is not clear whether FA can disaggregate post-translationally modified Aβ peptides, or whether it induces artifact by covalent modification during disaggregation. Of particular interest are Aβ peptides that have been covalently modified by 4-hydroxy-2-nonenal (HNE), an oxidative lipid degradation product produced in the vicinity of amyloid plaques that dramatically accelerates the aggregation of Aβ peptides.

OBJECTIVE: Test the ability of FA to disaggregate Aβ peptides modified by HNE and to induce covalent artifacts.

METHODS: Quantitative liquid-chromatography-tandem-mass spectrometry of monomeric Aβ peptides and identify covalently modified forms.

RESULTS: FA disaggregated ordinary Aβ fibrils but also induced the time-dependent formylation of at least 2 residue side chains in Aβ peptides, as well as oxidation of its methionine side chain. FA was unable to disaggregate Aβ peptides that had been covalently modified by HNE.

CONCLUSION: The inability of FA to disaggregate Aβ peptides modified by HNE prevents FA-based approaches from quantifying a pool of HNE-modified Aβ peptides in brain tissue that may have pathological significance.

%B J Alzheimers Dis %V 92 %P 499-511 %8 2023 Mar 21 %G eng %N 2 %R 10.3233/JAD-220940 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Posttraumatic Stress and Traumatic Brain Injury: Cognition, Behavior, and Neuroimaging Markers in Vietnam Veterans. %A Marcolini, Sofia %A Rojczyk, Philine %A Seitz-Holland, Johanna %A Koerte, Inga K %A Alosco, Michael L %A Bouix, Sylvain %X

BACKGROUND: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are common in Veterans and linked to behavioral disturbances, increased risk of cognitive decline, and Alzheimer's disease.

OBJECTIVE: We studied the synergistic effects of PTSD and TBI on behavioral, cognitive, and neuroimaging measures in Vietnam war Veterans.

METHODS: Data were acquired at baseline and after about one-year from male Veterans categorized into: PTSD, TBI, PTSD+TBI, and Veteran controls without PTSD or TBI. We applied manual tractography to examine white matter microstructure of three fiber tracts: uncinate fasciculus (N = 91), cingulum (N = 87), and inferior longitudinal fasciculus (N = 95). ANCOVAs were used to compare Veterans' baseline behavioral and cognitive functioning (N = 285), white matter microstructure, amyloid-β (N = 230), and tau PET (N = 120). Additional ANCOVAs examined scores' differences from baseline to follow-up.

RESULTS: Veterans with PTSD and PTSD+TBI, but not Veterans with TBI only, exhibited poorer behavioral and cognitive functioning at baseline than controls. The groups did not differ in baseline white matter, amyloid-β, or tau, nor in behavioral and cognitive functioning, and tau accumulation change. Progression of white matter abnormalities of the uncinate fasciculus in Veterans with PTSD compared to controls was observed; analyses in TBI and PTSD+TBI were not run due to insufficient sample size.

CONCLUSIONS: PTSD and PTSD+TBI negatively affect behavioral and cognitive functioning, while TBI does not contribute independently. Whether progressive decline in uncinate fasciculus microstructure in Veterans with PTSD might account for cognitive decline should be further studied. Findings did not support an association between PTSD, TBI, and Alzheimer's disease pathology based on amyloid and tau PET.

%B J Alzheimers Dis %V 95 %P 1427-1448 %8 2023 Oct 10 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/37694363?dopt=Abstract %R 10.3233/JAD-221304 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Potential Role of Selection Bias in the Association Between Coronary Atherosclerosis and Cognitive Impairment. %A Yahagi-Estevam, Maristella %A Farias-Itao, Daniela Souza %A Leite, Renata Elaine Paraizo %A Rodriguez, Roberta Diehl %A Pasqualucci, Carlos Augusto %A Nitrini, Ricardo %A Jacob-Filho, Wilson %A Power, Melinda C %A Suemoto, Claudia Kimie %X

BACKGROUND: Coronary atherosclerosis assessed in vivo was associated with cognitive impairment; however, conflicting findings have been reported in autopsy samples.

OBJECTIVE: Our aims were to assess the association between atherosclerotic stenosis in the coronary arteries and cognitive impairment and to investigate the possibility of selection bias in an autopsy study.

METHODS: Coronary arteries were collected, and the largest luminal stenosis was measured. Sociodemographic, clinical, and cognitive information were reported by a reliable next-of-kin. The association was tested using logistic and linear regressions adjusted for sociodemographic and clinical variables. We restricted the sample to individuals that were born in 1935 or earlier and stratified the analysis by cause of death to investigate the role of selection bias.

RESULTS: In 253 participants (mean age = 78.0±8.5 years old, 48% male), stenosis was not associated with cognitive impairment (OR = 0.85, 95% CI = 0.69; 1.06, p = 0.15). In individuals who were born before 1936 in the absence of cardiovascular disease as the cause of death, greater stenosis was associated with cognitive impairment (OR = 4.02, 95% CI = 1.39; 11.6, p = 0.01). On the other hand, this association was not present among those born in 1935 or earlier who died of cardiovascular diseases (OR = 0.83, 95% CI = 0.60; 1.16, p = 0.28).

CONCLUSION: We found that higher coronary stenosis was associated with cognitive impairment only in individuals born in 1935 or earlier and who had not died from cardiovascular diseases. Selection bias may be an important issue when investigating risk factors for chronic degenerative diseases in older individuals using autopsy samples.

%B J Alzheimers Dis %V 93 %P 1307-1316 %8 2023 Jun 13 %G eng %N 4 %R 10.3233/JAD-220820 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Precision Medicine Approach to Alzheimer's Disease: Rationale and Implications. %A Bredesen, Dale E %A Toups, Kat %A Hathaway, Ann %A Gordon, Deborah %A Chung, Henrianna %A Raji, Cyrus %A Boyd, Alan %A Hill, Benjamin D %A Hausman-Cohen, Sharon %A Attarha, Mouna %A Chwa, Won Jong %A Kurakin, Alexei %A Jarrett, Michael %K Alzheimer Disease %K Cognitive Dysfunction %K Humans %K Neurodegenerative Diseases %K Precision Medicine %X

The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer's disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review the rationale for a precision medicine approach in prevention and treatment of cognitive decline associated with AD. Results and implications from recent proof-of-concept clinical trials are presented. Randomized controlled trials, with much larger patient numbers, are likely to be significant to establishing precision medicine protocols as a standard of care for prevention and treatment of cognitive decline. Furthermore, combining this approach with the pharmaceutical approach offers the potential for enhanced outcomes. However, incorporating precision medicine approaches into everyday evaluation and care, as well as future clinical trials, would require fundamental changes in trial design, IRB considerations, funding considerations, laboratory evaluation, personalized treatment plans, treatment teams, and ultimately in reimbursement guidelines. Nonetheless, precision medicine approaches to AD, based on a novel model of AD pathophysiology, offer promise that has not been realized to date with monotherapeutic approaches.

%B J Alzheimers Dis %V 96 %P 429-437 %8 2023 %G eng %N 2 %R 10.3233/JAD-230467 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Preventing Neurocognitive Decline in Adults Aging with HIV: Implications for Practice and Research. %A Cody, Shameka L %A Miller, Gabe H %A Fazeli, Pariya L %A Wang, Ge %A Li, Wei %A Goodin, Burel R %A Vance, David E %K Aging %K Alzheimer Disease %K Comorbidity %K HIV Infections %K Humans %X

Mild to moderate forms of neurocognitive impairment persist among people living with HIV (PLWH), despite being virally suppressed on antiretroviral therapy. PLWH are disproportionally impacted by physiological and psychosocial comorbidities compared to those without HIV. As adults live longer with HIV, the neurocognitive burden of physiological and psychosocial stressors can impair everyday functioning and may contribute to the development of neurodegenerative diseases such as Alzheimer's disease. This article outlines neurocognitive consequences of everyday stressors in PLWH. While some lifestyle factors can exacerbate inflammatory processes and promote negative neurocognitive health, novel interventions including the use of cannabinoids may be neuroprotective for aging PLWH who are at risk for elevated levels of inflammation from comorbidities. Studies of integrated neurocognitive rehabilitation strategies targeting lifestyle factors are promising for improving neurocognitive health, and may over time, reduce the risk of Alzheimer's disease in PLWH.

%B J Alzheimers Dis %V 95 %P 753-768 %8 2023 %G eng %N 3 %R 10.3233/JAD-230203 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Progression from Prodromal Alzheimer's Disease to Mild Alzheimer's Disease Dementia in the Verubecestat APECS Study: Adjudicating Diagnostic Transitions. %A Voss, Tiffini %A Kost, James %A Mercer, Swati Pal %A Furtek, Christine %A Randolph, Christopher %A Lines, Christopher %A Egan, Michael F %A Cummings, Jeffrey L %X

BACKGROUND: Delay of progression from prodromal Alzheimer's disease (AD) to dementia is an important outcome in AD trials. Centralized adjudication is intended to improve the consistency of dementia diagnosis but has not been scrutinized.

OBJECTIVE: To evaluate centralized adjudication for determining progression to dementia compared with Site Investigator opinion or change in Clinical Dementia Rating (CDR).

METHODS: We used data from the 2-year APECS trial of verubecestat versus placebo in 1,451 prodromal AD participants. Cases were triggered for central adjudication if: 1) the Site Investigator judged the participant had progressed to dementia, or 2) the participant's CDR sum-of-boxes score increased ≥2 points from baseline. Post-hoc analyses were performed on pooled treatment-group data to compare methods of assessing progression.

RESULTS: 581/1,451 (40% ) participants had changes triggering adjudication and most (83% ) were confirmed as progression to dementia. Only 66% of those who met CDR criteria (regardless of whether they also met Site Investigator criteria) were adjudicated to have progressed to dementia and just 15% of those who met only CDR criteria were adjudicated to have progressed, representing 5% of progressors. In contrast, 99% of those who met Site Investigator criteria (regardless of whether they also met CDR criteria) were adjudicated to have progressed, and the same was true for those who met only Site Investigator criteria.

CONCLUSION: A positive Site Investigator opinion is an excellent predictor for a positive adjudication decision regarding onset of dementia. Conversely, sole use of CDR sum-of-boxes change ≥2 is inadequate. The benefit of centralized adjudication appears doubtful.

%B J Alzheimers Dis %V 92 %P 341-348 %8 2023 Mar 07 %G eng %N 1 %R 10.3233/JAD-220836 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging. %A Short, Meghan I %A Fohner, Alison E %A Skjellegrind, Håvard K %A Beiser, Alexa %A Gonzales, Mitzi M %A Satizabal, Claudia L %A Austin, Thomas R %A Longstreth, W T %A Bis, Joshua C %A Lopez, Oscar %A Hveem, Kristian %A Selbæk, Geir %A Larson, Martin G %A Yang, Qiong %A Aparicio, Hugo J %A McGrath, Emer R %A Gerszten, Robert E %A DeCarli, Charles S %A Psaty, Bruce M %A Vasan, Ramachandran S %A Zare, Habil %A Seshadri, Sudha %X

BACKGROUND: Alzheimer's disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults.

OBJECTIVE: To identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plasma proteome.

METHODS: Weighted co-expression network analysis of 1,305 plasma proteins identified four modules of co-expressed proteins, which were related to MRI brain volumes and risk of incident dementia over a median 20-year follow-up in Framingham Heart Study (FHS) Offspring cohort participants (n = 1,861). Analyses were replicated in the Cardiovascular Health Study (CHS) (n = 2,117, mean 6-year follow-up).

RESULTS: Two proteomic modules, one related to protein clearance and synaptic maintenance (M2) and a second to inflammation (M4), were associated with total brain volume in FHS (M2: p = 0.014; M4: p = 4.2×10-5). These modules were not significantly associated with hippocampal volume, white matter hyperintensities, or incident all-cause or AD dementia. Associations with TCBV did not replicate in CHS, an older cohort with a greater burden of comorbidities.

CONCLUSIONS: Proteome networks implicate an early role for biological pathways involving inflammation and synaptic function in preclinical brain atrophy, with implications for clinical dementia.

%B J Alzheimers Dis %V 96 %P 1767-1780 %8 2023 Dec 05 %G eng %N 4 %R 10.3233/JAD-230145 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Psychopharmacological Medication Use in Frontotemporal Dementia at the Time of Diagnosis: Comparison with Alzheimer's Disease. %A Katisko, Kasper %A Krüger, Johanna %A Soppela, Helmi %A Hartikainen, Päivi %A Haapasalo, Annakaisa %A Remes, Anne M %A Solje, Eino %K Alzheimer Disease %K Delayed Diagnosis %K Female %K Frontotemporal Dementia %K Humans %K Memantine %K Neurodegenerative Diseases %X

BACKGROUND: Due to the significant presence of neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) spectrum disorders, psychiatric misdiagnoses, diagnostic delay, and use of psychiatric treatments are common prior to the FTD diagnosis. Furthermore, treatment of diagnosed FTD patients mainly relies on off-label psychopharmacological approaches. Currently, limited real-world data are available regarding the actual use of psychopharmacological medications in FTD.

OBJECTIVE: To evaluate psychopharmacological medication use at the time of FTD diagnosis.

METHODS: Psychopharmacological medication use was evaluated in a Finnish FTD cohort containing 222 FTD patients, including the major clinical disease phenotypes (behavioral, language, and motor variants) and genetic patients carrying the C9orf72 repeat expansion. A cohort of 214 Alzheimer's disease (AD) patients was used as a neurodegenerative disease reference group.

RESULTS: Active use of psychopharmacological medications at the time of diagnosis was significantly more common in FTD compared to AD, especially in the case of antidepressants (26.1% versus 15.0%, OR = 2.01, p = 0.008), antipsychotics (23.9% versus 9.3%, OR = 3.15, p < 0.001), and mood-stabilizers (6.3% versus 1.9%, OR = 2.93, p = 0.085; not statistically significant), whereas the use of cholinesterase inhibitors or memantine was nearly nonexistent in FTD patients. Female gender and behavioral variant of FTD phenotype alongside with depressive and psychotic symptoms were the most prominent factors associating with the use of these medications among the FTD spectrum patients.

CONCLUSION: Use of off-label psychopharmacological medication and polypharmacy is substantially common at the time of FTD diagnosis. This likely reflects the challenges in using symptom-driven treatment approaches, especially prior to the eventual diagnosis.

%B J Alzheimers Dis %V 95 %P 677-685 %8 2023 %G eng %N 2 %R 10.3233/JAD-230494 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Racial/Ethnic Disparities in Misidentification of Dementia in Medicare Claims: Results from the Washington Heights-Inwood Columbia Aging Project. %A Zhu, Carolyn W %A Gu, Yian %A Cosentino, Stephanie %A Kociolek, Anton J %A Hernandez, Michelle %A Stern, Yaakov %X

BACKGROUND: Misidentification of dementia in Medicare claims is quite common.

OBJECTIVE: We examined potential race/ethnic disparities in misidentification of dementia in Medicare claims in a diverse cohort of older adults who underwent careful clinical assessment.

METHODS: Participants were enrolled the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, population-based, prospective study of cognitive aging in which dementia status was assessed using a rigorous clinical protocol. ICD-9-CM and ICD-10-CM diagnosis codes in all available Medicare claims (1999-2019) were compared to clinical dementia diagnosis and categorized into three mutually exclusive groups: 1) congruent-, 2) over-, and 3) under- identification during the study period. Multinomial logistic regression model was used to examine the relationship between race (White, African American/Black, other) and ethnicity (Hispanic/Latinx, non-Hispanic/Latinx) and congruency of dementia identification after controlling for clinical (cognition, function, comorbidities) and demographic characteristics (age, sex, education), and inpatient and outpatient utilization.

RESULTS: Across all person-years, 88.4% had congruent identification of dementia compared to clinical diagnosis, in 4.1% of the times participants were over-identified with dementia, and 7.5% of the times the participants were under-identified. Rates of misidentification was higher in minority participants than in White, non-Hispanic participants. Multivariable estimation results showed that the probability of over-identification with dementia was 2.2% higher for African American/Black than White (p = 0.05) and 2.7% higher for Hispanic participants than non-Hispanics (p = 0.03) participants. Differences in under-identification by race/ethnicity were not statistically significant.

CONCLUSIONS: African American/Black and Hispanic participants were more likely over-identified with dementia in Medicare claims.

%B J Alzheimers Dis %V 96 %P 359-368 %8 2023 Oct 24 %G eng %N 1 %R 10.3233/JAD-230584 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Re-Addressing Dementia by Network Medicine and Mechanism-Based Molecular Endotypes. %A Pacheco Pachado, Mayra %A Casas, Ana I %A Elbatreek, Mahmoud H %A Nogales, Cristian %A Guney, Emre %A Espay, Alberto J %A Schmidt, Harald H H W %K Aging %K Alzheimer Disease %K Amyloid %K Amyloid beta-Peptides %K Brain %K Humans %X

Alzheimer's disease (AD) and other forms of dementia are together a leading cause of disability and death in the aging global population, imposing a high personal, societal, and economic burden. They are also among the most prominent examples of failed drug developments. Indeed, after more than 40 AD trials of anti-amyloid interventions, reduction of amyloid-β (Aβ) has never translated into clinically relevant benefits, and in several cases yielded harm. The fundamental problem is the century-old, brain-centric phenotype-based definitions of diseases that ignore causal mechanisms and comorbidities. In this hypothesis article, we discuss how such current outdated nosology of dementia is a key roadblock to precision medicine and articulate how Network Medicine enables the substitution of clinicopathologic phenotypes with molecular endotypes and propose a new framework to achieve precision and curative medicine for patients with neurodegenerative disorders.

%B J Alzheimers Dis %V 96 %P 47-56 %8 2023 %G eng %N 1 %R 10.3233/JAD-230694 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Refining Risk for Alzheimer's Disease Among Heterozygous APOEɛ4 Carriers. %A Patel, Smita %A Wei, Jun %A Shi, Zhuqing %A Rifkin, Andrew S %A Zheng, S Lilly %A Gelfman, Elizabeth %A Duggan, David %A Helfand, Brian T %A Hulick, Peter J %A Xu, Jianfeng %K Alzheimer Disease %K Apolipoprotein E4 %K Apolipoproteins E %K Heterozygote %K Homozygote %K Humans %X

In a large population-based cohort, we show not all heterozygous APOEɛ4 carriers are at increased risk for Alzheimer's disease (AD); a significantly higher AD proportion was only found for ɛ3/ɛ4, not ɛ2/ɛ4. Among ɛ3/ɛ4 carriers (24% in the cohort), the AD proportion differed considerably by polygenic risk score (PRS). In particular, the AD proportion was lower than the entire cohort for subjects in the bottom 20-percentile PRS and was higher than that of homozygous ɛ4 carriers for subjects at the top 5th-percentile PRS. Family history was no longer a significant predictor of AD risk after adjusting APOE and PRS.

%B J Alzheimers Dis %V 94 %P 483-489 %8 2023 %G eng %N 2 %R 10.3233/JAD-230156 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Reliability and Validity of Self-Reported Vascular Risk Factors: Hypertension, Diabetes, and Heart Disease, in a Multi-Ethnic Community Based Study of Aging and Dementia. %A Lee, Annie J %A Sanchez, Didi %A Reyes-Dumeyer, Dolly %A Brickman, Adam M %A Lantigua, Rafael A %A Vardarajan, Badri N %A Mayeux, Richard %X

BACKGROUND: Queries for the presence of cardiovascular and cerebrovascular risk factors are typically assessed through self-report. However, the reliability and validity of self-reported cardiovascular and cerebrovascular risk factors remains inconsistent in aging research.

OBJECTIVE: To determine the reliability and validity of the most frequently self-reported vascular risk factors: hypertension, diabetes, and heart disease.

METHODS: 1,870 individuals aged 65 years or older among African Americans, Caribbean Hispanics, and white non-Hispanic individuals were recruited as part of a community study of aging and dementia. We assessed the reliability, validity, sensitivity, specificity, and percent agreement of self-reported hypertension, diabetes, and heart disease, in comparison with direct measures of blood pressure, hemoglobin A1c (HbA1c), and medication use. The analyses were subsequently stratified by age, sex, education, and ethnic group.

RESULTS: Reliability of self-reported for hypertension, diabetes, and heart disease was excellent. Agreement between self-reports and clinical measures was moderate for hypertension (kappa: 0.58), good for diabetes (kappa: 0.76-0.79), and moderate for heart disease (kappa: 0.45) differing slightly by age, sex, education, and ethnic group. Sensitivity and specificity for hypertension was 88.6% -78.1%, for diabetes was 87.7% -92.0% (HbA1c ≥6.5%) or 92.7% -92.8% (HbA1c ≥7%), and for heart disease was 85.8% -75.5%. Percent agreement of self-reported was 87.0% for hypertension, 91.6% -92.6% for diabetes, and 77.4% for heart disease.

CONCLUSION: Ascertainment of self-reported histories of hypertension, diabetes, and heart disease are reliable and valid compared to direct measurements or medication use.

%B J Alzheimers Dis %V 95 %P 275-285 %8 2023 Aug 29 %G eng %N 1 %R 10.3233/JAD-230374 %0 Journal Article %J J Alzheimers Dis %D 2023 %T A Remotely Coached Multimodal Lifestyle Intervention for Alzheimer's Disease Ameliorates Functional and Cognitive Outcomes. %A Roach, Jared C %A Rapozo, Molly K %A Hara, Junko %A Glusman, Gwênlyn %A Lovejoy, Jennifer %A Shankle, William R %A Hood, Leroy %X

BACKGROUND: Comprehensive treatment of Alzheimer's disease and related dementias (ADRD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. Personalized, multimodal therapies are needed to best prevent and treat Alzheimer's disease (AD).

OBJECTIVE: The Coaching for Cognition in Alzheimer's (COCOA) trial was a prospective randomized controlled trial to test the hypothesis that a remotely coached multimodal lifestyle intervention would improve early-stage AD.

METHODS: Participants with early-stage AD were randomized into two arms. Arm 1 (N = 24) received standard of care. Arm 2 (N = 31) additionally received telephonic personalized coaching for multiple lifestyle interventions. The primary outcome was a test of the hypothesis that the Memory Performance Index (MPI) change over time would be better in the intervention arm than in the control arm. The Functional Assessment Staging Test was assessed for a secondary outcome. COCOA collected psychometric, clinical, lifestyle, genomic, proteomic, metabolomic, and microbiome data at multiple timepoints (dynamic dense data) across two years for each participant.

RESULTS: The intervention arm ameliorated 2.1 [1.0] MPI points (mean [SD], p = 0.016) compared to the control over the two-year intervention. No important adverse events or side effects were observed.

CONCLUSION: Multimodal lifestyle interventions are effective for ameliorating cognitive decline and have a larger effect size than pharmacological interventions. Dietary changes and exercise are likely to be beneficial components of multimodal interventions in many individuals. Remote coaching is an effective intervention for early stage ADRD. Remote interventions were effective during the COVID pandemic.

%B J Alzheimers Dis %V 96 %P 591-607 %8 2023 Nov 07 %G eng %N 2 %R 10.3233/JAD-230403 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Resveratrol Mediated Regulation of Hippocampal Neuroregenerative Plasticity via SIRT1 Pathway in Synergy with Wnt Signaling: Neurotherapeutic Implications to Mitigate Memory Loss in Alzheimer's Disease. %A Surya, Kumar %A Manickam, Nivethitha %A Jayachandran, Kesavan Swaminathan %A Kandasamy, Mahesh %A Anusuyadevi, Muthuswamy %K Alzheimer Disease %K Amnesia %K Hippocampus %K Humans %K Neurogenesis %K Resveratrol %K Sirtuin 1 %K Wnt Signaling Pathway %X

Alzheimer's disease (AD) is a major form of dementia. Abnormal amyloidogenic event-mediated degeneration of cholinergic neurons in the cognitive centers of the brain has been attributed to neuropathological sequelae and behavioral deficits in AD. Besides, impaired adult neurogenesis in the hippocampus has experimentally been realized as an underlying cause of dementia regardless of neurodegeneration. Therefore, nourishing the neurogenic process in the hippocampus has been considered an effective therapeutic strategy to mitigate memory loss. In the physiological state, the Wnt pathway has been identified as a potent mitogenic generator in the hippocampal stem cell niche. However, downstream components of Wnt signaling have been noticed to be downregulated in AD brains. Resveratrol (RSV) is a potent Sirtuin1 (SIRT1) enhancer that facilitates neuroprotection and promotes neurogenesis in the hippocampus of the adult brain. While SIRT1 is an important positive regulator of Wnt signaling, ample reports indicate that RSV treatment strongly mediates the fate determination of stem cells through Wnt signaling. However, the possible therapeutic roles of RSV-mediated SIRT1 enhancement on the regulation of hippocampal neurogenesis and reversal of memory loss through the Wnt signaling pathway have not been addressed yet. Taken together, this review describes RSV-mediated effects on the regulation of hippocampal neurogenesis via the activation of SIRT1 in synergy with the Wnt signaling. Further, the article emphasizes a hypothesis that RSV treatment can provoke the activation of quiescent neural stem cells and prime their neurogenic capacity in the hippocampus via Wnt signaling in AD.

%B J Alzheimers Dis %V 94 %P S125-S140 %8 2023 %G eng %N s1 %R 10.3233/JAD-220559 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Retinal Functional and Structural Neural Indices: Potential Biomarkers for the Monitoring of Cerebral Neurodegeneration: The Maastricht Study. %A van der Heide, Frank C T %A Mokhtar, Sara %A Khanna, Anjani %A Said, Mozhda %A Henry, Ronald M A %A Kroon, Abraham A %A Dagnelie, Pieter C %A Eussen, Simone J P M %A Berendschot, Tos T J M %A Schouten, Jan S A G %A Schram, Miranda T %A van der Kallen, Carla J H %A van Greevenbroek, Marleen M J %A Wesselius, Anke %A Savelberg, Hans H C M %A Schaper, Nicolaas C %A Webers, Carroll A B %A Stehouwer, Coen D A %X

BACKGROUND: If retinal indices of neurodegeneration are to be biomarkers for the monitoring of cerebral neurodegeneration, it is important to establish whether potentially modifiable risk factors for dementia are associated with retinal neurodegenerative changes.

OBJECTIVE: To study associations of dementia risk factors with retinal sensitivity, an index of retinal neural function, and retinal nerve fiber layer (RNFL) thickness, an index of retinal neural structure.

METHODS: We used cross-sectional data from The Maastricht Study (up to 5,666 participants, 50.5% men, mean age 59.7), and investigated associations with regression analyses (adjusted for potential confounders).

RESULTS: Most risk factors under study (i.e., hyperglycemia, unhealthy diet, lower cardiorespiratory fitness, smoking, alcohol consumption, and hypertension) were significantly associated with lower retinal sensitivity and lower RNFL thickness.

CONCLUSION: Findings of this population-based study support the concept that retinal neural indices may be biomarkers for the monitoring of therapeutic strategies that aim to prevent early-stage cerebral neurodegeneration and, ultimately, dementia.

%B J Alzheimers Dis %V 93 %P 1471-1483 %8 2023 Jun 13 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/37182886?dopt=Abstract %R 10.3233/JAD-230104 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Rheumatoid Arthritis and Cognitive Impairment or Dementia: An Updated Review of Epidemiological Data. %A Sharma, Sneha R %A Chen, Yu %X

Rheumatoid arthritis (RA) is hypothesized to be associated with cognitive impairment and dementia, including Alzheimer's disease, through shared biological processes related to inflammation. It is important to elucidate this potential relationship as both conditions confer increased morbidity and even mortality among older adults. This narrative review provides a survey of recent epidemiologic studies, examining the association between rheumatoid arthritis and either dementia or cognitive impairment. Sixteen studies were included after searching in PubMed and EMBASE. All were published between 2012 and 2022 and were characterized as epidemiologic studies (either cohort, cross-sectional, or case-control). Studies varied in location, design, measures of exposure and outcome, and covariates considered. Of the 16 studies included, only five found statistically significant positive associations between RA and dementia or cognitive impairment. One study found an inverse relationship, while five studies found no associations at all. The remaining five studies found variable statistically significant associations between demographic or RA disease characteristics and cognitive measures. Given these mixed findings, further studies at both the mechanistic and population level are needed to clarify the possible shared biological underpinnings of these two conditions.

%B J Alzheimers Dis %V 95 %P 769-783 %8 2023 %G eng %N 3 %R 10.3233/JAD-230234 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Risk Factors for Longer-Term Mortality in Discharged Patients with Dementia and SARS-CoV-2 Infection: A Matched Case-Control Study. %A Chen, Shanquan %A Cardinal, Rudolf N %A Gräf, Stefan %A O'Brien, John T %A Underwood, Benjamin R %X

BACKGROUND: Persisting symptoms and increased mortality after SARS-CoV-2 infection has been described in COVID-19 survivors.

OBJECTIVE: We examined longer-term mortality in patients with dementia and SARS-CoV-2 infection.

METHODS: A retrospective matched case-control study of 165 patients with dementia who survived an acute hospital admission with COVID-19 infection, and 1325 patients with dementia who survived a hospital admission but without SARS-CoV-2 infection. Potential risk factors investigated included socio-demographic factors, clinical features, and results of investigations. Data were fitted using a Cox proportional hazard model.

RESULTS: Compared to patients with dementia but without SARS-CoV-2 infection, people with dementia and SARS-CoV-2 infection had a 4.4-fold risk of death (adjusted hazard ratio [aHR] = 4.44, 95% confidence interval [CI] 3.13-6.30) even beyond the acute phase of infection. This excess mortality could be seen up to 125 days after initial recovery but was not elevated beyond this time. Risk factors for COVID-19-associated mortality included prescription of antipsychotics (aHR = 3.06, 95% CI 1.40-6.69) and benzodiazepines (aHR = 3.00, 95% CI 1.28-7.03). Abnormalities on investigation associated with increased mortality included high white cell count (aHR = 1.21, 95% CI 1.04-1.39), higher absolute neutrophil count (aHR = 1.28, 95% CI 1.12-1.46), higher C-reactive protein (aHR = 1.01, 95% CI 1.00-1.02), higher serum sodium (aHR = 1.09, 95% CI 1.01-1.19), and higher ionized calcium (aHR = 1.03, 95% CI 1.00-1.06). The post-acute COVID mortality could be modeled for the first 120 days after recovery with a balanced accuracy of 87.2%.

CONCLUSION: We found an increased mortality in patients with dementia beyond the acute phase of illness. We identified several investigation results associated with increased mortality, and increased mortality in patients prescribed antipsychotics or benzodiazepines.

%B J Alzheimers Dis %V 92 %P 295-309 %8 2023 Mar 07 %G eng %N 1 %R 10.3233/JAD-221093 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Role of Interferon-α in Neurodegenerative Diseases: A Systematic Review. %A Hui, Brendan Su Mee %A Zhi, Lee Rui %A Retinasamy, Thaarvena %A Arulsamy, Alina %A Law, Christine Shing Wei %A Shaikh, Mohd Farooq %A Yeong, Keng Yoon %K Cytokines %K Databases, Factual %K Humans %K Interferon-alpha %K Neurodegenerative Diseases %X

BACKGROUND: Neurodegenerative diseases (NDs) impose significant financial and healthcare burden on populations all over the world. The prevalence and incidence of NDs have been observed to increase dramatically with age. Hence, the number of reported cases is projected to increase in the future, as life spans continues to rise. Despite this, there is limited effective treatment against most NDs. Interferons (IFNs), a family of cytokines, have been suggested as a promising therapeutic target for NDs, particularly IFN-α, which governs various pathological pathways in different NDs.

OBJECTIVE: This systematic review aimed to critically appraise the currently available literature on the pathological role of IFN-α in neurodegeneration/NDs.

METHODS: Three databases, Scopus, PubMed, and Ovid Medline, were utilized for the literature search.

RESULTS: A total of 77 journal articles were selected for critical evaluation, based on the inclusion and exclusion criteria. The studies selected and elucidated in this current systematic review have showed that IFN-α may play a deleterious role in neurodegenerative diseases through its strong association with the inflammatory processes resulting in mainly neurocognitive impairments. IFN-α may be displaying its neurotoxic function via various mechanisms such as abnormal calcium mineralization, activation of STAT1-dependent mechanisms, and increased quinolinic acid production.

CONCLUSION: The exact role IFN-α in these neurodegenerative diseases have yet to be determine due to a lack in more recent evidence, thereby creating a variability in the role of IFN-α. Future investigations should thus be conducted, so that the role played by IFN-α in neurodegenerative diseases could be delineated.

%B J Alzheimers Dis %V 94 %P S45-S66 %8 2023 %G eng %N s1 %R 10.3233/JAD-221081 %0 Journal Article %J J Alzheimers Dis %D 2023 %T S1PR2 Regulates Autophagy Through the AKT/mTOR Pathway to Promote Pathological Damage in Alzheimer's Disease. %A Wang, Xiaoping %A Huang, Rui %A Huang, Bin %A Li, Xiaojia %X

BACKGROUND: Alzheimer's disease (AD) is a fatal and debilitating neurodegenerative disease. Sphingosine-1-phosphate receptor 2 (S1PR2), one of the receptors of S1P, is a key regulatory factor for various diseases.

OBJECTIVE: This study aimed to explore the role and possible mechanism of S1PR2 in AD.

METHODS: S1PR2 expression in the AD mice was detected, and after intervening S1PR2 expression with sh-S1PR2 in AD mice, the behavioral changes, pathological lesions of the hippocampus, autophagy level, and AKT/mTOR pathway activation were analyzed. Furthermore, SH-SY5Y cells were induced by Aβ25-35 to construct an AD cell model, and the effects of sh-S1PR2 on proliferation, apoptosis, autophagy, and AKT/mTOR pathway of AD cells were investigated. In addition, the effects of pathway inhibitor rapamycin on model cells were further analyzed.

RESULTS: The expression of S1PR2 was significantly increased in AD mice, the sh-S1PR2 significantly improved behavioral dysfunction, alleviated pathological injury of the hippocampus, increased the number of neurons, and inhibited Aβ production and p-tau expression, showing a positive effect on the AD pathology. In addition, silencing of S1PR2 expression significantly promoted the autophagy level and inhibited the activation of the AKT/mTOR pathway in AD model mice. In vitro experiments further confirmed that sh-S1PR2 promoted cell proliferation, inhibited apoptosis, relieved cytopathology, promoted autophagy, and inhibited the activation of the AKT/mTOR pathway in the cell model. The use of rapamycin further confirmed the role of AKT/mTOR pathway-mediated autophagy in the regulation of AD by S1PR2.

CONCLUSION: S1PR2 promoted AD pathogenesis by inhibiting autophagy through the activation of AKT/mTOR pathway.

%B J Alzheimers Dis %V 96 %P 1489-1504 %8 2023 Dec 05 %G eng %N 4 %R 10.3233/JAD-230533 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Safety, Feasibility, and Potential Clinical Efficacy of 40 Hz Invisible Spectral Flicker versus Placebo in Patients with Mild-to-Moderate Alzheimer's Disease: A Randomized, Placebo-Controlled, Double-Blinded, Pilot Study. %A Agger, Mikkel Pejstrup %A Danielsen, Else Rubæk %A Carstensen, Marcus Schultz %A Nguyen, N Mai %A Horning, Maibritt %A Henney, Mark Alexander %A Jensen, Christopher Boe Ravn %A Baandrup, Anders Ohlhues %A Kjær, Troels Wesenberg %A Madsen, Kristoffer Hougaard %A Miskowiak, Kamilla %A Petersen, Paul Michael %A Høgh, Peter %K Alzheimer Disease %K Cognition %K Double-Blind Method %K Feasibility Studies %K Humans %K Pilot Projects %K Treatment Outcome %X

BACKGROUND: Recent studies suggested induction of 40 Hz neural activity as a potential treatment for Alzheimer's disease (AD). However, prolonged exposure to flickering light raises adherence and safety concerns, encouraging investigation of tolerable light stimulation protocols.

OBJECTIVE: To investigate the safety, feasibility, and exploratory measures of efficacy.

METHODS: This two-stage randomized placebo-controlled double-blinded clinical trial, recruited first cognitive healthy participants (n = 3/2 active/placebo), and subsequently patients with mild-to-moderate AD (n = 5/6, active/placebo). Participants were randomized 1:1 to receive either active intervention with 40 Hz Invisible Spectral Flicker (ISF) or placebo intervention with color and intensity matched non-flickering white light.

RESULTS: Few and mild adverse events were observed. Adherence was above 86.1% of intended treatment days, with participants remaining in front of the device for >51.3 min (60 max) and directed gaze >34.9 min. Secondary outcomes of cognition indicate a tendency towards improvement in the active group compared to placebo (mean: -2.6/1.5, SD: 6.58/6.53, active/placebo) at week 6. Changes in hippocampal and ventricular volume also showed no tendency of improvement in the active group at week 6 compared to placebo. At week 12, a potential delayed effect of the intervention was seen on the volume of the hippocampus in the active group compared to placebo (mean: 0.34/-2.03, SD: 3.26/1.18, active/placebo), and the ventricular volume active group (mean: -0.36/2.50, SD: 1.89/2.05, active/placebo), compared to placebo.

CONCLUSION: Treatment with 40 Hz ISF offers no significant safety or adherence concerns. Potential impact on secondary outcomes must be tested in larger scale clinical trials.

%B J Alzheimers Dis %V 92 %P 653-665 %8 2023 %G eng %N 2 %R 10.3233/JAD-221238 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Senescent Microglia Represent a Subset of Disease-Associated Microglia in P301S Mice. %A Ng, Pei Y %A Zhang, Cheng %A Li, Hu %A Baker, Darren J %X

BACKGROUND: The existence and contribution of microglia with senescent-like alterations in the pathogenesis of age-related neurodegenerative diseases like Alzheimer's disease (AD) have been suggested in recent years. However, the identification of this distinct microglial population in vivo has proven challenging, largely due to overlaps in the inflammatory phenotype of activated and senescent microglia. Furthermore, attempts at recapitulating senescence in microglia in vitro are limited.

OBJECTIVE: To identify and characterize senescent microglia that occur in vivo in an animal model of neurodegeneration driven by pathologic tau.

METHODS: We analyzed the RNA expression patterns of individual microglia from normal mice and the pathogenic tau P301 S PS19 mouse model. We have previously demonstrated that p16-expressing senescent microglia occur in these mice when neurodegeneration has occurred.

RESULTS: Here we identify a subset of disease-associated microglia with senescent features, notably characterized by the expression of Ccl4. This signature overlaps with established markers of senescence from other cell types.

CONCLUSION: Our characterization of senescent microglia can be used to better understand the role of senescent microglia in various age-related contexts, including whether clearance of senescent microglia represents a viable therapeutic option.

%B J Alzheimers Dis %V 95 %P 493-507 %8 2023 Sep 12 %G eng %N 2 %R 10.3233/JAD-230109 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Serotonin Degeneration and Amyloid-β Deposition in Mild Cognitive Impairment: Relationship to Cognitive Deficits. %A Smith, Gwenn S %A Kuwabara, Hiroto %A Yan, Haijuan %A Nassery, Najlla %A Yoon, Mark %A Kamath, Vidya %A Kraut, Michael %A Gould, Neda F %A Savonenko, Alena %A Coughlin, Jennifer M %A Lodge, Martin %A Pomper, Martin G %A Nandi, Ayon %A Holt, Daniel %A Dannals, Robert F %A Leoutsakos, Jeannie M %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Cognition %K Cognition Disorders %K Cognitive Dysfunction %K Humans %K Mice %K Positron-Emission Tomography %K Serotonin %X

BACKGROUND: Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in Alzheimer's disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to widespread cortical distribution of amyloid-β (Aβ).

OBJECTIVE: The present study evaluated the regional distribution of the serotonin transporter (5-HTT) and of Aβ in individuals with MCI and healthy older controls, as well as the contribution of 5-HTT and Aβ to cognitive deficits.

METHODS: Forty-nine MCI participants and 45 healthy older controls underwent positron emission tomography (PET) imaging of 5-HTT and Aβ, structural magnetic resonance imaging and neuropsychological assessments.

RESULTS: Lower cortical, striatal, and limbic 5-HTT and higher cortical Aβ was observed in MCIs relative to healthy controls. Lower 5-HTT, mainly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory and semantic, not phonemic fluency. Higher cortical A β was associated with greater deficits in auditory-verbal and visual-spatial memory and in semantic, not phonemic fluency. When modeling the association between cognition, gray matter volumes and Aβ, inclusion of 5-HTT in limbic and in select cortical regions significantly improved model fit for auditory-verbal and visual-spatial memory and semantic, but not phonemic fluency.

CONCLUSIONS: These results support the role of serotonin degeneration in the memory and semantic fluency deficits observed in MCI.

%B J Alzheimers Dis %V 96 %P 215-227 %8 2023 %G eng %N 1 %R 10.3233/JAD-230570 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Soluble TREM2, Alzheimer's Disease Pathology, and Risk for Progression of Cerebral Small Vessel Disease: A Longitudinal Study. %A Wu, Chao %A Ma, Ya-Hui %A Hu, Hao %A Zhao, Bing %A Tan, Lan %K Alzheimer Disease %K Biomarkers %K Cerebral Small Vessel Diseases %K Humans %K Longitudinal Studies %K Membrane Glycoproteins %K Myeloid Cells %K Neuroinflammatory Diseases %K Receptors, Immunologic %X

BackgroundUntil recently, studies on associations between neuroinflammation in vivo and cerebral small vessel disease (CSVD) are scarce. Cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a candidate biomarker of microglial activation and neuroinflammation, were found elevated in Alzheimer's disease (AD), but they have not been fully explored in CSVD.ObjectiveTo determine whether CSF sTREM2 levels are associated with the increased risk of CSVD progression.MethodsA total of 426 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included in this study. All participants underwent measurements of CSF sTREM2 and AD pathology (Aβ1-42, P-tau181P). The progression of CSVD burden and imaging markers, including cerebral microbleeds (CMBs), white matter hyperintensities and lacunes, were estimated based on neuroimaging changes. Logistic regression and moderation effect models were applied to explore associations of sTREM2 with CSVD progression and AD pathology.Results Higher CSF sTREM2 levels at baseline were associated with increased CSVD burden (OR = 1.28 [95% CI, 1.01-1.62]) and CMBs counts (OR = 1.32 [95% CI, 1.03-1.68]). Similarly, increased change rates of CSF sTREM2 might predict elevated CMBs counts (OR = 1.44 [95% CI, 1.05-1.98]). Participants with AD pathology (Aβ1-42 and P-tau181P) showed a stronger association between CSF sTREM2 and CSVD progression.ConclusionThis longitudinal study found a positive association between CSF sTREM2 and CSVD progression, suggesting that neuroinflammation might promote CSVD. Furthermore, neuroinflammation could be a shared pathogenesis of CSVD and AD at the early stage. Targeting neuroinflammation to intervene the progression of CSVD and AD warrants further investigation.

%B J Alzheimers Dis %V 92 %P 311-322 %8 2023 %G eng %N 1 %R 10.3233/JAD-220731 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Superior Global Cognition in Oldest-Old Is Associated with Resistance to Neurodegenerative Pathologies: Results from The 90+ Study. %A Biswas, Roshni %A Kawas, Claudia %A Montine, Thomas J %A Bukhari, Syed A %A Jiang, Luohua %A Corrada, Maria M %X

BACKGROUND: Some oldest-old individuals can maintain superior cognition despite advanced age. Little is known about the neuropathological changes in the brains of oldest-old superior cognitive performers.

OBJECTIVE: Our objective was to examine the associations between Alzheimer's disease (AD) and non-AD neuropathologic features in relation to superior cognitive performance in oldest-old individuals.

METHODS: We analyzed brain autopsy data from 102 participants with normal cognition from The 90+ Study. Superior global cognitive performers (SGCP) were defined as having Mini-Mental State Examination (MMSE) score ≥28 in the last visit 12 to 2 months before death. To examine the associations between individual and multiple comorbid neuropathologic features with SGCP status we used multiple logistic regression models adjusting for age, sex, and education.

RESULTS: Alzheimer's disease neuropathological change (ADNC) and low levels of vascular pathologic change were not associated with superior cognition. In contrast, participants with limbic (OR = 8.37; 95% CI: 1.48-47.44) and neocortical (OR = 10.80;95% CI: 1.03-113.82) Lewy body disease (LBD), or with hippocampal sclerosis (HS) (OR = 5.28; 95% CI: 1.10-25.47) were more likely to be non-SGCP. High total burden of multiple comorbid neuropathologic features was associated with a lower likelihood of being SGCP.

CONCLUSION: Oldest-old superior cognitive performers were resilient to ADNC and low levels of vascular pathologic change and were resistant to non-AD neurodegenerative changes and multiple comorbid neuropathologic features. Understanding the factors underlying the ability of superior cognitive performers to resist these changes might provide useful insights on maintenance of superior cognition despite advanced age.

%B J Alzheimers Dis %V 93 %P 561-575. %8 2023 May 16 %G eng %N 2 %R 10.3233/JAD-221062 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Tau Loss of Function, by Deletion or Aggregation, Contributes to Peripheral Insulin Resistance. %A Al-Lahham, Rabab %A Mendez, Nicolas %X

BACKGROUND: Several epidemiological data revealed an association between Alzheimer's disease (AD) and type 2 diabetes. Researchers concentrated on brain insulin resistance with little emphasis on the link between systemic insulin resistance and AD, despite the fact that the incidence of type 2 diabetes is higher in AD patients and that impairment in insulin signaling is a risk factor for AD.

OBJECTIVE: The goal of this study is to determine the role of systemic insulin resistance in the pathogenesis of Alzheimer's disease by evaluating the consequences of tau loss-of-function on peripheral insulin sensitivity.

METHODS: Primary hepatocytes isolated from transgenic mouse models (Tau KO, P301 L) and wild type mice (C57BL/6) were evaluated for their insulin sensitivity using glucose uptake assays as well as biochemical analysis of insulin signaling markers.

RESULTS: Our data show that tau deletion or loss of function promotes peripheral insulin resistance as seen in primary hepatocytes isolated from Tau KO and P301 L mice, respectively. Furthermore, exposure of wild-type primary hepatocytes to sub-toxic concentrations of tau oligomers results in a dose-dependent inhibition of glucose uptake, associated with downregulation of insulin signaling. Tau oligomers-induced inactivation of insulin signaling proteins was rescued by inhibition of p38 MAPK, suggesting the involvement of p38 MAPK.

CONCLUSIONS: This is the first study testing tau role in peripheral insulin resistance at the cellular level using multiple transgenic mouse models. Moreover, this study suggests that tau should be functional for insulin sensitivity, therefore, any loss of function by deletion or aggregation would result in insulin resistance.

%B J Alzheimers Dis %V 95 %P 1041-1058 %8 2023 Sep 26 %G eng %N 3 %R 10.3233/JAD-230392 %0 Journal Article %J J Alzheimers Dis %D 2023 %T TDP-43 Pathology in the Setting of Intermediate and High Alzheimer's Disease Neuropathologic Changes: A Preliminary Evaluation Across Ethnoracial Groups. %A Huie, Emily Z %A Escudero, Anthony %A Saito, Naomi %A Harvey, Danielle %A Nguyen, My-Le %A Lucot, Katherine L %A LaGrande, Jayne %A Mungas, Dan %A DeCarli, Charles %A Lamar, Melissa %A Schneider, Julie A %A Kapasi, Alifiya %A Rissman, Robert A %A Teich, Andrew F %A Dugger, Brittany N %X

BACKGROUND: Transactive Response DNA Binding Protein 43 kDa (TDP-43) pathology is frequently found in cases with Alzheimer's disease (AD). TDP-43 pathology is associated with hippocampal atrophy and greater AD severity denoted by cognition and clinical representation. Current TDP-43 pathology studies are predominantly based on non-Hispanic White cohorts.

OBJECTIVE: We sought to evaluate the presence of TDP-43 pathology across ethnoracial groups utilizing the National Alzheimer's Coordinating Center; a database containing data from over 29 institutions across the United States. Cases (N = 1,135: Hispanics/Latinos = 29, African Americans/Black Americans = 51, Asians/Asian Americans = 10, American Indians/Alaskan Natives = 2, non-Hispanic White = 1,043) with intermediate/high AD having data on TDP-43 pathology in the amygdala, hippocampus, entorhinal cortex, and neocortex.

METHODS: TDP-43 pathology frequency in each neuroanatomic region among ethnoracial groups were compared using generalized linear mixed effects models with center as a random effect adjusting for age at death, education, and gender.

RESULTS: Although groups were imbalanced, there was no significant difference across ethnoracial groups based on TDP-43 pathology (p = 0.84). With respect to neuroanatomical regions evaluated, there were no significant differences across ethnoracial groups (p-values > 0.06). There were also no significant differences for age at death and gender ratios across ethnoracial groups based on TDP-43 pathology. Although not statistically significant, TDP-43 pathology was present less often in Hispanic/Latinos (34%) when compared to non-Hispanic Whites (46%).

CONCLUSION: While this is a preliminary evaluation, it highlights the need for diverse cohorts and on TDP-43 pathology research across ethnoracial groups. This is the first study to our knowledge having a focus on the neuroanatomical distribution of TDP-43 deposits in Hispanic/Latino decedents with AD.

%B J Alzheimers Dis %V 91 %P 1291-1301 %8 2023 Feb 14 %G eng %N 4 %R 10.3233/JAD-220558 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Timing of Alzheimer's Disease by Intellectual Disability Level in Down Syndrome. %A Hartley, Sigan L %A Fleming, Victoria %A Schworer, Emily K %A Peven, Jamie %A Handen, Benjamin L %A Krinsky-McHale, Sharon %A Hom, Christy %A Lee, Laisze %A Tudorascu, Dana L %A Laymon, Charles %A Minhas, Davneet %A Luo, Weiquan %A Cohen, Annie %A Zaman, Shahid %A Ances, Beau M %A Mapstone, Mark %A Head, Elizabeth %A Lai, Florence %A Rosas, H Diana %A Klunk, William %A Christian, Bradley %X

BACKGROUND: Trisomy 21 causes Down syndrome (DS) and is a recognized cause of early-onset Alzheimer's disease (AD).

OBJECTIVE: The current study sought to determine if premorbid intellectual disability level (ID) was associated with variability in age-trajectories of AD biomarkers and cognitive impairments. General linear mixed models compared the age-trajectory of the AD biomarkers PET Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type, APOE status, biological sex, and site.

METHODS: Analyses involved adults with DS from the Alzheimer's Biomarkers Consortium-Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was based on IQ or mental age scores prior to dementia concerns. PET was acquired using [11C] PiB for Aβ, and [18F] AV-1451 for tau.

RESULTS: Cognitive data was available for 361 participants with a mean age of 45.22 (SD = 9.92) and PET biomarker data was available for 154 participants. There was not a significant effect of premorbid ID level by age on cognitive outcomes. There was not a significant effect of premorbid ID by age on PET Aβ or on tau PET. There was not a significant difference in age at time of study visit of those with mild cognitive impairment-DS or dementia by premorbid ID level.

CONCLUSION: Findings provide robust evidence of a similar time course in AD trajectory across premorbid ID levels, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials.

%B J Alzheimers Dis %V 95 %P 213-225 %8 2023 Aug 29 %G eng %N 1 %R 10.3233/JAD-230200 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Two-Year Changes in Physical Activity and Concurrent Changes in Cognitive Function in a Cohort of Adults with Metabolic Syndrome. %A Rognoni, Teresa %A Fernández-Matarrubia, Marta %A Martínez-González, Miguel Ángel %A Salas-Salvadó, Jordi %A Corella, Dolores %A Castañer, Olga %A Martínez, J Alfredo %A Alonso-Gómez, Ángel M %A Gómez-Gracia, Enrique %A Vioque, Jesús %A Romaguera, Dora %A López-Miranda, José %A Estruch, Ramón %A Tinahones, Francisco J %A Santos-Lozano, José Manuel %A Serra-Majem, Lluis %A Cano Ibañez, Naomi %A Tur, Josep A %A Micó Pérez, Rafael %A Pintó, Xavier %A Delgado-Rodríguez, Miguel %A Ortiz Ramos, María %A Vidal Martín, Josep %A Vázquez, Clotilde %A Daimiel, Lidia %A Ros, Emili %A Goñi-Ruiz, Nuria %A Babio, Nancy %A Sorlí, José V %A Schröder, Helmut %A García-Rios, Antonio %A Compañ-Gabucio, Laura %A Warnberg, Julia %A Zulet, M Ángeles %A Chaplin, Alice %A Sacanella, Emilio %A Bouzalmate-Hajjaj, Amira %A Tojal-Sierra, Lucas %A Damas-Fuentes, Miguel %A Vázquez, Zenaida %A Gómez-Martínez, Carlos %A Saiz, Carmen %A Malcampo, Mireia %A Ortiz-Morales, Ana M %A Martínez-Avilés, Vanessa %A García-Gavilan, Jesús %A Abete, Itziar %A Fitó, Montserrat %A Toledo, Estefanía %X

BACKGROUND: It has been proposed that physical activity (PA) could prevent cognitive decline.

OBJECTIVE: To evaluate the association between changes in PA and changes in cognitive function in a cohort of adults with metabolic syndrome.

METHODS: Longitudinal observational study including 5,500 adults (mean age 65 years, SD = 5; women = 49.3%) with metabolic syndrome. Participants underwent physical activity measurements and cognitive evaluation at baseline and at two-years of follow-up. PA was quantified using the Minnesota questionnaire-shortened version. Cognitive function was evaluated using a battery of tests: Mini-Mental Test Examination, Clock Drawing Test, Trail Making Test A and B, Verbal Fluency Test, and Digit Span. The primary outcome was change in cognition at two-year follow-up, as measured through the Global Composite Score (GCS) of all neuropsychological tests. Multivariable-adjusted linear regression models were fitted with baseline PA and their changes as the main exposures and changes in cognitive function as the outcome.

RESULTS: No significant association was found between PA levels (or their changes) and changes in cognitive function, as measured by the GCS. A greater increase in PA levels was associated with a more favorable two-year change in performance on the Trail Making Test A (Q4 versus Q1: b = -2.15, 95% CI -4.25 to -0.05; p-trend = 0.024). No significant association was found for other neuropsychological test.

CONCLUSION: Our results do not support an association between increases in PA and the evolution of the global cognitive function at two-year follow-up, but they suggested a possible beneficial effect of PA on attentional function in older adults.

%B J Alzheimers Dis %V 95 %P 887-899 %8 2023 Sep 26 %G eng %N 3 %R 10.3233/JAD-230105 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Type 2 Diabetes Comorbidity and Cognitive Decline in Patients with Alzheimer's Disease. %A Davidson, Skylar %A Allenback, Gayle %A Decourt, Boris %A Sabbagh, Marwan N %X

BACKGROUND: Although insulin dysregulation and resistance likely participate in Alzheimer's disease (AD) etiologies, little is known about the correlation between type 2 diabetes mellitus (T2DM) and the progression of cognitive decline in patients with AD.

OBJECTIVE: To determine whether AD patients with T2DM experience more rapid cognitive decline than those without T2DM.

METHODS: All cognitive performance data and the presence or absence of T2DM comorbidity in patients with AD were derived from the US National Alzheimer's Coordinating Center's (NACC) Uniform Data Set (UDS). A search of the UDS identified 3055 participants with AD who had more than one epoch completed. The data set culled clinically diagnosed AD dementia patients who were assessed for diabetes type identified during at least 1 visit. These patients were divided into 2 groups based on whether they had a diagnosis of T2DM. The data from these groups were then analyzed for differences in cognitive decline based on neuropsychological test battery scores and a Clinician Dementia Rating using a general linear model.

RESULTS: Comparisons of the mean scores for 16 selected tests from the neuropsychological test battery showed no significant differences in baseline scores and scores at subsequent visits between the T2DM and nondiabetic groups.

CONCLUSIONS: The results revealed no differences in cognitive decline metrics over the course of 5 visits in either study group. These data indicate that the presence of T2DM does not increase the rate of cognitive decline in AD. This finding contradicts expected disease burden and will need to be explored further.

%B J Alzheimers Dis %V 95 %P 1573-1584 %8 2023 Oct 10 %G eng %N 4 %R 10.3233/JAD-230489 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Understanding the Involvement of microRNAs in Mitochondrial Dysfunction and Their Role as Potential Biomarkers and Therapeutic Targets in Parkinson's Disease. %A Tryphena, Kamatham Pushpa %A Anuradha, Urati %A Kumar, Rohith %A Rajan, Shruti %A Srivastava, Saurabh %A Singh, Shashi Bala %A Khatri, Dharmendra Kumar %K Aged %K Biomarkers %K Humans %K MicroRNAs %K Mitochondria %K Neurodegenerative Diseases %K Parkinson Disease %X

Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting the elderly worldwide and causing significant movement impairments. The goal of PD treatment is to restore dopamine levels in the striatum and regulate movement symptoms. The lack of specific biomarkers for early diagnosis, as well as medication aimed at addressing the pathogenic mechanisms to decelerate the progression of dopaminergic neurodegeneration, are key roadblocks in the management of PD. Various pathogenic processes have been identified to be involved in the progression of PD, with mitochondrial dysfunction being a major contributor to the disease's pathogenesis. The regulation of mitochondrial functions is influenced by a variety of factors, including epigenetics. microRNAs (miRNAs) are epigenetic modulators involved in the regulation of gene expression and regulate a variety of proteins that essential for proper mitochondrial functioning. They are found to be dysregulated in PD, as evidenced by biological samples from PD patients and in vitro and in vivo research. In this article, we attempt to provide an overview of several miRNAs linked to mitochondrial dysfunction and their potential as diagnostic biomarkers and therapeutic targets in PD.

%B J Alzheimers Dis %V 94 %P S187-S202 %8 2023 %G eng %N s1 %R 10.3233/JAD-220449 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Unlocking Modifiable Risk Factors for Alzheimer's Disease: Does the Oral Microbiome Hold Some of the Keys? %A Loughman, Amy %A Adler, Christina J %A Macpherson, Helen %K Alzheimer Disease %K Amyloid beta-Peptides %K Gastrointestinal Microbiome %K Humans %K Microbiota %K Risk Factors %X

Advancing age is recognized as the primary risk factor for Alzheimer's disease (AD); however approximately one third of dementia cases are attributable to modifiable risk factors such as hypertension, diabetes, smoking, and obesity. Recent research also implicates oral health and the oral microbiome in AD risk and pathophysiology. The oral microbiome contributes to the cerebrovascular and neurodegenerative pathology of AD via the inflammatory, vascular, neurotoxic, and oxidative stress pathways of known modifiable risk factors. This review proposes a conceptual framework that integrates the emerging evidence regarding the oral microbiome with established modifiable risk factors. There are numerous mechanisms by which the oral microbiome may interact with AD pathophysiology. Microbiota have immunomodulatory functions, including the activation of systemic pro-inflammatory cytokines. This inflammation can affect the integrity of the blood-brain barrier, which in turn modulates translocation of bacteria and their metabolites to brain parenchyma. Amyloid-β is an antimicrobial peptide, a feature which may in part explain its accumulation. There are microbial interactions with cardiovascular health, glucose tolerance, physical activity, and sleep, suggesting that these modifiable lifestyle risk factors of dementia may have microbial contributors. There is mounting evidence to suggest the relevance of oral health practices and the microbiome to AD. The conceptual framework presented here additionally demonstrates the potential for the oral microbiome to comprise a mechanistic intermediary between some lifestyle risk factors and AD pathophysiology. Future clinical studies may identify specific oral microbial targets and the optimum oral health practices to reduce dementia risk.

%B J Alzheimers Dis %V 92 %P 1111-1129 %8 2023 %G eng %N 4 %R 10.3233/JAD-220760 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Untangling the Role of TREM2 in Conjugation with Microglia in Neuronal Dysfunction: A Hypothesis on a Novel Pathway in the Pathophysiology of Alzheimer's Disease. %A Basha, Sk Chand %A Ramaiah, Mekala Janaki %A Kosagisharaf, Jagannatha Rao %K Alzheimer Disease %K Amyloid beta-Peptides %K Humans %K Membrane Glycoproteins %K Microglia %K Neurons %K Receptors, Immunologic %X

Alzheimer's disease (AD) is a complex neurodegenerative disorder involving heterogenous pathophysiological characteristics, which has become a challenge to therapeutics. The major pathophysiology of AD comprises amyloid-β (Aβ), tau, oxidative stress, and apoptosis. Recent studies indicate the significance of Triggering receptor expressed on myeloid cells 2 (TREM2) and its mutant variants in AD. TREM2 are the transmembrane receptors of microglial cells that performs a broad range of physiological cell processes. Phagocytosis of Aβ is one of the physiological roles of TREM2, which plays a pivotal role in AD progression. R47H, a mutant variant of TREM2, increases the risk of AD by impairing TREM2-Aβ binding. Inconclusive evidence regarding the TREM2 signaling cascade mechanism of Aβ phagocytosis motivates the current review to propose a new hypothesis. The review systematically assesses the cross talk between TREM2 and other AD pathological domains and the influence of TREM2 on amyloid and tau seeding. Disease associated microglia (DAM), a novel state of microglia with unique transcriptional and functional signatures reported in neurodegenerative conditions, also depend on the TREM2 pathway for its differentiation. DAM is suggested to have a neuroprotective role. We hypothesize that TREM2, along with its signaling adaptors and endogenous proteins, play a key role in ameliorating Aβ clearance. We indicate that TREM2 has the potential to ameliorate the Aβ burden, though with differential clearance ability and may act as a potential therapeutic target.

%B J Alzheimers Dis %V 94 %P S319-S333 %8 2023 %G eng %N s1 %R 10.3233/JAD-221070 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Urinary Amino Acid-Conjugated Acrolein and Taurine as New Biomarkers for Detection of Dementia. %A Yoshida, Madoka %A Uemura, Takeshi %A Mizoi, Mutsumi %A Waragai, Masaaki %A Sakamoto, Akihiko %A Terui, Yusuke %A Kashiwagi, Keiko %A Igarashi, Kazuei %X

BACKGROUND: Dementia, including Alzheimer's disease (AD), is one of the serious diseases at advanced age, and its early detection is important for maintaining quality of life (QOL).

OBJECTIVE: In this study, we sought novel biomarkers for dementia in urine.

METHODS: Samples of urine were collected from 57 control subjects without dementia, 62 mild cognitive impairment (MCI) patients, and 42 AD patients. Mini-Mental State Examination (MMSE) was evaluated when subjects were examined by medical doctors. Urinary amino acid (lysine)-conjugated acrolein (AC-Acro) was measured using N ɛ -(3-formyl-3, 4-dehydropiperidine) lysine (FDP-Lys) ELISA kit, and taurine content was measured using a taurine assay kit. Values were normalized by creatinine content which was measured with the colorimetric assay kit.

RESULTS: We found that urinary amino acid (lysine)-conjugated acrolein (AC-Acro) and taurine negatively correlated with MMSE score and are significantly lower in dementia patients compared to the normal subjects. When AC-Acro and taurine were evaluated together with age using an artificial neural network model, median relative risk values for subjects with AD, subjects with mild cognitive impairment, and control subjects were 0.96, 0.53, and 0.06, respectively.

CONCLUSION: Since urine is relatively easy to collect, our findings provide a novel biomarker for dementia without invasiveness.

%B J Alzheimers Dis %V 92 %P 361-369 %8 2023 Mar 07 %G eng %N 1 %R 10.3233/JAD-220912 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Vacuolar Protein-Sorting Proteins Are Reduced Even Before Cognitive Decline in a Mouse Model of Alzheimer's Disease. %A Shinagawa, Hijiri %A Ohuchi, Kazuki %A Goto, Yuya %A Hashimoto, Kohei %A Kijima, Hideki %A Maekawa, Shogo %A Kurita, Hisaka %A Inden, Masatoshi %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Cognitive Dysfunction %K Humans %K Mice %K Protein Transport %K Vesicular Transport Proteins %X

Currently, interventions from the preclinical stage are considered necessary for the treatment of Alzheimer's disease (AD). Previous studies have reported that vacuolar protein-sorting protein (VPS), a retromer construct, is involved in the pathogenic mechanisms of AD and Parkinson's disease. This study evaluated VPS26, VPS29, and VPS35 before and after the onset of cognitive decline in an App knock-in mouse model of AD that more closely resembles the human pathology than previous AD models. The results showed that the expression of VPS26 and VPS35 decreased before the onset of cognitive decline, suggesting the possibility of anti-amyloid-β disease-modifying treatment targeting these proteins.

%B J Alzheimers Dis %V 96 %P 1011-1017 %8 2023 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/37980668?dopt=Abstract %R 10.3233/JAD-230686 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Validation of a Multivariate Prediction Model of the Clinical Progression of Alzheimer's Disease in a Community-Dwelling Multiethnic Cohort. %A Stallard, Eric %A Kociolek, Anton %A Jin, Zhezhen %A Ryu, Hyunnam %A Lee, Seonjoo %A Cosentino, Stephanie %A Zhu, Carolyn %A Gu, Yian %A Fernandez, Kayri %A Hernandez, Michelle %A Kinosian, Bruce %A Stern, Yaakov %X

BACKGROUND: The major aims of the three Predictors Studies have been to further our understanding of Alzheimer's disease (AD) progression sufficiently to predict the length of time from disease onset to major disease outcomes in individual patients with AD.

OBJECTIVES: To validate a longitudinal Grade of Membership (L-GoM) prediction algorithm developed using clinic-based, mainly white patients from the Predictors 2 Study in a statistically representative community-based sample of Hispanic (N = 211) and non-Hispanic (N = 62) older adults (with 60 males and 213 females) from the Predictors 3 Study and extend the algorithm to mild cognitive impairment (MCI).

METHODS: The L-GoM model was applied to data collected at the initial Predictors 3 visit for 150 subjects with AD and 123 with MCI. Participants were followed annually for up to seven years. Observed rates of survival and need for full-time care (FTC) were compared to those predicted by the algorithm.

RESULTS: Initial MCI/AD severity in Predictors 3 was substantially higher than among clinic-based AD patients enrolled at the specialized Alzheimer's centers in Predictors 2. The observed survival and need for FTC followed the L-GoM model trajectories in individuals with MCI or AD, except for N = 32 subjects who were initially diagnosed with AD but reverted to a non-AD diagnosis on follow-up.

CONCLUSION: These findings indicate that the L-GoM model is applicable to community-dwelling, multiethnic older adults with AD. They extend the use of the model to the prediction of outcomes for MCI. They also justify release of our L-GoM calculator at this time.

%B J Alzheimers Dis %V 95 %P 93-117 %8 2023 Aug 29 %G eng %N 1 %R 10.3233/JAD-220811 %0 Journal Article %J J Alzheimers Dis %D 2022 %T 3-Hydroxyacyl-CoA and Alcohol Dehydrogenase Activities of Mitochondrial Type 10 17β-Hydroxysteroid Dehydrogenase in Neurodegeneration Study. %A He, Xue-Ying %A Dobkin, Carl %A Brown, W Ted %A Yang, Song-Yu %X

BACKGROUND: Mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is necessary for brain cognitive function, but its studies were confounded by reports of Aβ-peptide binding alcohol dehydrogenase (ABAD), formerly endoplasmic reticulum-associated Aβ-peptide binding protein (ERAB), for two decades so long as ABAD serves as the alternative term of 17β-HSD10.

OBJECTIVE: To determine whether those ABAD reports are true or false, even if they were published in prestigious journals.

METHODS: 6xHis-tagged 17β-HSD10 was prepared and characterized by well-established experimental procedures.

RESULTS: The N-terminal 6xHis tag did not significantly interfere with the dehydrogenase activities of 17β-HSD10, but the kinetic constants of its 3-hydroxyacyl-CoA dehydrogenase activity are drastically distinct from those of ABAD, and it was not involved in ketone body metabolism as previously reported for ABAD. Furthermore, it was impossible to measure its generalized alcohol dehydrogenase activities underlying the concept of ABAD because the experimental procedures described in ABAD reports violated basic chemical and/or biochemical principles. More incredibly, both authors and journals had not yet agreed to make any corrigenda of ABAD reports.

CONCLUSION: Brain 17β-HSD10 plays a key role in neurosteroid metabolism and further studies in this area may lead to potential treatments of neurodegeneration including AD.

%B J Alzheimers Dis %V 88 %P 1487-1497 %8 2022 Aug 16 %G eng %N 4 %R 10.3233/JAD-220481 %0 Journal Article %J J Alzheimers Dis %D 2022 %T 5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Diagnostic Biomarkers for Late-Onset Alzheimer's Disease. %A Chen, Lei %A Shen, Qianqian %A Xu, Shunliang %A Yu, Hongzhuan %A Pei, Shengjie %A Zhang, Yangting %A He, Xin %A Wang, QiuZhen %A Li, Duo %K 5-Methylcytosine %K Aged %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Cell-Free Nucleic Acids %K DNA Methylation %K DNA, Neoplasm %K Epigenesis, Genetic %K Female %K High-Throughput Nucleotide Sequencing %K Humans %K Male %K Middle Aged %X

BACKGROUND: 5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification that is highly abundant in central nervous system. It has been reported that DNA 5hmC dysregulation play a critical role in Alzheimer's disease (AD) pathology. Changes in 5hmC signatures can be detected in circulating cell-free DNA (cfDNA), which has shown potential as a non-invasive liquid biopsy material.

OBJECTIVE: However, the genome-wide profiling of 5hmC in cfDNA and its potential for the diagnosis of AD has not been reported to date.

METHODS: We carried out a case-control study and used a genome-wide chemical capture followed by high-throughput sequencing to detect the genome-wide profiles of 5hmC in human cfDNA and identified differentially hydroxymethylated regions (DhMRs) in late-onset AD patients and the control.

RESULTS: We discovered significant differences of 5hmC enrichment in gene bodies which were linked to multiple AD pathogenesis-associated signaling pathways in AD patients compared with cognitively normal controls, indicating they can be well distinguished from normal controls by DhMRs in cfDNA. Specially, we identified 7 distinct genes (RABEP1, CPNE4, DNAJC15, REEP3, ROR1, CAMK1D, and RBFOX1) with predicting diagnostic potential based on their significant correlations with MMSE and MoCA scores of subjects.

CONCLUSION: The present results suggest that 5hmC markers derived from plasma cfDNA can served as an effective, minimally invasive biomarkers for clinical auxiliary diagnosis of late-onset AD.

%B J Alzheimers Dis %V 85 %P 573-585 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864677?dopt=Abstract %R 10.3233/JAD-215217 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Age-Related Oxidative Redox and Metabolic Changes Precede Intraneuronal Amyloid-β Accumulation and Plaque Deposition in a Transgenic Alzheimer's Disease Mouse Model. %A Pontrello, Crystal G %A McWhirt, Joshua M %A Glabe, Charles G %A Brewer, Gregory J %X

BACKGROUND: Many identified mechanisms could be upstream of the prominent amyloid-β (Aβ) plaques in Alzheimer's disease (AD).

OBJECTIVE: To profile the progression of pathology in AD.

METHODS: We monitored metabolic signaling, redox stress, intraneuronal amyloid-β (iAβ) accumulation, and extracellular plaque deposition in the brains of 3xTg-AD mice across the lifespan.

RESULTS: Intracellular accumulation of aggregated Aβ in the CA1 pyramidal cells at 9 months preceded extracellular plaques that first presented in the CA1 at 16 months of age. In biochemical assays, brain glutathione (GSH) declined with age in both 3xTg-AD and non-transgenic controls, but the decline was accelerated in 3xTg-AD brains from 2 to 4 months. The decline in GSH correlated exponentially with the rise in iAβ. Integrated metabolic signaling as the ratio of phospho-Akt (pAkt) to total Akt (tAkt) in the PI3kinase and mTOR pathway declined at 6, 9, and 12 months, before rising at 16 and 20 months. These pAkt/tAkt ratios correlated with both iAβ and GSH levels in a U-shaped relationship. Selective vulnerability of age-related AD-genotype-specific pAkt changes was greatest in the CA1 pyramidal cell layer. To demonstrate redox causation, iAβ accumulation was lowered in cultured middle-age adult 3xTg-AD neurons by treatment of the oxidized redox state in the neurons with exogenous cysteine.

CONCLUSION: The order of pathologic progression in the 3xTg-AD mouse was loss of GSH (oxidative redox shift) followed by an pAkt/tAkt metabolic shift in CA1, iAβ accumulation in CA1, and extracellular Aβ deposition. Upstream targets may prove strategically more effective for therapy before irreversible changes.

%B J Alzheimers Dis %V 90 %P 1501-1521 %8 2022 Dec 06 %G eng %N 4 %R 10.3233/JAD-220824 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Alteration of Gut Microbiota in Alzheimer's Disease and Their Relation to the Cognitive Impairment. %A Khedr, Eman M %A Omeran, Nehad %A Karam-Allah Ramadan, Haidi %A Ahmed, Gellan K %A Abdelwarith, Ahmed M %K Alzheimer Disease %K Bacteria %K Cognitive Dysfunction %K Dysbiosis %K Gastrointestinal Microbiome %K Humans %K RNA, Ribosomal, 16S %X

BACKGROUND: Dysbiosis of gut microbiota has been reported to be enrolled in the pathogenesis of Alzheimer's disease (AD). However, there is a lack of relevant studies on this topic in Egyptian patients with AD.

OBJECTIVE: To investigate different species of gut microbiota in Egyptian patients with AD and correlate microbiota bacterial abundance with clinical data.

METHODS: The study included 25 patients with AD and 25 healthy volunteers as age and sex-matched controls. Clinical data was taken for each patient, including medical history and examination; Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were assessed for each participant. Bacterial DNA was extracted from stool, and abundance quantified via qPCR using 16S rRNA group-specific primers.

RESULTS: Akkermansia, Enterobacteria, Bacteroidetes, Bacillus cereus, Prevotella, and Clostridium cluster IV were more abundant in the AD group than in the control group, although there was significantly less abundance of Bifidobacterium spp., Firmicutes, and Actinobacteria in patients with AD than in controls, whereas no such significance was found for lactic acid bacteria between both groups. Lactic acid bacteria and Prevotella abundance was negatively correlated with cognitive impairment (p = 0.03 with MMSE, and p = 0.03 with MoCA). Prevotella abundance was positively correlated with age of onset and duration of illness and negatively correlated with smoking and coronary heart disease (p = 0.007, p = 0.03, p = 0.035, and p = 0.047, respectively).

CONCLUSION: The current work highlighted a significant relationship between AD and gut microbiota dysbiosis. A higher abundance of Prevotella species and lactic acid bacteria was correlated with cognition.

%B J Alzheimers Dis %V 88 %P 1103-1114 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35754271?dopt=Abstract %R 10.3233/JAD-220176 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Alzheimer's Disease Diagnostics Using miRNA Biomarkers and Machine Learning. %A Xu, Amy %A Kouznetsova, Valentina L %A Tsigelny, Igor F %X

BACKGROUND: The current standard for Alzheimer's disease (AD) diagnosis is often imprecise, as with memory tests, and invasive or expensive, as with brain scans. However, the dysregulation patterns of miRNA in blood hold potential as useful biomarkers for the non-invasive diagnosis and even treatment of AD.

OBJECTIVE: The goal of this research is to elucidate new miRNA biomarkers and create a machine-learning (ML) model for the diagnosis of AD.

METHODS: We utilized pathways and target gene networks related to confirmed miRNA biomarkers in AD diagnosis and created multiple models to use for diagnostics based on the significant differences among miRNA expression between blood profiles (serum and plasma).

RESULTS: The best performing serum-based ML model, trained on filtered disease-specific miRNA datasets, was able to identify miRNA biomarkers with 92.0% accuracy and the best performing plasma-based ML model, trained on filtered disease-specific miRNA datasets, was able to identify miRNA biomarkers with 90.9% accuracy. Through analysis of AD implicated miRNA, thousands of descriptors reliant on target gene and pathways were created which can then be used to identify novel biomarkers and strengthen disease diagnosis.

CONCLUSION: Development of a ML model including miRNA and their genomic and pathway descriptors made it possible to achieve considerable accuracy for the prediction of AD.

%B J Alzheimers Dis %V 86 %P 841-859 %8 2022 Mar 22 %G eng %N 2 %R 10.3233/JAD-215502 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Alzheimer's Disease: Key Insights from Two Decades of Clinical Trial Failures. %A Kim, C Kwon %A Lee, Yin Rui %A Ong, Lynnett %A Gold, Michael %A Kalali, Amir %A Sarkar, Joydeep %K Alzheimer Disease %K Humans %X

Given the acknowledged lack of success in Alzheimer's disease (AD) drug development over the past two decades, the objective of this review was to derive key insights from the myriad failures to inform future drug development. A systematic and exhaustive review was performed on all failed AD compounds for dementia (interventional phase II and III clinical trials from ClinicalTrials.gov) from 2004 to the present. Starting with the initial ∼2,700 AD clinical trials, ∼550 trials met our initial criteria, from which 98 unique phase II and III compounds with various mechanisms of action met our criteria of a failed compound. The two recent reported phase III successes of aducanumab and oligomannate are very encouraging; however, we are awaiting real-world validation of their effectiveness. These two successes against the 98 failures gives a 2.0% phase II and III success rate since 2003, when the previous novel compound was approved. Potential contributing methodological factors for the clinical trial failures were categorized into 1) insufficient evidence to initiate the pivotal trials, and 2) pivotal trial design shortcomings. Our evaluation found that rational drug development principles were not always followed for AD therapeutics development, and the question remains whether some of the failed compounds may have shown efficacy if the principles were better adhered to. Several recommendations are made for future AD therapeutic development. The whole database of the 98 failed compounds is presented in the Supplementary Material.

%B J Alzheimers Dis %V 87 %P 83-100 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35342092?dopt=Abstract %R 10.3233/JAD-215699 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Alzheimer's Disease with Epileptiform EEG Activity: Abnormal Cortical Sources of Resting State Delta Rhythms in Patients with Amnesic Mild Cognitive Impairment. %A Babiloni, Claudio %A Noce, Giuseppe %A Di Bonaventura, Carlo %A Lizio, Roberta %A Eldellaa, Ali %A Tucci, Federico %A Salamone, Enrico M %A Ferri, Raffaele %A Soricelli, Andrea %A Nobili, Flavio %A Famá, Francesco %A Arnaldi, Dario %A Palma, Eleonora %A Cifelli, Pierangelo %A Marizzoni, Moira %A Stocchi, Fabrizio %A Bruno, Giuseppe %A Di Gennaro, Giancarlo %A Frisoni, Giovanni B %A Del Percio, Claudio %X

BACKGROUND: Patients with amnesic mild cognitive impairment due to Alzheimer's disease (ADMCI) typically show a "slowing" of cortical resting-state eyes-closed electroencephalographic (rsEEG) rhythms. Some of them also show subclinical, non-convulsive, and epileptiform EEG activity (EEA) with an unclear relationship with that "slowing."

OBJECTIVE: Here we tested the hypothesis that the "slowing" of rsEEG rhythms is related to EEA in ADMCI patients.

METHODS: Clinical and instrumental datasets in 62 ADMCI patients and 38 normal elderly (Nold) subjects were available in a national archive. No participant had received a clinical diagnosis of epilepsy. The eLORETA freeware estimated rsEEG cortical sources. The area under the receiver operating characteristic curve (AUROCC) indexed the accuracy of eLORETA solutions in the classification between ADMCI-EEA and ADMCI-noEEA individuals.

RESULTS: EEA was observed in 15% (N = 8) of the ADMCI patients. The ADMCI-EEA group showed: 1) more abnormal Aβ 42 levels in the cerebrospinal fluid as compared to the ADMCI-noEEA group and 2) higher temporal and occipital delta (

CONCLUSION: It can be speculated that in ADMCI-EEA patients, AD-related amyloid neuropathology may be related to an over-excitation in neurophysiological low-frequency (delta) oscillatory mechanisms underpinning cortical arousal and quiet vigilance.

%B J Alzheimers Dis %V 88 %P 903-931 %8 2022 Aug 02 %G eng %N 3 %R 10.3233/JAD-220442 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Analysis and Identification Genetic Effect of SARS-CoV-2 Infections to Alzheimer's Disease Patients by Integrated Bioinformatics. %A Wang, Fang %A Xu, Jia %A Xu, Shu-Jun %A Guo, Jie-Jie %A Wang, Feiming %A Wang, Qin-Wen %K Alzheimer Disease %K Computational Biology %K COVID-19 %K Databases, Genetic %K Gene Expression Profiling %K Humans %K Protein Interaction Maps %K SARS-CoV-2 %X

BACKGROUND: COVID-19 pandemic is a global crisis which results in millions of deaths and causes long-term neurological sequelae, such as Alzheimer's disease (AD).

OBJECTIVE: We aimed to explore the interaction between COVID-19 and AD by integrating bioinformatics to find the biomarkers which lead to AD occurrence and development with COVID-19 and provide early intervention.

METHODS: The differential expressed genes (DEGs) were found by GSE147507 and GSE132903, respectively. The common genes between COVID-19 and AD were identified. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interactions (PPI) network analysis were carried out. Hub genes were found by cytoscape. A multivariate logistic regression model was constructed. NetworkAnalyst was used for the analysis of TF-gene interactions, TF-miRNA coregulatory network, and Protein-chemical Interactions.

RESULTS: Forty common DEGs for AD and COVID-19 were found. GO and KEGG analysis indicated that the DEGs were enriched in the calcium signal pathway and other pathways. A PPI network was constructed, and 5 hub genes were identified (ITPR1, ITPR3, ITPKB, RAPGEF3, MFGE8). Four hub genes (ITPR1, ITPR3, ITPKB, RAPGEF3) which were considered as important factors in the development of AD that were affected by COVID-19 were shown by nomogram. Utilizing NetworkAnalyst, the interaction network of 4 hub genes and TF, miRNA, common AD risk genes, and known compounds is displayed, respectively.

CONCLUSION: COVID-19 patients are at high risk of developing AD. Vaccination is required. Four hub genes can be considered as biomarkers for prediction and treatment of AD development caused by COVID-19. Compounds with neuroprotective effects can be used as adjuvant therapy for COVID-19 patients.

%B J Alzheimers Dis %V 85 %P 729-744 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34776447?dopt=Abstract %R 10.3233/JAD-215086 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Anticholinergic Drug Burden and Neurocognitive Performance in the Study of Latinos-Investigation of Neurocognitive Aging. %A Posis, Alexander Ivan B %A Tarraf, Wassim %A Gonzalez, Kevin A %A Soria-Lopez, Jose A %A Léger, Gabriel C %A Stickel, Ariana M %A Daviglus, Martha L %A Lamar, Melissa %A Zeng, Donglin %A González, Hector M %X

BACKGROUND: Studies of cumulative anticholinergic drug burden on cognitive function and impairment are emerging, yet few for Hispanics/Latinos.

OBJECTIVE: To examine associations between anticholinergic use and neurocognitive performance outcomes among diverse Hispanics/Latinos.

METHODS: This prospective cohort study included diverse Hispanic/Latino participants, enrolled in the Study of Latinos-Investigation of Neurocognitive, from New York, Chicago, Miami, and San Diego (n = 6,249). Survey linear regression examined associations between anticholinergic use (measured during baseline [Visit 1] and average 7-year follow up [Visit 2]) with global cognition, episodic learning, memory, phonemic fluency, processing speed, executive functioning, and average 7-year change.

RESULTS: Anticholinergic use was associated with lower cognitive global cognition (β= -0.21; 95% CI [-0.36; -0.05]), learning (β= -0.27; 95% CI [-0.47; -0.07]), memory (β= -0.22; 95% CI [-0.41; -0.03]), and executive functioning (β= -0.22; 95% CI [-0.40; -0.03]) scores, particularly among those who took anticholinergics at both visits. Anticholinergic use was associated with faster decline in global cognition, learning, and verbal fluency (β: -0.28 [95% CI: -0.55, -0.01]; β: -0.28 [95% CI: -0.55, -0.01]; β: -0.25, [95% CI -0.47, -0.04], respectively). Sex modified associations between anticholinergic use with global cognition, learning, and executive functioning (F3 = 3.59, F3 = 2.84, F3 = 3.88, respectively).

CONCLUSION: Anticholinergic use was associated with lower neurocognitive performance, especially among those who used anticholinergics at both visits, among a study population of diverse Hispanics/Latinos. Findings will support evidence-based decisions regarding anticholinergic prescriptions and efforts to minimize cognitive impact.

%B J Alzheimers Dis %V 86 %P 53-65 %8 2022 Mar 08 %G eng %N 1 %R 10.3233/JAD-215247 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Antihypertensive Medication Class and the Risk of Dementia and Cognitive Decline in Older Adults: A Secondary Analysis of the Prospective HELIAD Cohort. %A Liampas, Ioannis %A Hatzimanolis, Alex %A Siokas, Vasileios %A Yannakoulia, Mary %A Kosmidis, Mary H %A Sakka, Paraskevi %A Hadjigeorgiou, Georgios M %A Scarmeas, Nikolaos %A Dardiotis, Efthimios %K Aged %K Angiotensin Receptor Antagonists %K Angiotensin-Converting Enzyme Inhibitors %K Antihypertensive Agents %K Calcium Channel Blockers %K Cognitive Dysfunction %K Dementia %K Diuretics %K Female %K Humans %K Hypertension %K Male %K Prospective Studies %X

BACKGROUND: It is unclear whether the main antihypertensive medication classes (diuretics, calcium channel blockers, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers (ARBs)) are associated with different risks of cognitive decline. Published evidence is conflicting and stems mainly from observational studies.

OBJECTIVE: To investigate the differential effects of antihypertensives on the risks of developing dementia and cognitive decline, with a specific focus on the vascular component of the mechanisms underlying these interactions.

METHODS: Older adults with a history of hypertension and without dementia were drawn from the population-based HELIAD cohort. Age-, gender-, education-, and antihypertensive medication- (five dichotomous exposures) adjusted Cox proportional-hazards models and generalized estimating equations were performed to appraise the associations of baseline antihypertensive therapy with dementia incidence and cognitive decline (quantified using a comprehensive neuropsychological battery). Analyses were subsequently adjusted for clinical vascular risk (dyslipidemia, diabetes mellitus, smoking, cardiovascular, and cerebrovascular history) and genetic susceptibility to stroke (using polygenic risk scores generated according to the MEGASTROKE consortium GWAS findings).

RESULTS: A total of 776 predominantly female participants (73.61±4.94 years) with hypertension and a mean follow-up of 3.02±0.82 years were analyzed. Baseline treatment was not associated with the risk of incident dementia. ARB users experienced a slower yearly global cognitive [2.5% of a SD, 95% CI = (0.1, 4.9)] and language [4.4% of a SD, 95% CI = (1.4, 7.4)] decline compared to non-users. The fully adjusted model reproduced similar associations for both global cognitive [β= 0.027, 95% CI =  (-0.003, 0.057)], and language decline [β= 0.063, 95% CI = (0.023, 0.104)].

CONCLUSION: ARBs may be superior to other antihypertensive agents in the preservation of cognition, an association probably mediated by vascular-independent mechanisms.

%B J Alzheimers Dis %V 89 %P 709-719 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35912747?dopt=Abstract %R 10.3233/JAD-220439 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Anti-Inflammatory Gene Therapy Improves Spatial Memory Performance in a Mouse Model of Alzheimer's Disease. %A Yoo, Tai June %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Anti-Inflammatory Agents %K Cognition %K Disease Models, Animal %K Female %K Genetic Therapy %K Immunity, Cellular %K Immunotherapy %K Injections, Intramuscular %K Interleukin-10 %K Interleukin-4 %K Male %K Mice %K Mice, Transgenic %K Spatial Memory %X

The immune system plays a critical role in neurodegenerative processes involved in Alzheimer's disease (AD). In this study, a gene-based immunotherapeutic method examined the effects of anti-inflammatory cellular immune response elements (CIREs) in the amyloid-β protein precursor (AβPP) mouse model. Bi-monthly intramuscular administration, beginning at either 4 or 6 months, and examined at 7.5 through 16 months, with plasmids encoding Interleukin (IL)-10, IL-4, TGF-β polynucleotides, or a combination thereof, into AβPP mice improved spatial memory performance. This work demonstrates an efficient gene therapy strategy to downregulate neuroinflammation, and possibly prevent or delay cognitive decline in AD.

%B J Alzheimers Dis %V 85 %P 1001-1008 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34897091?dopt=Abstract %R 10.3233/JAD-215270 %0 Journal Article %J J Alzheimers Dis %D 2022 %T APOEɛ4 Allele Moderates the Association Between Basal Forebrain Nuclei Volumes and Allocentric Navigation in Older Adults Without Dementia. %A Lerch, Ondřej %A Pařízková, Martina %A Vyhnálek, Martin %A Nedelska, Zuzana %A Hort, Jakub %A Laczó, Jan %X

BACKGROUND: Cholinergic deficit and medial temporal lobe (MTL) atrophy are hallmarks of Alzheimer's disease (AD) leading to early allocentric spatial navigation (aSN) impairment. APOEɛ4 allele (E4) is a major genetic risk factor for late-onset AD and contributes to cholinergic dysfunction. Basal forebrain (BF) nuclei, the major source of acetylcholine, project into multiple brain regions and, along with MTL and prefrontal cortex (PFC), are involved in aSN processing.

OBJECTIVE: We aimed to determine different contributions of individual BF nuclei atrophy to aSN in E4 positive and E4 negative older adults without dementia and assess whether they operate on aSN through MTL and PFC or independently from these structures.

METHODS: 120 participants (60 E4 positive, 60 E4 negative) from the Czech Brain Aging Study underwent structural MRI and aSN testing in real-space arena setting. Hippocampal and BF nuclei volumes and entorhinal cortex and PFC thickness were obtained. Associations between brain regions involved in aSN were assessed using MANOVA and complex model of mutual relationships was built using structural equation modelling (SEM).

RESULTS: Path analysis based on SEM modeling revealed that BF Ch1-2, Ch4p, and Ch4ai nuclei volumes were indirectly associated with aSN performance through MTL (pch1 - 2 = 0.039; pch4p = 0.042) and PFC (pch4ai = 0.044). In the E4 negative group, aSN was indirectly associated with Ch1-2 nuclei volumes (p = 0.015), while in the E4 positive group, there was indirect effect of Ch4p nucleus (p = 0.035).

CONCLUSION: Our findings suggest that in older adults without dementia, BF nuclei affect aSN processing indirectly, through MTL and PFC, and that APOE E4 moderates these associations.

%B J Alzheimers Dis %V 86 %P 155-171 %8 2022 Mar 08 %G eng %N 1 %R 10.3233/JAD-215034 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association Between High Serum Tetrahydrofolate and Low Cognitive Functions in the United States: A Cross-Sectional Study. %A Fan, Yaohua %A Liu, Wen %A Chen, Si %A Li, Mengzhu %A Zhao, Lijun %A Wu, Chunxiao %A Liu, Helu %A Zhu, Meiling %X

BACKGROUND: The relationship between serum folate status and cognitive functions is still controversial.

OBJECTIVE: To evaluate the association between serum tetrahydrofolate and cognitive functions.

METHODS: A total of 3,132 participants (60-80 years old) from the 2011-2014 NHANES were included in this cross-sectional study. The primary outcome measure was cognitive function assessment, determined by the Consortium to Establish a Registry for Alzheimer's Disease Word Learning Test (CERAD-WL), CERAD-Delayed Recall Test (CERAD-DR), Animal Fluency Test (AF), Digit Symbol Substitution Test (DSST), and global cognitive score. Generalized linear model (GLM), multivariate logistic regression models, weighted generalized additive models (GAM), and subgroup analyses were performed to evaluate the association between serum tetrahydrofolate and low cognitive functions.

RESULTS: In GLM, and the crude model, model 1, model 2 of multivariate logistic regression models, increased serum tetrahydrofolate was associated with reduced cognitive functions via AF, DSST, CERAD-WL, CERAD-DR, and global cognitive score (p <  0.05). In GAM, the inflection points were 1.1, 2.8, and 2.8 nmol/L tetrahydrofolate, determined by a two-piece wise linear regression model of AF, DSST, and global cognitive score, respectively. Also, in GAM, there were no non-linear relationship between serum tetrahydrofolate and low cognitive functions, as determined by CERAD-WL or CERAD-DR. The results of subgroup analyses found that serum tetrahydrofolate levels and reduced cognitive functions as determined by AF had significant interactions for age and body mass index. The association between high serum tetrahydrofolate level and reduced cognitive functions as determined using DSST, CERAD-WL, CERAD-DR, or global cognitive score had no interaction with the associations between cognition and gender, or age, or so on.

CONCLUSION: High serum tetrahydrofolate level is associated with significantly reduced cognitive function.

%B J Alzheimers Dis %V 89 %P 163-179 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-220058 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association Between Plasma Biomarkers of Amyloid, Tau, and Neurodegeneration with Cerebral Microbleeds. %A McCarter, Stuart J %A Lesnick, Timothy G %A Lowe, Val J %A Rabinstein, Alejandro A %A Przybelski, Scott A %A Algeciras-Schimnich, Alicia %A Ramanan, Vijay K %A Jack, Clifford R %A Petersen, Ronald C %A Knopman, David S %A Boeve, Bradley F %A Kantarci, Kejal %A Vemuri, Prashanthi %A Mielke, Michelle M %A Graff-Radford, Jonathan %X

BACKGROUND: Cerebral microbleeds (CMBs) are a common vascular pathology associated with future intracerebral hemorrhage. Plasma biomarkers of amyloid, tau, and neurodegeneration may provide a screening avenue to identify those with CMBs, but evidence is conflicting.

OBJECTIVE: To determine the association between plasma biomarkers (Aβ40, Aβ42, t-tau, p-tau181, p-tau217, neurofilament light chain (NfL)) and CMBs in a population-based study of aging and whether these biomarkers predict higher signal on Aβ-PET imaging in patients with multiple CMBs.

METHODS: 712 participants from the Mayo Clinic Study of Aging with T2 * GRE MRI and plasma biomarkers were included. Biomarkers were analyzed utilizing Simoa (Aβ40, Aβ42, t-tau, NfL) or Meso Scale Discovery (p-tau181, p-tau217) platforms. Cross-sectional associations between CMBs, plasma biomarkers and Aβ-PET were evaluated using hurdle models and multivariable regression models.

RESULTS: Among the 188 (26%) individuals with≥1 CMB, a lower plasma Aβ42/Aβ40 ratio was associated with more CMBs after adjusting for covariables (IRR 568.5 95% CI 2.8-116,127). No other biomarkers were associated with risk or number CMBs. In 81 individuals with≥2 CMBs, higher plasma t-tau, p-tau181, and p-tau217 all were associated with higher Aβ-PET signal, with plasma p-tau217 having the strongest predictive value (r2 0.603, AIC -53.0).

CONCLUSION: Lower plasma Aβ42/Aβ40 ratio and higher plasma p-tau217 were associated with brain amyloidosis in individuals with CMBs from the general population. Our results suggest that in individuals with multiple CMBs and/or lobar intracranial hemorrhage that a lower plasma Aβ42/Aβ40 ratio or elevated p-tau217 may indicate underlying cerebral amyloid angiopathy.

%B J Alzheimers Dis %V 87 %P 1537-1547 %8 2022 Jun 14 %G eng %N 4 %R 10.3233/JAD-220158 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association Between Serum Vitamins and the Risk of Alzheimer's Disease in Chinese Population. %A Liu, Xi-Xi %A Wu, Peng-Fei %A Liu, Ying-Zi %A Jiang, Ya-Ling %A Wan, Mei-Dan %A Xiao, Xue-Wen %A Yang, Qi-Jie %A Jiao, Bin %A Liao, Xin-Xin %A Wang, Jun-Ling %A Liu, Shao-Hui %A Zhang, Xuewei %A Shen, Lu %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Case-Control Studies %K China %K Female %K Folic Acid %K Humans %K Logistic Models %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Riboflavin %K Risk %K Vitamin B 12 %K Vitamin D %K Vitamin E %X

BACKGROUND: Alzheimer's disease (AD) is a chronic and fatal neurodegenerative disease; accumulating evidence suggests that vitamin deficiency is associated with the risk of AD. However, studies attempting to elucidate the relationship between vitamins and AD varied widely.

OBJECTIVE: This study aimed to investigate the relationship between serum vitamin levels and AD in a cohort of the Chinese population.

METHODS: A total of 368 AD patients and 574 healthy controls were recruited in this study; serum vitamin A, B1, B6, B9, B12, C, D, and E were measured in all participants.

RESULTS: Compared with the controls, vitamin B2, B9, B12, D, and E were significantly reduced in AD patients. Lower levels of vitamin B2, B9, B12, D, and E were associated with the risk of AD. After adjusting for age and gender, low levels of vitamin B2, B9, and B12 were still related to the risk of AD. In addition, a negative correlation was determined between vitamin E concentration and Activity of Daily Living Scale score while no significant association was found between serum vitamins and age at onset, disease duration, Mini-Mental State Examination, and Neuropsychiatric Inventory Questionnaire score.

CONCLUSION: We conclude that lower vitamin B2, B9, B12, D, and E might be associated with the risk of AD, especially vitamin B2, B9, and B12. And lower vitamin E might be related to severe ability impairment of daily activities.

%B J Alzheimers Dis %V 85 %P 829-836 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864672?dopt=Abstract %R 10.3233/JAD-215104 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association of Alzheimer's Disease with COVID-19 Susceptibility and Severe Complications: A Nationwide Cohort Study. %A Chung, Seok Jong %A Chang, Yoonkyung %A Jeon, Jimin %A Shin, Jae Il %A Song, Tae-Jin %A Kim, Jinkwon %K Alzheimer Disease %K Cohort Studies %K COVID-19 %K Humans %K Pandemics %K Retrospective Studies %K SARS-CoV-2 %X

BACKGROUND: Identification of patients at high susceptibility and high risk of developing serious complications related to coronavirus disease 2019 (COVID-19) infection is clinically important in the face of the COVID-19 pandemic.

OBJECTIVE: To investigate whether patients with Alzheimer's disease (AD) are more susceptible to COVID-19 infection and whether they have a higher risk of developing serious complications.

METHODS: We retrospectively reviewed the Korean nationwide population-based COVID-19 dataset for participants who underwent real-time reverse transcription polymerase chain reaction assays for COVID-19 between January 1 and June 4, 2020. A 1 : 3 ratio propensity score matching and binary logistic regression analysis were performed to investigate the association between AD and the susceptibility or severe complications (i.e., mechanical ventilation, intensive care unit admission, or death) of COVID-19.

RESULTS: Among 195,643 study participants, 5,725 participants had AD and 7,334 participants were diagnosed with COVID-19. The prevalence of participants testing positive for COVID-19 did not differ according to the presence of AD (p = 0.234). Meanwhile, AD was associated with an increased risk of severe COVID-19 complications (OR 2.25 [95% CI 1.54-3.28]). Secondary outcome analyses showed that AD patients had an increased risk for mortality (OR 3.09 [95% CI 2.00-4.78]) but were less likely to receive mechanical ventilation (OR 0.42 [95% CI 0.20-0.87]).

CONCLUSION: AD was not associated with increased susceptibility to COVID-19 infection, but was associated with severe COVID-19 complications, especially with mortality. Early diagnosis and active intervention are necessary for patients with AD suspected COVID-19 infection.

%B J Alzheimers Dis %V 87 %P 701-710 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275548?dopt=Abstract %R 10.3233/JAD-220031 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association of Aspirin Use with Reduced Risk of Developing Alzheimer's Disease in Elderly Ischemic Stroke Patients: A Retrospective Cohort Study. %A Gorenflo, Maria P %A Davis, Pamela B %A Kendall, Ellen K %A Olaker, Veronica R %A Kaelber, David C %A Xu, Rong %X

BACKGROUND: Currently there are no effective therapies to prevent or halt the development of Alzheimer's disease (AD). Multiple risk factors are involved in AD, including ischemic stroke (IS). Aspirin is often prescribed following IS to prevent blood clot formation. Observational studies have shown inconsistent findings with respect to the relationship between aspirin use and the risk of AD.

OBJECTIVE: To investigate the relationship between aspirin therapy after IS and the new diagnosis of AD in elderly patients.

METHODS: This retrospective cohort study leveraged a large database that contains over 90 million electronic health records to compare the hazard rates of AD after IS in elderly patients prescribed aspirin versus those not prescribed aspirin after propensity-score matching for relevant confounders.

RESULTS: At 1, 3, and 5 years after first IS, elderly patients prescribed aspirin were less likely to develop AD than those not prescribed aspirin: Hazard Ratio = 0.78 [0.65,0.94], 0.8 1 [0.70,0.94], and 0.76 [0.70,0.92].

CONCLUSION: Our findings suggest that aspirin use may prevent AD in patients with IS, a subpopulation at high risk of developing the disease.

%B J Alzheimers Dis %V 91 %P 697-704 %8 2023 Jan 17 %G eng %N 2 %R 10.3233/JAD-220901 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association of Brain Volume and Retinal Thickness in the Early Stages of Alzheimer's Disease. %A Mathew, Sunu %A WuDunn, Darrell %A Mackay, Devin D %A Vosmeier, Aaron %A Tallman, Eileen F %A Deardorff, Rachael %A Harris, Alon %A Farlow, Martin R %A Brosch, Jared R %A Gao, Sujuan %A Apostolova, Liana G %A Saykin, Andrew J %A Risacher, Shannon L %X

BACKGROUND: The eye has been considered a 'window to the brain,' and several neurological diseases including neurodegenerative conditions like Alzheimer's disease (AD) also show changes in the retina.

OBJECTIVE: To investigate retinal nerve fiber layer (RNFL) thickness and its association with brain volume via magnetic resonance imaging (MRI) in older adults with subjective or objective cognitive decline.

METHODS: 75 participants underwent ophthalmological and neurological evaluation including optical coherence tomography and MRI (28 cognitively normal subjects, 26 with subjective cognitive decline, 17 patients diagnosed with mild cognitive impairment, and 4 with AD). Differences in demographics, thickness of RNFL, and brain volume were assessed using ANCOVA, while partial Pearson correlations, covaried for age and sex, were used to compare thickness of the peripapillary RNFL with brain volumes, with p < 0.05 considered statistically significant.

RESULTS: Mean RNFL thickness was significantly correlated with brain volumes, including global volume (right eye r = 0.235 p = 0.046, left eye r = 0.244, p = 0.037), temporal lobe (right eye r = 0.242 p = 0.039, left eye r = 0.290, p = 0.013), hippocampal (right eye r = 0.320 p = 0.005, left eye r = 0.306, p = 0.008), amygdala (left eye r = 0.332, p = 0.004), and occipital lobe (right eye r = 0.264 p = 0.024) volumes.

CONCLUSION: RNFL thickness in both eyes was positively associated with brain volumes in subjects with subjective and objective cognitive decline. The RNFL, however, did not correlate with the disease, but the small sample number makes it important to conduct larger studies. RNFL thickness may be a useful non-invasive and inexpensive tool for detection of brain neurodegeneration and may assist with diagnosis and monitoring of progression and treatment in AD.

%B J Alzheimers Dis %V 91 %P 743-752 %8 2023 Jan 17 %G eng %N 2 %R 10.3233/JAD-210533 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association of Carotid Intima Media Thickening with Future Brain Region Specific Amyloid-β Burden. %A Baradaran, Hediyeh %A Peloso, Gina M %A Polak, Joseph F %A Killiany, Ronald J %A Ghosh, Saptaparni %A DeCarli, Charles S %A Thibault, Emma G %A Sperling, Reisa A %A Johnson, Keith A %A Beiser, Alexa %A Romero, Jose R %A Seshadri, Sudha %X

BACKGROUND: Carotid atherosclerosis is associated with cognitive impairment and dementia, though there is limited evidence of a direct link between carotid disease and amyloid-β (Aβ) burden.

OBJECTIVE: We studied the association of baseline and progressive carotid intima media thickness (CIMT) with Aβ on 11C-Pittsburgh Compound B (PiB) to determine if those with carotid atherosclerosis would have higher Aβ burden.

METHODS: We studied 47 participants from the Framingham Offspring cohort with carotid ultrasounds measuring CIMT at their 6th clinic examination (aged 49.5±5.7 years) and an average of 9.6 years later, and PiB imaging measuring Aβ on average 22.1 years post baseline. We used multivariate linear regression analyses to relate baseline, follow-up, mean, and progression of internal carotid artery (ICA) and common carotid artery (CCA) CIMT to Aβ in brain regions associated with Alzheimer's disease (AD) and related dementias (ADRD), adjusting for age, sex, and other vascular risk factors.

RESULTS: Participants with higher mean ICA IMT had more Aβ in the precuneus (beta±standard error [β±SE]: 0.466±0.171 mm, p = 0.01) and the frontal, lateral, and retrosplenial regions (β±SE: 0.392±0.164 mm, p = 0.022) after adjusting for age, sex, vascular risk factors, and medication use. We did not find an association between any CCA IMT measures and Aβ or progression of ICA or CCA IMT and Aβ.

CONCLUSION: Carotid atherosclerosis, as measured by ICA IMT, is associated with increased Aβ burden later in life. These findings support a link between vascular disease and AD/ADRD pathophysiology.

%B J Alzheimers Dis %V 89 %P 223-232 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-215679 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association of Cholinergic Basal Forebrain Volume and Functional Connectivity with Markers of Inflammatory Response in the Alzheimer's Disease Spectrum. %A Teipel, Stefan J %A Dyrba, Martin %A Ballarini, Tommaso %A Brosseron, Frederic %A Bruno, Davide %A Buerger, Katharina %A Cosma, Nicoleta-Carmen %A Dechent, Peter %A Dobisch, Laura %A Düzel, Emrah %A Ewers, Michael %A Fliessbach, Klaus %A Haynes, John D %A Janowitz, Daniel %A Kilimann, Ingo %A Laske, Christoph %A Maier, Franziska %A Metzger, Coraline D %A Munk, Matthias H %A Peters, Oliver %A Pomara, Nunzio %A Preis, Lukas %A Priller, Josef %A Rámirez, Alfredo %A Roy, Nina %A Scheffler, Klaus %A Schneider, Anja %A Schott, Björn H %A Spottke, Annika %A Spruth, Eike J %A Wagner, Michael %A Wiltfang, Jens %A Jessen, Frank %A Heneka, Michael T %K Aged %K Alzheimer Disease %K Basal Forebrain %K Biomarkers %K Cholinergic Agents %K Cognitive Dysfunction %K Cohort Studies %K Female %K Humans %K Inflammation %K Magnetic Resonance Imaging %K Male %X

BACKGROUND: Inflammation has been described as a key pathogenic event in Alzheimer's disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies.

OBJECTIVE: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum.

METHODS: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum.

RESULTS: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small.

CONCLUSION: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples.

%B J Alzheimers Dis %V 85 %P 1267-1282 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34924387?dopt=Abstract %R 10.3233/JAD-215196 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association of COVID-19 with New-Onset Alzheimer's Disease. %A Wang, Lindsey %A Davis, Pamela B %A Volkow, Nora D %A Berger, Nathan A %A Kaelber, David C %A Xu, Rong %K Aged %K Aged, 80 and over %K Alzheimer Disease %K COVID-19 %K COVID-19 Testing %K Female %K Humans %K Retrospective Studies %K SARS-CoV-2 %X

An infectious etiology of Alzheimer's disease has been postulated for decades. It remains unknown whether SARS-CoV-2 viral infection is associated with increased risk for Alzheimer's disease. In this retrospective cohort study of 6,245,282 older adults (age ≥65 years) who had medical encounters between 2/2020-5/2021, we show that people with COVID-19 were at significantly increased risk for new diagnosis of Alzheimer's disease within 360 days after the initial COVID-19 diagnosis (hazard ratio or HR:1.69, 95% CI: 1.53-1.72), especially in people age ≥85 years and in women. Our findings call for research to understand the underlying mechanisms and for continuous surveillance of long-term impacts of COVID-19 on Alzheimer's disease.

%B J Alzheimers Dis %V 89 %P 411-414 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35912749?dopt=Abstract %R 10.3233/JAD-220717 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Associations Between Brainstem Volume and Alzheimer's Disease Pathology in Middle-Aged Individuals of the Framingham Heart Study. %A Jacobs, Heidi I L %A O'Donnell, Adrienne %A Satizabal, Claudia L %A Lois, Cristina %A Kojis, Daniel %A Hanseeuw, Bernard J %A Thibault, Emma %A Sanchez, Justin S %A Buckley, Rachel F %A Yang, Qiong %A DeCarli, Charles %A Killiany, Ron %A Sargurupremraj, Muralidharan %A Sperling, Reisa A %A Johnson, Keith A %A Beiser, Alexa S %A Seshadri, Sudha %X

The brainstem is among the first regions to accumulate Alzheimer's disease (AD)-related hyperphosphorylated tau pathology during aging. We aimed to examine associations between brainstem volume and neocortical amyloid-β or tau pathology in 271 middle-aged clinically normal individuals of the Framingham Heart Study who underwent MRI and PET imaging. Lower volume of the medulla, pons, or midbrain was associated with greater neocortical amyloid burden. No associations were detected between brainstem volumes and tau deposition. Our results support the hypothesis that lower brainstem volumes are associated with initial AD-related processes and may signal preclinical AD pathology.

%B J Alzheimers Dis %V 86 %P 1603-1609 %8 2022 Apr 19 %G eng %N 4 %R 10.3233/JAD-215372 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Associations Between Intrathecal Levels of Vitamin D, Cytokines, and Core Biomarkers of Alzheimer's Disease: A Cross-Sectional Study. %A Soares, Jelena Zugic %A Valeur, Jørgen %A Šaltytė Benth, Jūratė %A Knapskog, Anne-Brita %A Selbæk, Geir %A Bogdanovic, Nenad %A Pettersen, Renate %X

BACKGROUND: Several studies have examined association between vitamin D levels in serum and cognition, but little is known of vitamin D levels in cerebrospinal fluid (CSF) and association with Alzheimer's disease (AD).

OBJECTIVE: In this cross-sectional, explorative study we investigated possible associations of vitamin D in CSF with biomarkers for AD, amyloid-β, tau protein/phosphorylated tau protein in CSF, and with the cytokines IL-6, IL-8, and TNF-α in CSF in patients with cognitive impairment and cognitively healthy controls.

METHODS: We included 100 outpatients ≥65 years referred for assessment of cognitive impairment and 76 age- and sex-matched cognitively healthy controls. Levels of 25-hydroxyvitamin D (25(OH)D), amyloid-β, tau protein and phosphorylated tau protein, as well as IL-6, IL-8, and TNF-α, were analyzed in CSF in both groups.

RESULTS: Higher levels of 25(OH)D in CSF in all groups together were associated with lower levels of tau protein (p = 0.01) and phosphorylated tau protein (p = 0.005). We found no association between 25(OH)D levels in CSF and pathological levels of amyloid-β in CSF nor levels of IL-6 or TNF-α in CSF. Higher levels of 25(OH)D in CSF were associated with higher levels of IL-8 in CSF (p = 0.002). However, vitamin D explained only 6% of variance in IL-8. There was no significant difference between the patient groups and the control group regarding the association between 25(OH)D in CSF and any of the three cytokines in CSF.

CONCLUSION: Participants with higher CSF levels of 25(OH)D exhibited reduced CSF levels of tau protein and phosphorylated tau protein.

%B J Alzheimers Dis %V 89 %P 825-834 %8 2022 Sep 27 %G eng %N 3 %R 10.3233/JAD-220407 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Associations Between Vascular Risk Factor and Perivascular Spaces in Adults with Intact Cognition, Mild Cognitive Impairment, and Dementia. %A Rundek, Tatjana %A Del Brutto, Victor %A Goryawala, Mohammed %A Dong, Chuanhui %A Agudelo, Christian %A Saporta, Anita Seixas %A Merritt, Stacy %A Camargo, Christian %A Ariko, Taylor %A Loewenstein, David A %A Duara, Ranjan %A Haq, Ihtsham %X

BACKGROUND: Perivascular spaces (PVS) are fluid-filled compartments surrounding small intracerebral vessels that transport fluid and clear waste.

OBJECTIVE: We examined associations between PVS count, vascular and neurodegenerative risk factors, and cognitive status among the predominantly Hispanic participants of the FL-VIP Study of Alzheimer's Disease Risk.

METHODS: Using brain MRI (n = 228), we counted PVS in single axial image through the basal ganglia (BG) and centrum semiovale (CSO). PVS per region were scored as 0 (none), 1 (<10), 2 (11-20), 3 (21-40), and 4 (>40). Generalized linear models examined PVS associations with vascular risk factors and a composite vascular comorbidity risk (VASCom) score.

RESULTS: Our sample (mean age 72±8 years, 61% women, 60% Hispanic, mean education 15±4 years, 33% APOE4 carriers) was 59% hypertensive, 21% diabetic, 66% hypercholesteremic, and 30% obese. Mean VASCom score was 2.3±1.6. PVS scores ranged from 0-4 in the BG (mean 1.3±0.7) and CSO (mean 1.2±0.9), and 0-7 combined (mean 2.5±1.4). In multivariable regression models, BG PVS was associated with age (β= 0.03/year, p <  0.0001), Hispanic ethnicity (β= 0.29, p = 0.01), education (β= 0.04/year, p = 0.04), and coronary bypass surgery (β= 0.93, p = 0.02). CSO PVS only associated with age (β= 0.03/year, p <  0.01). APOE4 and amyloid-β were not associated with PVS.

CONCLUSION: BG PVS may be a marker of subclinical cerebrovascular disease. Further research is needed to validate associations and identify mechanisms linking BG PVS and cerebrovascular disease markers. PVS may be a marker of neurodegeneration despite our negative preliminary findings and more research is warranted. The association between BG PVS and Hispanic ethnicity also requires further investigation.

%B J Alzheimers Dis %V 89 %P 437-448 %8 2022 Sep 13 %G eng %N 2 %R 10.3233/JAD-215585 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis. %A Frenzel, Stefan %A Bis, Josh C %A Gudmundsson, Elias F %A O'Donnell, Adrienne %A Simino, Jeannette %A Yaqub, Amber %A Bartz, Traci M %A Brusselle, Guy G O %A Bülow, Robin %A DeCarli, Charles S %A Ewert, Ralf %A Gharib, Sina A %A Ghosh, Saptaparni %A Gireud-Goss, Monica %A Gottesman, Rebecca F %A Ikram, M Arfan %A Knopman, David S %A Launer, Lenore J %A London, Stephanie J %A Longstreth, W T %A Lopez, Oscar L %A Melo van Lent, Debora %A O'Connor, George %A Satizabal, Claudia L %A Shrestha, Srishti %A Sigurdsson, Sigurdur %A Stubbe, Beate %A Talluri, Rajesh %A Vasan, Ramachandran S %A Vernooij, Meike W %A Völzke, Henry %A Wiggins, Kerri L %A Yu, Bing %A Beiser, Alexa S %A Gudnason, Vilmundur %A Mosley, Thomas %A Psaty, Bruce M %A Wolters, Frank J %A Grabe, Hans J %A Seshadri, Sudha %X

BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.

OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables.

METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.

RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.

CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

%B J Alzheimers Dis %V 90 %P 1073-1083 %8 2022 Nov 22 %G eng %N 3 %R 10.3233/JAD-220667 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Augmenting Imaging Biomarker Performance with Blood-Based Gene Expression Levels for Predicting Alzheimer's Disease Progression. %A Dobromyslin, Vitaly I %A Megherbi, Dalila B %X

BACKGROUND: Structural brain imaging metrics and gene expression biomarkers have previously been used for Alzheimer's disease (AD) diagnosis and prognosis, but none of these studies explored integration of imaging and gene expression biomarkers for predicting mild cognitive impairment (MCI)-to-AD conversion 1-2 years into the future.

OBJECTIVE: We investigated advantages of combining gene expression and structural brain imaging features for predicting MCI-to-AD conversion. Selection of the differentially expressed genes (DEGs) for classifying cognitively normal (CN) controls and AD patients was benchmarked against previously reported results.

METHODS: The current work proposes integrating brain imaging and blood gene expression data from two public datasets (ADNI and ANM) to predict MCI-to-AD conversion. A novel pipeline for combining gene expression data from multiple platforms is proposed and evaluated in the two independents patient cohorts.

RESULTS: Combining DEGs and imaging biomarkers for predicting MCI-to-AD conversion yielded 0.832-0.876 receiver operating characteristic (ROC) area under the curve (AUC), which exceeded the 0.808-0.840 AUC from using the imaging features alone. With using only three DEGs, the CN versus AD predictive model achieved 0.718, 0.858, and 0.873 cross-validation AUC for the ADNI, ANM1, and ANM2 datasets.

CONCLUSION: For the first time we show that combining gene expression and imaging biomarkers yields better predictive performance than using imaging metrics alone. A novel pipeline for combining gene expression data from multiple platforms is proposed and evaluated to produce consistent results in the two independents patient cohorts. Using an improved feature selection, we show that predictive models with fewer gene expression probes can achieve competitive performance.

%B J Alzheimers Dis %V 87 %P 583-594 %8 2022 May 17 %G eng %N 2 %R 10.3233/JAD-215640 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Automated Early Detection of Alzheimer's Disease by Capturing Impairments in Multiple Cognitive Domains with Multiple Drawing Tasks. %A Kobayashi, Masatomo %A Yamada, Yasunori %A Shinkawa, Kaoru %A Nemoto, Miyuki %A Nemoto, Kiyotaka %A Arai, Tetsuaki %X

BACKGROUND: Automatic analysis of the drawing process using a digital tablet and pen has been applied to successfully detect Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, most studies focused on analyzing individual drawing tasks separately, and the question of how a combination of drawing tasks could improve the detection performance thus remains unexplored.

OBJECTIVE: We aimed to investigate whether analysis of the drawing process in multiple drawing tasks could capture different, complementary aspects of cognitive impairments, with a view toward combining multiple tasks to effectively improve the detection capability.

METHODS: We collected drawing data from 144 community-dwelling older adults (27 AD, 65 MCI, and 52 cognitively normal, or CN) who performed five drawing tasks. We then extracted motion- and pause-related drawing features for each task and investigated the statistical associations of the features with the participants' diagnostic statuses and cognitive measures.

RESULTS: The drawing features showed gradual changes from CN to MCI and then to AD, and the changes in the features for each task were statistically associated with cognitive impairments in different domains. For classification into the three diagnostic categories, a machine learning model using the features from all five tasks achieved a classification accuracy of 75.2%, an improvement by 7.8% over that of the best single-task model.

CONCLUSION: Our results demonstrate that a common set of drawing features from multiple drawing tasks can capture different, complementary aspects of cognitive impairments, which may lead to a scalable way to improve the automated detection of AD and MCI.

%B J Alzheimers Dis %V 88 %P 1075-1089 %8 2022 Aug 02 %G eng %N 3 %R 10.3233/JAD-215714 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Avoiding Over-Reliance on Multi-Domain Interventions for Dementia Prevention. %A Daly, Timothy %A Mastroleo, Ignacio %A Migliaccio, Raffaella %K Alzheimer Disease %K Humans %K Risk Factors %K Risk Reduction Behavior %X

Given the unknown therapeutic value of targeting Alzheimer's disease pathology and the discovery of robust risk factors for dementia, non-pharmacological risk reduction (RR) is increasingly offered as an alternative to targeting Alzheimer's disease pathology. While RR will surely be a useful tool to make public health gains, we propose solutions to three possible issues with over-reliance on multi-domain interventions to achieve RR: limited individual impact, an exclusive focus on later life, and overlooking social determinants of dementia. We argue in favor of a broader debate within the research community and greater society about how different therapeutic avenues should be explored.

%B J Alzheimers Dis %V 90 %P 989-992 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275544?dopt=Abstract %R 10.3233/JAD-215647 %0 Journal Article %J J Alzheimers Dis %D 2022 %T B Vitamin Supplementation Slows Cognitive Decline in Mild Cognitive Impairment Patients with Frontal Lobe Atrophy. %A Gong, Xianmin %A Shi, Lin %A Wu, Yuanyuan %A Luo, Yishan %A Kwok, Timothy %X

BACKGROUND: The effects of B vitamins on mild cognitive impairment (MCI) patients' cognition have been mixed, suggesting the existence of moderating factors.

OBJECTIVE: A post hoc analysis of a negative B vitamin trial was performed to examine the potential modulating effect of regional brain atrophy on the cognitive response to B vitamins in MCI patients.

METHODS: In the 24-month randomized trial, 279 MCI outpatients took 500μ#x03BC;g methylcobalamin and 400μ#x03BC;g folic acid once per day or placebo tablets once per day. Sixty-four aspirin users were excluded from analysis as aspirin use has been found to have significant negative interaction effects. Subjects were followed up at months 12 and 24. The primary cognitive outcome was clinical dementia rating scale sum of boxes (CDR_SOB). In a subgroup of 83 subjects, MRI brain scans were performed at baseline to estimate regional brain atrophy ratios.

RESULTS: Among the trial subjects who had MRI data, B vitamin supplementation had no significant effect on CDR_SOB, despite having significant homocysteine lowering effects. The atrophy ratio of the left frontal lobe significantly moderated the effect of B vitamin supplementation on CDR_SOB, after adjusting for confounders, in that B vitamin supplementation was associated with lower CDR_SOB scores (i.e., better cognitive function) at the 24th month among those patients with above median atrophy ratios, but not among those with lower atrophy ratios, in the left frontal lobe.

CONCLUSION: B vitamins may be more effective in slowing down cognitive decline in MCI patients with atrophy in the left frontal lobe.

%B J Alzheimers Dis %V 89 %P 1453-1461 %8 2022 Oct 11 %G eng %N 4 %R 10.3233/JAD-220685 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Barriers to Effective Memory Assessments for Alzheimer's Disease. %A Parra, Mario A %K Alzheimer Disease %K Cognition %K Cognition Disorders %K Humans %K Longitudinal Studies %X

Recently, Alzheimer's Disease International (ADI) stressed that around 75% of people living with dementia globally are still not receiving a diagnosis. In this commentary, I reflect on how efforts towards better cognitive assessments, particularly of memory, can be aligned and harmonized to contribute to such needs. I highlight some barriers that ongoing collaborations and trials are facing and their potential drivers. I suggest some strategies that can help overcome them and in so doing, integrate research agendas. We need to ignite the debate towards strategies that can help level the playfield to tackle Alzheimer's disease with true global solutions.

%B J Alzheimers Dis %V 90 %P 981-988 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35147540?dopt=Abstract %R 10.3233/JAD-215445 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Behavioral and Psychological Symptoms of Dementia in Different Dementia Disorders: A Large-Scale Study of 10,000 Individuals. %A Schwertner, Emilia %A Pereira, Joana B %A Xu, Hong %A Secnik, Juraj %A Winblad, Bengt %A Eriksdotter, Maria %A Nägga, Katarina %A Religa, Dorota %K Alzheimer Disease %K Behavioral Symptoms %K Dementia, Vascular %K Frontotemporal Dementia %K Hallucinations %K Humans %K Parkinson Disease %X

BACKGROUND: The majority of individuals with dementia will suffer from behavioral and psychological symptoms of dementia (BPSD). These symptoms contribute to functional impairment and caregiver burden.

OBJECTIVE: To characterize BPSD in Alzheimer's disease (AD), vascular dementia (VaD), mixed (Mixed) dementia, Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and unspecified dementia in individuals residing in long-term care facilities.

METHODS: We included 10,405 individuals with dementia living in long-term care facilities from the Swedish registry for cognitive/dementia disorders (SveDem) and the Swedish BPSD registry. BPSD was assessed with the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH). Multivariate logistic regression models were used to evaluate the associations between dementia diagnoses and different BPSDs.

RESULTS: The most common symptoms were aberrant motor behavior, agitation, and irritability. Compared to AD, we found a lower risk of delusions (in FTD, unspecified dementia), hallucinations (FTD), agitation (VaD, PDD, unspecified dementia), elation/euphoria (DLB), anxiety (Mixed, VaD, unspecified dementia), disinhibition (in PDD), irritability (in DLB, FTD, unspecified dementia), aberrant motor behavior (Mixed, VaD, unspecified dementia), and sleep and night-time behavior changes (unspecified dementia). Higher risk of delusions (DLB), hallucinations (DLB, PDD), apathy (VaD, FTD), disinhibition (FTD), and appetite and eating abnormalities (FTD) were also found in comparison to AD.

CONCLUSION: Although individuals in our sample were diagnosed with different dementia disorders, they all exhibited aberrant motor behavior, agitation, and irritability. This suggests common underlying psychosocial or biological mechanisms. We recommend prioritizing these symptoms while planning interventions in long-term care facilities.

%B J Alzheimers Dis %V 87 %P 1307-1318 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35491774?dopt=Abstract %R 10.3233/JAD-215198 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Better Subjective Sleep Quality Partly Explains the Association Between Self-Reported Physical Activity and Better Cognitive Function. %A Cheval, Boris %A Maltagliati, Silvio %A Sieber, Stefan %A Cullati, Stéphane %A Zou, Liye %A Ihle, Andreas %A Kramer, Arthur F %A Yu, Qian %A Sander, David %A Boisgontier, Matthieu P %K Cognition %K Exercise %K Humans %K Self Report %K Sleep %K Sleep Quality %X

BACKGROUND: Physical activity has been associated with better cognitive function and better sleep quality. Yet, whether the beneficial effect of physical activity on cognitive function can be explained by an indirect pathway involving better sleep quality is unclear.

OBJECTIVE: To investigate whether sleep quality mediates the association between physical activity and cognitive function in adults 50 years of age or older.

METHODS: 86,541 community-dwelling European adults were included in the study. Physical activity and sleep quality were self-reported. Indicators of cognitive function (immediate recall, delayed recall, verbal fluency) were assessed using objective tests. All measures were collected six times between 2004 and 2017. The mediation was tested using multilevel mediation analyses.

RESULTS: Results showed that self-reported physical activity was associated with better self-reported sleep quality, which was associated with better performance in all three indicators of cognitive function, demonstrating an indirect effect of physical activity on cognitive function through sleep quality. The mediating effect of sleep quality accounted for 0.41%, 1.46%, and 8.88% of the total association of physical activity with verbal fluency, immediate recall, and delayed recall, respectively.

CONCLUSION: These findings suggest that self-reported sleep quality partly mediates the association between self-reported physical activity and cognitive function. These results need to be confirmed by device-based data of physical activity and sleep quality.

%B J Alzheimers Dis %V 87 %P 919-931 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35404276?dopt=Abstract %R 10.3233/JAD-215484 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Bifidobacterium breve MCC1274 Supplementation Increased the Plasma Levels of Metabolites with Potential Anti-Oxidative Activity in APP Knock-In Mice. %A Ohno, Kazuya %A Abdelhamid, Mona %A Zhou, Chunyu %A Jung, Cha-Gyun %A Michikawa, Makoto %X

BACKGROUND: We previously reported the effects of a probiotic strain, Bifidobacterium breve MCC1274, in improving cognitive function in preclinical and clinical studies. Recently, we demonstrated that supplementation of this strain led to decreased amyloid-β production, attenuated microglial activation, and suppressed inflammation reaction in the brain of APP knock-in (AppNL - G - F) mice.

OBJECTIVE: In this study, we investigated the plasma metabolites to reveal the mechanism of action of this probiotic strain in this Alzheimer's disease (AD)-like model.

METHODS: Three-month-old mice were orally supplemented with B. breve MCC1274 or saline for four months and their plasma metabolites were comprehensively analyzed using CE-FTMS and LC-TOFMS.

RESULTS: Principal component analysis showed a significant difference in the plasma metabolites between the probiotic and control groups (PERMANOVA, p = 0.03). The levels of soy isoflavones (e.g., genistein) and indole derivatives of tryptophan (e.g., 5-methoxyindoleacetic acid), metabolites with potent anti-oxidative activities were significantly increased in the probiotic group. Moreover, there were increased levels of glutathione-related metabolites (e.g., glutathione (GSSG)_divalent, ophthalmic acid) and TCA cycle-related metabolites (e.g., 2-Oxoglutaric acid, succinic acid levels) in the probiotic group. Similar alternations were observed in the wild-type mice by the probiotic supplementation.

CONCLUSION: These results suggest that the supplementation of B. breve MCC1274 enhanced the bioavailability of potential anti-oxidative metabolites from the gut and addressed critical gaps in our understanding of the gut-brain axis underlying the mechanisms of the probiotic action of this strain in the improvement of cognitive function.

%B J Alzheimers Dis %V 89 %P 1413-1425 %8 2022 Oct 11 %G eng %N 4 %R 10.3233/JAD-220479 %0 Journal Article %J J Alzheimers Dis %D 2022 %T A Bioinformatics Approach Toward Unravelling the Synaptic Molecular Crosstalk Between Alzheimer's Disease and Diabetes. %A Alves, Steven R %A da Cruz E Silva, Cristóvão %A Martins, Ilka %A Henriques, Ana Gabriela %A da Cruz E Silva, Odete A B %X

BACKGROUND: Increasing evidence links impaired brain insulin signaling and insulin resistance to the development of Alzheimer's disease (AD).

OBJECTIVE: This evidence prompted a search for molecular players common to AD and diabetes mellitus (DM).

METHODS: The work incorporated studies based on a primary care-based cohort (pcb-Cohort) and a bioinformatics analysis to identify central nodes, that are key players in AD and insulin signaling (IS) pathways. The interactome for each of these key proteins was retrieved and network maps were developed for AD and IS. Synaptic enrichment was performed to reveal synaptic common hubs.

RESULTS: Cohort analysis showed that individuals with DM exhibited a correlation with poor performance in the Mini-Mental State Examination (MMSE) cognitive test. Additionally, APOE ɛ2 allele carriers appear to potentially be relatively more protected against both DM and cognitive deficits. Ten clusters were identified in this network and 32 key synaptic proteins were common to AD and IS. Given the relevance of signaling pathways, another network was constructed focusing on protein kinases and protein phosphatases, and the top 6 kinase nodes (LRRK2, GSK3B, AKT1, EGFR, MAPK1, and FYN) were further analyzed.

CONCLUSION: This allowed the elaboration of signaling cascades directly impacting AβPP and tau, whereby distinct signaling pathway play a major role and strengthen an AD-IS link at a molecular level.

%B J Alzheimers Dis %V 86 %P 1917-1933 %8 2022 Apr 19 %G eng %N 4 %R 10.3233/JAD-215059 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Blood Pressure and Later-Life Cognition in Hispanic and White Adults (BP-COG): A Pooled Cohort Analysis of ARIC, CARDIA, CHS, FOS, MESA, and NOMAS. %A Levine, Deborah A %A Gross, Alden L %A Briceño, Emily M %A Tilton, Nicholas %A Whitney, Rachael %A Han, Dehua %A Giordani, Bruno J %A Sussman, Jeremy B %A Hayward, Rodney A %A Burke, James F %A Elkind, Mitchell S V %A Moran, Andrew E %A Tom, Sarah %A Gottesman, Rebecca F %A Gaskin, Darrell J %A Sidney, Stephen %A Yaffe, Kristine %A Sacco, Ralph L %A Heckbert, Susan R %A Hughes, Timothy M %A Lopez, Oscar L %A Allen, Norrina Bai %A Galecki, Andrzej T %X

BACKGROUND: Ethnic differences in cognitive decline have been reported. Whether they can be explained by differences in systolic blood pressure (SBP) is uncertain.

OBJECTIVE: Determine whether cumulative mean SBP levels explain differences in cognitive decline between Hispanic and White individuals.

METHODS: Pooled cohort study of individual participant data from six cohorts (1971-2017). The present study reports results on SBP and cognition among Hispanic and White individuals. Outcomes were changes in global cognition (GC) (primary), executive function (EF) (secondary), and memory standardized as t-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1 SD difference in cognition. Median follow-up was 7.7 (Q1-Q3, 5.2-20.1) years.

RESULTS: We included 24,570 participants free of stroke and dementia: 2,475 Hispanic individuals (median age, cumulative mean SBP at first cognitive assessment, 67 years, 132.5 mmHg; 40.8% men) and 22,095 White individuals (60 years,134 mmHg; 47.3% men). Hispanic individuals had slower declines in GC, EF, and memory than White individuals when all six cohorts were examined. Two cohorts recruited Hispanic individuals by design. In a sensitivity analysis, Hispanic individuals in these cohorts had faster decline in GC, similar decline in EF, and slower decline in memory than White individuals. Higher time-varying cumulative mean SBP was associated with faster declines in GC, EF, and memory in all analyses. After adjusting for time-varying cumulative mean SBP, differences in cognitive slopes between Hispanic and White individuals did not change.

CONCLUSION: We found no evidence that cumulative mean SBP differences explained differences in cognitive decline between Hispanic and White individuals.

%B J Alzheimers Dis %V 89 %P 1103-1117 %8 2022 Sep 27 %G eng %N 3 %R 10.3233/JAD-220366 %0 Journal Article %J J Alzheimers Dis %D 2022 %T A Blood Test for Alzheimer's Disease: It's about Time or Not Ready for Prime Time? %A Galasko, Douglas R %A Grill, Joshua D %A Lingler, Jennifer H %A Heidebrink, Judith L %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Hematologic Tests %K Humans %K tau Proteins %X

A blood test for Alzheimer's disease is now available for clinical use in persons with cognitive impairment. This is an extraordinary milestone, though the amyloid-based PrecivityAD™ test is not without limitations. Pre and post-test counseling are essential. Phosphorylated tau blood tests are likely to follow soon. When used in conjunction with an appropriate clinical evaluation, blood tests provide the opportunity for an early, accurate, and accessible diagnosis of Alzheimer's disease. Standalone use, however, carries a significant risk of misinterpretation and is strongly discouraged. Now is the time to develop appropriate use criteria to guide the use of these promising assays.

%B J Alzheimers Dis %V 90 %P 963-966 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35147543?dopt=Abstract %R 10.3233/JAD-215490 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Blood Tests for Alzheimer's Disease: Increasing Efforts to Expand and Diversify Research Participation Is Critical for Widespread Validation and Acceptance. %A Karikari, Thomas K %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Hematologic Tests %K Humans %K tau Proteins %X

The recent academic and commercial development, and regulatory approvals, of blood-based Alzheimer's disease (AD) biomarkers are breakthrough developments of immense potential. However, clinical validation studies and therapeutic trial applications are limited almost exclusively to non-Hispanic White cohorts often including highly-educated, high-earning participants. This commentary argues that the true benefits of blood tests for AD will be realized by active inclusion of diverse groups including minoritized populations, people of socioeconomic status different from those included in existing cohorts, and residents of low- and middle-income countries. The article discusses key factors that are critical for a successful implementation of diversity programs.

%B J Alzheimers Dis %V 90 %P 967-974 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35491788?dopt=Abstract %R 10.3233/JAD-215730 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Brain Tissue-Derived Extracellular Vesicles in Alzheimer's Disease Display Altered Key Protein Levels Including Cell Type-Specific Markers. %A Huang, Yiyao %A Driedonks, Tom A P %A Cheng, Lesley %A Rajapaksha, Harinda %A Routenberg, David A %A Nagaraj, Rajini %A Redding, Javier %A Arab, Tanina %A Powell, Bonita H %A Pletniková, Olga %A Troncoso, Juan C %A Zheng, Lei %A Hill, Andrew F %A Mahairaki, Vasiliki %A Witwer, Kenneth W %X

BACKGROUND: Brain tissue-derived extracellular vesicles (bdEVs) play neurodegenerative and protective roles, including in Alzheimer's disease (AD). Extracellular vesicles (EVs) may also leave the brain to betray the state of the CNS in the periphery. Only a few studies have profiled the proteome of bdEVs and source brain tissue. Additionally, studies focusing on bdEV cell type-specific surface markers are rare.

OBJECTIVE: We aimed to reveal the pathological mechanisms inside the brain by profiling the tissue and bdEV proteomes in AD patients. In addition, to indicate targets for capturing and molecular profiling of bdEVs in the periphery, CNS cell-specific markers were profiled on the intact bdEV surface.

METHODS: bdEVs were separated and followed by EV counting and sizing. Brain tissue and bdEVs from age-matched AD patients and controls were then proteomically profiled. Total tau (t-tau), phosphorylated tau (p-tau), and antioxidant peroxiredoxins (PRDX) 1 and 6 were measured by immunoassay in an independent bdEV separation. Neuron, microglia, astrocyte, and endothelia markers were detected on intact EVs by multiplexed ELISA.

RESULTS: Overall, concentration of recovered bdEVs was not affected by AD. Proteome differences between AD and control were more pronounced for bdEVs than for brain tissue. Levels of t-tau, p-tau, PRDX1, and PRDX6 were significantly elevated in AD bdEVs compared with controls. Release of certain cell-specific bdEV markers was increased in AD.

CONCLUSION: Several bdEV proteins are involved in AD mechanisms and may be used for disease monitoring. The identified CNS cell markers may be useful tools for peripheral bdEV capture.

%B J Alzheimers Dis %V 90 %P 1057-1072 %8 2022 Nov 22 %G eng %N 3 %R 10.3233/JAD-220322 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Burden of Insomnia and Sleep Disturbances and the Impact of Sleep Treatments in Patients with Probable or Possible Alzheimer's Disease: A Structured Literature Review. %A Benca, Ruth %A Herring, W Joseph %A Khandker, Rezaul %A Qureshi, Zaina P %K Alzheimer Disease %K Caregivers %K Humans %K Prospective Studies %K Quality of Life %K Sleep %K Sleep Initiation and Maintenance Disorders %K Sleep Wake Disorders %X

BACKGROUND: Sleep disturbances are frequent in Alzheimer's disease (AD).

OBJECTIVE: To summarize the impact of sleep disturbances on AD patients and their caregivers and the effects of currently available sleep therapies.

METHODS: Published studies (January 1985-March 2020) assessing the burden associated with insomnia/sleep disturbances in the AD population and insomnia treatment effects were identified by searching PubMed, Embase, and Cochrane Library and screened against inclusion criteria.

RESULTS: 58 studies assessing patient and caregiver burden, institutionalization, and insomnia treatments in AD patients with sleep disturbances were identified. Sleep disturbances were associated with worse cognition, functional ability, and behavioral and neuropsychological functioning. Health status and quality of life of both patients and caregivers were reduced in the presence of sleep disturbances. Sleep disturbances were also associated with institutionalization. Although significant associations between sleep problems and clinical outcomes were apparent, there was generally no control for other influencing factors (e.g., cognitive status). Bright light and behavioral therapies as well as drugs showed some promise in AD patients, but studies were primarily small and limited data were available, particularly in regard to the effect on associated clinical burden.

CONCLUSION: Sleep disturbances are a significant problem for AD patients and caregivers, associated with behavioral and psychological problems and cognitive decline. However, they remain poorly characterized and under-researched. As the global population is aging and AD is on thes rise, data from larger, prospective trials are required to fully understand the clinical correlates of sleep disturbances and the impact insomnia treatments can have.

%B J Alzheimers Dis %V 86 %P 83-109 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35001893?dopt=Abstract %R 10.3233/JAD-215324 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Can Diet Supplements of Macular Pigment of Lutein, Zeaxanthin, and Meso-zeaxanthin Affect Cognition? %A Wang, Hongwei %A Wang, Ge %A Billings, Rebecca %A Li, Daniel %A Haase, Shakaye R %A Wheeler, Pariya F %A Vance, David E %A Li, Wei %X

BACKGROUND: Lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) are collectively called macular pigment. MZ can be converted from L in the macula. In the recent decade, many studies have been performed to investigate the effects for taking carotenoids, especially L and Z or L, Z, and MZ, as diet supplements on human health.

OBJECTIVE: We examined if diet supplements of L + Z or L + Z + MZ have effects on cognitive function in adults.

METHODS: A systemic literature search was performed in March 2021 with the following keywords: lutein, zeaxanthin, meso-zeaxanthin, cognition, cognitive, and macular pigment. The searched databases included Medline EBSCOhost, Scopus, Elsevier, Cochrane Library, ProQuest, and ClinicalTrials.gov. Findings from eight clinical trials were presented as the strongest evidence on the studied topic.

RESULTS: Most studies have found that macular pigments (L + Z) in blood or macula are positively correlated with cognitive performance. As an index of the amount of macular pigments in the brain, macular pigment optical density is related to cognitive performance in adults. In addition, there is an inverse relationship between a higher amount of macular pigment in the blood and lower risk of mild cognitive impairments or Alzheimer's disease. Based on the findings from the clinical trials, diet supplements of L + Z or L + Z + MZ are associated with improved cognition in adults.

CONCLUSION: The diet supplements of L + Z or L + Z+MZ are associated with better cognitive functioning, which may be via their beneficial effects on the vision.

%B J Alzheimers Dis %V 87 %P 1079-1087 %8 2022 May 31 %G eng %N 3 %R 10.3233/JAD-215736 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Cancer and Vascular Comorbidity Effects on Dementia Risk and Neuropathology in the Oldest-Old. %A Lachner, Christian %A Day, Gregory S %A Camsari, Gamze Balci %A Kouri, Naomi %A Ertekin-Taner, Nilufer %A Boeve, Bradley F %A Labuzan, Sydney A %A Lucas, John A %A Thompson, E Aubrey %A Siddiqui, Habeeba %A Crook, Julia E %A Cabrera-Rodriguez, Janisse N %A Josephs, Keith A %A Petersen, Ronald C %A Dickson, Dennis W %A Reichard, R Ross %A Mielke, Michelle M %A Knopman, David S %A Graff-Radford, Neill R %A Murray, Melissa E %X

BACKGROUND: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes.

OBJECTIVE: Investigate vascular and cancer contributions to dementia and neuropathology in oldest-old.

METHODS: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology.

RESULTS: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95-106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19-0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39-163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17-0.78]; p <  0.01) and lower Braak stage (p = 0.01).

CONCLUSION: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-β plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

%B J Alzheimers Dis %V 90 %P 405-417 %8 2022 Oct 25 %G eng %N 1 %R 10.3233/JAD-220440 %0 Journal Article %J J Alzheimers Dis %D 2022 %T "Captive by the Uncertainty"-Experiences with Anticipatory Guidance for People Living with Dementia and Their Caregivers at a Specialty Dementia Clinic. %A Shafir, Adi %A Ritchie, Christine S %A Garrett, Sarah B %A Bernstein Sideman, Alissa %A Naasan, Georges %A Merrilees, Jennifer %A Widera, Eric %A Flint, Lynn %A Harrison, Krista L %K Aged %K Alzheimer Disease %K Caregivers %K Dementia %K Female %K Humans %K Male %K Qualitative Research %K Uncertainty %X

BACKGROUND: After a diagnosis of Alzheimer's disease and related disorders, people living with dementia (PWD) and caregivers wonder what disease trajectory to expect and how to plan for functional and cognitive decline. This qualitative study aimed to identify patient and caregiver experiences receiving anticipatory guidance about dementia from a specialty dementia clinic.

OBJECTIVE: To examine PWD and caregiver perspectives on receiving anticipatory guidance from a specialty dementia clinic.

METHODS: We conducted semi-structured interviews with PWD, and active and bereaved family caregivers, recruited from a specialty dementia clinic. Interviews were recorded, transcribed, and systematically summarized. Thematic analysis identified anticipatory guidance received from clinical or non-clinical sources and areas where respondents wanted additional guidance.

RESULTS: Of 40 participants, 9 were PWD, 16 were active caregivers, and 15 were bereaved caregivers. PWD had a mean age of 75 and were primarily male (n = 6/9); caregivers had a mean age of 67 and were primarily female (n = 21/31). Participants felt they received incomplete or "hesitant" guidance on prognosis and expected disease course via their clinicians and filled the gap with information they found via the internet, books, and support groups. They appreciated guidance on behavioral, safety, and communication issues from clinicians, but found more timely and advance guidance from other non-clinical sources. Guidance on legal and financial planning was primarily identified through non-clinical sources.

CONCLUSION: PWD and caregivers want more information about expected disease course, prognosis, and help planning after diagnosis. Clinicians have an opportunity to improve anticipatory guidance communication and subsequent care provision.

%B J Alzheimers Dis %V 86 %P 787-800 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35124641?dopt=Abstract %R 10.3233/JAD-215203 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Caregiver Tele-Assistance for Reduction of Emotional Distress During the COVID-19 Pandemic. Psychological Support to Caregivers of People with Dementia: The Italian Experience. %A Rotondo, Emanuela %A Galimberti, Daniela %A Mercurio, Matteo %A Giardinieri, Giulia %A Forti, Sara %A Vimercati, Roberto %A Borracci, Vittoria %A Fumagalli, Giorgio G %A Pietroboni, Anna M %A Carandini, Tiziana %A Nobili, Alessandro %A Scarpini, Elio %A Arighi, Andrea %K Aged %K Aged, 80 and over %K Caregiver Burden %K Caregivers %K COVID-19 %K Dementia %K Female %K Humans %K Italy %K Male %K Middle Aged %K Psychological Distress %K Psychosocial Support Systems %K Quality of Life %K Surveys and Questionnaires %K Telephone %X

BACKGROUND: COVID-19 pandemic worsened vulnerability of patients with dementia (PWD). This new reality associated with government restriction and isolation worsened stress burden and psychological frailties in PWD caregivers.

OBJECTIVE: To give tele-psychological support to caregivers and evaluate the effect of this intervention by quantifying stress burden and quality of life during the first COVID-19 lockdown.

METHODS: 50 caregivers were divided into two groups: "Caregiver-focused group" (Cg) and "Patient-focused group" (Pg). Both groups received telephone contact every 2 weeks over a 28-week period, but the content of the call was different: in Cg, caregivers answered questions about the state of the PWD but also explored their own emotional state, stress burden, and quality of life. In Pg instead, telephone contacts were focused only on the PWD, and no evaluation regarding the caregiver mood or state of stress was made. Psychometric scales were administered to evaluate COVID-19 impact, stress burden, and quality of life.

RESULTS: Considering the time of intervention, from baseline (W0) to W28, Zarit Burden Interview and Quality of Life-caregiver questionnaires remained unchanged in Cg as compared with baseline (p > 0.05), whereas they worsened significantly in Pg (p < 0.01), showing increased stress over time and decreased quality of life in this group. Moreover, Impact on Event Scale values improved over the weeks in Cg (p = 0.015), while they remained unchanged in Pg (p = 0.483).

CONCLUSION: Caregivers who received telephone support about their mood and stress burden did not worsen their psychological state during the time of intervention, as did instead those who did not get such support.

%B J Alzheimers Dis %V 85 %P 1045-1052 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34806608?dopt=Abstract %R 10.3233/JAD-215185 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Cerebral Volumetric Correlates of Apathy in Alzheimer's Disease and Cognitively Normal Older Adults: Meta-Analysis, Label-Based Review, and Study of an Independent Cohort. %A Chaudhary, Shefali %A Zhornitsky, Simon %A Chao, Herta H %A van Dyck, Christopher H %A Li, Chiang-Shan R %K Aged %K Alzheimer Disease %K Apathy %K Atrophy %K Basal Ganglia %K Brain %K Cognitive Dysfunction %K Cohort Studies %K Gray Matter %K Gyrus Cinguli %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Prefrontal Cortex %X

BACKGROUND: Affecting nearly half of the patients with Alzheimer's disease (AD), apathy is associated with higher morbidity and reduced quality of life. Basal ganglia and cortical atrophy have been implicated in apathy. However, the findings have varied across studies and left unclear whether subdomains of apathy may involve distinct neuroanatomical correlates.

OBJECTIVE: To identify neuroanatomical correlates of AD-associated apathy.

METHODS: We performed a meta-analysis and label-based review of the literature. Further, following published routines of voxel-based morphometry, we aimed to confirm the findings in an independent cohort of 19 patients with AD/mild cognitive impairment and 25 healthy controls assessed with the Apathy Evaluation Scale.

RESULTS: Meta-analysis of 167 AD and 56 healthy controls showed convergence toward smaller basal ganglia gray matter volume (GMV) in apathy. Label-based review showed anterior cingulate, putamen, insula, inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) atrophy in AD apathy. In the independent cohort, with small-volume-correction, right putamen and MTG showed GMVs in negative correlation with Apathy Evaluation Scale total, behavioral, and emotional scores, and right IFG with emotional score (p < 0.05 family-wise error (FWE)-corrected), controlling for age, education, intracranial volume, and depression. With the Mini-Mental State Examination scores included as an additional covariate, the correlation of right putamen GMV with behavioral and emotional score, right MTG GMV with total and emotional score, and right IFG GMV with emotional score were significant.

CONCLUSION: The findings implicate putamen, MTG and IFG atrophy in AD associated apathy, potentially independent of cognitive impairment and depression, and suggest potentially distinct volumetric correlates of apathy.

%B J Alzheimers Dis %V 85 %P 1251-1265 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34924392?dopt=Abstract %R 10.3233/JAD-215316 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Cerebrospinal Fluid Sphingomyelins in Alzheimer's Disease, Neurodegeneration, and Neuroinflammation. %A Morrow, Autumn %A Panyard, Daniel J %A Deming, Yuetiva K %A Jonaitis, Erin %A Dong, Ruocheng %A Vasiljevic, Eva %A Betthauser, Tobey J %A Kollmorgen, Gwendlyn %A Suridjan, Ivonne %A Bayfield, Anna %A Van Hulle, Carol A %A Zetterberg, Henrik %A Blennow, Kaj %A Carlsson, Cynthia M %A Asthana, Sanjay %A Johnson, Sterling C %A Engelman, Corinne D %X

BACKGROUND: Sphingomyelin (SM) levels have been associated with Alzheimer's disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available.

OBJECTIVE: Here, we seek to build on our understanding of the role of SM metabolites in AD by studying a broad range of CSF SMs and biomarkers of AD, neurodegeneration, and neuroinflammation.

METHODS: Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n = 502), we analyzed the relationship between the levels of 12 CSF SMs, and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models.

RESULTS: No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, α-synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs.

CONCLUSION: The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific.

%B J Alzheimers Dis %V 90 %P 667-680 %8 2022 Nov 08 %G eng %N 2 %R 10.3233/JAD-220349 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Characterization of Mild Cognitive Impairment and Dementia among Community-Dwelling Mexican Americans and Non-Hispanic Whites. %A O'Bryant, Sid E %A Petersen, Melissa %A Hall, James %A Johnson, Leigh A %A Barber, Robert %A Phillips, Nicole %A Braskie, Meredith N %A Yaffe, Kristine %A Rissman, Robert %A Toga, Arthur %X

BACKGROUND: Despite tremendous advancements in the field, our understanding of mild cognitive impairment (MCI) and Alzheimer's disease (AD) among Mexican Americans remains limited.

OBJECTIVE: The aim of this study was to characterize MCI and dementia among Mexican Americans and non-Hispanic whites.

METHODS: Baseline data were analyzed from n = 1,705 (n = 890 Mexican American; n = 815 non-Hispanic white) participants enrolled in the Health and Aging Brain Study-Health Disparities (HABS-HD).

RESULTS: Among Mexican Americans, age (OR = 1.07), depression (OR = 1.09), and MRI-based neurodegeneration (OR = 0.01) were associated with dementia, but none of these factors were associated with MCI. Among non-Hispanic whites, male gender (OR = 0.33), neighborhood deprivation (OR = 1.34), depression (OR = 1.09), and MRI-based neurodegeneration (OR = 0.03) were associated with MCI, while depression (OR = 1.09) and APOEɛ4 genotype (OR = 4.38) were associated with dementia.

CONCLUSION: Findings from this study revealed that the demographic, clinical, sociocultural and biomarker characteristics of MCI and dementia are different among Mexican Americans as compared to non-Hispanic whites.

%B J Alzheimers Dis %V 90 %P 905-915 %8 2022 Nov 08 %G eng %N 2 %R 10.3233/JAD-220300 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Chronic Renin-Angiotensin System Activation Induced Neuroinflammation: Common Mechanisms Underlying Hypertension and Dementia? %A Tran, Shirley %A Kuruppu, Sanjaya %A Rajapakse, Niwanthi W %K Angiotensin I %K Angiotensin II %K Animals %K Antihypertensive Agents %K Brain %K Cytokines %K Dementia, Vascular %K Humans %K Hypertension %K Inflammation %K Peptide Fragments %K Renin-Angiotensin System %X

Hypertension is a major risk factor for the pathogenesis of vascular dementia and Alzheimer's disease. Chronic activation of the renin-angiotensin system (RAS) contributes substantially to neuroinflammation. We propose that neuroinflammation arising from chronic RAS activation can initiate and potentiate the onset of hypertension and related dementia. Neuroinflammation induced by chronic activation of the RAS plays a key role in the pathogenesis of dementia. Increased levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and transforming growth factor (TGF)-β have been reported in brain tissue of vascular dementia patients and animal models of vascular dementia induced by either angiotensin II infusion or transverse aortic coarctation. It is proposed that neuronal cell death and synaptic dysfunction induced by neuroinflammation lead to cognitive impairment in dementia. The neuroprotective RAS pathway, regulated by angiotensin-converting enzyme 2 (ACE2) which converts angiotensin II into angiotensin-(1-7), can attenuate hypertension and dementia. Furthermore, the use of anti-hypertensive medications in preventing dementia or cognitive decline in hypertensive patients and animal models of dementia have mostly been beneficial. Current evidence suggests a strong link between RAS induced neuroinflammation and the onset of hypertension and dementia, which warrants further investigation. Strategies to counteract an overactive RAS and enhance the neuroprotective arm of the RAS may help prevent or improve cognitive impairment associated with hypertension.

%B J Alzheimers Dis %V 85 %P 943-955 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34897090?dopt=Abstract %R 10.3233/JAD-215231 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Circulating Cell-Free Genomic DNA Is Associated with an Increased Risk of Dementia and with Change in Cognitive and Physical Function. %A Nidadavolu, Lolita S %A Feger, Danielle %A Wu, Yuqiong %A Grodstein, Francine %A Gross, Alden L %A Bennett, David A %A Walston, Jeremy D %A Oh, Esther S %A Abadir, Peter M %X

BACKGROUND: Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA).

OBJECTIVE: The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults.

METHODS: We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education.

RESULTS: Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up.

CONCLUSION: This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty.

%B J Alzheimers Dis %V 89 %P 1233-1240 %8 2022 Oct 11 %G eng %N 4 %R 10.3233/JAD-220301 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Clinical and Imaging Determinants of Neurocognitive Disorders in Post-Acute COVID-19 Patients with Cognitive Complaints. %A Andriuta, Daniela %A Si-Ahmed, Cherifa %A Roussel, Martine %A Constans, Jean-Marc %A Makki, Malek %A Aarabi, Ardalan %A Basille, Damien %A Andrejak, Claire %A Godefroy, Olivier %K Cognition %K COVID-19 %K Humans %K Leukoaraiosis %K Magnetic Resonance Imaging %K Neurocognitive Disorders %K Neuropsychological Tests %K Oxygen %K White Matter %X

BACKGROUND: Neurocognitive disorders (NCDs) are a part of the post-acute coronavirus disease (COVID-19) syndrome. No study has specifically evaluated NCDs in post-acute COVID-19 patients with cognitive complaints or their MRI determinants.

OBJECTIVE: To characterize NCDs in post-acute COVID-19 patients with cognitive complaints. The secondary objectives were to assess their clinical and MRI determinants.

METHODS: We included 46 patients with a post-acute COVID-19 cognitive complaint referred to the Amiens University Hospital Memory Center. They underwent a neuropsychological assessment and 36 had cerebral MRI. The G3 overall summary score was the sum of the mean z scores for the executive function, language, and action speed domains. Neuropsychological profiles were compared in a general linear model. Clinical determinants were analyzed by stepwise linear regression. White matter hyperintensities (WMH) masks were analyzed using parcel-based WMH symptom mapping to identify the locations of WMHs associated with cognitive performance.

RESULTS: Repeated ANOVA showed a group effect (p = 0.0001) due to overall lower performance for patients and a domain effect (p = 0.0001) due to a lower (p = 0.007) action speed score. The G3 overall summary score was significantly associated with solely the requirement for oxygen (R2 = 0.319, p = 0.031). WHMs were associated with the G3 overall summary score in the following structures, all right-sided (p < 0.01): superior frontal region, postcentral region, cingulum, cortico-spinal tract, inferior longitudinal fasciculus, internal capsule, and posterior segment of the arcuate fasciculus.

CONCLUSION: Post-acute COVID-19 patients with cognitive complaints had NCD, with prominent action slowing, significantly associated with the acute phase oxygen requirement and a right-sided WMH structure pattern.

%B J Alzheimers Dis %V 87 %P 1239-1250 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35431242?dopt=Abstract %R 10.3233/JAD-215506 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Clinical Utility of Cerebrospinal Fluid Aβ42 and Tau Measures in Diagnosing Mild Cognitive Impairment in Early Onset Dementia. %A Hosseini, Akram A %A Brown, Thomas %A Mannino, Luca %A Gran, Bruno %A Junaid, Kehinde %A Mukaetova-Ladinska, Elizabeta B %X

BACKGROUND: The differentiation of a preclinical or prodromal Alzheimer's disease (AD) is challenging particularly in patients with early onset Alzheimer's or related dementias (EOARD). We report our experience on diagnostic lumbar puncture to diagnose EOARD at a tertiary neurocognitive referral center in Nottingham, England from March 2018 to October 2020.

OBJECTIVE: To assess amyloid-β42 (Aβ42), total tau, and Thr181-phosphorylated tau (p-tau) measurements in the cerebrospinal fluid (CSF) in patients with mild cognitive impairment (MCI) and in relation to their follow-up cognitive performance.

METHODS: Thirty participants aged 32-68 years old (mean 59 years; 57% female) were included. Clinical diagnosis was based on clinical presentation, neurocognitive profile, neuroradiological features (MRI, FDG-PET CT) and CSF Aβ42, total tau, and p-tau measurements.

RESULTS: Patients with MCI who progressed to AD (prodromal AD) had significantly higher CSF total (797.63 pg/ml) and p-tau (82.31 pg/ml), and lower Aβ42 levels (398.94 pg/ml) in comparison to their counterparts with stable MCI (total tau 303.67 pg/ml, p-tau 43.56 pg/ml, Aβ42 873.44 pg/ml) (p <  0.01 for CSF total and p-tau measures and p <  0.0001 for CSF Aβ42 measures). None of the CSF biomarkers correlated with any of the cognitive performance measures. Principal component analysis confirmed that the clinical diagnosis of MCI secondary to AD, namely prodromal AD (as per NIA-AA criteria) in younger adults, was associated with decreased CSF Aβ42.

CONCLUSION: In early onset AD, low levels of CSF Aβ42 appear to be more sensitive than total and p-tau measures in differentiating AD MCI from other forms of dementia. Further work on larger samples of EOARD in clinical practice will address the cost effectiveness of making an earlier diagnosis.

%B J Alzheimers Dis %V 87 %P 771-780 %8 2022 May 17 %G eng %N 2 %R 10.3233/JAD-215650 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Cognitive Decline Risk Stratification in People with Late-Onset Epilepsy of Unknown Etiology: An Electroencephalographic Connectivity and Graph Theory Pilot Study. %A Costa, Cinzia %A Vecchio, Fabrizio %A Romoli, Michele %A Miraglia, Francesca %A Nardi Cesarini, Elena %A Alù, Francesca %A Calabresi, Paolo %A Rossini, Paolo Maria %K Aged %K Cognitive Dysfunction %K Dementia %K Electroencephalography %K Epilepsy %K Female %K Humans %K Male %K Neuropsychological Tests %K Pilot Projects %K Risk Assessment %X

BACKGROUND: Although people with late onset epilepsy of unknown etiology (LOEU) are at higher risk of cognitive decline compared to the general population, we still lack affordable tools to predict and stratify their risk of dementia.

OBJECTIVE: This pilot-study investigates the potential application of electroencephalography (EEG) network small-world (SW) properties in predicting cognitive decline among patients with LOEU.

METHODS: People diagnosed with LOEU and normal cognitive examination at the time of epilepsy diagnosis were included. Cerebrospinal fluid biomarkers, brain imaging, and neuropsychological assessment were performed at the time of epilepsy diagnosis. Baseline EEG was analyzed for SW properties. Patients were followed-up over time with neuropsychological testing to define the trajectory of cognitive decline.

RESULTS: Over 5.1 years of follow-up, among 24 patients diagnosed with LOEU, 62.5% were female, mean age was 65.3 years, thirteen developed mild cognitive impairment (MCI), and four developed dementia. Patients with LOEU developing MCI had lower values of SW coefficients in the delta (p = 0.03) band and higher SW values in the alpha frequency bands (p = 0.02) compared to patients having normal cognition at last follow-up. The two separate ANOVAs, for low and alpha bands, confirmed an interaction between SW and cognitive decline at follow-up. A similar gradient was confirmed for patients developing dementia compared to those with normal cognitive function as well as to those developing MCI.

CONCLUSION: Baseline EEG analysis through SW is worth investigating as an affordable, widely available tool to stratify LOEU patients for their risk of cognitive decline.

%B J Alzheimers Dis %V 88 %P 893-901 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34842184?dopt=Abstract %R 10.3233/JAD-210350 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Cognitive Function Associated with Gut Microbial Abundance in Sucrose and S-Adenosyl-L-Methionine (SAMe) Metabolic Pathways. %A Jeong, Sohyun %A Huang, Li-Kai %A Tsai, Ming-Ju %A Liao, Yi-Tyng %A Lin, Yow-Sien %A Hu, Chaur-Jong %A Hsu, Yi-Hsiang %K Alzheimer Disease %K Cognition %K Cognitive Dysfunction %K Gastrointestinal Microbiome %K Humans %K Metabolic Networks and Pathways %K RNA, Ribosomal, 16S %K S-Adenosylmethionine %K Sucrose %X

BACKGROUND: Differential abundance of gut microbiota has found to be associated with Alzheimer's disease (AD). However, the relative abundance of gut microbiota between dementia and mild cognitive impairment (MCI) in AD is not well studied.

OBJECTIVE: We attempted to identify differentially enriched gut microbes and their metabolic pathways in AD patients with dementia comparing to AD patients with MCI.

METHODS: Fecal samples were collected at Shuang Ho Hospital, Taipei Medical University, Taiwan and analyzed by whole metagenomic sequencing technique. For normal controls without AD (NC), 16S rRNA sequencing was obtained from the Taiwan Microbiome Database. A total of 48 AD (38 dementia and 10 MCI defined by cognitive function scores) and 50 NC were included. Microbiome alpha and beta diversities were estimated. Differentially enriched microbes were identified with HAllA, MaAsLin, DESeq2, and LEfSe statistical modeling approaches.

RESULTS: We found significantly increased abundance of Firmicutes but decreased abundance of Bacteroidetes at phylum level in AD compared to NC. In AD patients, cognitive function scores were negatively associated with abundance of Blautia hydrogenotrophica (Firmicutes), Anaerotruncus colihominis (Firmicutes), and Gordonibacter pamelaeae (Actinobacteria). In addition, microbial abundance in the sucrose and S-Adenosyl-L-methionine (SAMe) metabolic pathways was more enriched in AD with MCI than AD with dementia and significantly associated with higher cognitive function scores.

CONCLUSION: Gut microbe community diversity was similar in AD patients regardless of MCI or dementia status. However, differential analyses probed in lower-level taxa and metabolic pathways suggested that specific gut microbes in Firmicutes and Actinobacteria might involve in cognitive decline.

%B J Alzheimers Dis %V 87 %P 1115-1130 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35431236?dopt=Abstract %R 10.3233/JAD-215090 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Cognitive, Functional, and Emotional Changes During the COVID-19 Pandemic in Greek Patients with Neurocognitive Disorders. %A Tsiakiri, Anna %A Vlotinou, Pinelopi %A Terzoudi, Aikaterini %A Heliopoulos, Ioannis %A Vadikolias, Konstantinos %K Aged %K Cognition %K Cognitive Dysfunction %K Communicable Disease Control %K COVID-19 %K Greece %K Humans %K Neurocognitive Disorders %K Neuropsychological Tests %K Pandemics %X

BACKGROUND: Prolonged periods of social deprivation, such as COVID-19-related lockdowns, are associated with deleterious effects on cognitive functions.

OBJECTIVE: The aim of this study was to gauge the effect of prolonged social isolation on the cognitive function of older adults with neurocognitive disorders.

METHODS: We recruited 125 older adults with minor or major neurocognitive disorders divided into two groups. The control group was tested at the first period of the study (October 2018-May 2019), whereas the experimental group was evaluated at the second chronological period of the study (October 2020-May 2021) during the second wave of COVID-19. Neuropsychological tests were performed at baseline and six months after baseline.

RESULTS: In the control group, significant changes in the scores from the Montreal Cognitive Assessment (MoCA; p = 0.049) and the Functional Rating Scale for Symptoms of Dementia (FRSSD; p = 0.005) were found between baseline and follow-up assessments, whereas no changes were identified in Mini-Mental State Examination (MMSE; p = 0.229) and Geriatric Depression Scale (GDS; p = 0.619) scores. In the experimental group, the scores from all neuropsychological tests (MoCA, MMSE, GDS, and FRSSD; p < 0.001 for all) were significantly different at follow-up when compared with those at baseline measurements. Moreover, significant deterioration of specific functions assessed in MMSE and FRSSD was detected, especially in the experimental group.

CONCLUSION: This study highlights cognitive functions directly affected by social deprivation of individuals with neurocognitive disorders. The findings can be used in the rehabilitation from confinement and its negative consequences.

%B J Alzheimers Dis %V 88 %P 537-547 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35599488?dopt=Abstract %R 10.3233/JAD-220118 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Combinational Drug Repurposing from Genetic Networks Applied to Alzheimer's Disease. %A Nabirotchkin, Serguei %A Bouaziz, Jan %A Glibert, Fabrice %A Mandel, Jonas %A Foucquier, Julie %A Hajj, Rodolphe %A Callizot, Noëlle %A Cholet, Nathalie %A Guedj, Mickaël %A Cohen, Daniel %X

BACKGROUND: Human diseases are multi-factorial biological phenomena resulting from perturbations of numerous functional networks. The complex nature of human diseases explains frequently observed marginal or transitory efficacy of mono-therapeutic interventions. For this reason, combination therapy is being increasingly evaluated as a biologically plausible strategy for reversing disease state, fostering the development of dedicated methodological and experimental approaches. In parallel, genome-wide association studies (GWAS) provide a prominent opportunity for disclosing human-specific therapeutic targets and rational drug repurposing.

OBJECTIVE: In this context, our objective was to elaborate an integrated computational platform to accelerate discovery and experimental validation of synergistic combinations of repurposed drugs for treatment of common human diseases.

METHODS: The proposed approach combines adapted statistical analysis of GWAS data, pathway-based functional annotation of genetic findings using gene set enrichment technique, computational reconstruction of signaling networks enriched in disease-associated genes, selection of candidate repurposed drugs and proof-of-concept combinational experimental screening.

RESULTS: It enables robust identification of signaling pathways enriched in disease susceptibility loci. Therapeutic targeting of the disease-associated signaling networks provides a reliable way for rational drug repurposing and rapid development of synergistic drug combinations for common human diseases.

CONCLUSION: Here we demonstrate the feasibility and efficacy of the proposed approach with an experiment application to Alzheimer's disease.

%B J Alzheimers Dis %V 88 %P 1585-1603 %8 2022 Aug 16 %G eng %N 4 %R 10.3233/JAD-220120 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Comparative Analysis of Alzheimer's Disease Cerebrospinal Fluid Biomarkers Measurement by Multiplex SOMAscan Platform and Immunoassay-Based Approach. %A Timsina, Jigyasha %A Gomez-Fonseca, Duber %A Wang, Lihua %A Do, Anh %A Western, Dan %A Álvarez, Ignacio %A Aguilar, Miquel %A Pastor, Pau %A Henson, Rachel L %A Herries, Elizabeth %A Xiong, Chengjie %A Schindler, Suzanne E %A Fagan, Anne M %A Bateman, Randall J %A Farlow, Martin %A Morris, John C %A Perrin, Richard %A Moulder, Krista %A Hassenstab, Jason %A Chhatwal, Jasmeer %A Mori, Hiroshi %A Sung, Yun Ju %A Cruchaga, Carlos %X

BACKGROUND: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated.

OBJECTIVE: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer's disease (AD) and neurodegeneration: NfL, Neurogranin, sTREM2, VILIP-1, and SNAP-25.

METHODS: We compared biomarkers measured in ADNI (N = 689), Knight-ADRC (N = 870), DIAN (N = 115), and Barcelona-1 (N = 92) cohorts. Raw protein values were transformed using z-score in order to combine measures from the different studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson's correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms.

RESULTS: Neurogranin, VILIP-1, and NfL showed high correlation between SOMAscan and immunoassay measures (r >  0.9). sTREM2 had a fair correlation (r >  0.6), whereas SNAP-25 showed weak correlation (r = 0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures.

CONCLUSION: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1, and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers.

%B J Alzheimers Dis %V 89 %P 193-207 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-220399 %0 Journal Article %J J Alzheimers Dis %D 2022 %T A Comparison of Behavioral and Psychological Symptoms of Dementia (BPSD) and BPSD Sub-Syndromes in Early-Onset and Late-Onset Alzheimer's Disease. %A Altomari, Natalia %A Bruno, Francesco %A Laganà, Valentina %A Smirne, Nicoletta %A Colao, Rosanna %A Curcio, Sabrina %A Di Lorenzo, Raffaele %A Frangipane, Francesca %A Maletta, Raffaele %A Puccio, Gianfranco %A Bruni, Amalia Cecilia %K Affective Symptoms %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apathy %K Behavioral Symptoms %K Dementia %K Female %K Humans %K Italy %K Male %K Middle Aged %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Psychomotor Agitation %K Psychotic Disorders %K Severity of Illness Index %X

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) have a large impact on the quality of life of patients with Alzheimer's disease (AD). Few studies have compared BPSD between early-onset (EOAD) and late-onset (LOAD) patients, finding conflicting results.

OBJECTIVE: The aims of this study were to: 1) characterize the presence, overall prevalence, and time of occurrence of BPSD in EOAD versus LOAD; 2) estimate the prevalence over time and severity of each BPSD in EOAD versus LOAD in three stages: pre-T0 (before the onset of the disease), T0 (from onset to 5 years), and T1 (from 5 years onwards); 3) track the manifestation of BPSD sub-syndromes (i.e., hyperactivity, psychosis, affective, and apathy) in EOAD versus LOAD at T0 and T1.

METHODS: The sample includes 1,538 LOAD and 387 EOAD diagnosed from 1996 to 2018. Comprehensive assessment batteries, including the Neuropsychiatric Inventory (NPI), were administered at the first medical assessment and at different follow-up period.

RESULTS: The overall prevalence for the most of BPSD was significantly higher in EOAD compared to LOAD whereas most BPSD appeared significantly later in EOAD patients. Between the two groups, from pre-T0 to T1 we recorded a different pattern of BPSD prevalence over time as well as for BPSD sub-syndromes at T0 and T1. Results on severity of BPSD did not show significant differences.

CONCLUSION: EOAD and LOAD represent two different forms of a single entity not only from a neuropathological, cognitive, and functional level but also from a psychiatric point of view.

%B J Alzheimers Dis %V 85 %P 691-699 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864668?dopt=Abstract %R 10.3233/JAD-215061 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Comparison of Steady-State Pharmacokinetics of Donepezil Transdermal Delivery System with Oral Donepezil. %A Tariot, Pierre N %A Braeckman, Rene %A Oh, Charles %K Adolescent %K Adult %K Alzheimer Disease %K Cross-Over Studies %K Donepezil %K Humans %K Middle Aged %K Young Adult %X

BACKGROUND: Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States.

OBJECTIVE: To compare steady-state pharmacokinetics of once-weekly 10-mg/d and 5-mg/d Corplex™ donepezil transdermal delivery systems (TDS) with once-daily 10-mg oral donepezil.

METHODS: Open-label, randomized, crossover study (NCT04617782) enrolled healthy participants aged 18-55 years. All participants received 5-mg/d donepezil TDS during the 5-week Period 1, followed by 10-mg/d TDS or 10-mg/d oral donepezil in the 5-week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state on Week 5.

RESULTS: All 60 enrolled participants received 5-mg/d TDS, 55 received 10-mg/d TDS, and 56 received oral donepezil. Adjusted geometric mean ratio (% [90% CI]) for maximum plasma concentration and area under the plasma concentration versus time curve (0-168 h) were 88.7 (81.7-96.2) and 108.6 (100.5-117.4) for 10-mg/d and 86.1 (79.8-92.9) and 105.3 (97.6-113.6) for dose-normalized 5-mg/d TDS and were generally within the 80% -125% range for establishing bioequivalence with oral donepezil. Skin adhesion was similar for both TDSs (>80% of patches remaining ≥75% adhered throughout the wear period). Overall incidence of adverse events (AEs) was similar across treatments. Compared with 10-mg/d TDS, oral donepezil was associated with higher incidence of gastrointestinal and nervous system AEs (14.5% versus 53.6% and 14.5% versus 30.4%, respectively).

CONCLUSION: Donepezil TDSs are bioequivalent to oral donepezil at steady state and have a safety profile that supports their use in treating dementia of the Alzheimer type.

%B J Alzheimers Dis %V 90 %P 161-172 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/36120781?dopt=Abstract %R 10.3233/JAD-220530 %0 Journal Article %J J Alzheimers Dis %D 2022 %T A Comparison of Well-Being of Carers of People with Dementia and Their Ability to Manage Before and During the COVID-19 Pandemic: Findings from the IDEAL Study. %A Gamble, Laura D %A Parker, Sophie %A Quinn, Catherine %A Bennett, Holly Q %A Martyr, Anthony %A Sabatini, Serena %A Pentecost, Claire %A Collins, Rachel %A Dawson, Eleanor %A Hunt, Anna %A Allan, Louise %A Burns, Alistair %A Litherland, Rachael %A Victor, Christina %A Matthews, Fiona E %A Clare, Linda %K Adaptation, Psychological %K Caregivers %K COVID-19 %K Dementia %K Humans %K Pandemics %K Quality of Life %X

BACKGROUND: Social restriction measures imposed to curb the spread of COVID-19 in the United Kingdom impacted on carers of people with dementia, limiting access to support services and increasing perceived burden of caring. Few studies have compared data collected both during and before the pandemic to examine the effect of these changes.

OBJECTIVE: To explore whether the COVID-19 pandemic affected the well-being of carers of people with dementia living in the community, and their ability to cope with their caring responsibilities.

METHODS: Analysis was conducted on two groups of carers who were enrolled in the IDEAL programme; the 'pre-pandemic group' (n = 312), assessed at two time points prior to the pandemic, and the 'pandemic group', assessed prior to and several months into the pandemic (n = 156). For the pre-pandemic group, carers were matched 2:1 to carers in the pandemic group on certain characteristics. Differences in change over time between the two groups on self-reported well-being, quality of life, coping, perceived competence, and role captivity, were investigated using mixed effect modelling.

RESULTS: Compared to the pre-pandemic group, those in the pandemic group appeared to cope better and had more stable self-rated competency and role captivity. They did not differ in terms of well-being or quality of life.

CONCLUSIONS: Despite reports of negative impacts on carers early in the pandemic, the findings suggest the pandemic had little negative longer-term impact on carers of people with dementia, and in fact they appeared to have a more positive attitude towards coping several months into the pandemic.

%B J Alzheimers Dis %V 88 %P 679-692 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35634850?dopt=Abstract %R 10.3233/JAD-220221 %0 Journal Article %J J Alzheimers Dis %D 2022 %T The Correlation of Tau Levels with Blood Monocyte Count in Patients with Alzheimer's Disease. %A Sun, Hao-Lun %A Zhou, Fa-Ying %A Chen, Dong-Wan %A Tan, Cheng-Rong %A Zeng, Gui-Hua %A Liu, Yu-Hui %A Wang, Jun %A Bu, Xian-Le %A Wang, Yan-Jiang %A Li, Hui-Yun %A Jin, Wang-Sheng %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Brain %K Cognitive Dysfunction %K Cohort Studies %K Female %K Humans %K Male %K Monocytes %K tau Proteins %X

BACKGROUND: Recent studies have shown that monocytes can phagocytize the tau protein, which may ameliorate tau-type pathology in Alzheimer's disease (AD). However, there are few clinical studies on the relationship between monocytes and tau-type pathology in AD patients.

OBJECTIVE: We aimed to explore changes in peripheral monocytes and their association with tau protein in AD patients.

METHODS: A total of 127 clinically diagnosed AD patients and 100 age- and sex-matched cognitively normal controls were recruited for analysis of the correlation of plasma tau levels with the blood monocyte count. Cerebrospinal fluid (CSF) samples from 46 AD patients and 88 controls were further collected to analyze the correlation of CSF tau and amyloid-β (Aβ) levels with the blood monocyte count. 105 clinically diagnosed mild cognitive impairment (MCI) patients and 149 age- and sex-matched cognitively normal controls were recruited from another cohort for verification.

RESULTS: Compared to normal controls, AD patients showed a significant reduction in the blood monocyte count. In addition, the monocyte count of AD patients was negatively correlated with CSF t-tau and p-tau levels but not with plasma tau levels. In normal people, monocyte count lack correlation with tau levels both in plasma and CSF. Monocyte count were not correlated with CSF Aβ levels in either group but were negatively correlated with CSF tau/Aβ42 levels in the AD group. We had further verified the correlations of monocyte count with CSF tau levels in another cohort.

CONCLUSION: This study suggests that monocytes may play an important role in the clearance of tau protein in the brain.

%B J Alzheimers Dis %V 85 %P 1321-1328 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34924377?dopt=Abstract %R 10.3233/JAD-210692 %0 Journal Article %J J Alzheimers Dis %D 2022 %T COVID-19 and Neurodegenerative Diseases: Prion-Like Spread and Long-Term Consequences. %A Baazaoui, Narjes %A Iqbal, Khalid %K Aged %K COVID-19 %K Dementia %K Humans %K Neurodegenerative Diseases %K Prions %K SARS-CoV-2 %X

COVID-19 emerged as a global pandemic starting from Wuhan in China and spread at a lightning speed to the rest of the world. One of the potential long-term outcomes that we speculate is the development of neurodegenerative diseases as a long-term consequence of SARS-CoV-2 especially in people that have developed severe neurological symptoms. Severe inflammatory reactions and aging are two very strong common links between neurodegenerative diseases and COVID-19. Thus, patients that have very high viral load may be at high risk of developing long-term adverse neurological consequences such as dementia. We hypothesize that people with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and aged people are at higher risk of getting the COVID-19 than normal adults. The basis of this hypothesis is the fact that SARS-CoV-2 uses as a receptor angiotensin-converting enzyme 2 to enter the host cell and that this interaction is calcium-dependent. This could then suggest a direct relationship between neurodegenerative diseases, ACE-2 expression, and the susceptibility to COVID-19. The analysis of the available literature showed that COVID-19 virus is neurotropic and was found in the brains of patients infected with this virus. Furthermore, that the risk of having the infection increases with dementia and that infected people with severe symptoms could develop dementia as a long-term consequence. Dementia could be developed following the acceleration of the spread of prion-like proteins. In the present review we discuss current reports concerning the prevalence of COVID-19 in dementia patients, the individuals that are at high risk of suffering from dementia and the potential acceleration of prion-like proteins spread following SARS-CoV-2 infection.

%B J Alzheimers Dis %V 88 %P 399-416 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35599487?dopt=Abstract %R 10.3233/JAD-220105 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Dementia Research on Facebook and Twitter: Current Practice and Challenges. %A Hrincu, Viorica %A An, Zijian %A Joseph, Kenneth %A Jiang, Yu Fei %A Robillard, Julie M %K Dementia %K Humans %K Social Media %X

BACKGROUND: Social media is a powerful tool for engaging diverse audiences in dementia research. However, there is little data summarizing current content exchange in this context.

OBJECTIVE: To inform ethical dementia research engagement on social media, we characterized current practices by analyzing public social media posts.

METHODS: We retrieved Facebook (2-year period, N = 7,896) and Twitter (1-year period, N = 9,323) posts containing dementia research-related keywords using manual and machine learning-based search strategies. We performed qualitative and quantitative content and sentiment analyses on random samples (10%) of the posts.

RESULTS: Top Facebook users were advocacy (45%) and health organizations (25%). On Twitter, academics/researchers were the largest user group. Prevention was the most frequently coded theme (Facebook 30%; Twitter 26%), followed by treatment (Facebook 15%; Twitter 18%). Diagnostics had the highest Facebook engagement. Sharing knowledge was the primary form of content exchange (Facebook 63%; Twitter 80%). Most shared journal articles were peer-reviewed and open access. Emotional tone was overall more positive on Facebook. Justice was a prominent ethics topic regarding inequalities related to identity and intersecting modes of marginalization in dementia research.

CONCLUSION: The findings indicate the importance of social media as an engagement tool of current topics in health research and reveal areas of potential for increased engagement. These data can inform consensus-based best practices for ethical social media application in dementia research.

%B J Alzheimers Dis %V 90 %P 447-459 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/36155513?dopt=Abstract %R 10.3233/JAD-220525 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Demonstration of Clinical Meaningfulness of the Integrated Alzheimer's Disease Rating Scale (iADRS): Association Between Change in iADRS Scores and Patient and Caregiver Health Outcomes. %A Wessels, Alette M %A Belger, Mark %A Johnston, Joseph A %A Yu, Youying %A Rentz, Dorene M %A Dowsett, Sherie A %A Chandler, Julie %K Alzheimer Disease %K Caregivers %K Clinical Trials as Topic %K Cognitive Dysfunction %K Humans %K Observational Studies as Topic %K Outcome Assessment, Health Care %K Quality of Life %X

BACKGROUND: The integrated Alzheimer's Disease Rating Scale (iADRS) is a validated cognitive/functional composite that effectively captures cognitive and functional decline over a broad spectrum of disease. The clinical meaningfulness of change on iADRS can be supported by establishing an association with changes on important health outcome measures.

OBJECTIVE: To evaluate the relationship between change on the iADRS and changes in health outcomes in individuals with mild cognitive impairment (MCI) due to Alzheimer's disease (AD), or mild or moderate AD dementia using placebo data from four AD clinical trials and data from one AD observational study.

METHODS: Analysis of covariate (ANCOVA) models were used to estimate the relationship between 18-month change on the iADRS and changes on health outcome measures (related to cost, quality of life, and caregiver burden). The regression coefficients for the iADRS were used to compute impact of natural disease progression and disease-modifying treatment on health outcomes. Additional ANCOVAs were conducted to understand whether cognition and/or function was the underlying explanation of any association between iADRS and health outcome change.

RESULTS: Across datasets and disease stages, a worsening on the iADRS was significantly associated with increased societal costs, caregiver burden (time and distress) and worsening in measures of patient quality of life.

CONCLUSION: Decline on the iADRS was associated with worsening in health outcome measures. These findings suggest that the iADRS can be used in clinical trials as a proxy measure of clinically meaningful outcomes of AD progression.

%B J Alzheimers Dis %V 88 %P 577-588 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35694928?dopt=Abstract %R 10.3233/JAD-220303 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Detecting Alzheimer's Disease Using Natural Language Processing of Referential Communication Task Transcripts. %A Liu, Ziming %A Paek, Eun Jin %A Yoon, Si On %A Casenhiser, Devin %A Zhou, Wenjun %A Zhao, Xiaopeng %K Aged %K Alzheimer Disease %K Cognitive Dysfunction %K Communication %K Humans %K Natural Language Processing %K Speech %X

BACKGROUND: People with Alzheimer's disease (AD) often demonstrate difficulties in discourse production. Referential communication tasks (RCTs) are used to examine a speaker's capability to select and verbally code the characteristics of an object in interactive conversation.

OBJECTIVE: In this study, we used contextualized word representations from Natural language processing (NLP) to evaluate how well RCTs are able to distinguish between people with AD and cognitively healthy older adults.

METHODS: We adapted machine learning techniques to analyze manually transcribed speech transcripts in an RCT from 28 older adults, including 12 with AD and 16 cognitively healthy older adults. Two approaches were applied to classify these speech transcript samples: 1) using clinically relevant linguistic features, 2) using machine learned representations derived by a state-of-art pretrained NLP transfer learning model, Bidirectional Encoder Representation from Transformer (BERT) based classification model.

RESULTS: The results demonstrated the superior performance of AD detection using a designed transfer learning NLP algorithm. Moreover, the analysis showed that transcripts of a single image yielded high accuracies in AD detection.

CONCLUSION: The results indicated that RCT may be useful as a diagnostic tool for AD, and that the task can be simplified to a subset of images without significant sacrifice to diagnostic accuracy, which can make RCT an easier and more practical tool for AD diagnosis. The results also demonstrate the potential of RCT as a tool to better understand cognitive deficits from the perspective of discourse production in people with AD.

%B J Alzheimers Dis %V 86 %P 1385-1398 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35213368?dopt=Abstract %R 10.3233/JAD-215137 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Diabetic Retinopathy Predicts Risk of Alzheimer's Disease: A Danish Registry-Based Nationwide Cohort Study. %A Pedersen, Frederik Nørregaard %A Stokholm, Lonny %A Pouwer, Frans %A Hass Rubin, Katrine %A Peto, Tunde %A Frydkjær-Olsen, Ulrik %A Thykjær, Anne Suhr %A Andersen, Nis %A Andresen, Jens %A Bek, Toke %A La Cour, Morten %A Heegaard, Steffen %A Højlund, Kurt %A Kawasaki, Ryo %A Hajari, Javad Nouri %A Ohm Kyvik, Kirsten %A Laugesen, Caroline Schmidt %A Schielke, Katja Christina %A Simó, Rafael %A Grauslund, Jakob %K Alzheimer Disease %K Cohort Studies %K Denmark %K Diabetes Mellitus %K Diabetic Retinopathy %K Humans %K Registries %K Risk Factors %X

BACKGROUND: Retinal neurodegeneration is evident in early diabetic retinopathy (DR) which may be associated with other neurodegenerative diseases like Alzheimer's disease (AD).

OBJECTIVE: To investigate diabetes and DR as a risk marker of present and incident AD.

METHODS: A register-based cohort study was performed. We included 134,327 persons with diabetes above 60 years of age, who had attended DR screening, and 651,936 age- and gender-matched persons without diabetes.

RESULTS: At baseline, the prevalence of AD was 0.7% and 1.3% among patients with and without diabetes, respectively. In a multivariable regression model, patients with diabetes were less likely to have AD at baseline (adjusted OR 0.63, 95% CI 0.59-0.68). During follow-up, incident AD was registered for 1473 (0.35%) and 6,899 (0.34%) persons with and without diabetes, respectively. Compared to persons without diabetes, persons with diabetes and no DR had a lower risk to develop AD (adjusted HR 0.87, 95% CI 0.81-0.93), while persons with diabetes and DR had higher risk of AD (adjusted HR 1.24, 95% CI 1.08-1.43). When persons with diabetes and no DR were used as references, a higher risk of incident AD was observed in persons with DR (adjusted HR 1.34, 95% CI 1.18-1.53).

CONCLUSION: Individuals with diabetes without DR were less likely to develop AD compared to persons without diabetes. However, individuals with DR had a 34% higher risk of incident AD, which raise the question whether screening for cognitive impairment should be done among individuals with DR.

%B J Alzheimers Dis %V 86 %P 451-460 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35068460?dopt=Abstract %R 10.3233/JAD-215313 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Digital Technologies to Prevent Social Isolation and Loneliness in Dementia: A Systematic Review. %A Rai, Harleen Kaur %A Kernaghan, David %A Schoonmade, Linda %A Egan, Kieren J %A Pot, Anne Margriet %K Dementia %K Digital Technology %K Humans %K Loneliness %K Quality of Life %K Social Isolation %X

BACKGROUND: Dementia poses significant and sustained challenges to global society. Diagnosis can lead to increased feelings of loneliness and social isolation. People with dementia living alone are particularly at risk. Considering the growing number of technologies proposed to aid people with dementia address social isolation and loneliness, we reviewed the existing literature.

OBJECTIVE: To collate and summarize current evidence for digital technologies to prevent social isolation and loneliness for people with dementia.

METHODS: Following the PRISMA guidelines, we systematically searched five databases to identify studies of digital technologies designed to support or prevent social isolation or loneliness for people with dementia. Pre-specified outcomes included social isolation, loneliness, and quality of life. We used deductive thematic analysis to synthesize the major themes emerging from the studies.

RESULTS: Ten studies met our inclusion criteria where all studies reported improvements in quality of life and seven reported benefits regarding social inclusion or a reduction in loneliness. Technologies were varied across purpose, delivery format, theoretical models, and levels of personalization. Two studies clearly described the involvement of people with dementia in the study design and five technologies were available outside the research context.

CONCLUSION: There is limited- but increasing- evidence that technologies hold potential to improve quality of life and reduce isolation/loneliness for people with dementia. Results presented are largely based in small-scale research studies. Involvement of people with dementia was limited and few research concepts are reaching implementation. Closer collaboration with people with dementia to provide affordable, inclusive, and person-centered solutions is urgently required.

%B J Alzheimers Dis %V 90 %P 513-528 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/36120780?dopt=Abstract %R 10.3233/JAD-220438 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Dimethyl Fumarate is a Potential Therapeutic Option for Alzheimer's Disease. %A Sun, Xiaodi %A Suo, Xinjun %A Xia, Xianyou %A Yu, Chunshui %A Dou, Yan %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Antioxidants %K Cell Survival %K Dimethyl Fumarate %K Disease Models, Animal %K Hippocampus %K Inflammation %K Male %K Memory Disorders %K Mice %K Mice, Inbred C57BL %K Neurons %K NF-E2-Related Factor 2 %K NF-kappa B %K Oxidative Stress %K Protective Agents %K Reactive Oxygen Species %X

BACKGROUND: Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2 pathway. Since both oxidative stress and inflammation are involved in Alzheimer's disease (AD), DMF is a potential therapeutic option for AD.

OBJECTIVE: This study aims to test the therapeutic effects of DMF on AD model mice and to reveal its underlying molecular mechanisms.

METHODS: Cell viability assay and in vitro immunofluorescence imaging were used to evaluate the antioxidant effect of DMF on embryonic mouse hippocampal neurons. Behavioral test and brain magnetic resonance imaging were used to assess the therapeutic effects of DMF on spatial learning and memory as well as hippocampal volume in AD model mice with and without Nrf2 knockdown. Western blotting was used to analyze the expression of antioxidant enzymes and molecules associated with AD-related pathological pathways.

RESULTS: DMF inhibits reactive oxygen species overproduction and protects neurons without Nrf2 knockdown from death. DMF reduces amyloid-β induced memory impairment and hippocampal atrophy in AD model mice rather than in Nrf2 knockdown AD mice. DMF delays the progression of AD by activating the Nrf2 pathway to enhance the expression of downstream antioxidant enzymes and inhibits lipid peroxidation, apoptosis, inflammation, mitochondrial dysfunction and amyloid-β deposition.

CONCLUSION: These results indicate that DMF is a potential therapeutic option for AD through its antioxidant, anti-inflammatory, anti-apoptotic, and other anti-AD effects by activating the Nrf2 pathway.

%B J Alzheimers Dis %V 85 %P 443-456 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34842188?dopt=Abstract %R 10.3233/JAD-215074 %0 Journal Article %J J Alzheimers Dis %D 2022 %T DNA Damage Increases Secreted Aβ40 and Aβ42 in Neuronal Progenitor Cells: Relevance to Alzheimer's Disease. %A Welty, Starr %A Thathiah, Amantha %A Levine, Arthur Samuel %X

BACKGROUND: Recent studies suggest a strong association between neuronal DNA damage, elevated levels of amyloid-β (Aβ), and regions of the brain that degenerate in Alzheimer's disease (AD).

OBJECTIVE: To investigate the nature of this association, we tested the hypothesis that extensive DNA damage leads to an increase in Aβ40 and Aβ42 generation.

METHODS: We utilized an immortalized human neuronal progenitor cell line (NPCs), ReN VM GA2. NPCs or 20 day differentiated neurons were treated with hydrogen peroxide or etoposide and allowed to recover for designated times. Sandwich ELISA was used to assess secreted Aβ40 and Aβ42. Western blotting, immunostaining, and neutral comet assay were used to evaluate the DNA damage response and processes indicative of AD pathology.

RESULTS: We determined that global hydrogen peroxide damage results in increased cellular Aβ40 and Aβ42 secretion 24 h after treatment in ReN GA2 NPCs. Similarly, DNA double strand break (DSB)-specific etoposide damage leads to increased Aβ40 and Aβ42 secretion 2 h and 4 h after treatment in ReN GA2 NPCs. In contrast, etoposide damage does not increase Aβ40 and Aβ42 secretion in post-mitotic ReN GA2 neurons.

CONCLUSION: These findings provide evidence that in our model, DNA damage is associated with an increase in Aβ secretion in neuronal progenitors, which may contribute to the early stages of neuronal pathology in AD.

%B J Alzheimers Dis %V 88 %P 177-190 %8 2022 Jun 28 %G eng %N 1 %R 10.3233/JAD-220030 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Does Loss of Integrity of the Cingulum Bundle Link Amyloid-β Accumulation and Neurodegeneration in Alzheimer's Disease? %A Vlegels, Naomi %A Ossenkoppele, Rik %A van der Flier, Wiesje M %A Koek, Huiberdina L %A Reijmer, Yael D %A Wisse, Laura Em %A Biessels, Geert Jan %X

BACKGROUND: Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial Aβ deposition and local neurodegeneration.

OBJECTIVE: Here, we test the hypothesis that the cingulum bundle links Aβ deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy.

METHODS: 21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer's Disease Neuroimaging Initiative (ADNI, replication sample) with available Aβ-PET scan, T1-weighted and diffusion-weighted MRI were included. Aβ load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant.

RESULTS: We found at most a weak association between cingulate Aβ and MTL volume (added R2 <0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate Aβ or MTL volume (added R2 <0.01). Various sensitivity analyses (Aβ-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results.

CONCLUSION: These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus Aβ deposition and MTL atrophy.

%B J Alzheimers Dis %V 89 %P 39-49 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-220024 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Effect of Probiotic Bifidobacterium breve in Improving Cognitive Function and Preventing Brain Atrophy in Older Patients with Suspected Mild Cognitive Impairment: Results of a 24-Week Randomized, Double-Blind, Placebo-Controlled Trial. %A Asaoka, Daisuke %A Xiao, Jinzhong %A Takeda, Tsutomu %A Yanagisawa, Naotake %A Yamazaki, Takahiro %A Matsubara, Yoichiro %A Sugiyama, Hideki %A Endo, Noemi %A Higa, Motoyuki %A Kasanuki, Koji %A Ichimiya, Yosuke %A Koido, Shigeo %A Ohno, Kazuya %A Bernier, Francois %A Katsumata, Noriko %A Nagahara, Akihito %A Arai, Heii %A Ohkusa, Toshifumi %A Sato, Nobuhiro %K Aged %K Aged, 80 and over %K Atrophy %K Bifidobacterium breve %K Brain %K Cognition %K Cognitive Dysfunction %K Double-Blind Method %K Humans %K Probiotics %X

BACKGROUND: Probiotics have been reported to ameliorate cognitive impairment.

OBJECTIVE: We investigated the effect of the probiotic strain Bifidobacterium breve MCC1274 (A1) in enhancing cognition and preventing brain atrophy of older patients with mild cognitive impairment (MCI).

METHODS: In this RCT, 130 patients aged from 65 to 88 years old with suspected MCI received once daily either probiotic (B. breve MCC1274, 2×1010 CFU) or placebo for 24 weeks. Cognitive functions were assessed by ADAS-Jcog and MMSE tests. Participants underwent MRI to determine brain atrophy changes using Voxel-based Specific Regional Analysis System for Alzheimer's disease (VSRAD). Fecal samples were collected for the analysis of gut microbiota composition.

RESULTS: Analysis was performed on 115 participants as the full analysis set (probiotic 55, placebo 60). ADAS-Jcog subscale "orientation" was significantly improved compared to placebo at 24 weeks. MMSE subscales "orientation in time" and "writing" were significantly improved compared to placebo in the lower baseline MMSE (< 25) subgroup at 24 weeks. VSRAD scores worsened in the placebo group; probiotic supplementation tended to suppress the progression, in particular among those subjects with progressed brain atrophy (VOI Z-score ≥1.0). There were no marked changes in the overall composition of the gut microbiota by the probiotic supplementation.

CONCLUSION: Improvement of cognitive function was observed on some subscales scores only likely due to the lower sensitiveness of these tests for MCI subjects. Probiotics consumption for 24 weeks suppressed brain atrophy progression, suggesting that B. breve MCC1274 helps prevent cognitive impairment of MCI subjects.

%B J Alzheimers Dis %V 88 %P 75-95 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35570493?dopt=Abstract %R 10.3233/JAD-220148 %0 Journal Article %J J Alzheimers Dis %D 2022 %T The Effectiveness of GRADIOR: A Neuropsychological Rehabilitation Program for People with Mild Cognitive Impairment and Mild Dementia. Results of a Randomized Controlled Trial After 4 and 12 Months of Treatment. %A Diaz Baquero, Angie A %A Franco-Martín, Manuel A %A Parra Vidales, Esther %A Toribio-Guzmán, José Miguel %A Bueno-Aguado, Yolanda %A Martínez Abad, Fernando %A Perea Bartolomé, María V %A Asl, Aysan Mahmoudi %A van der Roest, Henriëtte G %X

BACKGROUND: Computer-based cognitive training programs have been developed with promising results on the maintenance/improvement of cognitive performance in people with dementia.

OBJECTIVE: The objective was to evaluate the effectiveness of the cognitive rehabilitation program "GRADIOR" in people with mild cognitive impairment and mild dementia.

METHOD: This study was a single-blind multicenter randomized clinical trial. Participants were recruited from hospitals/day centers. The experimental group (EG) and control group (CG) received computer-based cognitive training (CCT) and routine daily care, respectively. Outcome measures at T0: baseline, T1: at 4 months, T2: at 12 months were compared within and between-groups.

RESULTS: Significant differences or important effect sizes were detected at the intragroup and intergroup level for most variables, observing a trend of improvement and/or maintenance at 4 months by Visual Reasoning of Cambridge Cognitive Examination (CAMCOG), Digit and Arithmetic of WAIS-III, Semantic Verbal Fluency, Mini-Mental State Exam (MMSE), Trail Making Test (TMT)-A-Mistakes and at 12 months by Visual Reasoning of CAMCOG, Digit Symbol of WAIS-III, TMT-B-mistakes, Visual Memory of Rivermead Behavioural Memory Test, Lexical Verbal Fluency-P, Yesavage's Geriatric Depression Scale (GDS), TMT-A-time scales whose objective was to evaluate some executive functions and/or the memory. The CG presented a worsening trend for most of the measures towards 12 months. There was also a significant interaction between "time and group" for MMSE (F = 8.971; p = 0.03; η 2 = 0.019) and the GDS (F = 3.414; p = 0.04; η 2 = 0.041), as well as small effect sizes for TMT-A-time (F = 1.641; p = 0.21; η 2 = 0.021) and TMT-A-mistakes (F = 0.908; p = 0.41; η 2 = 0.019).

CONCLUSION: CCT with GRADIOR has been proved to benefit cognitive functions (ISRCTN:15742788).

%B J Alzheimers Dis %V 86 %P 711-727 %8 2022 Mar 22 %G eng %N 2 %R 10.3233/JAD-215350 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Effects of a 6-Month Multifaceted Diet and Exercise Intervention on Cognition in Older Adults at Risk of Cognitive Decline: The PONDER Double-Blind, Placebo-Controlled Randomized Trial. %A Macpherson, Helen %A Brownell, Sarah %A Harris, Elizabeth %A Duckham, Rachel L %A O'Connell, Stella %A Meyer, Barbara J %A Mirzaee, Sam %A Daly, Robin M %X

BACKGROUND: Multidomain interventions which incorporate exercise and dietary supplementation to target both cognitive and physical health domains may be an important approach to delay cognitive decline.

OBJECTIVE: The Protein Omega-3 aNd vitamin D Exercise Research (PONDER) study investigated the effects of a 6-month multifaceted intervention in community-dwelling older adults with subjective memory impairment on cognition (primary outcome), physical function, and body composition with a further 6-month follow up for cognition (secondary outcomes).

METHODS: Single-center, community-based, parallel-group, randomized, double-blind placebo-controlled trial involving a 6-month multifaceted intervention with a further follow-up at 12 months. A total of 147 participants [mean age 70.2 years (SD 6.1), 70% female] were randomized to a multimodal exercise program consisting of twice-weekly supervised resistance and aerobic training, combined with a daily omega-3 (900 mg EPA, 600 mg DHA), vitamin D (1000 IU) and protein (20 g) supplement (n = 73), or a control condition (n = 74) comprising stretching/flexibility sessions combined with a placebo. The primary outcome was a composite CogState measure and Trail-Making Test B-A.

RESULTS: There were no significant between-group differences in the change of cognition at 6 or 12 months or physical function outcomes at 6 months, but the intervention significantly improved total lean mass compared to controls [0.72 kg (95% CI 0.26-1.19), p = 0.001].

CONCLUSION: A multi-faceted intervention including an omega-3, vitamin D and protein-enriched supplement with twice-weekly exercise training did not provide any benefits to cognitive or physical function in older adults with subjective memory impairment, despite improvements in lean mass.

%B J Alzheimers Dis %V 89 %P 247-263 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-220234 %0 Journal Article %J J Alzheimers Dis %D 2022 %T The Efficacy and Safety of Alzheimer's Disease Therapies: An Updated Umbrella Review. %A Fan, Fangcheng %A Liu, Hua %A Shi, Xiaojie %A Ai, Yangwen %A Liu, Qingshan %A Cheng, Yong %K Activities of Daily Living %K Alzheimer Disease %K Amino Acids %K Cholinesterase Inhibitors %K Cognition %K Donepezil %K Galantamine %K Ginkgo biloba %K Humans %K Nootropic Agents %K Patient Safety %K Plant Extracts %K Rivastigmine %X

BACKGROUND: Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer's disease (AD) are sparse.

OBJECTIVE: We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients.

METHODS: We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles.

RESULTS: Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD.

CONCLUSION: Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD.

%B J Alzheimers Dis %V 85 %P 1195-1204 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34924395?dopt=Abstract %R 10.3233/JAD-215423 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Environmental Enrichment Effects on the Brain-Derived Neurotrophic Factor Expression in Healthy Condition, Alzheimer's Disease, and Other Neurodegenerative Disorders. %A Cutuli, Debora %A Landolfo, Eugenia %A Petrosini, Laura %A Gelfo, Francesca %K Alzheimer Disease %K Animals %K Brain %K Brain-Derived Neurotrophic Factor %K Cognition %K Disease Models, Animal %K Environment %K Humans %K Neurodegenerative Diseases %K Neuronal Plasticity %X

Brain-derived neurotrophic factor (BDNF), a protein belonging to the neurotrophin family, is known to be heavily involved in synaptic plasticity processes that support brain development, post-lesion regeneration, and cognitive performances, such as learning and memory. Evidence indicates that BDNF expression can be epigenetically regulated by environmental stimuli and thus can mediate the experience-dependent brain plasticity. Environmental enrichment (EE), an experimental paradigm based on the exposure to complex stimulations, constitutes an efficient means to investigate the effects of high-level experience on behavior, cognitive processes, and neurobiological correlates, as the BDNF expression. In fact, BDNF exerts a key role in mediating and promoting EE-induced plastic changes and functional improvements in healthy and pathological conditions. This review is specifically aimed at providing an updated framework of the available evidence on the EE effects on brain and serum BDNF levels, by taking into account both changes in protein expression and regulation of gene expression. A further purpose of the present review is analyzing the potential of BDNF regulation in coping with neurodegenerative processes characterizing Alzheimer's disease (AD), given BDNF expression alterations are described in AD patients. Moreover, attention is also paid to EE effects on BDNF expression in other neurodegenerative disease. To investigate such a topic, evidence provided by experimental studies is considered. A deeper understanding of environmental ability in modulating BDNF expression in the brain may be fundamental in designing more tuned and effective applications of complex environmental stimulations as managing approaches to AD.

%B J Alzheimers Dis %V 85 %P 975-992 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34897089?dopt=Abstract %R 10.3233/JAD-215193 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Evaluation of the Accuracy of Cognitive Screening Tests in Detecting Dementia Associated with Alzheimer's Disease: A Hierarchical Bayesian Latent Class Meta-Analysis. %A Wang, Xiaonan %A Li, Fengjie %A Gao, Qi %A Jiang, Zhen %A Abudusaimaiti, Xiayidanmu %A Yao, Jiangyue %A Zhu, Huiping %K Alzheimer Disease %K Bayes Theorem %K Cognition %K Cognitive Dysfunction %K Humans %K Mental Status and Dementia Tests %K Neuropsychological Tests %X

BACKGROUND: Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) are neuropsychological tests commonly used by physicians for screening cognitive dysfunction of Alzheimer's disease (AD). Due to different imperfect reference standards, the performance of MoCA and MMSE do not reach consensus. It is necessary to evaluate the consistence and differentiation of MoCA and MMSE in the absence of a gold standard for AD.

OBJECTIVE: We aimed to assess the accuracy of MoCA and MMSE in screening AD without a gold standard reference test.

METHODS: Studies were identified from PubMed, Web of Science, CNKI, Chinese Wanfang Database, China Science and Technology Journal Database, and Cochrane Library. Our search was limited to studies published in English and Chinese before August 2021. A hierarchical Bayesian latent class model was performed in meta-analysis when the gold standard was absent.

RESULTS: A total of 67 studies comprising 5,554 individuals evaluated for MoCA and 76,862 for MMSE were included in this meta-analysis. The pooled sensitivity was 0.934 (95% CI 0.905 to 0.954) for MoCA and 0.883 (95% CI 0.859 to 0.903) for MMSE, while the pooled specificity was 0.899 (95% CI 0.859 to 0.928) for MoCA and 0.903 (95% CI 0.879 to 0.923) for MMSE. MoCA was useful to rule out dementia associated with AD with lower negative likelihood ratio (LR-) (0.074, 95% CI 0.051 to 0.108). MoCA showed better performance with higher diagnostic odds ratio (DOR) (124.903, 95% CI 67.459 to 231.260).

CONCLUSION: MoCA had better performance than MMSE in screening dementia associated with AD from patients with mild cognitive impairment or healthy controls.

%B J Alzheimers Dis %V 87 %P 285-304 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275533?dopt=Abstract %R 10.3233/JAD-215394 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Evoked Cortical Depolarizations Before and After the Amyloid Plaque Accumulation: Voltage Imaging Study. %A Zhu, Mei Hong %A Jogdand, Aditi H %A Jang, Jinyoung %A Nagella, Sai C %A Das, Brati %A Milosevic, Milena M %A Yan, Riqiang %A Antic, Srdjan D %X

BACKGROUND: In Alzheimer's disease (AD), synaptic dysfunction is thought to occur many years before the onset of cognitive decline.

OBJECTIVE: Detecting synaptic dysfunctions at the earliest stage of AD would be desirable in both clinic and research settings.

METHODS: Population voltage imaging allows monitoring of synaptic depolarizations, to which calcium imaging is relatively blind. We developed an AD mouse model (APPswe/PS1dE9 background) expressing a genetically-encoded voltage indicator (GEVI) in the neocortex. GEVI was restricted to the excitatory pyramidal neurons (unlike the voltage-sensitive dyes).

RESULTS: Expression of GEVI did not disrupt AD model formation of amyloid plaques. GEVI expression was stable in both AD model mice and Control (healthy) littermates (CTRL) over 247 days postnatal. Brain slices were stimulated in layer 2/3. From the evoked voltage waveforms, we extracted several parameters for comparison AD versus CTRL. Some parameters (e.g., temporal summation, refractoriness, and peak latency) were weak predictors, while other parameters (e.g., signal amplitude, attenuation with distance, and duration (half-width) of the evoked transients) were stronger predictors of the AD condition. Around postnatal age 150 days (P150) and especially at P200, synaptically-evoked voltage signals in brain slices were weaker in the AD groups versus the age- and sex-matched CTRL groups, suggesting an AD-mediated synaptic weakening that coincides with the accumulation of plaques. However, at the youngest ages examined, P40 and P80, the AD groups showed differentially stronger signals, suggesting "hyperexcitability" prior to the formation of plaques.

CONCLUSION: Our results indicate bidirectional alterations in cortical physiology in AD model mice; occurring both prior (P40-80), and after (P150-200) the amyloid deposition.

%B J Alzheimers Dis %V 88 %P 1443-1458 %8 2022 Aug 16 %G eng %N 4 %R 10.3233/JAD-220249 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Excretion of Amyloid-β in the Gastrointestinal Tract and Regulation by the Gut Microbiota. %A Wu, Shijing %A Hu, Li %A Lin, Jiajing %A Li, Kanglan %A Ye, Shicai %A Zhu, Shaoping %A Liu, Zhou %X

BACKGROUND: Amyloid-β (Aβ) is important in the etiology of Alzheimer's disease (AD). Removal of Aβ from the brain is a major strategy for the prevention and treatment of AD.

OBJECTIVE: To clarify whether Aβ 42 can be cleared by intestinal excretion and whether the gut microbiota (GM) can affect the excretory clearance of Aβ 42 in the peripheral blood and intestines.

METHODS: Male 8-month-old C57BL6 mice were maintained on either normal chow or received broad-spectrum antibiotics in their drinking water for one week. Sterile saline, fluorescein isothiocyanate (FITC), or FITC-Aβ 42 (fluorescein isothiocyanate-labeled amyloid-β 42 peptides) was injected 1 h before FITC, or FITC-Aβ 42 was injected 1 h before sampling. Related changes of Aβ 42 before and after injection were evaluated.

RESULTS: FITC-Aβ 42 was injected into mice through the tail vein and could later be detected in feces. Furthermore, the fecal concentrations of FITC-Aβ 42 were higher in mice that had been fed antibiotics to alter their GM than in normal mice. However, the FITC-Aβ 42 concentrations in blood showed the opposite pattern.

CONCLUSION: Aβ 42 can be excreted into the intestinal lumen and is regulated by the GM.

%B J Alzheimers Dis %V 90 %P 1153-1162 %8 2022 Nov 22 %G eng %N 3 %R 10.3233/JAD-220705 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Expression Changes in Mitochondrial Genes Affecting Mitochondrial Morphology, Transmembrane Potential, Fragmentation, Amyloidosis, and Neuronal Cell Death Found in Brains of Alzheimer's Disease Patients. %A Castora, Frank J %A Kerns, Kimberly A %A Pflanzer, Haley K %A Hitefield, Naomi L %A Gershon, Blake %A Shugoll, Jason %A Shelton, Morgan %A Coleman, Randolph A %X

BACKGROUND: Alzheimer's disease (AD) is a neurological disease that has both a genetic and non-genetic origin. Mitochondrial dysfunction is a critical component in the pathogenesis of AD as deficits in oxidative capacity and energy production have been reported.

OBJECTIVE: Nuclear-encoded mitochondrial genes were studied in order to understand the effects of mitochondrial expression changes on mitochondrial function in AD brains. These expression data were to be incorporated into a testable mathematical model for AD used to further assess the genes of interest as therapeutic targets for AD.

METHODS: RT2-PCR arrays were used to assess expression of 84 genes involved in mitochondrial biogenesis in AD brains. A subset of mitochondrial genes of interest was identified after extensive Ingenuity Pathway Analysis (IPA) (Qiagen). Further filtering of this subset of genes of interest was achieved by individual qPCR analyses. Expression values from this group of genes were included in a mathematical model being developed to identify potential therapeutic targets.

RESULTS: Nine genes involved in trafficking proteins to mitochondria, morphology of mitochondria, maintenance of mitochondrial transmembrane potential, fragmentation of mitochondria and mitochondrial dysfunction, amyloidosis, and neuronal cell death were identified as significant to the changes seen. These genes include TP53, SOD2, CDKN2A, MFN2, DNM1L, OPA1, FIS1, BNIP3, and GAPDH.

CONCLUSION: Altered mitochondrial gene expression indicates that a subset of nuclear-encoded mitochondrial genes compromise multiple aspects of mitochondrial function in AD brains. A new mathematical modeling system may provide further insights into potential therapeutic targets.

%B J Alzheimers Dis %V 90 %P 119-137 %8 2022 Oct 25 %G eng %N 1 %R 10.3233/JAD-220161 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Frontal Atrophy and Executive Dysfunction Relate to Complex Numbers Impairment in Progressive Supranuclear Palsy. %A Howard, Erica %A Ballinger, Samantha %A Kinney, Nikolas G %A Balgenorth, Yvonne %A Ehrhardt, Annabess %A Phillips, Jeffrey S %A Irwin, David J %A Grossman, Murray %A Cousins, Katheryn A Q %X

BACKGROUND: Previous research finds a range of numbers impairments in Parkinsonian syndromes (PS), but has largely focused on how visuospatial impairments impact deficits in basic numerical processes (e.g., magnitude judgments, chunking). Differentiation between these basic functions and more complex numerical processes often utilized in everyday tasks may help elucidate neurocognitive and neuroanatomic bases of numbers deficits in PS.

OBJECTIVE: To test neurocognitive and neuroanatomic correlates of complex numerical processing in PS, we assessed number abilities, neuropsychological performance, and cortical thickness in progressive supranuclear palsy (PSP) and Lewy body spectrum disorders (LBSD).

METHODS: Fifty-six patients (LBSD = 35; PSP = 21) completed a Numbers Battery, including basic and complex numerical tasks. The Mini-Mental State Exam (MMSE), letter fluency (LF), and Judgment of Line Orientation (JOLO) assessed global, executive, and visuospatial functioning respectively. Mann-Whitney U tests compared neuropsychological testing and rank-transformed analysis of covariance (ANCOVA) compared numbers performance between groups while adjusting for demographic variables. Spearman's and partial correlations related numbers performance to neuropsychological tasks. Neuroimaging assessed cortical thickness in disease groups and demographically-matched healthy controls.

RESULTS: PSP had worse complex numbers performance than LBSD (F = 6.06, p = 0.02) but similar basic numbers performance (F = 0.38, p >  0.1), covarying for MMSE and sex. Across syndromes, impaired complex numbers performance was linked to poor LF (rho = 0.34, p = 0.01) but not JOLO (rho = 0.23, p >  0.05). Imaging revealed significant frontal atrophy in PSP compared to controls, which was associated with worse LF and complex numbers performance.

CONCLUSION: PSP demonstrated selective impairments in complex numbers processing compared to LBSD. This complex numerical deficit may relate to executive dysfunction and frontal atrophy.

%B J Alzheimers Dis %V 88 %P 1553-1566 %8 2022 Aug 16 %G eng %N 4 %R 10.3233/JAD-215327 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Functional Neurophysiological Biomarkers of Early-Stage Alzheimer's Disease: A Perspective of Network Hyperexcitability in Disease Progression. %A Tok, Sean %A Ahnaou, Abdallah %A Drinkenburg, Wilhelmus %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Biomarkers %K Disease Progression %K Humans %K Nervous System Physiological Phenomena %K Neurophysiology %K tau Proteins %X

Network hyperexcitability (NH) has recently been suggested as a potential neurophysiological indicator of Alzheimer's disease (AD), as new, more accurate biomarkers of AD are sought. NH has generated interest as a potential indicator of certain stages in the disease trajectory and even as a disease mechanism by which network dysfunction could be modulated. NH has been demonstrated in several animal models of AD pathology and multiple lines of evidence point to the existence of NH in patients with AD, strongly supporting the physiological and clinical relevance of this readout. Several hypotheses have been put forward to explain the prevalence of NH in animal models through neurophysiological, biochemical, and imaging techniques. However, some of these hypotheses have been built on animal models with limitations and caveats that may have derived NH through other mechanisms or mechanisms without translational validity to sporadic AD patients, potentially leading to an erroneous conclusion of the underlying cause of NH occurring in patients with AD. In this review, we discuss the substantiation for NH in animal models of AD pathology and in human patients, as well as some of the hypotheses considering recently developed animal models that challenge existing hypotheses and mechanisms of NH. In addition, we provide a preclinical perspective on how the development of animal models incorporating AD-specific NH could provide physiologically relevant translational experimental data that may potentially aid the discovery and development of novel therapies for AD.

%B J Alzheimers Dis %V 88 %P 809-836 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34420957?dopt=Abstract %R 10.3233/JAD-210397 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Glucometabolic Changes Are Associated with Structural Gray Matter Alterations in Prodromal Dementia. %A Gentreau, Mélissa %A Reynes, Christelle %A Sabatier, Robert %A Maller, Jerome J %A Meslin, Chantal %A Deverdun, Jeremy %A Le Bars, Emmanuelle %A Raymond, Michel %A Berticat, Claire %A Artero, Sylvaine %X

BACKGROUND: Glucometabolic changes, such as high glycemic load (GL) diet and insulin resistance (IR), are potential risk factor of Alzheimer's disease (AD). Yet, the effect of these factors on brain alterations that contribute to AD pathology has not been clearly demonstrated.

OBJECTIVE: We aimed to assess the relationship of GL and IR with gray matter volumes involved in prodromal dementia.

METHODS: GL and Triglyceride-Glucose (TyG) index, an IR surrogate marker, were calculated in 497 participants who underwent magnetic resonance imaging (MRI). The gray matter volumes most related to prodromal dementia/mild cognitive impairment (diagnosed in 18/158 participants during the 7-year follow-up) were identified using a data-driven machine learning algorithm.

RESULTS: Higher GL diet was associated with reduced amygdala volume. The TyG index was negatively associated with the hippocampus, amygdala, and putamen volumes.

CONCLUSION: These results suggest that GL and IR are associated with lower gray matter volumes in brain regions involved in AD pathology.

%B J Alzheimers Dis %V 89 %P 1293-1302 %8 2022 Oct 11 %G eng %N 4 %R 10.3233/JAD-220490 %0 Journal Article %J J Alzheimers Dis %D 2022 %T High Soluble Amyloid-β42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer's Disease-Causing Mutations. %A Sturchio, Andrea %A Dwivedi, Alok K %A Malm, Tarja %A Wood, Matthew J A %A Cilia, Roberto %A Sharma, Jennifer S %A Hill, Emily J %A Schneider, Lon S %A Graff-Radford, Neill R %A Mori, Hiroshi %A Nübling, Georg %A El Andaloussi, Samir %A Svenningsson, Per %A Ezzat, Kariem %A Espay, Alberto J %X

BACKGROUND: In amyloid-positive individuals at risk for Alzheimer's disease (AD), high soluble 42-amino acid amyloid-β (Aβ42) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort.

OBJECTIVE: To test the hypothesis that high Aβ42 preserves normal cognition in amyloid-positive individuals with Alzheimer's disease (AD)-causing mutations (APP, PSEN1, or PSEN2) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau).

METHODS: Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression.

RESULTS: Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8% ) meeting criteria for progression after 3.3±2.0 years. Soluble Aβ42 levels were higher among CDR non-progressors than CDR progressors. Higher Aβ42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19-0.67; p = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68-0.96; p = 0.018). CSF Aβ42 levels predicting lower risk of progression increased with higher SUVR levels.

CONCLUSION: High CSF Aβ42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.

%B J Alzheimers Dis %V 90 %P 333-348 %8 2022 Oct 25 %G eng %N 1 %R 10.3233/JAD-220808 %0 Journal Article %J J Alzheimers Dis %D 2022 %T HMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD24. %A Hu, Li-Tian %A Xie, Xiao-Yong %A Zhou, Gui-Feng %A Wen, Qi-Xin %A Song, Li %A Luo, Biao %A Deng, Xiao-Juan %A Pan, Qiu-Ling %A Chen, Guo-Jun %X

BACKGROUND: Accumulation of hyperphosphorylated Tau (pTau) contributes to the formation of neurofibrillary tangles in Alzheimer's disease (AD), and targeting Tau/pTau metabolism has emerged as a therapeutic approach. We have previously reported that mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2 (HMGCS2) is involved in AD by promoting autophagic clearance of amyloid-β protein precursor via ketone body-associated mechanism, whether HMGCS2 may also regulate Tau metabolism remains elusive.

OBJECTIVE: The present study was to investigate the role of HMGCS2 in Tau/p degradation.

METHODS: The protein levels of Tau and pTau including pT217 and pT181, as well as autophagic markers LAMP1 and LC3-II were assessed by western blotting. The differentially regulated genes by HMGCS2 were analyzed by RNA sequencing. Autophagosomes were assessed by transmission electron microscopy.

RESULTS: HMGCS2 significantly decreased Tau/pTau levels, which was paralleled by enhanced formation of autophagic vacuoles and prevented by autophagic regulators chloroquine, bafilomycin A1, 3-methyladenine, and rapamycin. Moreover, HMGCS2-induced alterations of LAMP1/LC3-II and Tau/pTau levels were mimicked by ketone body acetoacetate or β-hydroxybutyrate. Further RNA-sequencing identified ankyrin repeat domain 24 (ANKRD24) as a target gene of HMGCS2, and silencing of ANKRD24 reduced LAMP1/LC3-II levels, which was accompanied by the altered formation of autophagic vacuoles, and diminished the effect of HMGCS2 on Tau/pTau.

CONCLUSION: HMGCS2 promoted autophagic clearance of Tau/pTau, in which ketone body and ANKRD24 played an important role.

%B J Alzheimers Dis %V 91 %P 407-426 %8 2023 Jan 03 %G eng %N 1 %R 10.3233/JAD-220640 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Impact of COVID-19 on 'Living Well' with Mild-to-Moderate Dementia in the Community: Findings from the IDEAL Cohort. %A Clare, Linda %A Martyr, Anthony %A Gamble, Laura D %A Pentecost, Claire %A Collins, Rachel %A Dawson, Eleanor %A Hunt, Anna %A Parker, Sophie %A Allan, Louise %A Burns, Alistair %A Hillman, Alexandra %A Litherland, Rachael %A Quinn, Catherine %A Matthews, Fiona E %A Victor, Christina %K Activities of Daily Living %K Adult %K Aged %K Aged, 80 and over %K Caregivers %K COVID-19 %K Dementia %K Female %K Humans %K Male %K Middle Aged %K Neighborhood Characteristics %K Quality of Life %K SARS-CoV-2 %X

BACKGROUND: Negative impacts of the COVID-19 pandemic on people with dementia have been widely-documented, but most studies have relied on carer reports and few have compared responses to information collected before the pandemic.

OBJECTIVE: We aimed to explore the impact of the pandemic on community-dwelling individuals with mild-to-moderate dementia and compare responses with pre-pandemic data.

METHODS: During the second wave of the pandemic, we conducted structured telephone interviews with 173 people with dementia and 242 carers acting as informants, all of whom had previously participated in the IDEAL cohort. Where possible, we benchmarked responses against pre-pandemic data.

RESULTS: Significant perceived negative impacts were identified in cognitive and functional skills and ability to engage in self-care and manage everyday activities, along with increased levels of loneliness and discontinuity in sense of self and a decline in perceived capability to 'live well'. Compared to pre-pandemic data, there were lower levels of pain, depression, and anxiety, higher levels of optimism, and better satisfaction with family support. There was little impact on physical health, mood, social connections and relationships, or perceptions of neighborhood characteristics.

CONCLUSION: Efforts to mitigate negative impacts of pandemic-related restrictions and restore quality of life could focus on reablement to address the effects on participation in everyday activities, creating opportunities for social contact to reduce loneliness, and personalized planning to reconnect people with their pre-COVID selves. Such efforts may build on the resilience demonstrated by people with dementia and carers in coping with the pandemic.

%B J Alzheimers Dis %V 85 %P 925-940 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34776448?dopt=Abstract %R 10.3233/JAD-215095 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Impaired Experience-Dependent Refinement of Place Cells in a Rat Model of Alzheimer's Disease. %A Broussard, John I %A Redell, John B %A Maynard, Mark E %A Zhao, Jing %A Moore, Anthony %A Mills, Rachel W %A Hood, Kimberly N %A Underwood, Erica %A Roysam, Badrinath %A Dash, Pramod K %X

BACKGROUND: Hippocampal place cells play an integral role in generating spatial maps. Impaired spatial memory is a characteristic pathology of Alzheimer's disease (AD), yet it remains unclear how AD influences the properties of hippocampal place cells.

OBJECTIVE: To record electrophysiological activity in hippocampal CA1 neurons in freely-moving 18-month-old male TgF344-AD and age-matched wild-type (WT) littermates to examine place cell properties.

METHODS: We implanted 32-channel electrode arrays into the CA1 subfield of 18-month-old male WT and TgF344-AD (n = 6/group) rats. Ten days after implantation, single unit activity in an open field arena was recorded across days. The spatial information content, in-field firing rate, and stability of each place cell was compared across groups. Pathology was assessed by immunohistochemical staining, and a deep neural network approach was used to count cell profiles.

RESULTS: Aged TgF344-AD rats exhibited hippocampal amyloid-β deposition, and a significant increase in Iba1 immunoreactivity and microglia cell counts. Place cells from WT and TgF344-AD rat showed equivalent spatial information, in-field firing rates, and place field stability when initially exposed to the arena. However, by day 3, the place cells in aged WT rats showed characteristic spatial tuning as evidenced by higher spatial information content, stability, and in-field firing rates, an effect not seen in TgF344-AD rats.

CONCLUSION: These findings support the notion that altered electrophysiological properties of place cells may contribute to the learning and memory deficits observed in AD.

%B J Alzheimers Dis %V 86 %P 1907-1916 %8 2022 Apr 19 %G eng %N 4 %R 10.3233/JAD-215023 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Importance of Accounting for Regional Differences in Modifiable Risk Factors for Alzheimer's Disease and Related Dementias: The Case for Tailored Interventions. %A Hoffmann, Coles M %A Nianogo, Roch A %A Yaffe, Kristine %A Rosenwohl-Mack, Amy %A Carrasco, Anna %A Barnes, Deborah E %X

BACKGROUND: We recently estimated that 36.9% of Alzheimer's disease and related dementias (ADRD) cases in the US may be attributable to modifiable risk factors, but it is not known whether national estimates generalize to specific states or regions.

OBJECTIVE: To compare national estimates of modifiable risk factors of ADRD to California, overall and by sex and race/ethnicity, and to estimate number of cases potentially preventable by reducing the prevalence of key risk factors by 25%.

METHODS: Adults ≥18 years who participated in the Behavioral Risk Factor Surveillance Survey in California (n = 9,836) and the US (n = 378,615). We calculated population attributable risks (PARs) for eight risk factors (physical inactivity, current smoking, depression, low education, diabetes mellitus, midlife obesity, midlife hypertension, and hearing loss) and compared estimates in California and the U.S.

RESULTS: In California, overall, 28.9% of ADRD cases were potentially attributable to the combination of risk factors, compared to 36.9% in the U.S. The top three risk factors were the same in California and the U.S., although their relative importance differed (low education [CA:14.9%; U.S.:11.7% ], midlife obesity [CA:14.9%; U.S.:17.7% ], and physical inactivity [CA:10.3%; U.S.:11.8% ]). The number of ADRD cases attributable to the combined risk factors was 199,246 in California and 2,287,683 in the U.S. If the combined risk factors were reduced by 25%, we could potentially prevent more than 40,000 cases in California and 445,000 cases in the U.S.

CONCLUSION: Our findings highlight the importance of examining risk factors of ADRD regionally, and within sex and race/ethnic groups to tailor dementia risk reduction strategies.

%B J Alzheimers Dis %V 89 %P 563-570 %8 2022 Sep 13 %G eng %N 2 %R 10.3233/JAD-220278 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Improved Alzheimer's Disease versus Frontotemporal Lobar Degeneration Differential Diagnosis Combining EEG and Neurochemical Biomarkers: A Pilot Study. %A Laton, Jorne %A Van Schependom, Jeroen %A Goossens, Joery %A Wiels, Wietse %A Sieben, Anne %A De Deyn, Peter Paul %A Goeman, Johan %A Streffer, Johannes %A van der Zee, Julie %A Martin, Jean-Jacques %A Van Broeckhoven, Christine %A De Vos, Maarten %A Bjerke, Maria %A Nagels, Guy %A Engelborghs, Sebastiaan %X

BACKGROUND: Distinguishing between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) results in poor diagnostic accuracy.

OBJECTIVE: To investigate the utility of electroencephalography (EEG)-based biomarkers in comparison and in addition to established cerebrospinal fluid (CSF) biomarkers in the AD versus FTLD differential diagnosis.

METHODS: The study cohort comprised 37 AD and 30 FTLD patients, of which 17 AD and 9 FTLD patients had definite diagnoses. All participants had CSF neurochemical (NCM) biomarker analyses (Aβ1-42, T-tau, P-tau181, and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks were extracted in four regions resulting in four dominant frequencies. This produced eight features (4 NCM + 4 EEG).

RESULTS: When NCM and EEG markers were combined, the diagnostic accuracy increased significantly. In the whole group, the accuracy went up from 79% (NCM) to almost 82%, while in the definite group only, it went up from around 85% to almost 95% . Two differences in the occurrence of the dominant EEG frequency were discovered: people lacking a clear dominant peak almost all had definite AD, while people with two peaks more often had FTLD.

CONCLUSION: Combining EEG with NCM biomarkers resulted in differential diagnostic accuracies of 82% in clinically diagnosed AD and FTD patients and of 95% in patients having a definite diagnosis, which was significantly better than with EEG or NCM biomarkers alone. This suggests that NCM and EEG markers are complementary, revealing different aspects of the disease and therefore confirms again their relevance in developing additional diagnosis tools.

%B J Alzheimers Dis %V 90 %P 1739-1747 %8 2022 Dec 06 %G eng %N 4 %R 10.3233/JAD-220693 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Improved Prediction of Amyloid-β and Tau Burden Using Hippocampal Surface Multivariate Morphometry Statistics and Sparse Coding. %A Wu, Jianfeng %A Su, Yi %A Zhu, Wenhui %A Jalili Mallak, Negar %A Lepore, Natasha %A Reiman, Eric M %A Caselli, Richard J %A Thompson, Paul M %A Chen, Kewei %A Wang, Yalin %X

BACKGROUND: Amyloid-β (Aβ) plaques and tau protein tangles in the brain are the defining 'A' and 'T' hallmarks of Alzheimer's disease (AD), and together with structural atrophy detectable on brain magnetic resonance imaging (MRI) scans as one of the neurodegenerative ('N') biomarkers comprise the "ATN framework" of AD. Current methods to detect Aβ/tau pathology include cerebrospinal fluid (invasive), positron emission tomography (PET; costly and not widely available), and blood-based biomarkers (promising but mainly still in development).

OBJECTIVE: To develop a non-invasive and widely available structural MRI-based framework to quantitatively predict the amyloid and tau measurements.

METHODS: With MRI-based hippocampal multivariate morphometry statistics (MMS) features, we apply our Patch Analysis-based Surface Correntropy-induced Sparse coding and max-pooling (PASCS-MP) method combined with the ridge regression model to individual amyloid/tau measure prediction.

RESULTS: We evaluate our framework on amyloid PET/MRI and tau PET/MRI datasets from the Alzheimer's Disease Neuroimaging Initiative. Each subject has one pair consisting of a PET image and MRI scan, collected at about the same time. Experimental results suggest that amyloid/tau measurements predicted with our PASCP-MP representations are closer to the real values than the measures derived from other approaches, such as hippocampal surface area, volume, and shape morphometry features based on spherical harmonics.

CONCLUSION: The MMS-based PASCP-MP is an efficient tool that can bridge hippocampal atrophy with amyloid and tau pathology and thus help assess disease burden, progression, and treatment effects.

%B J Alzheimers Dis %V 91 %P 637-651 %8 2023 Jan 17 %G eng %N 2 %R 10.3233/JAD-220812 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Incidence and Outcomes of SARS-CoV-2 Infection in Older Adults Living with Dementia: A Population-Based Cohort Study. %A Cascini, Silvia %A Agabiti, Nera %A Marino, Claudia %A Acampora, Anna %A Balducci, Maria %A Calandrini, Enrico %A Davoli, Marina %A Bargagli, Anna Maria %X

BACKGROUND: The identification of risk factors for SARS-CoV-2 infection and mortality in patients with dementia is a key aspect to support clinical decisions and public health interventions.

OBJECTIVE: To assess the incidence of SARS-CoV-2 infection and COVID-19 related death in a cohort of patients with dementia residing in the Lazio region and to investigate predicting factors for both infection and mortality.

METHODS: This population-based study used information from administrative databases and the SARS-CoV-2 infection surveillance system. Patients with dementia (age ≥65) were enrolled as of December 31, 2019 and followed-up until February 28, 2021. Cumulative risk of infection and death within 60 days of infection onset, and age-standardized incidence (SIR) and mortality (SMR) ratios were calculated. Logistic regression models were applied to identify factors associated with infection and mortality.

RESULTS: Among 37,729 dementia patients, 2,548 had a diagnosis of SARS-CoV-2 infection. The crude risk of infection was 6.7% . An increase in risk of infection was observed both in women (SIR 1.72; 95% CI 1.64-1.80) and men (SIR 1.43; 95% CI 1.33-1.54). Pneumonia, cerebrovascular and blood diseases, femur fracture, anxiety, antipsychotic and antithrombotic use were associated with an increased risk of infection. The crude risk of death was 31.0%, the SMRs 2.32 (95% CI 2.05-2.65) for men, and 2.82 (95% CI 2.55-3.11) for women. Factors associated with mortality included: male gender, age ≥85, symptoms at the diagnosis, antipsychotic and systemic antibiotics treatment.

CONCLUSION: These findings emphasize the need of close and tailored monitoring of dementia patients to reduce the impact of COVID-19 on this fragile population.

%B J Alzheimers Dis %V 89 %P 681-693 %8 2022 Sep 13 %G eng %N 2 %R 10.3233/JAD-220369 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Increased Functional Connectivity of the Precuneus in Individuals with a Family History of Alzheimer's Disease. %A Green, Zachary D %A Vidoni, Eric D %A Swerdlow, Russell H %A Burns, Jeffrey M %A Morris, Jill K %A Honea, Robyn A %X

BACKGROUND: First-degree relatives of individuals with late-onset Alzheimer's disease (AD) have increased risk for AD, with children of affected parents at an especially high risk.

OBJECTIVE: We aimed to investigate default mode network connectivity, medial temporal cortex volume, and cognition in cognitively healthy (CH) individuals with (FH+) and without (FH-) a family history of AD, alongside amnestic mild cognitive impairment (aMCI) and AD individuals, to determine the context and directionality of dysfunction in at-risk individuals. Our primary hypothesis was that there would be a linear decline (CH FH- > CH FH+ > aMCI > AD) within the risk groups on all measures of AD risk.

METHODS: We used MRI and fMRI to study cognitively healthy individuals (n = 28) with and without AD family history (FH+ and FH-, respectively), those with aMCI (n = 31) and early-stage AD (n = 25). We tested connectivity within the default mode network, as well as measures of volume and thickness within the medial temporal cortex and selected seed regions.

RESULTS: As expected, we identified decreased medial temporal cortex volumes in the aMCI and AD groups compared to cognitively healthy groups. We also observed patterns of connectivity across risk groups that suggest a nonlinear relationship of change, such that the FH+ group showed increased connectivity compared to the FH- and AD groups (CH FH+ > CH FH- > aMCI > AD). This pattern emerged primarily in connectivity between the precuneus and frontal regions.

CONCLUSION: These results add to a growing literature that suggests compensatory brain function in otherwise cognitively healthy individuals with a family history of AD.

%B J Alzheimers Dis %V 91 %P 559-571 %8 2023 Jan 17 %G eng %N 2 %R 10.3233/JAD-210326 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Informal Caregivers' Attitude Toward Dementia: The Impact of Dementia Knowledge, Confidence in Dementia Care, and the Behavioral and Psychological Symptoms of the Person with Dementia. A Cross-Sectional Study. %A Teichmann, Birgit %A Gkioka, Mara %A Kruse, Andreas %A Tsolaki, Magda %K Attitude %K Caregivers %K Cross-Sectional Studies %K Dementia %K Humans %K Surveys and Questionnaires %X

BACKGROUND: Dementia is rapidly increasing worldwide due to demographic aging. More than two-thirds of patients are cared by family members. The quality of care depends on the caregivers' attitude toward dementia influencing patient care decisions.

OBJECTIVE: The aim of this study is to examine the factors that influence the caregivers' attitude and whether there is an association between participation in a psycho-educational program and attitude.

METHODS: We performed a cross-sectional study using a structured closed-ended questionnaire to retrieve socio-demographic information from caregivers and the persons with dementia (N = 86). The study included validated scales such as the Dementia Attitude Scale, the Dementia Knowledge Assessment Tool 2, the Positive Aspects of Caregiving, the Zarit Burden Interview, the Confidence in Dementia Scale, and Spielberger's State-Trait Anxiety Inventory, as well as a neuropsychological battery to assess the condition of people with dementia.

RESULTS: Our final model explains 55.6% of the total variance and shows a significant correlation of five factors with attitude toward dementia: confidence, behavioral and psychological symptoms of dementia, anxiety as a trait, positive aspects of caregiving, and dementia knowledge. The caregivers who participated in a psycho-educational program showed a significantly more positive attitude toward dementia, better dementia knowledge, higher confidence in dementia care, and lower anxiety as a state.

CONCLUSION: The strong correlation of attitude and knowledge, as well as confidence in dementia care, supports the tripartite model of attitude, which hypothesizes the interrelation of affect, cognition, and behavior.

%B J Alzheimers Dis %V 88 %P 971-984 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35723101?dopt=Abstract %R 10.3233/JAD-215731 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Insulin-Like Growth Factor, Inflammation, and MRI Markers of Alzheimer's Disease in Predominantly Middle-Aged Adults. %A Wittfeld, Katharina %A Raman, Mekala R %A Conner, Sarah C %A Aslam, Asra %A Teumer, Alexander %A Nauck, Matthias %A Hosten, Norbert %A Habes, Mohamad %A DeCarli, Charles %A Vasan, Ramachandran S %A Beiser, Alexa S %A Himali, Jayandra J %A Seshadri, Sudha %A Grabe, Hans J %A Satizabal, Claudia L %X

BACKGROUND: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults.

OBJECTIVE: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation.

METHODS: We included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons.

RESULTS: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], -0.05 [-0.09, -0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes.

CONCLUSION: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife.

%B J Alzheimers Dis %V 88 %P 311-32 %8 2022 Jun 28 %G eng %N 1 %R 10.3233/JAD-220356 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Integrating the Synergy of the Gut Microbiome into Regenerative Medicine: Relevance to Neurological Disorders. %A Preethy, Senthilkumar %A Ranganathan, Natarajan %A Raghavan, Kadalraja %A Dedeepiya, Vidyasagar Devaprasad %A Ikewaki, Nobunao %A Abraham, Samuel J K %K Gastrointestinal Microbiome %K Humans %K Nervous System Diseases %K Regenerative Medicine %K Stem Cells %K Tissue Engineering %X

A new paradigm of cell therapy-based approaches as a solution to several diseases caused by damage or loss of cells/tissues leading to organ failure heralded the birth of a new branch in medicine called regenerative medicine (RM), which was further fueled by in vitro cell expansion and tissue engineering (TE) technologies, including the ability to grow embryonic stem cells, induce pluripotent stem cells, and so on. RM addresses organ failure by repair, regeneration, or restoration, rejuvenation using cells, stem cells, or progenitor cells as tools having added cell-derived products also as a tool, and extracellular matrix component-based support, either direct or indirect (e.g., matrix induced autologous chondrocyte implantation) using scaffolds. Now, the main objective of RM is to solve the functional loss of cells that have evolved from cells as tools to cell-derived factors and scaffolds per se as tools. In this context, an important yet indispensable group of cells that constitute the major portion of the human body in terms of the number of cells having several essential roles to play, both directly and indirectly, starting from digestion and the immune system to the growing evidence of influencing neuronal function, aging, and carcinogenesis has been ignored. We would like to focus on these in this review as they should essentially be considered as a tool of RM, especially for neurological disorders for their vital role. What we are indicating is the second genome or the gut microbiome.

%B J Alzheimers Dis %V 87 %P 1451-1460 %8 2022 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/35466942?dopt=Abstract %R 10.3233/JAD-220313 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Interaction Between Diet and Microbiota in the Pathophysiology of Alzheimer's Disease: Focus on Polyphenols and Dietary Fibers. %A Ticinesi, Andrea %A Mancabelli, Leonardo %A Carnevali, Luca %A Nouvenne, Antonio %A Meschi, Tiziana %A Del Rio, Daniele %A Ventura, Marco %A Sgoifo, Andrea %A Angelino, Donato %K Alzheimer Disease %K Animals %K Diet %K Diet, Mediterranean %K Dietary Fiber %K Humans %K Microbiota %K Polyphenols %X

Animal studies increasingly indicate that the gut microbiota composition and function can be involved in the pathophysiology and progression of Alzheimer's disease (AD) at multiple levels. However, few studies have investigated this putative gut-brain axis in human beings, and none of them considered diet as a determinant of intestinal microbiota composition. Epidemiological studies highlight that a high intake of fruit and vegetables, such as that typical of the Mediterranean diet, can modulate AD progression. Thus, nutritional interventions are being increasingly studied as a possible non-pharmacological strategy to slow down the progression of AD. In particular, polyphenols and fibers represent the nutritional compounds with the higher potential of counterbalancing the pathophysiological mechanisms of dementia due to their antioxidant, anti-inflammatory, and anti-apoptotic properties. These actions are mediated by the gut microbiota, that can transform polyphenols and fibers into biologically active compounds including, among others, phenyl-γ-valerolactones, urolithins, butyrate, and other short-chain fatty acids. In this review, the complex mechanisms linking nutrition, gut microbiota composition, and pathophysiology of cognitive decline in AD are discussed, with a particular focus on the role of polyphenols and fibers. The gaps between pre-clinical and clinical studies are particularly emphasized, as well as the urgent need for studies comprehensively evaluating the link between nutrition, microbiome, and clinical aspects of AD.

%B J Alzheimers Dis %V 86 %P 961-982 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35147544?dopt=Abstract %R 10.3233/JAD-215493 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Investigating Casual Associations Among Gut Microbiota, Metabolites, and Neurodegenerative Diseases: A Mendelian Randomization Study. %A Ning, Jing %A Huang, Shu-Yi %A Chen, Shi-Dong %A Zhang, Ya-Ru %A Huang, Yu-Yuan %A Yu, Jin-Tai %K Alzheimer Disease %K Amyotrophic Lateral Sclerosis %K Gastrointestinal Microbiome %K Genome-Wide Association Study %K Humans %K Mendelian Randomization Analysis %K Neurodegenerative Diseases %K Parkinson Disease %K Risk Factors %K Serotonin %X

BACKGROUND: Recent studies had explored that gut microbiota was associated with neurodegenerative diseases (including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)) through the gut-brain axis, among which metabolic pathways played an important role. However, the underlying causality remained unclear.

OBJECTIVE: Our study aimed to evaluate potential causal relationships between gut microbiota, metabolites, and neurodegenerative diseases through Mendelian randomization (MR) approach.

METHODS: We selected genetic variants associated with gut microbiota traits (N = 18,340) and gut microbiota-derived metabolites (N = 7,824) from genome-wide association studies. Summary statistics of neurodegenerative diseases were obtained from IGAP (AD, 17,008 cases; 37,154 controls), IPDGC (PD, 37,688 cases; 141,779 controls), and IALSC (ALS, 20,806 cases; 59,804 controls) respectively.

RESULTS: Greater abundance of Ruminococcus (OR, 1.245; 95% CI, 1.103-1.405; p = 0.0004) was found significantly related to higher risk of ALS. Besides, our study found suggestive associations of Actinobacteria, Lactobacillaceae, Faecalibacterium, Ruminiclostridium, and Lachnoclostridium with AD, of Lentisphaerae, Lentisphaeria, Oxalobacteraceae, Victivallales, Bacillales, Eubacteriumhalliigroup, Anaerostipes, and Clostridiumsensustricto1 with PD, and of Lachnospira, Fusicatenibacter, Catenibacterium, and Ruminococcusgnavusgroup with ALS. Our study also revealed suggestive associations between 12 gut microbiome-dependent metabolites and neurodegenerative diseases. Glutamine was related to lower risk of AD. For the serotonin pathway, serotonin was found as a protective factor of PD, while kynurenine as a risk factor for ALS.

CONCLUSION: Our study firstly applied a two-sample MR approach to detect causal relationships among gut microbiota, gut metabolites, and neurodegenerative diseases. Our findings may provide new targets for treatments and may offer valuable insights for further studies on the underlying mechanisms.

%B J Alzheimers Dis %V 87 %P 211-222 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275534?dopt=Abstract %R 10.3233/JAD-215411 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Investigating Causal Relations Between Circulating Metabolites and Alzheimer's Disease: A Mendelian Randomization Study. %A Huang, Shu-Yi %A Yang, Yu-Xiang %A Zhang, Ya-Ru %A Kuo, Kevin %A Li, Hong-Qi %A Shen, Xue-Ning %A Chen, Shi-Dong %A Chen, Ke-Liang %A Dong, Qiang %A Tan, Lan %A Yu, Jin-Tai %K Alzheimer Disease %K Apolipoproteins B %K Cholesterol %K Genome-Wide Association Study %K Glutamine %K Humans %K Mendelian Randomization Analysis %K Polymorphism, Single Nucleotide %K Risk Factors %X

BACKGROUND: Metabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer's disease (AD). However, the causal relationships between metabolism and AD are poorly understood.

OBJECTIVE: We aimed to investigate the causal association between circulating metabolites and risk of AD through two-sample Mendelian randomization (MR) approach.

METHODS: Genetic associations with 123 circulating metabolic traits were utilized as exposures. Summary statistics data from International Genomics of Alzheimer's Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD, and 272,244 controls). We utilized inverse-variance weighted method as primary method.

RESULTS: We found significantly increased risks of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio[OR] = 3.18; 95% confidence interval[CI]: 1.52-6.66, p = 0.0022), glycoprotein acetyls (OR = 1.21; 95% CI: 1.05-1.39, p = 0.0093), total cholesterol (OR = 2.73; 95% CI: 1.41-5.30, p = 0.0030), and low-density lipoprotein (LDL) cholesterol (OR = 2.34; 95% CI: 1.53-3.57, p = 0.0001). Whereas glutamine (OR = 0.81; 95% CI: 0.71-0.92, p = 0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD.

CONCLUSION: Our findings suggest causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect.

%B J Alzheimers Dis %V 87 %P 463-477 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275550?dopt=Abstract %R 10.3233/JAD-220050 %0 Journal Article %J J Alzheimers Dis %D 2022 %T An Investigation into the Effects of Outer Membrane Vesicles and Lipopolysaccharide of Porphyromonas gingivalis on Blood-Brain Barrier Integrity, Permeability, and Disruption of Scaffolding Proteins in a Human in vitro Model. %A Pritchard, Anna Barlach %A Fabian, Zsolt %A Lawrence, Clare L %A Morton, Glyn %A Crean, StJohn %A Alder, Jane E %X

BACKGROUND: The effects of the key pathogens and virulence factors associated with gum disease such as Porphyromonas gingivalis (P. gingivalis) on the central nervous system is of great interest with respect to development of neuropathologies and hence therapeutics and preventative strategies. Chronic infections and associated inflammation are known to weaken the first line of defense for the brain, the blood-brain barrier (BBB).

OBJECTIVE: The focus of this study is to utilize an established human in vitro BBB model to evaluate the effects of P. gingivalis virulence factors lipopolysaccharide (LPS) and outer membrane vesicles (OMVs) on a primary-derived human model representing the neurovascular unit of the BBB.

METHODS: Changes to the integrity of the BBB after application of P. gingivalis LPS and OMVs were investigated and correlated with transport of LPS. Additionally, the effect of P. gingivalis LPS and OMVs on human brain microvascular endothelial cells in monolayer was evaluated using immunofluorescence microscopy.

RESULTS: The integrity of the BBB model was weakened by application of P. gingivalis LPS and OMVs, as measured by a decrease in electrical resistance and a recovery deficit was seen in comparison to the controls. Application of P. gingivalis OMVs to a monoculture of human brain microvascular endothelial cells showed disruption of the tight junction zona occludens protein (ZO-1) compared to controls.

CONCLUSION: These findings show that the integrity of tight junctions of the human BBB could be weakened by association with P. gingivalis virulence factors LPS and OMVs containing proteolytic enzymes (gingipains).

%B J Alzheimers Dis %V 86 %P 343-364 %8 2022 Mar 08 %G eng %N 1 %R 10.3233/JAD-215054 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Isolated Amyloid-β Pathology Is Associated with Preserved Cortical Plasticity in APOE4 Alzheimer's Disease Patients. %A Assogna, Martina %A Motta, Caterina %A Bonní, Sonia %A Borghi, Ilaria %A Casula, Elias P %A Martorana, Alessandro %A Koch, Giacomo %X

BACKGROUND: Long-term potentiation (LTP) like-cortical plasticity impairment and cholinergic neurotransmission deficits have been widely demonstrated in Alzheimer's disease (AD) patients.

OBJECTIVE: In this study we aim to investigate the neurophysiological features underlying cognitive decline in AD patients according to the National Institute on Aging-Alzheimer's Association (NIA-AA) classification and APOE genotype.

METHODS: 65 newly diagnosed AD patients were enrolled. APOE genotype and lumbar puncture for the analysis of cerebrospinal fluid biomarkers were performed for diagnostic purposes. Patients were subdivided upon NIA-AA criteria, according to the presence of biomarkers of Aβ amyloid deposition (A) and fibrillar tau (T), in four groups: A+/T-E4 (n = 9), A+/T-E3 (n = 18), A+/T+ E4 (n = 21), and A+/T+ E3 (n = 17). We applied intermittent theta burst stimulation over the primary motor cortex to assess LTP-like cortical plasticity and short latency afferent inhibition (SAI) protocol to investigate central cholinergic activity. Patients were followed over 24 months. Cognitive decline was evaluated considering changes in Mini-Mental State Examination scores respect to the baseline.

RESULTS: A+/T-E4 patients showed preserved LTP-like cortical plasticity as compared to A+/T-E3 and to A+/T+ patients independently from genotype (p <  0.001). In addition, A+/T-E4 patients showed a slower cognitive decline with respect to A+/T+ E4 (-0.5±2.12 versus -6.05±4.95; post-hoc p = 0.004) and to A+/T+ E3 patients (-4.12±4.14; post-hoc p = 0.028). No differences were found for SAI protocol (p >  0.05).

CONCLUSION: Our results suggest that APOE4 in patients with isolated amyloid pathology could exert positive effects on LTP-like cortical plasticity with a consequent slower cognitive decline.

%B J Alzheimers Dis %V 86 %P 773-778 %8 2022 Mar 22 %G eng %N 2 %R 10.3233/JAD-215218 %0 Journal Article %J J Alzheimers Dis %D 2022 %T It's Groundhog Day! What Can the History of Science Say About the Crisis in Alzheimer's Disease Research? %A Jacobs, Noortje %A Theunissen, Bert %K Alzheimer Disease %K Amyloid %K Humans %X

For years now, Alzheimer's disease (AD) research has been stuck in a Groundhog-Day scenario: an endless time loop with no breakthrough in sight. Disagreement about the validity of the field's dominant approach, based on the Amyloid Cascade Hypothesis, has led to a seemingly unresolvable trench war between proponents and critics. Our paper evaluates the recent scientific literature on AD from a historical and philosophical perspective. We show that AD research is a classic example of the boundary work at play in a field in crisis: both parties deploy historical and philosophical references to illustrate what counts as good and bad science, as proper scientific method and appropriate scientific conduct. We also show that boundary work has proved unable to point a way out of the deadlock and argue that the science system's tools for establishing scientific quality, such as peer review and the grant system, are unlikely to resolve the crisis. Rather, they consolidate the dominant model's position even more. In conclusion, we suggest that some kind of reverse boundary-work is needed that reopens the discussion on the nature of AD, an issue that has never been settled scientifically. Drawing on historical and philosophical work, we make clear that the definition of AD as a biomedical disease for which a cure can be found has consequences, not only for funding opportunities, but also for patients and their lives. A reconsideration of the desirability of these consequences may lead to different choices with respect to research priorities and patient care.

%B J Alzheimers Dis %V 90 %P 1401-1415 %8 2022 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/36278350?dopt=Abstract %R 10.3233/JAD-220569 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Late-Onset Alcohol Abuse as a Presenting Symptom of Neurodegenerative Diseases. %A de Paula França Resende, Elisa %A Ketelle, Robin %A Karydas, Anna %A Allen, Isabel %A Grinberg, Lea T %A Spina, Salvatore %A Seeley, William W %A Perry, David C %A Miller, Bruce %A Naasan, Georges %X

BACKGROUND: The association between lifetime alcohol abuse and a higher risk to develop dementia is well known. However, it is unknown whether older adults who begin abusing alcohol late in life have an underlying neurodegenerative disease.

OBJECTIVE: Identify the frequency of lifelong alcohol abuse (L-AA), late-onset alcohol abuse (LO-AA), and alcohol abuse as a first symptom of dementia (AA-FS) in patients with neurodegenerative diseases.

METHODS: Cross-sectional retrospective study of patients evaluated at an academic referral center with a clinical diagnosis of behavioral variant frontotemporal dementia (bvFTD), Alzheimer-type dementia (AD), and semantic variant primary progressive aphasia (svPPA) (n = 1,518). The presence of alcohol abuse was screened with the National Alzheimer's Coordinating Center questionnaire. L-AA was defined as onset <  40 years, LO-AA as onset ≥40 years, and AA-FS was defined when the abuse started within the first three years from symptom onset.

RESULTS: The frequency of LO-AA was 2.2% (n = 33/1,518). LO-AA was significantly more frequent in patients with bvFTD than AD (7.5%, n = 13/173 versus 1.3%, n = 16/1,254, CI:1.0;11.4%), but not svPPA (4.4%, n = 4/91, CI: -4.4;10.7%). Similarly, AA-FS was more frequent in bvFTD patients than AD (5.7%, n = 10/173 versus 0.7%, n = 9/1,254, CI:0.5% ;9.5%), but not svPPA (2.2%, n = 2/91, CI:-2.4;9.1%).

CONCLUSION: LO-AA can be a presenting symptom of dementia, especially bvFTD. Alcohol abuse onset later in life should prompt a clinical investigation into the possibility of an underlying neurodegenerative process because delay in diagnosis and treatment may increase patient and caregiver burden. The results need to be interpreted with caution due to the limitations of the study.

%B J Alzheimers Dis %V 86 %P 1073-1080 %8 2022 Apr 05 %G eng %N 3 %R 10.3233/JAD-215369 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Lipid Peroxidation as a Marker of Apathy and Executive Dysfunction in Patients at Risk for Vascular Cognitive Impairment. %A Bawa, Kritleen K %A Ba, Joycelyn %A Kiss, Alex %A Wang, RuoDing %A Feng, Vivian %A Swardfager, Walter %A Andreazza, Ana %A Gallagher, Damien %A Marotta, Giovanni %A Herrmann, Nathan %A Lanctôt, Krista L %X

BACKGROUND: The co-occurrence of apathy and executive dysfunction, a correlate of vascular cognitive impairment (VCI), is highly prevalent, yet facilitating factors are largely unknown.

OBJECTIVE: This study investigates the relationship between lipid peroxidation, apathy, and executive dysfunction in patients at risk for VCI.

METHODS: In participants with coronary artery disease, who are at a high risk of VCI, apathy (Apathy Evaluation Scale), and executive function (composite z-score based on age and education population norms from trails making test B, animal naming, and phonemic fluency tests) were assessed. Serum concentrations of an early (lipid hydroperoxide (LPH)) and late (8-isoprostane (8-ISO)) lipid peroxidation marker, were measured and the 8-ISO/LPH ratio was calculated.

RESULTS: Participants (n = 206, age±SD = 63.0±7.5, 80% men, total years of education = 15.9±3.4, AES score = 28.3±8.8, executive function = 0±1) demonstrated significantly different 8-ISO/LPH ratios between groups (F(3, 202) = 10.915, p <  0.001) with increasing levels in the following order: no apathy or executive dysfunction, only executive dysfunction (executive function composite score≤-1), only apathy (AES≥28), and both apathy and executive dysfunction. A model adjusting for demographics showed that lipid peroxidation was associated with both apathy (B(SE) = 4.63 (0.954), t = 4.852, p <  0.001) and executive function (B(SE) = -0.19 (0.079), t = -2.377, p = 0.018). However, when controlling for both demographics and vascular risk factors, lipid peroxidation was associated with only apathy (B(SE) = 3.11 (0.987), t = 3.149, p = 0.002).

CONCLUSION: The results highlight a potentially important involvement of lipid peroxidation in the co-occurrence of apathy and executive dysfunction in those at risk for VCI.

%B J Alzheimers Dis %V 89 %P 733-743 %8 2022 Sep 13 %G eng %N 2 %R 10.3233/JAD-220274 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Lipid Rafts Act as a Common Platform for Amyloid-β Oligomer-Induced Alzheimer's Disease Pathology. %A Kawarabayashi, Takeshi %A Nakamura, Takumi %A Sato, Kaoru %A Seino, Yusuke %A Ichii, Sadanobu %A Nakahata, Naoko %A Takatama, Masamitsu %A Westaway, David %A George-Hyslop, Peter St %A Shoji, Mikio %X

BACKGROUND: Amyloid-β (Aβ) oligomers induce the overproduction of phosphorylated tau and neurodegeneration. These cascades gradually cause cognitive impairment in Alzheimer's disease (AD). While each pathological event in AD has been studied in detail separately, the spatial and temporal relationships between pathological events in AD remain unclear.

OBJECTIVE: We demonstrated that lipid rafts function as a common platform for the pathological cascades of AD.

METHODS: Cellular and synaptosomal lipid rafts were prepared from the brains of Aβ amyloid model mice (Tg2576 mice) and double transgenic mice (Tg2576 x TgTauP301L mice) and longitudinally analyzed.

RESULTS: Aβ dimers, the cellular prion protein (PrPc), and Aβ dimer/PrPc complexes were detected in the lipid rafts. The levels of Fyn, the phosphorylated NR2B subunit of the N-methyl-D-aspartate receptor, glycogen synthase kinase 3β, total tau, phosphorylated tau, and tau oligomers increased with Aβ dimer accumulation in both the cellular and synaptosomal lipid rafts. Increases in the levels of these molecules were first seen at 6 months of age and corresponded with the early stages of Aβ accumulation in the amyloid model mice.

CONCLUSION: Lipid rafts act as a common platform for the progression of AD pathology. The findings of this study suggest a novel therapeutic approach to AD, involving the modification of lipid raft components and the inhibition of their roles in the sequential pathological events of AD.

%B J Alzheimers Dis %V 87 %P 1189-1203 %8 2022 May 31 %G eng %N 3 %R 10.3233/JAD-215662 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Longitudinal Changes in Resting-State Functional Connectivity and Gray Matter Volume Are Associated with Conversion to Hearing Impairment in Older Adults. %A Fitzhugh, Megan C %A Pa, Judy %X

BACKGROUND: Hearing loss was recently identified as a modifiable risk factor for dementia although the potential mechanisms explaining this relationship are unknown.

OBJECTIVE: The current study examined longitudinal change in resting-state fMRI functional connectivity and gray matter volume in individuals who developed a hearing impairment compared to those whose hearing remained normal.

METHODS: This study included 440 participants from the UK Biobank: 163 who had normal hearing at baseline and impaired hearing at follow-up (i.e., converters, mean age = 63.11±6.33, 53% female) and 277 who had normal hearing at baseline and maintained normal hearing at follow-up (i.e., non-converters, age = 63.31±5.50, 50% female). Functional connectivity was computed between a priori selected auditory seed regions (left and right Heschl's gyrus and cytoarchitectonic subregions Te1.0, Te1.1, and Te1.2) and select higher-order cognitive brain networks. Gray matter volume within these same regions was also obtained.

RESULTS: Converters had increased connectivity from left Heschl's gyrus to left anterior insula and from right Heschl's gyrus to right anterior insula, and decreased connectivity between right Heschl's gyrus and right hippocampus, compared to non-converters. Converters also had reduced gray matter volume in left hippocampus and left lateral visual cortex compared to non-converters.

CONCLUSION: These findings suggest that conversion to a hearing impairment is associated with altered brain functional connectivity and gray matter volume in the attention, memory, and visual processing regions that were examined in this study.

%B J Alzheimers Dis %V 86 %P 905-918 %8 2022 Mar 22 %G eng %N 2 %R 10.3233/JAD-215288 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Low-Dose Radiation Therapy Reduces Amyloid Load in Young 3xTg-AD Mice. %A Ceyzériat, Kelly %A Tournier, Benjamin B %A Millet, Philippe %A Dipasquale, Giovanna %A Koutsouvelis, Nikolaos %A Frisoni, Giovanni B %A Garibotto, Valentina %A Zilli, Thomas %X

BACKGROUND: Low-dose radiation therapy (LD-RT) has been shown to decrease amyloidosis or inflammation in systemic diseases and has recently been proposed as possible treatment of Alzheimer's disease (AD). A positive effect of LD-RT on tauopathy, the other marker of AD, has also been suggested. These effects have been shown in preclinical studies, but their mechanisms are still not well understood.

OBJECTIVE: This study aimed to evaluate if anti-amyloid and anti-inflammatory effects of LD-RT can be observed at an early stage of the disease. Its impact on tauopathy and behavioral alterations was also investigated.

METHODS: The whole brain of 12-month-old 3xTg-AD mice was irradiated with 10 Gy in 5 daily fractions of 2 Gy. Mice underwent behavioral tests before and 8 weeks post treatment. Amyloid load, tauopathy, and neuroinflammation were measured using histology and/or ELISA.

RESULTS: Compared with wild-type animals, 3xTg-AD mice showed a moderate amyloid and tau pathology restricted to the hippocampus, a glial reactivity restricted to the proximity of amyloid plaques. LD-RT significantly reduced Aβ 42 aggregated forms (-71%) in the hippocampus and tended to reduce other forms in the hippocampus and frontal cortex but did not affect tauopathy or cognitive performance. A trend for neuroinflammation markers reduction was also observed.

CONCLUSION: When applied at an early stage, LD-RT reduced amyloid load and possibly neuroinflammation markers, with no impact on tauopathy. The long-term persistence of these beneficial effects of LD-RT should be evaluated in future studies.

%B J Alzheimers Dis %V 86 %P 641-653 %8 2022 Mar 22 %G eng %N 2 %R 10.3233/JAD-215510 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Medial Temporal Atrophy in Posterior Cortical Atrophy and Its Relationship to the Cingulate Island Sign. %A Josephs, Kennedy A %A Pham, Nha Trang Thu %A Graff-Radford, Jonathan %A Machulda, Mary M %A Lowe, Val J %A Whitwell, Jennifer L %K Alzheimer Disease %K Atrophy %K Fluorodeoxyglucose F18 %K Humans %K Lewy Body Disease %K Magnetic Resonance Imaging %K Positron-Emission Tomography %X

BACKGROUND: It has been hypothesized that medial temporal sparing may be related to preserved posterior cingulate metabolism and the cingulate island sign (CIS) on [18F]fluorodeoxyglucose (FDG) PET in posterior cortical atrophy (PCA).

OBJECTIVE: To assess the severity of medial temporal atrophy in PCA and determine whether the presence of a CIS is related to medial temporal sparing.

METHODS: Fifty-five PCA patients underwent MRI and FDG-PET. The degree and symmetry of medial temporal atrophy on MRI was visually assessed using a five-point scale for both hemispheres. Visual assessments of FDG-PET coded the presence/absence of a CIS and whether the CIS was symmetric or asymmetric. Hippocampal volumes and a quantitative CIS were also measured.

RESULTS: Medial temporal atrophy was most commonly mild or moderate, was symmetric in 55% of patients, and when asymmetric was most commonly worse on the right (76%). Older age and worse memory performance were associated with greater medial temporal atrophy. The CIS was observed in 44% of the PCA patients and was asymmetric in 50% of these. The patients with a CIS showed greater medial temporal asymmetry, but did not show lower medial temporal atrophy scores, compared to those without a CIS. Hippocampal volumes were not associated with quantitative CIS.

CONCLUSION: Mild medial temporal atrophy is a common finding in PCA and is associated with memory impairment. However, medial temporal sparing was not related to the presence of a CIS in PCA.

%B J Alzheimers Dis %V 86 %P 491-498 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35068459?dopt=Abstract %R 10.3233/JAD-215263 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Metabolic Factors Are Related to Brain Amyloid Among Mexican Americans: A HABS-HD Study. %A O'Bryant, Sid E %A Petersen, Melissa %A Hall, James %A Johnson, Leigh %X

BACKGROUND: Despite the tremendous amount of research on Alzheimer's disease (AD) biomarkers, very little data is available regarding the fundamental biomarkers of AD among Mexican Americans.

OBJECTIVE: Here we sought to examine the link between metabolic markers and brain amyloid among Mexican Americans as compared to non-Hispanic whites from the Health & Aging Brain Study -Health Disparities (HABS-HD) cohort.

METHODS: PET amyloid (florbetaben) data was analyzed from 34 Mexican American and 22 non-Hispanic white participants.

RESULTS: Glucagon (t = 3.84, p <  0.001) and insulin (t = -2.56, p = 0.02) were both significantly related to global SUVR levels among Mexican Americans. Glucagon and insulin were both related to most ROIs. No metabolic markers were significantly related to brain amyloid levels among non-Hispanic whites.

CONCLUSION: Metabolic markers are related to brain amyloid burden among Mexican Americans. Given the increased risk for diabetes, additional research is needed to determine the impact of diabetes on core AD biomarkers among this underserved population.

%B J Alzheimers Dis %V 86 %P 1745-1750 %8 2022 Apr 19 %G eng %N 4 %R 10.3233/JAD-215620 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Mild Cognitive Impairment, Reversion Rates, and Associated Factors: Comparison of Two Diagnostic Approaches. %A Overton, Marieclaire %A Sjögren, Benjamin %A Elmståhl, Sölve %A Rosso, Aldana %X

BACKGROUND: As mild cognitive impairment (MCI) is typically used to identify prodromal stages of dementia, it is essential to identify MCI criteria with high diagnostic stability and prediction of dementia. Moreover, further investigation into pinpointing key factors for reversion is required to foresee future prognosis of MCI patients accurately.

OBJECTIVE: To explore disparities in diagnostic stability by examining reversion rates produced by two operationalizations of the MCI definition: the widely applied Petersen criteria and a version of the Neuropsychological (NP) criteria and to identify cognitive, lifestyle, and health related factors for reversion.

METHODS: MCI was retrospectively classified in a sample from the Swedish community-based study Good Aging in Skåne with the Petersen criteria (n = 744, median follow-up = 7.0 years) and the NP criteria (n = 375, median follow-up, 6.7 years), respectively. Poisson regression models estimated the effect of various factors on the likelihood of incident reversion.

RESULTS: Reversion rates were 323/744 (43.4%, 95% confidence intervals (CI): 39.8; 47.0) and 181/375 (48.3% 95% CI: 43.2; 53.5) for the Petersen criteria and NP criteria, respectively. Participants with impairment in a single cognitive domain, regular alcohol consumption, living with someone, older age, and lower body mass index had a higher likelihood of reverting to normal.

CONCLUSION: Reversion rates were similar for Petersen and NP criteria indicating that one definition is not superior to the other regarding diagnostic stability. Additionally, the results highlight important aspects such as multiple domain MCI, cohabitation, and the role of alcohol on predicting the trajectory of those diagnosed with MCI.

%B J Alzheimers Dis %V 91 %P 585-601 %8 2023 Jan 17 %G eng %N 2 %R 10.3233/JAD-220597 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Mild Traumatic Brain Injury is Related to Elevated Cerebrospinal Fluid Tau in Alzheimer's Disease Dementia. %A LoBue, Christian %A Kelley, Brendan J %A Hart, John %A Helphrey, Jessica %A Schaffert, Jeff %A Cullum, C Munro %A Peters, Matthew E %A Douglas, Peter M %X

Few studies have examined an association between mild traumatic brain injury (mTBI) and Alzheimer's disease (AD). For this reason, we compared an AD dementia group with an mTBI history (n = 10) to a matched AD control group (n = 20) on measures of cognitive function, cerebral glucose metabolism, and markers of amyloid and tau deposition. Only a trend and medium-to-large effect size for higher phosphorylated and total tau was identified for the mTBI group. A history of mTBI may be associated with greater tau in AD, indicating a potential pathway for increasing risk for AD, though further evaluation with larger samples is needed.

%B J Alzheimers Dis %V 87 %P 1491-1496 %8 2022 Jun 14 %G eng %N 4 %R 10.3233/JAD-220112 %0 Journal Article %J J Alzheimers Dis %D 2022 %T A Mitochondrial DNA Haplogroup Defines Patterns of Five-Year Cognitive Change. %A Watts, Amber %A Chalise, Prabhakar %A Hu, Jinxiang %A Hui, Dongwei %A Pa, Judy %A Andrews, Shea J %A Michaelis, Elias K %A Swerdlow, Russell H %X

BACKGROUND: Mitochondrial DNA (mtDNA) may play a role in Alzheimer's disease (AD) and cognitive decline. A particular haplogroup of mtDNA, haplogroup J, has been observed more commonly in patients with AD than in cognitively normal controls.

OBJECTIVE: We used two mtDNA haplogroups, H and J, to predict change in cognitive performance over five years. We hypothesized that haplogroup J carriers would show less cognitive resilience.

METHODS: We analyzed data from 140 cognitively normal older adults who participated in the University of Kansas Alzheimer's Disease Research Center clinical cohort between 2011 and 2020. We used factor analysis to create three composite scores (verbal memory, attention, and executive function) from 11 individual cognitive tests. We performed latent growth curve modeling to describe trajectories of cognitive performance and change adjusting for age, sex, years of education, and APOE ɛ4 allele carrier status. We compared haplogroup H, the most common group, to haplogroup J, the potential risk group.

RESULTS: Haplogroup J carriers had significantly lower baseline performance and slower rates of improvement on tests of verbal memory compared to haplogroup H carriers. We did not observe differences in executive function or attention.

CONCLUSION: Our results reinforce the role of mtDNA in changes to cognitive function in a domain associated with risk for dementia, verbal memory, but not with other cognitive domains. Future research should investigate the distinct mechanisms by which mtDNA might affect performance on verbal memory as compared to other cognitive domains across haplogroups.

%B J Alzheimers Dis %V 89 %P 913-922 %8 2022 Sep 27 %G eng %N 3 %R 10.3233/JAD-220298 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Mitochondrial Targeting of Amyloid-β Protein Precursor Intracellular Domain Induces Hippocampal Cell Death via a Mechanism Distinct from Amyloid-β. %A Sandberg, Alexandra A %A Manning, Evan %A Wilkins, Heather M %A Mazzarino, Randall %A Minckley, Taylor %A Swerdlow, Russell H %A Patterson, David %A Qin, Yan %A Linseman, Daniel A %X

BACKGROUND: Amyloid-β (Aβ) is a principal cleavage product of amyloid-β protein precursor (AβPP) and is widely recognized as a key pathogenic player in Alzheimer's disease (AD). Yet, there is increasing evidence of a neurotoxic role for the AβPP intracellular domain (AICD) which has been proposed to occur through its nuclear function. Intriguingly, there is a γ-secretase resident at the mitochondria which could produce AICD locally.

OBJECTIVE: We examined the potential of AICD to induce neuronal apoptosis when targeted specifically to the mitochondria and compared its mechanism of neurotoxicity to that of Aβ.

METHODS: We utilized transient transfection of HT22 neuronal cells with bicistronic plasmids coding for DsRed and either empty vector (Ires), Aβ, AICD59, or mitochondrial-targeted AICD (mitoAICD) in combination with various inhibitors of pathways involved in apoptosis.

RESULTS: AICD induced significant neuronal apoptosis only when targeted to the mitochondria. Apoptosis required functional mitochondria as neither Aβ nor mitoAICD induced significant toxicity in cells devoid of mitochondrial DNA. Both glutathione and a Bax inhibitor protected HT22 cells from either peptide. However, inhibition of the mitochondrial permeability transition pore only protected from Aβ, while pan-caspase inhibitors uniquely rescued cells from mitoAICD.

CONCLUSION: Our results show that AICD displays a novel neurotoxic function when targeted to mitochondria. Moreover, mitoAICD induces apoptosis via a mechanism that is distinct from that of Aβ. These findings suggest that AICD produced locally at mitochondria via organelle-specific γ-secretase could act in a synergistic manner with Aβ to cause mitochondrial dysfunction and neuronal death in AD.

%B J Alzheimers Dis %V 86 %P 1727-1744 %8 2022 Apr 19 %G eng %N 4 %R 10.3233/JAD-215108 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Monitoring Alzheimer's Disease Progression in Mild Cognitive Impairment Stage Using Machine Learning-Based FDG-PET Classification Methods. %A Beheshti, Iman %A Geddert, Natasha %A Perron, Jarrad %A Gupta, Vinay %A Albensi, Benedict C %A Ko, Ji Hyun %X

BACKGROUND: We previously introduced a machine learning-based Alzheimer's Disease Designation (MAD) framework for identifying AD-related metabolic patterns among neurodegenerative subjects.

OBJECTIVE: We sought to assess the efficiency of our MAD framework for tracing the longitudinal brain metabolic changes in the prodromal stage of AD.

METHODS: MAD produces subject scores using five different machine-learning algorithms, which include a general linear model (GLM), two different approaches of scaled subprofile modeling, and two different approaches of a support vector machine. We used our pre-trained MAD framework, which was trained based on metabolic brain features of 94 patients with AD and 111 age-matched cognitively healthy (CH) individuals. The MAD framework was applied on longitudinal independent test sets including 54 CHs, 51 stable mild cognitive impairment (sMCI), and 39 prodromal AD (pAD) patients at the time of the clinical diagnosis of AD, and two years prior.

RESULTS: The GLM showed excellent performance with area under curve (AUC) of 0.96 in distinguishing sMCI from pAD patients at two years prior to the time of the clinical diagnosis of AD while other methods showed moderate performance (AUC: 0.7-0.8). Significant annual increment of MAD scores were identified using all five algorithms in pAD especially when it got closer to the time of diagnosis (p <  0.001), but not in sMCI. The increased MAD scores were also significantly associated with cognitive decline measured by Mini-Mental State Examination in pAD (q <  0.01).

CONCLUSION: These results suggest that MAD may be a relevant tool for monitoring disease progression in the prodromal stage of AD.

%B J Alzheimers Dis %V 89 %P 1493-150 %8 2022 Oct 11 %G eng %N 4 %R 10.3233/JAD-220585 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-β and Tau Pathology in Middle-Aged Adults: The Framingham Study. %A Weinstein, Galit %A O'Donnell, Adrienne %A Davis-Plourde, Kendra %A Zelber-Sagi, Shira %A Ghosh, Saptaparni %A DeCarli, Charles S %A Thibault, Emma G %A Sperling, Reisa A %A Johnson, Keith A %A Beiser, Alexa S %A Seshadri, Sudha %X

BACKGROUND: Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimer's disease pathology is unclear.

OBJECTIVE: To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-β (Aβ) and tau pathology.

METHODS: The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011-2014) and 2 (2008-2011), respectively. Participants underwent 11C-Pittsburgh Compound-B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aβ, adjusting for potential confounders and multiple comparisons.

RESULTS: Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 >  1.3). Prevalent NAFLD was not associated with Aβ or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (β= 1.03±0.33, p = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (β= 2.01±0.47, p <  0.001; β= 1.60±0.53, p = 0.007, and β= 1.59±0.47, p = 0.003 and β= 1.60±0.42, p = 0.001, respectively) and to Aβ deposition overall and in the inferior temporal and parahippocampal regions (β= 1.93±0.47, p <  0.001; β= 1.59±0.38, p <  0.001, and β= 1.52±0.54, p = 0.008, respectively).

CONCLUSION: This study suggests a possible association between liver fibrosis and early Alzheimer's disease pathology, independently of cardio-metabolic risk factors.

%B J Alzheimers Dis %V 86 %P 1371-1383 %8 2022 Apr 05 %G eng %N 3 %R 10.3233/JAD-215409 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Noninvasive Antemortem Detection of Retinal Prions by a Fluorescent Tracer. %A Aguilar-Calvo, Patricia %A Sevillano, Alejandro M %A Rasool, Suhail %A Cao, Kevin J %A Randolph, Lyndsay M %A Rissman, Robert A %A Sarraf, Stella T %A Yang, Jerry %A Sigurdson, Christina J %X

BACKGROUND: Neurodegenerative diseases are widespread yet challenging to diagnose and stage antemortem. As an extension of the central nervous system, the eye harbors retina ganglion cells vulnerable to degeneration, and visual symptoms are often an early manifestation of neurodegenerative disease.

OBJECTIVE: Here we test whether prion protein aggregates could be detected in the eyes of live mice using an amyloid-binding fluorescent probe and high-resolution retinal microscopy.

METHODS: We performed retinal imaging on an experimental mouse model of prion-associated cerebral amyloid angiopathy in a longitudinal study. An amyloid-binding fluorophore was intravenously administered, and retinal imaging was performed at timepoints corresponding to early, mid-, and terminal prion disease. Retinal amyloid deposits were quantified and compared to the amyloid load in the brain.

RESULTS: We report that by mid-prion disease (50% timepoint), discrete fluorescent foci appeared adjacent to the optic disc. By later timepoints, the fluorescent foci partly surrounded the optic disc and tracked along retinal vasculature.

CONCLUSION: The progression of perivascular amyloid can be directly monitored in the eye by live imaging, illustrating the utility of this technology for diagnosing and monitoring the progression of cerebral amyloid-angiopathy.

%B J Alzheimers Dis %V 88 %P 1137-1145 %8 2022 Aug 02 %G eng %N 3 %R 10.3233/JAD-220314 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Novel Invisible Spectral Flicker Induces 40 Hz Neural Entrainment with Similar Spatial Distribution as 40 Hz Stroboscopic Light. %A Agger, Mikkel Pejstrup %A Carstensen, Marcus Schultz %A Henney, Mark Alexander %A Hansen, Luna Skytte %A Baandrup, Anders Ohlhues %A Nguyen, Mai %A Petersen, Paul Michael %A Madsen, Kristoffer Hougaard %A Kjær, Troels Wesenberg %X

BACKGROUND: Exposure to 40 Hz stroboscopic light, for one hour a day, has previously been published as a potential treatment option for Alzheimer's disease in animal models. However, exposure for an hour a day to 40 Hz stroboscopic light can be strenuous and examining other types of 40 Hz inducing stimuli is paramount if chronic treatment is wanted.

OBJECTIVE: A core assumption behind ensuring a therapeutic outcome is that the visual stimuli can induce 40 Hz gamma entrainment. Here, we examine whether a specific visual stimulus, 40 Hz invisible spectral flicker (ISF), can induce gamma entrainment and how it differs from both continuous light (CON) and 40 Hz stroboscopic light (STROBE).

METHODS: The study included non-simultaneous EEG-fMRI neuroimaging of 13 young healthy volunteers during light exposure. Each light condition (i.e., CON, ISF, or STROBE) was active for 30 seconds followed immediately by the next.

RESULTS: Entrainment of 40 Hz neural activity were significantly higher signal-to-noise ratio during exposure to ISF (mean: 3.03, 95% CI 2.07 to 3.99) and STROBE (mean: 12.04, 95% CI 10.18 to 13.87) compared to CON. Additionally STROBE had a higher entrainment than ISF (mean: 9.01, 95% CI 7.16 to 12.14).

CONCLUSION: This study presents a novel method of 40 Hz entrainment using ISF. This enables the possibility of future randomized placebo-controlled clinical trials with acceptable double blinding due to the essentially imperceivable flicker, which is expected to substantially reduce discomfort compared to interventions with stroboscopic flicker.

%B J Alzheimers Dis %V 88 %P 335-344 %8 2022 Jun 28 %G eng %N 1 %R 10.3233/JAD-220081 %0 Journal Article %J J Alzheimers Dis %D 2022 %T A Novel Panel of Plasma Proteins Predicts Progression in Prodromal Alzheimer's Disease. %A Araújo, Daniella Castro %A Veloso, Adriano Alonso %A Gomes, Karina Braga %A de Souza, Leonardo Cruz %A Ziviani, Nivio %A Caramelli, Paulo %X

BACKGROUND: A cheap and minimum-invasive method for early identification of Alzheimer's disease (AD) pathogenesis is key to disease management and the success of emerging treatments targeting the prodromal phases of the disease.

OBJECTIVE: To develop a machine learning-based blood panel to predict the progression from mild cognitive impairment (MCI) to dementia due to AD within a four-year time-to-conversion horizon.

METHODS: We created over one billion models to predict the probability of conversion from MCI to dementia due to AD and chose the best-performing one. We used Alzheimer's Disease Neuroimaging Initiative (ADNI) data of 379 MCI individuals in the baseline visit, from which 176 converted to AD dementia.

RESULTS: We developed a machine learning-based panel composed of 12 plasma proteins (ApoB, Calcitonin, C-peptide, CRP, IGFBP-2, Interleukin-3, Interleukin-8, PARC, Serotransferrin, THP, TLSP 1-309, and TN-C), and which yielded an AUC of 0.91, accuracy of 0.91, sensitivity of 0.84, and specificity of 0.98 for predicting the risk of MCI patients converting to dementia due to AD in a horizon of up to four years.

CONCLUSION: The proposed machine learning model was able to accurately predict the risk of MCI patients converting to dementia due to AD in a horizon of up to four years, suggesting that this model could be used as a minimum-invasive tool for clinical decision support. Further studies are needed to better clarify the possible pathophysiological links with the reported proteins.

%B J Alzheimers Dis %V 88 %P 549-561 %8 2022 Jul 19 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35662125?dopt=Abstract %R 10.3233/JAD-220256 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Obesity-Associated Neurodegeneration Pattern Mimics Alzheimer's Disease in an Observational Cohort Study. %A Morys, Filip %A Potvin, Olivier %A Zeighami, Yashar %A Vogel, Jacob %A Lamontagne-Caron, Rémi %A Duchesne, Simon %A Dagher, Alain %X

BACKGROUND: Excess weight in adulthood leads to health complications such as diabetes, hypertension, or dyslipidemia. Recently, excess weight has also been related to brain atrophy and cognitive decline. Reports show that obesity is linked with Alzheimer's disease (AD)-related changes, such as cerebrovascular damage or amyloid-β accumulation. However, to date no research has conducted a direct comparison between brain atrophy patterns in AD and obesity.

OBJECTIVE: Here, we compared patterns of brain atrophy and amyloid-β/tau protein accumulation in obesity and AD using a sample of over 1,300 individuals from four groups: AD patients, healthy controls, obese otherwise healthy individuals, and lean individuals.

METHODS: We age- and sex-matched all groups to the AD-patients group and created cortical thickness maps of AD and obesity. This was done by comparing AD patients with healthy controls, and obese individuals with lean individuals. We then compared the AD and obesity maps using correlation analyses and permutation-based tests that account for spatial autocorrelation. Similarly, we compared obesity and AD brain maps with amyloid-β and tau protein maps from other studies.

RESULTS: Obesity maps were highly correlated with AD maps but were not correlated with amyloid-β/tau protein maps. This effect was not accounted for by the presence of obesity in the AD group.

CONCLUSION: Our research confirms that obesity-related grey matter atrophy resembles that of AD. Excess weight management could lead to improved health outcomes, slow down cognitive decline in aging, and lower the risk for AD.

%B J Alzheimers Dis %V 91 %P 1059-1071 %8 2023 Jan 31 %G eng %N 3 %R 10.3233/JAD-220535 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Olfactory Bulb Integrity in Frontotemporal Dementia and Alzheimer's Disease. %A Carnemolla, Sarah %A Kumfor, Fiona %A Liang, Cheng Tao %A Foxe, David %A Ahmed, Rebekah %A Piguet, Olivier %X

BACKGROUND: Olfactory dysfunction is highly prevalent in dementia syndromes, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). The structural integrity of the olfactory bulb (OB) is thought to play a critical role in odor detection and identification, but no MRI study has measured OB volume in FTD, or measured OB volume longitudinally in AD.

OBJECTIVE: To measure OB volume in FTD and AD patients longitudinally using MRI.

METHODS: This study measured OB volumes using MRI in patients diagnosed with behavioral-variant FTD (n = 55), semantic dementia (n = 34), progressive non-fluent aphasia (n = 30), AD (n = 50), and healthy age-matched controls (n = 55) at their first visit to a dementia research clinic ('baseline'). Imaging data in patients 12-months later were analyzed where available (n = 84) for longitudinal assessment. Volumes of subcortical and cortical olfactory regions ('olfactory network') were obtained via surface-based morphometry.

RESULTS: Results revealed that in AD and FTD at baseline, OB volumes were similar to controls, whereas volumes of olfactory network regions were significantly reduced in all patient groups except in progressive non-fluent aphasia. Longitudinal data revealed that OB volume became significantly reduced (10-25% volume reduction) in all dementia groups with disease progression.

CONCLUSION: Olfactory dysfunction is common in patients diagnosed with AD or FTD, but our results indicate that there is no detectable volume loss to the OBs upon first presentation to the clinic. Our findings indicate that the OBs become detectably atrophied later in the disease process. OB atrophy indicates the potential usefulness for OBs to be targeted in interventions to improve olfactory function.

%B J Alzheimers Dis %V 89 %P 51-66 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-220080 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Oral Health Status in Subjects with Amnestic Mild Cognitive Impairment and Alzheimer's Disease: Data from the Zabút Aging Project. %A Panzarella, Vera %A Mauceri, Rodolfo %A Baschi, Roberta %A Maniscalco, Laura %A Campisi, Giuseppina %A Monastero, Roberto %K Aging %K Alzheimer Disease %K Case-Control Studies %K Cognitive Dysfunction %K Cohort Studies %K Humans %K Male %K Neuropsychological Tests %K Oral Health %K Quality of Life %X

BACKGROUND: The relationship between Alzheimer's disease (AD) and periodontitis has been recently investigated with heterogenous results.

OBJECTIVE: This study aims to evaluate the oral health status and its relationship with cognitive impairment of participants, enrolled in the Zabút Aging Project, a community-based cohort study performed in a rural community in Sicily, Italy.

METHODS: A case-control study (20 subjects with AD, 20 with amnestic mild cognitive impairment [aMCI], and 20 controls) was conducted. The protocol included a comprehensive medical and cognitive-behavioral examination. Full-mouth evaluation, microbial analysis of subgingival plaque samples (by RT-PCR analysis), and oral health-related quality of life (OHR-QoL) were evaluated.

RESULTS: The decayed, missing, and filled teeth (DMFT) total score of AD subjects was significantly higher than aMCI (p = 0.009) and controls (p = 0.001). Furthermore, the "M" component of DMFT (i.e., the number of missing teeth) was significantly higher in AD than in aMCI (p < 0.001) and controls (p < 0.001). A Poisson regression model revealed that age (p < 0.001), male gender (p = 0.001), and AD (p = 0.001) were positively correlated with DMFT. Concerning oral microbial load, the presence of Fusobacterium nucleatum was significantly higher in AD than in controls (p = 0.02), and a higher load of Treponema denticola was found in aMCI than with AD (p = 0.004). OHR-QoL scores did not differ among the groups.

CONCLUSION: The current research suggests that AD is associated with chronic periodontitis, which is capable of determining tooth loss due to the pathogenicity of Fusobacterium nucleatum. These data remain to be confirmed in larger population-based cohorts.

%B J Alzheimers Dis %V 87 %P 173-183 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32508326?dopt=Abstract %R 10.3233/JAD-200385 %0 Journal Article %J J Alzheimers Dis %D 2022 %T The Outcome of Patients with Amyloid-Negative Amnestic Mild Cognitive Impairment. %A Cardoso, Sandra %A Silva, Dina %A Alves, Luísa %A Guerreiro, Manuela %A Mendonça, Alexandre de %X

BACKGROUND: Patients with amnestic mild cognitive impairment (aMCI) are usually at an initial stage of Alzheimer's disease (AD). However, some patients with aMCI do not present biomarkers of amyloid pathology characteristic of AD. The significance of amyloid-negative aMCI is not presently clear.

OBJECTIVE: To know the etiology and prognosis of amyloid-negative aMCI.

METHODS: Patients who fulfilled criteria for aMCI and were amyloid negative were selected from a large cohort of non-demented patients with cognitive complaints and were followed with clinical and neuropsychological assessments.

RESULTS: Few amyloid-negative aMCI had evidence of neurodegeneration at the baseline, as reflected in cerebrospinal fluid elevated tau protein levels. About half of the patients remained essentially stable for long periods of time. Others manifested a psychiatric disorder that was not apparent at baseline, namely major depression or bipolar disorder. Remarkably, about a quarter of patients developed neurodegenerative disorders other than AD, mostly frontotemporal dementia or Lewy body disease.

CONCLUSION: Amyloid-negative aMCI is a heterogeneous condition. Many patients remain clinically stable, but others may later manifest psychiatric conditions or evolve to neurodegenerative disorders. Prudence is needed when communicating to the patient and family the results of biomarkers, and clinical follow-up should be advised.

%B J Alzheimers Dis %V 86 %P 629-640 %8 2022 Mar 22 %G eng %N 2 %R 10.3233/JAD-215465 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Passive Immunotherapy Targeting Tau Oligomeric Strains Reverses Tauopathy Phenotypes in Aged Human-Tau Mice in a Mouse Model-Specific Manner. %A Bittar, Alice %A Al-Lahham, Rabab %A Bhatt, Nemil %A Moore, Kenya %A Montalbano, Mauro %A Jerez, Cynthia %A Fung, Leiana %A McAllen, Salome %A Ellsworth, Anna %A Kayed, Rakez %X

BACKGROUND: Tau oligomers are one of the most toxic species, displaying prion-like strains which have different conformations resulting in different tauopathies. Passive immunotherapy targeting different tau species is a promising therapeutic approach. Age is one of the greatest risk factors; however, most immunotherapy studies are done in young to middle-aged mice tauopathy models, which is not representative of the many clinical trials done with older humans with established tauopathies.

OBJECTIVE: We utilized two different clones of tau oligomer monoclonal antibodies (TOMAs) in aged Htau and JNPL3 mouse models to investigate the potential of passive immunotherapy.

METHODS: Aged mice received a single intravenous injection of 120 μg/animal of either TOMA1, TOMA3 clones or a non-specific IgG. Their cognitive functions were assessed one-week post-injection using Y-maze and novel object recognition tests. Brain tissues were analyzed using biochemical and immunological assays.

RESULTS: TOMA 1 and 3 rescues cognitive phenotypes in aged animals in a mouse model-specific manner, indicative by a reduction in tau oligomers levels. The TOMAs were shown to have strong reactivity with different tau oligomeric species in the different mouse models in vitro and ex vivo.

CONCLUSION: This is the first study testing tau passive immunotherapy in aged animals and supports our previous reports on of the role of oligomeric tau in disease progression further validating the potential of TOMAs to rescue the late-stage disease pathology and phenotype. Moreover, this study suggests that multiple tau oligomeric strains exist in aged animals; therefore, it is of great importance to further characterize these strains.

%B J Alzheimers Dis %V 90 %P 1103-1122 %8 2022 Nov 22 %G eng %N 3 %R 10.3233/JAD-220518 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Pelargonidin and Berry Intake Association with Alzheimer's Disease Neuropathology: A Community-Based Study. %A Agarwal, Puja %A Holland, Thomas M %A James, Bryan D %A Cherian, Laurel J %A Aggarwal, Neelum T %A Leurgans, Sue E %A Bennett, David A %A Schneider, Julie A %X

BACKGROUND: An anthocyanidin, pelargonidin, primarily found in berries, has antioxidant and anti-inflammatory properties, and is associated with better cognition and reduced Alzheimer's dementia risk.

OBJECTIVE: This study investigated if pelargonidin or berry intake is associated with Alzheimer's disease (AD) neuropathology in human brains.

METHODS: The study was conducted among 575 deceased participants (age at death = 91.3±6.1 years; 70% females) of the Rush Memory and Aging Project, with dietary data (assessed using a food frequency questionnaire) and neuropathological evaluations. Calorie-adjusted pelargonidin intake was modeled in quartiles and berry intake as continuous (servings/week). Mean amyloid-beta load and phosphorylated tau neuronal neurofibrillary tangle density across multiple cortical regions were assessed using immunohistochemistry. Global AD pathology burden, a quantitative summary score of neurofibrillary tangles, and diffuse and neuritic plaques using Bielschowsky silver stains in multiple brain regions, was also assessed.

RESULTS: In a linear regression model adjusted for age at death, sex, education, APOE ɛ4 status, vitamin E, and vitamin C, participants in the highest quartile of pelargonidin intake when compared to those in the lowest quartile, had less amyloid-β load (β (SE) = -0.293 (0.14), p = 0.038), and fewer phosphorylated tau tangles (β (SE) = -0.310, p = 0.051). Among APOE ɛ4 non-carriers, higher strawberry (β (SE) = -0.227 (0.11), p = 0.037) and pelargonidin (Q4 versus Q1: β (SE) = -0.401 (0.16), p = 0.011; p trend = 0.010) intake was associated with less phosphorylated tau tangles, no association was observed in APOE ɛ4 carriers. Berry intake was not associated with AD pathology. However, excluding participants with dementia or mild cognitive impairment at baseline, strawberry (p = 0.004) and pelargonidin (ptrend = 0.007) intake were associated with fewer phosphorylated tau tangles.

CONCLUSION: Higher intake of pelargonidin, a bioactive present in strawberries, is associated with less AD neuropathology, primarily phosphorylated tau tangles.

%B J Alzheimers Dis %V 88 %P 653-661 %8 2022 Jul 19 %G eng %N 2 %R 10.3233/JAD-215600 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Peptidylarginine Deiminase and Alzheimer's Disease. %A Wang, Lai %A Chen, Hongyang %A Tang, Jing %A Guo, Zhengwei %A Wang, Yanming %K Alzheimer Disease %K Animals %K Cerebral Cortex %K Citrulline %K Hippocampus %K Humans %K Isoenzymes %K Protein Processing, Post-Translational %K Protein-Arginine Deiminases %X

Peptidylarginine deiminases (PADs) are indispensable enzymes for post-translational modification of proteins, which can convert Arg residues on the surface of proteins to citrulline residues. The PAD family has five isozymes, PAD1, 2, 3, 4, and 6, which have been found in multiple tissues and organs. PAD2 and PAD4 were detected in cerebral cortex and hippocampus from human and rodent brain. In the central nervous system, abnormal expression and activation of PADs are involved in the pathological changes and pathogenesis of Alzheimer's disease (AD). This article reviews the classification, distribution, and function of PADs, with an emphasis on the relationship between the abnormal activation of PADs and AD pathogenesis, diagnosis, and the therapeutic potential of PADs as drug targets for AD.

%B J Alzheimers Dis %V 85 %P 473-484 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34842193?dopt=Abstract %R 10.3233/JAD-215302 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Perivascular Space Predicts Brain Hypometabolism of Individuals with Underlying Amyloid Pathology. %A Shi, Xiaolei %A Zhou, Nan %A Sun, Bin %A Wu, Yongshun %A Hu, Yachun %A Ning, Yuping %X

BACKGROUND: Reduced signal on fluorodeoxyglucose-positron emission tomography (FDG-PET) is a valid proxy for neurodegeneration in Alzheimer's disease (AD). Perivascular space (PVS) is believed to be associated with AD pathology and cognitive decline.

OBJECTIVE: This study aimed to investigate the associations of PVS with FDG-PET and cognitive performance based on the burden of amyloid pathology.

METHODS: We used magnetic resonance imaging (MRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). MRI-visible PVS in basal ganglia (BG) and centrum semi-oval (CSO) were visually classified as: none/mild, moderate or frequent/severe. The association of PVS with brain FDG-PET was explored based on the burden of amyloid pathology, where a cerebrospinal fluid (CSF) t-tau/Aβ42 with the ratio≥0.27 was defined as high amyloid pathology. Moreover, the relationships between PVS and cognitive performance variables (ADNI-MEM and ADNI-EF) were studied.

RESULTS: For participants with higher tau/Aβ42 ratio, CSO-PVS severity was independently associated with lower FDG-PET. There were significant interaction effects between moderate or frequent/severe CSO-PVS and time on FDG decline in people with high amyloid pathology. The interaction between CSO-PVS and time (follow-up) was consistently associated with ADNI-MEM and ADNI-EF decline in individuals with high amyloid pathology.

CONCLUSION: The study established the differential utility of PVS in BG and CSO for predicting brain metabolism. These findings suggest that CSO-PVS serves as a contributing factor to brain metabolism and cognitive decline associated with amyloid pathology.

%B J Alzheimers Dis %V 90 %P 1329-1337 %8 2022 Nov 22 %G eng %N 3 %R 10.3233/JAD-220426 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Plasma Amyloid and in vivo Brain Amyloid in Late Middle-Aged Hispanics. %A Rippon, Brady %A Palta, Priya %A Tahmi, Mouna %A Sherwood, Greysi %A Soto, Luisa %A Cespedes, Sandino %A Mesen, Yanette %A He, Hengda %A Laing, Krystal %A Moreno, Herman %A Teresi, Jeanne %A Razlighi, Qolamreza %A Brickman, Adam M %A Zetterberg, Henrik %A Luchsinger, Jose A %X

BACKGROUND: Determining amyloid positivity is possible with cerebrospinal fluid and brain imaging of amyloid, but these methods are invasive and expensive.

OBJECTIVE: To relate plasma amyloid-β (Aβ), measured using Single-molecule array (Simoatrademark) assays, to in vivo brain Aβ, measured using positron emission tomography (PET), examine the accuracy of plasma Aβ to predict brain Aβ positivity, and the relation of APOE ɛ4 with plasma Aβ.

METHODS: We performed a cross-sectional analysis in a cohort of 345 late middle-aged Hispanic men and women (age 64 years, 72% women). Our primary plasma variable was Aβ 42/Aβ 40 ratio measured with Simoa. Brain Aβ burden was measured as global SUVR with 18F-Florbetaben PET examined continuously and categorically.

RESULTS: Plasma Aβ 42/Aβ 40 ratio was inversely associated with global Aβ SUVR (β= -0.13, 95% Confidence Interval (CI): -0.23, -0.03; p = 0.013) and Aβ positivity (Odds Ratio: 0.59, 95% CI: 0.38, 0.91; p = 0.016), independent of demographics and APOE ɛ4. ROC curves (AUC = 0.73, 95% CI: 0.64, 0.82; p <  0.0001) showed that the optimal threshold for plasma Aβ 42/Aβ 40 ratio in relation to brain Aβ positivity was 0.060 with a sensitivity of 82.4% and specificity of 62.8% . APOE ɛ4 carriers had lower Aβ 42/Aβ 40 ratio and a higher Aβ positivity determined with the Aβ 42/Aβ 40 ratio threshold of 0.060.

CONCLUSION: Plasma Aβ 42/Aβ 40 ratio assayed using Simoa is weakly correlated with in vivo brain amyloid and has limited accuracy in screening for amyloid positivity and for studying risk factors of brain amyloid burden when in vivo imaging is not feasible.

%B J Alzheimers Dis %V 87 %P 1229-1238 %8 2022 May 31 %G eng %N 3 %R 10.3233/JAD-210391 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Plasma Cholesterol Levels as Potential Nutritional Biomarkers for Lewy Body Dementia. %A Dou, Yuchao %A Liu, Shuai %A Li, Yuqing %A Wu, Hao %A Chen, Hui %A Ji, Yong %X

BACKGROUND: The relationship between cholesterol level and the risk of developing Alzheimer's disease has been well established, but the relationship between cholesterol level and Lewy body dementia (LBD) is still not well known.

OBJECTIVE: The aim of this case-control study was to explore the association between blood cholesterol levels and LBD in Chinese older adults.

METHODS: A total of 65 patients with LBD and 110 older adult controls were enrolled during the study period. The levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and fasting glucose were measured separately. The associations between LBD, blood cholesterol levels, and fasting glucose levels were assessed using multiple binary logistic regression analyses adjusted for multiple covariates.

RESULTS: Increased plasma LDL-C levels and lower HDL-C levels were independently associated with the risk of LBD in models adjusted for age, sex, education, alcohol use status, smoking status, and vascular disorders. Higher fasting glucose levels may be associated with the risk of LBD.

CONCLUSION: The results of this study suggest that elevated levels of LDL-C and reduced levels of HDL-C were associated with LBD development and therefore are potential nutritional risk factors for LBD. Adjusting diet and individualized and effective cholesterol-lowering therapy in high-risk adults may aid in the prevention or management of LBD.

%B J Alzheimers Dis %V 86 %P 779-786 %8 2022 Mar 22 %G eng %N 2 %R 10.3233/JAD-215295 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Plasma Myeloperoxidase as a Potential Biomarker of Patient Response to Anti-Dementia Treatment in Alzheimer's Disease. %A Wright, Joy R %A Deen, Quazi Fahm E %A Stevenson, Anna %A Telford-Cooke, Leolie %A Parker, Craig %A Martin-Ruiz, Carmen %A Steinert, Joern R %A Kalaria, Raj N %A Mukaetova-Ladinska, Elizabeta B %X

BACKGROUND: Myeloperoxidase (MPO), a neutrophil-derived pro-inflammatory protein, co-localizes with amyloid-β (Aβ) plaques in Alzheimer's disease (AD). Anti-dementia treatment may facilitate efflux of Aβ and associated plaque proteins from the brain to the peripheral circulation, therefore providing potential biomarkers for the monitoring of donor response to drug treatment.

OBJECTIVE: We investigated the diagnostic utility of MPO as a biomarker of AD, and how anti-dementia treatment alters plasma MPO concentration.

METHODS: Thirty-two AD patients were recruited, and plasma collected pre-drug administration (baseline), and 1- and 6-months post-treatment. All patients received cholinesterase inhibitors (ChEIs). At baseline and 6 months, patients underwent neuropsychological assessment. Forty-nine elderly healthy individuals with normal cognitive status served as controls. Plasma MPO concentration was measured by ELISA.

RESULTS: AD drug naïve patients had similar plasma MPO concentration to their control counterparts (p >  0.05). Baseline MPO levels positively correlated with Neuropsychiatric Inventory score (r = 0.5080; p = 0.011) and carer distress (r = 0.5022; p = 0.012). Following 1-month ChEI treatment, 84.4% of AD patients exhibited increased plasma MPO levels (p <  0.001), which decreased at 6 months (p <  0.001). MPO concentration at 1 month was greatest in AD patients whose memory deteriorated during the study period (p = 0.028), and for AD patients with deterioration in Cornell assessment score (p = 0.044).

CONCLUSION: Whereas baseline MPO levels did not differentiate between healthy and AD populations, baseline MPO positively correlated with initial Neuropsychiatric Inventory evaluation. Post-treatment, transient MPO upregulation in ChEI-treated patients may reflect worse therapeutic outcome. Further studies are required to assess the potential of plasma MPO as an AD therapeutic biomarker.

%B J Alzheimers Dis %V 89 %P 1483-1492 %8 2022 Oct 11 %G eng %N 4 %R 10.3233/JAD-220642 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Polygenic Scores of Alzheimer's Disease Risk Genes Add Only Modestly to APOE in Explaining Variation in Amyloid PET Burden. %A Ramanan, Vijay K %A Heckman, Michael G %A Przybelski, Scott A %A Lesnick, Timothy G %A Lowe, Val J %A Graff-Radford, Jonathan %A Mielke, M %A Jack, Clifford R %A Knopman, David S %A Petersen, Ronald C %A Ross, Owen A %A Vemuri, Prashanthi %X

BACKGROUND: Brain accumulation of amyloid-β is a hallmark event in Alzheimer's disease (AD) whose underlying mechanisms are incompletely understood. Case-control genome-wide association studies have implicated numerous genetic variants in risk of clinically diagnosed AD dementia.

OBJECTIVE: To test for associations between case-control AD risk variants and amyloid PET burden in older adults, and to assess whether a polygenic measure encompassing these factors would account for a large proportion of the unexplained variance in amyloid PET levels in the wider population.

METHODS: We analyzed data from the Mayo Clinic Study of Aging (MCSA) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Global cortical amyloid PET burden was the primary outcome. The 38 gene variants from Wightman et al. (2021) were analyzed as predictors, with PRSice-2 used to assess the collective phenotypic variance explained.

RESULTS: Known AD risk variants in APOE, PICALM, CR1, and CLU were associated with amyloid PET levels. In aggregate, the AD risk variants were strongly associated with amyloid PET levels in the MCSA (p = 1.51×10-50) and ADNI (p = 3.21×10-64). However, in both cohorts the non-APOE variants uniquely contributed only modestly (MCSA = 2.1%, ADNI = 4.4%) to explaining variation in amyloid PET levels.

CONCLUSION: Additional case-control AD risk variants added only modestly to APOE in accounting for individual variation in amyloid PET burden, results which were consistent across independent cohorts with distinct recruitment strategies and subject characteristics. Our findings suggest that advancing precision medicine for dementia may require integration of strategies complementing case-control approaches, including biomarker-specific genetic associations, gene-by-environment interactions, and markers of disease progression and heterogeneity.

%B J Alzheimers Dis %V 88 %P 1615-1625 %8 2022 Aug 16 %G eng %N 4 %R 10.3233/JAD-220164 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Post-Stroke Cognitive Impairment: Epidemiology, Risk Factors, and Management. %A Huang, Yu-Yuan %A Chen, Shi-Dong %A Leng, Xin-Yi %A Kuo, Kevin %A Wang, Zuo-Teng %A Cui, Mei %A Tan, Lan %A Wang, Kai %A Dong, Qiang %A Yu, Jin-Tai %K Aged %K Cognitive Dysfunction %K Humans %K Prevalence %K Risk Factors %K Stroke %X

Stroke, characterized as a neurological deficit of cerebrovascular cause, is very common in older adults. Increasing evidence suggests stroke contributes to the risk and severity of cognitive impairment. People with cognitive impairment following stroke often face with quality-of-life issues and require ongoing support, which have a profound effect on caregivers and society. The high morbidity of post-stroke cognitive impairment (PSCI) demands effective management strategies, in which preventive strategies are more appealing, especially those targeting towards modifiable risk factors. In this review article, we attempt to summarize existing evidence and knowledge gaps on PSCI: elaborating on the heterogeneity in current definitions, reporting the inconsistent findings in PSCI prevalence in the literature, exploring established or less established predictors, outlining prevention and treatment strategies potentially effective or currently being tested, and proposing promising directions for future research.

%B J Alzheimers Dis %V 86 %P 983-999 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35147548?dopt=Abstract %R 10.3233/JAD-215644 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Potential Involvement of Varicella Zoster Virus in Alzheimer's Disease via Reactivation of Quiescent Herpes Simplex Virus Type 1. %A Cairns, Dana M %A Itzhaki, Ruth F %A Kaplan, David L %X

BACKGROUND: Varicella zoster virus (VZV) has been implicated in Alzheimer's disease (AD), and vaccination against shingles, caused by VZV, has been found to decrease the risk of AD/dementia. VZV might reside latently in brain, and on reactivation might cause direct damage leading to AD, as proposed for herpes simplex virus type 1 (HSV-1), a virus strongly implicated in AD. Alternatively, shingles could induce neuroinflammation and thence, reactivation of HSV-1 in brain.

OBJECTIVE: To investigate these possibilities by comparing the effects of VZV and HSV-1 infection of cultured cells, and the action of VZV infection on cells quiescently infected with HSV-1.

METHODS: We infected human-induced neural stem cell (hiNSC) cultures with HSV-1 and/or VZV and sought the presence of AD-related phenotypes such as amyloid-β (Aβ) and P-tau accumulation, gliosis, and neuroinflammation.

RESULTS: Cells infected with VZV did not show the main AD characteristics, Aβ and P-tau accumulation, which HSV-1 does cause, but did show gliosis and increased levels of pro-inflammatory cytokines, suggesting that VZV's action relating to AD/dementia is indirect. Strikingly, we found that VZV infection of cells quiescently infected with HSV-1 causes reactivation of HSV-1 and consequent AD-like changes, including Aβ and P-tau accumulation.

CONCLUSION: Our results are consistent with the suggestion that shingles causes reactivation of HSV1 in brain and with the protective effects against AD of various vaccines, as well as the decrease in herpes labialis reported after certain types of vaccination. They support an indirect role for VZV in AD/dementia via reactivation of HSV-1 in brain.

%B J Alzheimers Dis %V 88 %P 1189-1200 %8 2022 Aug 02 %G eng %N 3 %R 10.3233/JAD-220287 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Potential Mechanisms Underlying Resistance to Dementia in Non-Demented Individuals with Alzheimer's Disease Neuropathology. %A Kok, Frédérique K %A van Leerdam, Suzanne L %A de Lange, Elizabeth C M %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Hippocampus %K Humans %K Plaque, Amyloid %K Synapses %X

Alzheimer's disease (AD) is the most common form of dementia and typically characterized by the accumulation of amyloid-β plaques and tau tangles. Intriguingly, there also exists a group of elderly which do not develop dementia during their life, despite the AD neuropathology, the so-called non-demented individuals with AD neuropathology (NDAN). In this review, we provide extensive background on AD pathology and normal aging and discuss potential mechanisms that enable these NDAN individuals to remain cognitively intact. Studies presented in this review show that NDAN subjects are generally higher educated and have a larger cognitive reserve. Furthermore, enhanced neural hypertrophy could compensate for hippocampal and cingulate neural atrophy in NDAN individuals. On a cellular level, these individuals show increased levels of neural stem cells and 'von Economo neurons'. Furthermore, in NDAN brains, binding of Aβ oligomers to synapses is prevented, resulting in decreased glial activation and reduced neuroinflammation. Overall, the evidence stated here strengthens the idea that some individuals are more resistant to AD pathology, or at least show an elongation of the asymptomatic state of the disease compared to others. Insights into the mechanisms underlying this resistance could provide new insight in understanding normal aging and AD itself. Further research should focus on factors and mechanisms that govern the NDAN cognitive resilience in order to find clues on novel biomarkers, targets, and better treatments of AD.

%B J Alzheimers Dis %V 87 %P 51-81 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275527?dopt=Abstract %R 10.3233/JAD-210607 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Precision Medicine Approach to Alzheimer's Disease: Successful Pilot Project. %A Toups, Kat %A Hathaway, Ann %A Gordon, Deborah %A Chung, Henrianna %A Raji, Cyrus %A Boyd, Alan %A Hill, Benjamin D %A Hausman-Cohen, Sharon %A Attarha, Mouna %A Chwa, Won Jong %A Jarrett, Michael %A Bredesen, Dale E %X

BACKGROUND: Effective therapeutics for Alzheimer's disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy.

OBJECTIVE: To determine whether a precision medicine approach to Alzheimer's disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial.

METHODS: Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t = 0, 3, 6, and 9 months.

RESULTS: All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer's Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved.

CONCLUSION: Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.

%B J Alzheimers Dis %V 88 %P 1411-1421 %8 2022 Aug 16 %G eng %N 4 %R 10.3233/JAD-215707 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Pre-Diagnostic Symptoms of Young-Onset Dementia in the General Practice up to Five Years Before Diagnosis. %A Hendriks, Stevie %A Peetoom, Kirsten %A Tange, Huibert %A van Bokhoven, Marloes A %A van der Flier, Wiesje M %A Bakker, Christian %A Papma, Janne M %A Koopmans, Raymond %A Verhey, Frans %A Köhler, Sebastian %A de Vugt, Marjolein %X

BACKGROUND: Young-onset dementia (YOD) has many underlying etiologies, leading to a large heterogeneity in first symptoms. This makes it difficult for general practitioners (GPs) to recognize YOD.

OBJECTIVE: Identify early symptoms that are more common in the pre-diagnostic phase of YOD.

METHODS: We performed a case-control study nested in a primary-care registry on 89 cases and 162 matched controls, where we compared symptoms of people with YOD up to 5 years before diagnosis to their matched control group without YOD. The variables included in this study were International Classification of Primary Care codes and symptoms extracted from written GP notes and categorized in groups. We used Generalized Equation Estimation to analyze symptom's time-trajectories and logistic regression and ROC-curves to analyze differences in number of symptom categories reported.

RESULTS: Cognitive symptoms were more common in people with YOD 5 years before diagnosis, affective symptoms 4 years before diagnosis, social symptoms 3 years, behavioral symptoms 2 years, and daily functioning disturbances 1 year before diagnosis. The ROC-curve suggested that reporting two or more symptom categories at the GP gave the best trade-off between sensitivity (85%) and specificity (77% ), for the highest percentage of correctly diagnosed persons.

CONCLUSION: This study showed people with YOD present differently than people without YOD. However, it may still be difficult for GPs to use these symptom categories to distinguish people with YOD, since the symptoms also occur in people with other diseases. A combination of reported symptom categories increases the probability of an underlying cause of YOD.

%B J Alzheimers Dis %V 88 %P 229-239 %8 2022 Jun 28 %G eng %N 1 %R 10.3233/JAD-220215 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Prevalence of Depressive Symptoms in a Memory Clinic Cohort: A Retrospective Study. %A Loreto, Flavia %A Fitzgerald, Anna %A Golemme, Mara %A Gunning, Stephen %A Win, Zarni %A Patel, Neva %A Carswell, Christopher %A Perry, Richard %A Kennedy, Angus %A Edison, Paul %A Malhotra, Paresh %X

BACKGROUND: Depression has been suggested to be a cause of reversible cognitive impairment but also a risk factor for neurodegenerative disease. Studies suggest that depression prevalence may be high in early onset dementia, particularly Alzheimer's disease, but this has not been systematically assessed in a biomarker-validated clinical dementia cohort to date.

OBJECTIVE: To examine the prevalence, features, and association with amyloid pathology of lifetime depressive symptoms in a memory clinic cohort meeting appropriate use criteria for amyloid PET imaging.

METHODS: We included 300 patients from a single-center memory clinic cohort that received diagnostic biomarker evaluation with amyloid PET imaging according to appropriate use criteria. History of lifetime depressive symptoms was retrospectively assessed through structured review of clinical correspondence.

RESULTS: One hundred forty-two (47%) patients had a history of significant depressive symptoms ('D+'). Of these, 89% had ongoing symptoms and 60% were on antidepressants at the time of presentation to our Clinic. Depressive symptoms were equally highly prevalent in the amyloid-positive and the heterogeneous group of amyloid-negative patients.

CONCLUSION: Approximately half of patients who meet appropriate use criteria for amyloid PET had a history of depressive symptoms. We suggest that depression is an important feature of both neurodegenerative and non-neurodegenerative cognitive impairment and may contribute to the diagnostic uncertainty behind referral to amyloid PET.

%B J Alzheimers Dis %V 88 %P 1179-1187 %8 2022 Aug 02 %G eng %N 3 %R 10.3233/JAD-220170 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Prions and Neurodegenerative Diseases: A Focus on Alzheimer's Disease. %A Crestini, Alessio %A Santilli, Francesca %A Martellucci, Stefano %A Carbone, Elena %A Sorice, Maurizio %A Piscopo, Paola %A Mattei, Vincenzo %K alpha-Synuclein %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Humans %K Neurofibrillary Tangles %K Neurons %K Prion Proteins %K Protein Aggregation, Pathological %K Randomized Controlled Trials as Topic %K Receptor, Metabotropic Glutamate 5 %K tau Proteins %X

Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer's disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC. Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.

%B J Alzheimers Dis %V 85 %P 503-518 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864675?dopt=Abstract %R 10.3233/JAD-215171 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Probiotic Bifidobacterium breve Prevents Memory Impairment Through the Reduction of Both Amyloid-β Production and Microglia Activation in APP Knock-In Mouse. %A Abdelhamid, Mona %A Zhou, Chunyu %A Ohno, Kazuya %A Kuhara, Tetsuya %A Taslima, Ferdous %A Abdullah, Mohammad %A Jung, Cha-Gyun %A Michikawa, Makoto %K Amyloid beta-Peptides %K Animals %K Bifidobacterium breve %K Brain %K Disease Models, Animal %K Hippocampus %K Memory Disorders %K Mice %K Mice, Transgenic %K Microglia %K Probiotics %X

BACKGROUND: Probiotic supplementation reestablishes microbiome diversity and improves brain function in Alzheimer's disease (AD); their molecular mechanisms, however, have not yet been fully illustrated.

OBJECTIVE: We investigated the effects of orally supplemented Bifidobacterium breve MCC1274 on cognitive function and AD-like pathologies in AppNL-G-F mice.

METHODS: Three-month-old AppNL-G-F mice were orally supplemented with B. breve MCC1274 for four months. The short-term memory function was evaluated using a novel object recognition test. Amyloid plaques, amyloid-β (Aβ) levels, Aβ fibril, amyloid-β protein precursor and its processing enzymes, its metabolic products, glial activity, and cell proliferation in the subgranular zone of the dentate gyrus were evaluated by immunohistochemistry, Aβ ELISA, western blotting, and immunofluorescence staining. The mRNA expression levels of pro- and anti-inflammatory cytokines were determined by qRT-PCR analysis.

RESULTS: We found that the oral B. breve MCC1 274 supplementation prevented memory impairment in AppNL-G-F mice and decreased hippocampal Aβ levels through the enhancement of the a-disintegrin and metalloproteinase 10 (ADAM10) level. Moreover, administration of the probiotic activated the ERK/HIF-1α signaling pathway responsible for increasing the ADAM10 level and also attenuated microglial activation, which in turn led to reduction in the mRNA expression levels of pro-inflammatory cytokines in the brain. In addition, B. breve MCC1274 supplementation increased the level of synaptic proteins in the hippocampus.

CONCLUSION: Our findings support the possibility that oral B. breve MCC1274 supplementation might be used as a potential preventive therapy for AD progression.

%B J Alzheimers Dis %V 85 %P 1555-1571 %8 2022 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/34958017?dopt=Abstract %R 10.3233/JAD-215025 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Progression from Subjective Cognitive Decline to Mild Cognitive Impairment or Dementia: The Role of Baseline Cognitive Performance. %A Jester, Dylan J %A Vyhnálek, Martin %A Andel, Ross %A Marková, Hana %A Nikolai, Tomas %A Laczó, Jan %A Matuskova, Veronika %A Cechova, Katerina %A Sheardova, Katerina %A Hort, Jakub %X

BACKGROUND: Older adults with subjective cognitive decline (SCD) are at an increased risk of progression to mild cognitive impairment (MCI) or dementia. However, few have examined the specific cognitive tests that are associated with progression.

OBJECTIVE: This study examined performance on 18 neuropsychological tests among participants with SCD who later progressed to MCI or dementia.

METHODS: We included 131 participants from the Czech Brain Aging Study that had SCD at baseline. They completed a comprehensive neuropsychological battery including cognitive tests from the Uniform Data Set 2.0 enriched by the verbal memory test Rey Auditory Verbal Learning Test (RAVLT) and Rey-Osterrieth Complex Figure Test (ROCFT).

RESULTS: Fifty-five participants progressed: 53% to non-amnestic MCI (naMCI), 44% to amnestic MCI (aMCI), and 4% to dementia. Scoring one SD below the mean at baseline on the RAVLT 1 and RAVLT 1-5 was associated with 133% (RAVLT 1; HR: 2.33 [1.50, 3.62]) and 122% (RAVLT 1-5; HR: 2.22 [1.55, 3.16]) greater risk of progression to MCI or dementia over 3.84 years on average. Worse performance on the RAVLT 5, RAVLT 1-5, RAVLT 30, and ROCFT-Recall was associated with progression to aMCI whereas worse performance on the RAVLT 1, TMT B, and Boston Naming Test was associated with progression to naMCI.

CONCLUSION: At baseline, lower verbal memory performance was most strongly associated with progression to aMCI whereas lower executive or language performance was most strongly associated with progression to naMCI.

%B J Alzheimers Dis %V 86 %P 1763-1774 %8 2022 Apr 19 %G eng %N 4 %R 10.3233/JAD-215291 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Proteomic Profiles of Neurodegeneration Among Mexican Americans and Non-Hispanic Whites in the HABS-HD Study. %A O'Bryant, Sid E %A Zhang, Fan %A Petersen, Melissa %A Hall, James R %A Johnson, Leigh A %A Yaffe, Kristine %A Braskie, Meredith %A Vig, Rocky %A Toga, Arthur W %A Rissman, Robert A %X

BACKGROUND: Hispanics are expected to experience the largest increase in Alzheimer's disease (AD) and AD related dementias over the next several decades. However, few studies have examined biomarkers of AD among Mexican Americans, the largest segment of the U.S. Hispanic population.

OBJECTIVE: We sought to examine proteomic profiles of an MRI-based marker of neurodegeneration from the AT(N) framework among a multi-ethnic, community-dwelling cohort.

METHODS: Community-dwelling Mexican Americans and non-Hispanic white adults and elders were recruited. All participants underwent comprehensive assessments including an interview, functional exam, clinical labs, informant interview, neuropsychological testing, and 3T MRI of the brain. A neurodegeneration MRI meta-ROI biomarker for the AT(N) framework was calculated.

RESULTS: Data was examined from n = 1,291 participants. Proteomic profiles were highly accurate for detecting neurodegeneration (i.e., N+) among both Mexican Americans (AUC = 1.0) and non-Hispanic whites (AUC = 0.98). The proteomic profile of N + was different between ethnic groups. Further analyses revealed that the proteomic profiles of N + varied by diagnostic status (control, MCI, dementia) and ethnicity (Mexican American versus non-Hispanic whites) though diagnostic accuracy was high for all classifications.

CONCLUSION: A proteomic profile of neurodegeneration has tremendous value and point towards novel diagnostic and intervention opportunities. The current findings demonstrate that the underlying biological factors associated with neurodegeneration are different between Mexican Americans versus non-Hispanic whites as well as at different levels of disease progression.

%B J Alzheimers Dis %V 86 %P 1243-1254 %8 2022 Apr 05 %G eng %N 3 %R 10.3233/JAD-210543 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Psychosis as a Treatment Target in Dementia: A Roadmap for Designing Interventions. %A Agüera-Ortiz, Luis %A Babulal, Ganesh M %A Bruneau, Marie-Andrée %A Creese, Byron %A D'Antonio, Fabrizia %A Fischer, Corinne E %A Gatchel, Jennifer R %A Ismail, Zahinoor %A Kumar, Sanjeev %A McGeown, William J %A Mortby, Moyra E %A Nuñez, Nicolas A %A de Oliveira, Fabricio F %A Pereiro, Arturo X %A Ravona-Springer, Ramit %A Rouse, Hillary J %A Wang, Huali %A Lanctôt, Krista L %K Caregivers %K Dementia %K Hallucinations %K Humans %K Psychotic Disorders %K Schizophrenia %X

Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials.

%B J Alzheimers Dis %V 88 %P 1203-1228 %8 2022 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/35786651?dopt=Abstract %R 10.3233/JAD-215483 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Race Differences in the Association Between Sleep Medication Use and Risk of Dementia. %A Leng, Yue %A Stone, Katie L %A Yaffe, Kristine %X

BACKGROUND: The effect of sleep medications on cognition in older adults is controversial, possibly dependent upon sleep quality, and may differ by race.

OBJECTIVE: To determine the longitudinal association between sleep medication use and incident dementia over 15 years, and to explore whether the association is independent of nighttime sleep disturbances and if it differs by race.

METHODS: We examined 3,068 community-dwelling older adults (aged 74.1±2.9 years, 41.7% Black, 51.5% female) without dementia. Sleep medication use was recorded three times by asking "Do you take sleeping pills or other medications to help you sleep?" with the response options: "Never (0)", "Rarely (≤1/month)", "Sometimes (2-4/month)", "Often (5-15/month)", or "Almost Always (16-30/month)". Incident dementia was defined using hospitalization records, dementia medication prescription or clinically significant decline in global cognition.

RESULTS: 138 (7.71%) of Whites and 34 (2.66%) of Blacks reported taking sleep medications "often or almost always". Whites were almost twice as likely to take all prescription hypnotics. 617 participants developed dementia over the follow-up. After adjustment for all covariates, participants who reported taking sleep medications ≥ 5/month versus ≤1/month were significantly more likely to develop dementia, and the association was only observed among Whites (HR = 1.79,1.21-2.66) but not Blacks (HR = 0.84,0.38-1.83); p for interaction = 0.048. Further adjustment for nighttime sleep did not appreciably alter the results. The association was similar for the cumulative frequency of sleep medication use and remained after introducing a time lag of 3 years.

CONCLUSION: Frequent sleep medication use was associated with an increased risk of dementia in White older adults. Further research is needed to determine underlying mechanisms.

%B J Alzheimers Dis %V 91 %P 1133-1139 %8 2023 Jan 31 %G eng %N 3 %R 10.3233/JAD-221006 %0 Journal Article %J J Alzheimers Dis %D 2022 %T The Relationship Between Prior Cancer Diagnosis and All-Cause Dementia Progression Among US Adults. %A Fowler, Mackenzie E %A Wright, Nicole C %A Triebel, Kristen %A Rocque, Gabrielle B %A Irvin, Ryan %A Kennedy, Richard E %X

BACKGROUND: Cancer-related cognitive impairment (CRCI), a frequent effect of cancer and its treatments, shares common cognitive symptoms with dementia syndromes. Cross-sectional studies demonstrate an inverse relationship between cancer and dementia. However, the longitudinal relationship between dementia decline and cancer has not been investigated.

OBJECTIVE: To evaluate the association between cancer and longitudinal progression of dementia.

METHODS: We extracted electronic health record data from July 2003 to February 2020 from a single academic medical center. We identified dementia and cancer history prior to dementia using ICD-9/10 codes. We measured cognitive decline with the Alabama Brief Cognitive Screener (ABCs). We used adjusted linear mixed models to estimate baseline cognition and rate of progression by cancer history, including differences by race.

RESULTS: The study included 3,809 participants with dementia, of which 672 (17.6%) had cancer history. Those with cancer history had higher baseline cognition (β: 0.62, 95% CI: -0.02-1.25), but similar rate of decline. Non-Hispanic Blacks had lower cognitive scores at baseline and throughout follow-up regardless of cancer status compared to non-Hispanic Whites and other races/ethnicities with and without cancer history.

CONCLUSION: In this longitudinal retrospective study, participants with cancer history demonstrate better cognition at dementia diagnosis and no difference in cognitive decline than those without cancer history. Smoking and comorbidities attenuate this association and results indicate non-Hispanic Blacks have worse cognitive outcomes in dementia regardless of cancer history than other race/ethnicity groups. Further exploration of the role of smoking, comorbidities, and race/ethnicity on cancer and dementia-related cognitive decline is needed.

%B J Alzheimers Dis %V 88 %P 521-535 %8 2022 Jul 19 %G eng %N 2 %R 10.3233/JAD-220054 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Relationship Between the Gut Microbiota and Alzheimer's Disease: A Systematic Review. %A González Cordero, Elisa Marina %A Cuevas-Budhart, Miguel Angel %A Pérez Morán, Diana %A Trejo Villeda, Miguel Angel %A Gomez-Del-Pulgar Gª-Madrid, Mercedes %K Alzheimer Disease %K Brain %K Brain-Gut Axis %K Cognitive Dysfunction %K Gastrointestinal Microbiome %K Humans %X

BACKGROUND: In recent years, scientific research on the gut microbiota and their relationship with some diseases, including neurological ones, has notably increased. As a result of these investigations, the so-called gut-brain axis arises. Despite its influence on the evolution and development of cognitive impairment, the gut-brain axis is little defined and demonstrated.

OBJECTIVE: To provide the best scientific evidence available on the relationship between the gut microbiota and Alzheimer's disease.

METHOD: Systematic and narrative review of the information generated in the last 5 years in national and international databases, in English and Spanish.

RESULTS: Eight observational studies were selected, carried out in humans and, therefore, suitable for inclusion in this review.

CONCLUSION: The results of these studies support the hypothesis that there is a relationship between the gut microbiota and cognitive disorders through the gut-brain axis. However, today, there is a substantial lack of human studies, especially clinical trials, which makes it difficult to formulate clinical recommendations on this topic.

%B J Alzheimers Dis %V 87 %P 519-528 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35367961?dopt=Abstract %R 10.3233/JAD-215224 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Relationship Between Weight-Change Patterns and Cognitive Function: A Retrospective Study. %A Gong, Hong-Jian %A Tang, Xingyao %A Chai, Yin-He %A Qiao, Yu-Shun %A Xu, Hui %A Patel, Ikramulhaq %A Zhang, Jin-Yan %A Simó, Rafael %A Zhou, Jian-Bo %X

BACKGROUND: Obesity has been linked to cognitive impairment. However, how changes in body mass index (BMI) over the life course influence cognitive function remains unclear.

OBJECTIVE: The influence of distinct weight-change patterns from young adulthood to midlife and late adulthood on cognitive function in older adults was explored.

METHODS: A total of 5,809 individuals aged≥60 years were included and categorized into four groups on the basis of BMI change patterns. Cognitive function was assessed using four cognition tests in the baseline survey. The relationship between the weight-change patterns and cognition was evaluated using regression models.

RESULTS: In comparison with participants who remained at non-obese, those moving from the non-obese to obese weight-change pattern from young (25 years of age) to middle adulthood showed lower Digit Symbol Substitution Test (DSST) scores (β= -1.28; 95% confidence interval [CI]: -2.24 to -0.32). A non-obese to obese change pattern from age 25 years of age to 10 years before baseline was associated with a higher risk of DSST impairment (odds ratio = 1.40; 95% CI: 1.09 to 1.79). In comparison with participants whose heaviest weight was recorded after 60 years of age, those with the heaviest weight between 18 and 40 years of age had lower DSST scores (β= -1.46; 95% CI: -2.77 to -1.52).

CONCLUSION: Our results suggest that the transition from the non-obese to obese category in early adulthood and appearance of the heaviest weight between 18 and 40 years of age are associated with lower cognitive function in later life.

%B J Alzheimers Dis %V 91 %P 1085-1095 %8 2023 Jan 31 %G eng %N 3 %R 10.3233/JAD-220788 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Relationships Between the Deposition of Amyloid-β and Tau Protein and Glymphatic System Activity in Alzheimer's Disease: Diffusion Tensor Image Study. %A Ota, Miho %A Sato, Noriko %A Nakaya, Moto %A Shigemoto, Yoko %A Kimura, Yukio %A Chiba, Emiko %A Yokoi, Yuma %A Tsukamoto, Tadashi %A Matsuda, Hiroshi %X

BACKGROUND: Amyloid-β (Aβ) and tau protein accumulation in the brain is thought to be one of the causes of Alzheimer's disease (AD). Recent study found that the glymphatic system was waste drainage system in the brain and promoting the elimination of Aβ and tau protein.

OBJECTIVE: Objective: We evaluated the relationships between the glymphatic system activity and Aβ and tau protein deposition.

METHODS: Subjects were 21 patients with AD and 36 healthy subjects who underwent diffusion tensor imaging (DTI) scan and the positron emission tomography using with the Aβ tracer: 11C-PiB and the tau/inflammatory tracer: 18F-THK5351. We computed diffusion tensor image analysis along the perivascular space (DTI-ALPS) index as the proxy of glymphatic system activity and estimated the relationships between the DTI-ALPS index and Aβ and tau protein/inflammatory deposition.

RESULTS: We found significant negative correlations between DTI-ALPS index and the standard uptake value ratio (SUVR) of 11C-PiB in the bilateral temporal and left parietal cortices and left posterior cingulate gyrus in all subjects. Further, we detected significant negative correlations between DTI-ALPS index and the SUVR of 18F-THK5351 in the bilateral temporal cortices and right parietal cortex in all participants, too.

CONCLUSION: Our data suggested that DTI-ALPS index was a good biomarker for the evaluation of Aβ and tau deposition and neuroinflammation, and this marker might be effective to estimate the glymphatic system activity.

%B J Alzheimers Dis %V 90 %P 295-303 %8 2022 Oct 25 %G eng %N 1 %R 10.3233/JAD-220534 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Rheumatoid Arthritis, Cognitive Impairment, and Neuroimaging Biomarkers: Results from the Mayo Clinic Study of Aging. %A Vassilaki, Maria %A Crowson, Cynthia S %A Davis Iii, John M %A Duong, Stephanie Q %A Jones, David T %A Nguyen, Aivi %A Mielke, Michelle M %A Vemuri, Prashanthi %A Myasoedova, Elena %K Aged %K Aging %K Alzheimer Disease %K Amyloid %K Amyloid beta-Peptides %K Amyloidosis %K Arthritis, Rheumatoid %K Biomarkers %K Brain %K Cognitive Dysfunction %K Female %K Fluorodeoxyglucose F18 %K Humans %K Magnetic Resonance Imaging %K Male %K Neuroimaging %K Positron-Emission Tomography %X

BACKGROUND: Observational studies suggested that dementia risk in patients with rheumatoid arthritis (RA) is higher than in the general population.

OBJECTIVE: To examine the associations of RA with cognitive decline and dementia, and neuroimaging biomarkers of aging, Alzheimer's disease, and vascular pathology in adult participants in the Mayo Clinic Study of Aging (MCSA).

METHODS: Participants with RA were matched 1:3 on age, sex, education, and baseline cognitive diagnosis to participants without RA. RA cases with MRI were also matched with non-cases with available MRI. All available imaging studies (i.e., amyloid and FDG PET, sMRI, and FLAIR) were included. The study included 104 participants with RA and 312 without RA (mean age (standard deviation, SD) 75.0 (10.4) years, 33% male and average follow-up (SD) 4.2 (3.8) years).

RESULTS: Groups were similar in cognitive decline and risk of incident dementia. Among participants with neuroimaging, participants with RA (n = 33) and without RA (n = 98) had similar amyloid burden and neurodegeneration measures, including regions sensitive to aging and dementia, but greater mean white matter hyperintensity volume relative to the total intracranial volume (mean (SD)% : 1.12 (0.57)% versus 0.76 (0.69)% of TIV, p = 0.01), and had higher mean (SD) number of cortical infarctions (0.24 (0.44) versus 0.05 (0.33), p = 0.02).

CONCLUSION: Although cognitive decline and dementia risk were similar in participants with and without RA, participants with RA had more abnormal cerebrovascular pathology on neuroimaging. Future studies should examine the mechanisms underlying these changes and potential implications for prognostication and prevention of cognitive decline in RA.

%B J Alzheimers Dis %V 89 %P 943-954 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35964191?dopt=Abstract %R 10.3233/JAD-220368 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Risk of Alzheimer's Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching. %A Bukhbinder, Avram S %A Ling, Yaobin %A Hasan, Omar %A Jiang, Xiaoqian %A Kim, Yejin %A Phelps, Kamal N %A Schmandt, Rosemarie E %A Amran, Albert %A Coburn, Ryan %A Ramesh, Srivathsan %A Xiao, Qian %A Schulz, Paul E %K Adult %K Aged %K Alzheimer Disease %K Chronic Disease %K Cohort Studies %K Female %K Humans %K Influenza, Human %K Male %K Middle Aged %K Propensity Score %K Vaccination %X

BACKGROUND: Prior studies have found a reduced risk of dementia of any etiology following influenza vaccination in selected populations, including veterans and patients with serious chronic health conditions. However, the effect of influenza vaccination on Alzheimer's disease (AD) risk in a general cohort of older US adults has not been characterized.

OBJECTIVE: To compare the risk of incident AD between patients with and without prior influenza vaccination in a large US claims database.

METHODS: Deidentified claims data spanning September 1, 2009 through August 31, 2019 were used. Eligible patients were free of dementia during the 6-year look-back period and≥65 years old by the start of follow-up. Propensity-score matching (PSM) was used to create flu-vaccinated and flu-unvaccinated cohorts with similar baseline demographics, medication usage, and comorbidities. Relative risk (RR) and absolute risk reduction (ARR) were estimated to assess the effect of influenza vaccination on AD risk during the 4-year follow-up.

RESULTS: From the unmatched sample of eligible patients (n = 2,356,479), PSM produced a sample of 935,887 flu-vaccinated-unvaccinated matched pairs. The matched sample was 73.7 (SD, 8.7) years of age and 56.9% female, with median follow-up of 46 (IQR, 29-48) months; 5.1% (n = 47,889) of the flu-vaccinated patients and 8.5% (n = 79,630) of the flu-unvaccinated patients developed AD during follow-up. The RR was 0.60 (95% CI, 0.59-0.61) and ARR was 0.034 (95% CI, 0.033-0.035), corresponding to a number needed to treat of 29.4.

CONCLUSION: This study demonstrates that influenza vaccination is associated with reduced AD risk in a nationwide sample of US adults aged 65 and older.

%B J Alzheimers Dis %V 88 %P 1061-1074 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35723106?dopt=Abstract %R 10.3233/JAD-220361 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Risk of Dementia in Cancer Survivors: A Meta-Analysis of Population-Based Cohort Studies. %A Zhang, Dan-Dan %A Ou, Ya-Nan %A Fu, Yan %A Wang, Zhi-Bo %A Huang, Liang-Yu %A Tan, Lan %A Yu, Jin-Tai %X

BACKGROUND: A negative association between cancer and Alzheimer's disease (AD) was revealed.

OBJECTIVE: We aimed to further explore the dementia risk among cancer survivors and then among cancer survivors who received cancer treatment in subsequent subgroup analyses.

METHODS: Databases of PubMed, Embase, and Cochrane Library were systematically searched from inception to April 1, 2021, following PRISMA and MOOSE guidelines. Relative risks (RR) of dementia were pooled by a random-effects model stratifying the data by potential confounding factors to explore the heterogeneity. This study is registered with PROSPERO, number CRD42021250654.

RESULTS: A total of 36 studies were included in this meta-analysis, of which 16 studies were about the risk of dementia in cancer survivors, and 20 studies were about the risk of dementia in survivors who accepted cancer treatment. The pooled RR reached 0.89 ([95% CI = 0.82-0.97], I2 = 97.9%) for dementia and 0.89 ([0.83-0.95], I2 = 92.6%) for AD in cancer survivors compared with non-cancer controls. Notably, both dementia risk and AD risk significantly decreased in survivors of colon, leukemia, small intestine, and thyroid cancers (RR ranged from 0.64 to 0.92). Furthermore, prostate cancer patients treated with androgen deprivation therapy exhibited a significantly increased risk of dementia (RR:1.18 [1.09-1.27], I2 = 89.5%) and AD (RR:1.17 [1.08-1.25], I2 = 81.3%), with evidence of between-study heterogeneity.

CONCLUSION: Currently, available evidence suggests that the risk of dementia among cancer survivors is decreased. However, large-scale prospective cohort studies are warranted to further prove the association.

%B J Alzheimers Dis %V 89 %P 367-380 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-220436 %0 Journal Article %J J Alzheimers Dis %D 2022 %T The Role of Amyloid, Tau, and APOE Genotype on the Relationship Between Informant-Reported Sleep Disturbance and Alzheimer's Disease Risks. %A Kim, Hyun %A Levine, Alina %A Cohen, Daniel %A Gehrman, Philip %A Zhu, Xi %A Devanand, Davangere P %A Lee, Seonjoo %A Goldberg, Terry E %X

BACKGROUND: The association between sleep and Alzheimer's disease (AD) biomarkers are well-established, but little is known about how they interact to change the course of AD.

OBJECTIVE: To determine the potential interaction between sleep disturbance and Aβ, tau, and APOE4 on brain atrophy and cognitive decline.

METHODS: Sample included 351 participants (mean age 72.01 ± 6.67, 50.4%female) who were followed for approximately 5 years as part of the Alzheimer's Disease Neuroimaging Initiative. Informant-reported sleep disturbance (IRSD) was measured using the Neuropsychiatric Inventory (NPI). Changes in magnetic resonance imaging (MRI)-measured AD signature brain regions and cognitive performance and IRSD's interaction with cerebrospinal fluid amyloid-β (Aβ42) and p-Tau depositions and APOE4 status were examined using the linear mixed models.

RESULTS: Baseline IRSD was not significantly associated with the rate of atrophy after adjusting for covariates (age, sex, education, total NPI severity score, and sleep medications). However, there was a significant interaction between IRSD and AD biomarkers on faster atrophy rates in multiple brain regions, including the cortical and middle temporal volumes. Post-hoc analyses indicated that Aβ and p-Tau/Aβ predicted a faster decline in these regions/domains in IRSD, compared with biomarker-negative individuals with IRSD (ps≤0.001). There was a significant IRSD*APOE4 interaction for brain atrophy rate (ps≤0.02) but not for cognition.

CONCLUSION: IRSD may increase the future risk of AD by contributing to faster brain atrophy and cognitive decline when combined with the presence of AD biomarkers and APOE4. Early intervention for sleep disturbance could help reduce the risk of developing AD.

%B J Alzheimers Dis %V 87 %P 1567-1580 %8 2022 Jun 14 %G eng %N 4 %R 10.3233/JAD-215417 %0 Journal Article %J J Alzheimers Dis %D 2022 %T The Role of Amyloid-β, Tau, and α-Synuclein Proteins as Putative Blood Biomarkers in Patients with Cerebral Amyloid Angiopathy. %A Piccarducci, Rebecca %A Caselli, Maria Chiara %A Zappelli, Elisa %A Ulivi, Leonardo %A Daniele, Simona %A Siciliano, Gabriele %A Ceravolo, Roberto %A Mancuso, Michelangelo %A Baldacci, Filippo %A Martini, Claudia %X

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β protein (Aβ) within brain blood vessels that develops in elderly people and Alzheimer's disease (AD) patients. Therefore, the investigation of biomarkers able to differentiate CAA patients from AD patients and healthy controls (HC) is of great interest, in particular in peripheral fluids.

OBJECTIVE: The current study aimed to detect the neurodegenerative disease (ND)-related protein (i.e., Aβ 1 - 40, Aβ 1 - 42, tau, and α-synuclein) levels in both red blood cells (RBCs) and plasma of CAA patients and HC, evaluating their role as putative peripheral biomarkers for CAA.

METHODS: For this purpose, the proteins' concentration was quantified in RBCs and plasma by homemade immunoenzymatic assays in an exploratory cohort of 20 CAA patients and 20 HC.

RESULTS: The results highlighted a significant increase of Aβ 1 - 40 and α-synuclein concentrations in both RBCs and plasma of CAA patients, while higher Aβ 1 - 42 and t-tau levels were detected only in RBCs of CAA individuals compared to HC. Moreover, Aβ 1 - 42/Aβ 1 - 40 ratio increased in RBCs and decreased in plasma of CAA patients. The role of these proteins as candidate peripheral biomarkers easily measurable with a blood sample in CAA needs to be confirmed in larger studies.

CONCLUSION: In conclusion, we provide evidence concerning the possible use of blood biomarkers for contributing to CAA diagnosis and differentiation from other NDs.

%B J Alzheimers Dis %V 89 %P 1039-1049 %8 2022 Sep 27 %G eng %N 3 %R 10.3233/JAD-220216 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Safety and Efficacy of Monoclonal Antibodies for Alzheimer's Disease: A Systematic Review and Meta-Analysis of Published and Unpublished Clinical Trials. %A Lacorte, Eleonora %A Ancidoni, Antonio %A Zaccaria, Valerio %A Remoli, Giulia %A Tariciotti, Leonardo %A Bellomo, Guido %A Sciancalepore, Francesco %A Corbo, Massimo %A Lombardo, Flavia L %A Bacigalupo, Ilaria %A Canevelli, Marco %A Piscopo, Paola %A Vanacore, Nicola %K Alzheimer Disease %K Amyloid %K Amyloidogenic Proteins %K Amyloidosis %K Antibodies, Monoclonal %K Cognitive Dysfunction %K Humans %X

BACKGROUND: Monoclonal antibodies (mAbs) are currently among the most investigated targets for potential disease-modifying therapies in Alzheimer's disease (AD).

OBJECTIVE: Our objectives were to identify all registered trials investigating mAbs in MCI due to AD or AD at any stage, retrieve available published and unpublished data from all registered trials, and analyze data on safety and efficacy outcomes.

METHODS: A systematic search of all registered trials on ClinicalTrials.gov and EUCT was performed. Available results were searched on both platforms and on PubMed, ISI Web of Knowledge, and The Cochrane Library.

RESULTS: Overall, 101 studies were identified on 27 mAbs. Results were available for 50 trials investigating 12 mAbs. For 18 trials, data were available from both published and unpublished sources, for 21 trials only from published sources, and for 11 trials only from unpublished sources. Meta-analyses of amyloid-related imaging abnormalities (ARIA) events showed overall risk ratios of 10.65 for ARIA-E and of 1.75 for ARIA-H. The meta-analysis of PET-SUVR showed an overall significant effect of mAbs in reducing amyloid (SMD -0.88), but when considering clinical efficacy, data on CDR-SB showed that treated patients had a statistically significant but clinically non-relevant lower worsening (MD -0.15).

CONCLUSION: Our results suggest that the risk-benefit profile of mAbs remains unclear. Research should focus on clarifying the effect of amyloid on cognitive decline, providing data on treatment response rate, and accounting for minimal clinically important difference. Research on mAbs should also investigate the possible long-term impact of ARIA events, including potential factors predicting their onset.

%B J Alzheimers Dis %V 87 %P 101-129 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275549?dopt=Abstract %R 10.3233/JAD-220046 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/MET, Fosgonimeton, in Healthy Volunteers and Subjects with Alzheimer's Disease: Randomized, Placebo-Controlled, Double-Blind, Phase I Clinical Trial. %A Hua, Xue %A Church, Kevin %A Walker, William %A L'Hostis, Philippe %A Viardot, Geoffrey %A Danjou, Philippe %A Hendrix, Suzanne %A Moebius, Hans J %K Aged %K Alzheimer Disease %K Area Under Curve %K Dose-Response Relationship, Drug %K Double-Blind Method %K Healthy Volunteers %K Hepatocyte Growth Factor %K Humans %K Male %X

BACKGROUND: Fosgonimeton (ATH-1017) is being developed as a first-in-class regenerative therapy for people with Alzheimer's disease (AD) and dementia; potentially improving dementia symptoms and altering disease progression by reversing synaptic disconnection and neuronal loss.

OBJECTIVE: This randomized, double-blind, placebo-controlled phase I trial (NCT03298672) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of fosgonimeton.

METHODS: Fosgonimeton was administered once daily via subcutaneous injection to 88 subjects. The single ascending dose study enrolled healthy young male subjects (n = 48; age, 33.4±6.3 years; dose, 2, 6, 20, 40, 60, or 90 mg); the multiple ascending dose study enrolled healthy elderly subjects (n = 29; age, 63.8±4.0 years; dose, 20, 40, 60, or 80 mg; 9-day duration); and the fixed-dose study enrolled AD subjects (n = 11; age, 69.2±7.1 years; dose, 40 mg; 9-day duration). Quantitative electroencephalogram (qEEG) and event-related potential (ERP) P300 measured neurophysiological signals following fosgonimeton treatment, supporting brain penetration and target engagement.

RESULTS: Fosgonimeton and placebo were shown to be safe and well-tolerated across all doses. Pharmacokinetic results for fosgonimeton were dose-proportional, with no sex effect or accumulation over 9 days. The main effect of fosgonimeton on qEEG was acute and sustained gamma power induction. In AD subjects, there was a significant effect toward ERP P300 latency normalization compared with placebo (p = 0.027; n = 7 at 40 mg fosgonimeton versus n = 4 placebo).

CONCLUSION: These results support the continued development of fosgonimeton as a novel therapeutic for people with AD and dementia. The fast-onset normalization of ERP P300 latency in AD subjects suggests enhancement of synaptic function and potential procognitive effects.

%B J Alzheimers Dis %V 86 %P 1399-1413 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35180125?dopt=Abstract %R 10.3233/JAD-215511 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Salivary Proteomics Reveals Significant Changes in Relation to Alzheimer's Disease and Aging. %A Contini, Cristina %A Serrao, Simone %A Manconi, Barbara %A Olianas, Alessandra %A Iavarone, Federica %A Bizzarro, Alessandra %A Masullo, Carlo %A Castagnola, Massimo %A Messana, Irene %A Diaz, Giacomo %A Cabras, Tiziana %X

BACKGROUND: Aging is a risk factor for several pathologies as Alzheimer's disease (AD). Great interest exists, therefore, in discovering diagnostic biomarkers and indicators discriminating biological aging and health status. To this aim, omic investigations of biological matrices, as saliva, whose sampling is easy and non-invasive, offer great potential.

OBJECTIVE: Investigate the salivary proteome through a statistical comparison of the proteomic data by several approaches to highlight quali-/quantitative variations associated specifically either to aging or to AD occurrence, and, thus, able to classify the subjects.

METHODS: Salivary proteomic data of healthy controls under-70 (adults) and over-70 (elderly) years old, and over-70 AD patients, obtained by liquid chromatography/mass spectrometry, were analyzed by multiple Mann-Whitney test, Kendall correlation, and Random-Forest (RF) analysis.

RESULTS: Almost all the investigated proteins/peptides significantly decreased in relation to aging in elderly subjects, with or without AD, in comparison with adults. AD subjects exhibited the highest levels of α-defensins, thymosin β4, cystatin B, S100A8 and A9. Correlation tests also highlighted age/disease associated differences. RF analysis individuated quali-/quantitative variations in 20 components, as oxidized S100A8 and S100A9, α-defensin 3, P-B peptide, able to classify with great accuracy the subjects into the three groups.

CONCLUSION: The findings demonstrated a strong change of the salivary protein profile in relation to the aging. Potential biomarkers candidates of AD were individuated in peptides/proteins involved in antimicrobial defense, innate immune system, inflammation, and in oxidative stress. RF analysis revealed the feasibility of the salivary proteome to discriminate groups of subjects based on age and health status.

%B J Alzheimers Dis %V 89 %P 605-622 %8 2022 Sep 13 %G eng %N 2 %R 10.3233/JAD-220246 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Scavenging Reactive Oxygen Species Decreases Amyloid-β Levels via Activation of PI3K/Akt/GLUT1 Pathway in N2a/APP695swe Cells. %A Peng, Yan %A Zhang, Li %A Zhou, Fanlin %A Wang, Yangyang %A Zhang, Xiong %A Fan, Jianing %A Li, Shijie %A Li, Xiaoju %A Li, Yu %X

BACKGROUND: Dysregulated glucose metabolism in the brain is considered to be one of the key causes of Alzheimer's disease (AD). Abnormal glucose uptake in AD is tightly associated with decreased levels of glucose transporter 1 (GLUT1) and GLUT3 in the brain, but the underlying mechanisms remain unclear.

OBJECTIVE: We aimed to explore the cause and mechanism of impaired glucose uptake in AD.

METHODS: N2a/WT and N2a/APP695swe cells were cultured in vitro, and cellular glucose uptake and ATP content, as well as the expression of GLUT1, GLUT3, and PI3K/Akt pathway members, were detected. Intracellular reactive oxygen species (ROS) levels were detected by flow cytometry. After treatment with the ROS scavenger N-acetyl-L-cysteine (NAC), the above indicators were detected again.

RESULTS: GLUT1 expression was significantly decreased (p = 0.0138) in N2a/APP695swe cells, while GLUT3 expression was no statistical difference (p >  0.05). After NAC treatment, PI3K and Akt phosphorylation levels, GLUT1 expression, glucose uptake and ATP levels were remarkably increased (p = 0.0006, p = 0.0008, p = 0.0009, p = 0.0001, p = 0.0013), while Aβ levels were significantly decreased (p = 0.0058, p = 0.0066). After addition of the PI3K inhibitor LY29004, GLUT1 expression was reduced (p = 0.0008), and Aβ levels were increased (p = 0.0009, p = 0.0117). In addition, increases in glucose uptake and ATP levels induced by the Akt activator SC79 were hindered by the GLUT1 inhibitor WZB117 (p = 0.0002, p = 0.0005). Aβ levels were decreased after SC79 treatment and increased after WZB117 treatment (p = 0.0212, p = 0.0006).

CONCLUSION: Taken together, scavenging of ROS prevents from Aβ deposition via activation of the PI3K/Akt/GLUT1 pathway, and improved the impaired glucose uptake in N2a/APP695swe cells.

%B J Alzheimers Dis %V 90 %P 185-198 %8 2022 Oct 25 %G eng %N 1 %R 10.3233/JAD-220610 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Serum Levels of α-Klotho Are Correlated with Cerebrospinal Fluid Levels and Predict Measures of Cognitive Function. %A Kundu, Payel %A Zimmerman, Benjamin %A Quinn, Joseph F %A Kaye, Jeffrey %A Mattek, Nora %A Westaway, Shawn K %A Raber, Jacob %X

BACKGROUND: α-klotho might play a role in neurodegenerative diseases.

OBJECTIVE: To determine levels of α-klotho and apoE in serum and cerebrospinal fluid (CSF) samples and their relationship with the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR).

METHODS: All subjects were between age 39 to 83+ (n = 94). CDR and MMSE were administered to all participants. CSF was collected in the early afternoon by lumbar puncture.

RESULTS: Serum and CSF levels of α-klotho are positively correlated and both predict scores on the MMSE and CDR, regardless of sex or apoE4 status.

CONCLUSION: Our results demonstrate that α-klotho may be an important biomarker of cognitive health and neurodegeneration, and that relatively non-invasive sampling of α-klotho from serum is likely highly reflective of CSF levels.

%B J Alzheimers Dis %V 86 %P 1471-1481 %8 2022 Apr 05 %G eng %N 3 %R 10.3233/JAD-215719 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Sex Differences in Behavior and Molecular Pathology in the 5XFAD Model. %A Sil, Annesha %A Erfani, Arina %A Lamb, Nicola %A Copland, Rachel %A Riedel, Gernot %A Platt, Bettina %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Disease Models, Animal %K Female %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Pathology, Molecular %K Presenilin-1 %K Sex Characteristics %X

BACKGROUND: The prevalence of Alzheimer's disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD.

OBJECTIVE: Here, we studied behavior and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, versus their wild-type littermate controls, to compare both sex- and genotype-dependent differences.

METHODS: A novel behavioral paradigm was utilized (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and western blotting.

RESULTS: Female 5XFAD mice had higher levels of human APP and amyloid-β and heightened inflammation versus males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with subtle deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance.

CONCLUSION: The impact of sex on AD-relevant phenotypes is in line with human data and emphasizes the necessity of appropriate study design and reporting. Differential molecular profiles observed in male versus female mice offer insights into possible protective mechanisms, and hence treatment strategies.

%B J Alzheimers Dis %V 85 %P 755-778 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864660?dopt=Abstract %R 10.3233/JAD-210523 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Sex-Specific Patterns of Body Mass Index Relationship with White Matter Connectivity. %A Rahmani, Farzaneh %A Wang, Qing %A McKay, Nicole S %A Keefe, Sarah %A Hantler, Nancy %A Hornbeck, Russ %A Wang, Yong %A Hassenstab, Jason %A Schindler, Suzanne %A Xiong, Chengjie %A Morris, John C %A Benzinger, Tammie L S %A Raji, Cyrus A %X

BACKGROUND: Obesity is an increasingly recognized modifiable risk factor for Alzheimer's disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity.

OBJECTIVE: We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity.

METHODS: A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm.

RESULTS: We identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status.

CONCLUSION: BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD.

%B J Alzheimers Dis %V 86 %P 1831-1848 %8 2022 Apr 19 %G eng %N 4 %R 10.3233/JAD-215329 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Shortening of Saccades as a Possible Easy-to-Use Biomarker to Detect Risk of Alzheimer's Disease. %A Hannonen, Sanna %A Andberg, Sami %A Kärkkäinen, Virve %A Rusanen, Minna %A Lehtola, Juha-Matti %A Saari, Toni %A Korhonen, Ville %A Hokkanen, Laura %A Hallikainen, Merja %A Hänninen, Tuomo %A Leinonen, Ville %A Kaarniranta, Kai %A Bednarik, Roman %A Koivisto, Anne M %K Alzheimer Disease %K Biomarkers %K Cognitive Dysfunction %K Humans %K Neuropsychological Tests %K Saccades %X

BACKGROUND: Wide-ranging functional defects in eye movements have been reported in Alzheimer's disease (AD) dementia. The detection of abnormal eye movements and reading problems may identify persons at risk of AD when clear clinical symptoms are lacking.

OBJECTIVE: To examine whether computer-based eye-tracking (ET) analysis of King-Devick (KD) test results differentiates cognitively healthy persons from persons with minor problems in cognitive testing or diagnosed mild AD.

METHODS: We recruited 78 participants (57 non-demented, 21 with mild AD) who underwent neurological examination, the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological test battery (CERAD-NB), and a Clinical Dementia Rating (CDR) interview. The non-demented participants were further divided into control (normal CERAD subtests, mean MMSE = 28) and objective mild cognitive impairment (MCI; decline in at least one CERAD memory score, mean MMSE = 27) groups. The KD reading test was performed using computer-based ET. The total time used for the reading test, errors made, fixation and saccade durations, and saccade amplitudes were analyzed.

RESULTS: We found significant differences between the control, objective MCI, and AD groups in regard to the mean saccade amplitude (3.58, 3.33, and 3.21 ms, respectively, p < 0.03) and duration (27.1, 25.3, and 24.8 ms, respectively, p < 0.05). The KD error scores in the AD group differed significantly (p < 0.01) from the other groups.

CONCLUSION: Computed ET analysis of the KD test may help detect persons with objective MCI early when clear clinical symptoms are lacking. The portable device for ET is easy to use in primary health care memory clinics.

%B J Alzheimers Dis %V 88 %P 609-618 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35662117?dopt=Abstract %R 10.3233/JAD-215551 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Single Nucleus Transcriptome Data from Alzheimer's Disease Mouse Models Yield New Insight into Pathophysiology. %A Weller, Andrew E %A Ferraro, Thomas N %A Doyle, Glenn A %A Reiner, Benjamin C %A Crist, Richard C %A Berrettini, Wade H %X

BACKGROUND: 5XFAD humanized mutant mice and Trem2 knockout (T2KO) mice are two mouse models relevant to the study of Alzheimer's disease (AD)-related pathology.

OBJECTIVE: To determine hippocampal transcriptomic and polyadenylation site usage alterations caused by genetic mutations engineered in 5XFAD and T2KO mice.

METHODS: Employing a publicly available single-nucleus RNA sequencing dataset, we used Seurat and Sierra analytic programs to identify differentially expressed genes (DEGs) and differential transcript usage (DTU), respectively, in hippocampal cell types from each of the two mouse models. We analyzed cell type-specific DEGs further using Ingenuity Pathway Analysis (IPA).

RESULTS: We identified several DEGs in both neuronal and glial cell subtypes in comparisons of wild type (WT) versus 5XFAD and WT versus T2KO mice, including Ttr, Fth1, Pcsk1n, Malat1, Rpl37, Rtn1, Sepw1, Uba52, Mbp, Arl6ip5, Gm26917, Vwa1, and Pgrmc1. We also observed DTU in common between the two comparisons in neuronal and glial subtypes, specifically in the genes Prnp, Rbm4b, Pnisr, Opcml, Cpne7, Adgrb1, Gabarapl2, Ubb, Ndfip1, Car11, and Stmn4. IPA identified 3 statistically significant canonical pathways that appeared in multiple cell types and that overlapped between 5XFAD and T2KO comparisons to WT, including 'FXR/RXR Activation', 'LXR/RXR Activation', and 'Acute Phase Response Signaling'.

CONCLUSION: DEG, DTU, and IPA findings, derived from two different mouse models of AD, highlight the importance of energy imbalance and inflammatory processes in specific hippocampal cell types, including subtypes of neurons and glial cells, in the development of AD-related pathology. Additional studies are needed to further characterize these findings.

%B J Alzheimers Dis %V 90 %P 1233-1247 %8 2022 Nov 22 %G eng %N 3 %R 10.3233/JAD-220391 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Small RNA Sequencing in the Tg4-42 Mouse Model Suggests the Involvement of snoRNAs in the Etiology of Alzheimer's Disease. %A Lio, Chit Tong %A Kacprowski, Tim %A Klaedtke, Maik %A Jensen, Lars R %A Bouter, Yvonne %A Bayer, Thomas A %A Kuss, Andreas W %X

BACKGROUND: The Tg4-42 mouse model for sporadic Alzheimer's disease (AD) has unique features, as the neuronal expression of wild type N-truncated Aβ4-42 induces an AD-typical neurological phenotype in the absence of plaques. It is one of the few models developing neuron death in the CA1 region of the hippocampus. As such, it could serve as a powerful tool for preclinical drug testing and identification of the underlying molecular pathways that drive the pathology of AD.

OBJECTIVE: The aim of this study was to use a differential co-expression analysis approach for analyzing a small RNA sequencing dataset from a well-established murine model in order to identify potentially new players in the etiology of AD.

METHODS: To investigate small nucleolar RNAs in the hippocampus of Tg4-42 mice, we used RNA-Seq data from this particular tissue and, instead of analyzing the data at single gene level, employed differential co-expression analysis, which takes the comparison to gene pair level and thus affords a new angle to the interpretation of these data.

RESULTS: We identified two clusters of differentially correlated small RNAs, including Snord55, Snord57, Snord49a, Snord12, Snord38a, Snord99, Snord87, Mir1981, Mir106b, Mir30d, Mir598, and Mir99b. Interestingly, some of them have been reported to be functionally relevant in AD pathogenesis, as AD biomarkers, regulating tau phosphorylation, TGF-β receptor function or Aβ metabolism.

CONCLUSION: The majority of snoRNAs for which our results suggest a potential role in the etiology of AD were so far not conspicuously implicated in the context of AD pathogenesis and could thus point towards interesting new avenues of research in this field.

%B J Alzheimers Dis %V 87 %P 1671-1681 %8 2022 Jun 14 %G eng %N 4 %R 10.3233/JAD-220110 %0 Journal Article %J J Alzheimers Dis %D 2022 %T The Spectrum of Alzheimer-Type Pathology in Cognitively Normal Individuals. %A Walker, Jamie M %A Dehkordi, Shiva Kazempour %A Schaffert, Jeff %A Goette, William %A White Iii, Charles L %A Richardson, Timothy E %A Zare, Habil %X

BACKGROUND: The strongest risk factor for the development of Alzheimer's disease (AD) is age. The progression of Braak stage and Thal phase with age has been demonstrated. However, prior studies did not include cognitive status.

OBJECTIVE: We set out to define normative values for Alzheimer-type pathologic changes in individuals without cognitive decline, and then define levels that would qualify them to be resistant to or resilient against these changes.

METHODS: Utilizing neuropathology data obtained from the National Alzheimer's Coordinating Center (NACC), we demonstrate the age-related progression of Alzheimer-type pathologic changes in cognitively normal individuals (CDR = 0, n = 542). With plots generated from these data, we establish standard lines that may be utilized to measure the extent to which an individual's Alzheimer-type pathology varies from the estimated normal range of pathology.

RESULTS: Although Braak stage and Thal phase progressively increase with age in cognitively normal individuals, the Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque score and Alzheimer's disease neuropathologic change remain at low levels.

CONCLUSION: These findings suggest that an increasing burden of neuritic plaques is a strong predictor of cognitive decline, whereas, neurofibrillary degeneration and amyloid-β (diffuse) plaque deposition, both to some degree, are normal pathologic changes of aging that occur in almost all individuals regardless of cognitive status. Furthermore, we have defined the amount of neuropathologic change in cognitively normal individuals that would qualify them to be "resilient" against the pathology (significantly above the normative values for age, but still cognitively normal) or "resistant" to the development of pathology (significantly below the normative values for age).

%B J Alzheimers Dis %V 91 %P 683-695 %8 2023 Jan 17 %G eng %N 2 %R 10.3233/JAD-220898 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Subjective Cognitive Decline: Is a Resilient Personality Protective Against Progression to Objective Cognitive Impairment? Findings from Two Community-Based Cohort Studies. %A Aschwanden, Damaris %A Sutin, Angelina R %A Ledermann, Thomas %A Luchetti, Martina %A Stephan, Yannick %A Sesker, Amanda A %A Zhu, Xianghe %A Terracciano, Antonio %X

BACKGROUND: Subjective cognitive decline (SCD) is related to personality functioning and risk of subsequent objective cognitive impairment.

OBJECTIVE: The aim of this study was to examine whether lower neuroticism and higher conscientiousness-resilient personality traits-protect against conversion from SCD to objective cognitive impairment in two longitudinal community-based cohorts.

METHODS: Data from the Health and Retirement Study (N = 1,741, Mean age = 68.64 years, Follow-up mean = 7.34 years) and the National Health and Aging Trends Survey (N = 258, Mean age = 79.34 years, Follow-up mean = 4.31 years) were analyzed using Cox regression analysis, controlling for sociodemographic covariates, symptoms of anxiety and depression, and apolipoprotein ɛ4.

RESULTS: The pooled results showed that lower neuroticism and higher conscientiousness were associated with decreased risk of conversion from SCD to objective cognitive impairment.

CONCLUSION: Among individuals with SCD, those with a resilient personality may have more cognitive and psychological reserve to maintain cognitive functioning and delay conversion to objective cognitive impairment. The findings further contribute to a better understanding of personality along the cognitive continuum: The observed effect sizes were smaller than those reported in cognitively normal individuals but larger than in individuals with mild cognitive impairment. Personality could provide useful information to identify individuals with SCD who may develop objective cognitive impairment-namely those who hold a vulnerable personality (higher neuroticism, lower conscientiousness).

%B J Alzheimers Dis %V 89 %P 87-105 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-220319 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Supplementation With Carotenoids, Omega-3 Fatty Acids, and Vitamin E Has a Positive Effect on the Symptoms and Progression of Alzheimer's Disease. %A Nolan, John M %A Power, Rebecca %A Howard, Alan N %A Bergin, Paula %A Roche, Warren %A Prado-Cabrero, Alfonso %A Pope, George %A Cooke, John %A Power, Tommy %A Mulcahy, Riona %X

BACKGROUND: Preliminary work by our center has reported behavior and functional benefits in patients with Alzheimer's disease (AD) following targeted micronutritional supplementation.

OBJECTIVE: To build on the existing exploratory research and investigate the impact of these micronutrients on the natural progression of AD in a randomized controlled trial.

METHODS: Patients with mild-moderate AD consumed daily 1 g fish oil (of which 500 mg DHA, 150 mg EPA), 22 mg carotenoids (10 mg lutein, 10 mg meso-zeaxanthin, 2 mg zeaxanthin), and 15 mg vitamin E or placebo for 12 months in a double-blind, placebo-controlled, randomized clinical trial. Carotenoids, ω-3FAs, and vitamin E were quantified in blood. Carotenoids were also measured in skin. AD severity was measured using the mini-mental state examination and dementia severity rating scale tools. Behavior, mood, and memory were measured using an informant-based questionnaire.

RESULTS: Following 12 months of supplementation, the active group (n = 50) compared to the placebo group (n = 27), demonstrated statistically significant improvements in skin carotenoid measurements, blood carotenoids, ω-3FAs, and vitamin E concentrations (p <  0.05, for all). The active group also performed better in objective measures of AD severity (i.e., memory and mood), with a statistically significant difference reported in the clinical collateral for memory (p <  0.001).

CONCLUSION: Exponential increases in the prevalence of AD and its relentless progressive nature is driving the need for interventions that help to ameliorate symptoms and improve quality of life in AD patients. Given the positive outcomes demonstrated in this trial, this combined micronutrient dietary supplement should be considered in the overall management of AD.

%B J Alzheimers Dis %V 90 %P 233-249 %8 2022 Oct 25 %G eng %N 1 %R 10.3233/JAD-220556 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Systemic Injection of Aged Blood Plasma in Adult C57BL/6 Mice Induces Neurophysiological Impairments in the Hippocampal CA1. %A Huffels, Christiaan F M %A van Dijk, Roland E %A Karst, Henk %A Meye, Frank J %A Hol, Elly M %A Middeldorp, Jinte %X

BACKGROUND: Aging is characterized by systemic alterations and forms an important risk factor for Alzheimer's disease. Recently, it has been indicated that blood-borne factors present in the systemic milieu contribute to the aging process. Exposing young mice to aged blood plasma results in impaired neurogenesis and synaptic plasticity in the dentate gyrus, as well as impaired cognition. Vice versa, treating aged mice with young blood plasma rescues impairments associated with aging.

OBJECTIVE: Whether blood-borne factors are sufficient to drive impairments outside the dentate gyrus, how they impact neurophysiology, and how the functional outcome compares to impairments found in mouse models for AD is still unclear.

METHODS: Here, we treated adult mice with blood plasma from aged mice and assessed neurophysiological parameters in the hippocampal CA1.

RESULTS: Mice treated with aged blood plasma show significantly impaired levels of long-term potentiation (LTP), similar to those present in APP/PS1 mice. These impaired levels of LTP in plasma-treated mice are associated with alterations in basic properties of glutamatergic transmission and the enhanced activity of voltage-gated Ca2 + channels.

CONCLUSION: Together, the data presented in this study show that blood-borne factors are sufficient to drive neurophysiological impairments in the hippocampal CA1.

%B J Alzheimers Dis %V 89 %P 283-297 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-220337 %0 Journal Article %J J Alzheimers Dis %D 2022 %T A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer's Disease. %A Lynn, Jessica %A Park, Mingi %A Ogunwale, Christiana %A Acquaah-Mensah, George K %K Alzheimer Disease %K Animals %K Biomarkers %K Brain Chemistry %K Cognitive Dysfunction %K Diabetes Mellitus, Type 2 %K Glucose %K Glycation End Products, Advanced %K Humans %K Inflammation %K Insulin Resistance %K Oxidative Stress %K Randomized Controlled Trials as Topic %X

Dementias, including the type associated with Alzheimer's disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as "type 3 diabetes". In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3β, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities.

%B J Alzheimers Dis %V 85 %P 485-501 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34842187?dopt=Abstract %R 10.3233/JAD-210612 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer's Disease Model Mice. %A Eastman, Guillermo %A Sharlow, Elizabeth R %A Lazo, John S %A Bloom, George S %A Sotelo-Silveira, José R %X

BACKGROUND: Defining cellular mechanisms that drive Alzheimer's disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD.

OBJECTIVE: To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2 -/- ) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling).

METHODS: Identical starting pools of bulk RNA were used for RNA-Seq and Ribo-Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels. Regulated genes were functionally evaluated by gene ontology tools.

RESULTS: Compared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to AβPP metabolism associated with neurotoxicity and neuroprotection.

CONCLUSION: This work represents the first genome-wide study of brain translatome regulation in animal models of AD and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain.

%B J Alzheimers Dis %V 86 %P 365-386 %8 2022 Mar 08 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35034904?dopt=Abstract %R 10.3233/JAD-215357 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Traumatic Brain Injury and Risk of Alzheimer's Disease and Related Dementias in the Population. %A Mielke, Michelle M %A Ransom, Jeanine E %A Mandrekar, Jay %A Turcano, Pierpaolo %A Savica, Rodolfo %A Brown, Allen W %X

BACKGROUND: Epidemiological studies examining associations between traumatic brain injury (TBI) and Alzheimer's disease and related dementias (ADRD) have yielded conflicting results, which may be due methodological differences.

OBJECTIVE: To examine the relationship between the presence and severity of TBI and risk of ADRD using a population-based cohort with medical record abstraction for confirmation of TBI and ADRD.

METHODS: All TBI events among Olmsted County, Minnesota residents aged >  40 years from 1985-1999 were confirmed by manual review and classified by severity. Each TBI case was randomly matched to two age-, sex-, and non-head injury population-based referents without TBI. For TBI events with non-head trauma, the Trauma Mortality Prediction Model was applied to assign an overall measure of non-head injury severity and corresponding referents were matched on this variable. Medical records were manually abstracted to confirm ADRD diagnosis. Cox proportional hazards models examined the relationship between TBI and severity with risk of ADRD.

RESULTS: A total of 1,418 residents had a confirmed TBI (865 Possible, 450 Probable, and 103 Definite) and were matched to 2,836 referents. When combining all TBI severities, the risk of any ADRD was significantly higher for those with a confirmed TBI compared to referents (HR = 1.32, 95% CI: 1.11, 1.58). Stratifying by TBI severity, Probable (HR = 1.42, 95% CI: 1.05, 1.92) and Possible (HR = 1.29, 95% CI: 1.02-1.62) TBI was associated with an increased risk of ADRD, but not Definite TBI (HR = 1.22, 95% CI: 0.68, 2.18).

CONCLUSION: Our analyses support including TBI as a potential risk factor for developing ADRD.

%B J Alzheimers Dis %V 88 %P 1049-1059 %8 2022 Aug 02 %G eng %N 3 %R 10.3233/JAD-220159 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Undiagnosed Dementia Is Associated with Poor Physical Function in Older Adults. %A McGrath, Ryan %A Robinson-Lane, Sheria G %A Klawitter, Lukus %A Rhee, Yeong %A Hamm, Jeremy M %A McCourt, Mark E %A Parker, Kelly %A Hackney, Kyle J %X

BACKGROUND: Older adults with a cognitive impairment, including those not yet diagnosed, may have deficits in their physical function.

OBJECTIVE: We sought to determine the associations of cognitive impairment consistent with dementia (CICD) diagnosis status on handgrip strength, gait speed, and functional disability in older adults.

METHODS: The analytical sample included 8,383 adults aged ≥65-years without history of stroke, cancers, neurological conditions, or brain damage who participated in at least one-wave of the 2010-2016 waves of the Health and Retirement Study. A handgrip dynamometer measured handgrip strength. Men with handgrip strength

RESULTS: Persons with undiagnosed CICD had 1.37 (95% confidence interval (CI): 1.04-1.80) greater odds for weakness and 2.02 (CI: 1.39-2.94) greater odds for slow gait speed. Older adults with diagnosed CICD had 2.29 (CI: 1.32-3.97) greater odds for slowness and 1.85 (CI: 1.19-2.90) greater odds for functional disability.

CONCLUSION: Screening for CICD could be recommended when defects in physical function are observed in older adults.

%B J Alzheimers Dis %V 89 %P 473-482 %8 2022 Sep 13 %G eng %N 2 %R 10.3233/JAD-220257 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Visually Identified Tau 18F-MK6240 PET Patterns in Symptomatic Alzheimer's Disease. %A Krishnadas, Natasha %A Huang, Kun %A Schultz, Stephanie A %A Doré, Vincent %A Bourgeat, Pierrick %A Goh, Anita M Y %A Lamb, Fiona %A Bozinovski, Svetlana %A Burnham, Samantha C %A Robertson, Joanne S %A Laws, Simon M %A Maruff, Paul %A Masters, Colin L %A Villemagne, Victor L %A Rowe, Christopher C %X

BACKGROUND: In Alzheimer's disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice.

OBJECTIVE: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles.

METHODS: Tau 18F-MK6240 PET images of 151 amyloid-β positive participants with mild cognitive impairment (MCI) and dementia were visually rated as: tau negative, limbic predominant (LP), MTL-sparing, and Typical by two readers. Groups were evaluated for differences in age, APOE ɛ4 carriage, hippocampal volumes, and cognition (MMSE, composite memory and non-memory scores). Voxel-wise contrasts were also performed.

RESULTS: Visual rating resulted in 59.6% classified as Typical, 17.9% as MTL-sparing, 9.9% LP, and 12.6% as tau negative. Intra-rater and inter-rater reliability was strong (Cohen's kappa values of 0.89 and 0.86 respectively). Tracer retention in a "hook"-like distribution on sagittal sequences was observed in the LP and Typical groups. The visually classified MTL-sparing group had lower APOE ɛ4 carriage and relatively preserved hippocampal volumes. Higher MTL tau was associated with greater amnestic cognitive impairment. High cortical tau was associated with greater impairments on non-memory domains of cognition, and individuals with high cortical tau were more likely to have dementia than MCI.

CONCLUSION: Tau distribution patterns can be visually identified using 18F-MK6240 PET and are associated with differences in APOE ɛ4 carriage, hippocampal volumes, and cognition.

%B J Alzheimers Dis %V 88 %P 1627-1637 %8 2022 Aug 16 %G eng %N 4 %R 10.3233/JAD-215558 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Weight Loss and Alzheimer's Disease in Down Syndrome. %A Fleming, Victoria %A Helsel, Brian C %A Ptomey, Lauren T %A Rosas, H Diana %A Handen, Benjamin %A Laymon, Charles %A Christian, Bradley T %A Head, Elizabeth %A Mapstone, Mark %A Lai, Florence %A Krinsky-McHale, Sharon %A Zaman, Shahid %A Ances, Beau M %A Lee, Joseph H %A Hartley, Sigan L %X

BACKGROUND: Virtually all adults with Down syndrome (DS) develop Alzheimer's disease (AD) pathology, but research gaps remain in understanding early signs of AD in DS.

OBJECTIVE: The goal of the present study was to determine if unintentional weight loss is part of AD in DS. The specific aims were to: 1) examine relation between chronological age, weight, AD pathology, and AD-related cognitive decline were assessed in a large cohort of adults with DS, and 2) determine if baseline PET amyloid-β (Aβ) and tau PET status (-versus+) and/or decline in memory and mental status were associated with weight loss prior to AD progression.

METHODS: Analyses included 261 adults with DS. PET data were acquired using [11C] PiB for Aβ and [18F] AV-1451 for tau. Body mass index (BMI) was calculated from weight and height. Direct measures assessed dementia and memory. Clinical AD status was determined using a case consensus process. Percent weight decline across 16-20 months was assessed in a subset of participants (n = 77).

RESULTS: Polynomial regressions indicated an 0.23 kg/m2 decrease in BMI per year beginning at age 36.5 years, which occurs alongside the period during which Aβ and tau increase and memory and mental status decline. At a within-person level, elevated Aβ, decline in memory and mental status were associated with higher percent weight loss across 16-20 months.

CONCLUSION: Unintentional weight loss occurs alongside Aβ deposition and prior to onset of AD dementia, and thus may be a useful sign of AD in DS.

%B J Alzheimers Dis %V 91 %P 1215-1227 %8 2023 Jan 31 %G eng %N 3 %R 10.3233/JAD-220865 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Yoga Prevents Gray Matter Atrophy in Women at Risk for Alzheimer's Disease: A Randomized Controlled Trial. %A Krause-Sorio, Beatrix %A Siddarth, Prabha %A Kilpatrick, Lisa %A Milillo, Michaela M %A Aguilar-Faustino, Yesenia %A Ercoli, Linda %A Narr, Katherine L %A Khalsa, Dharma S %A Lavretsky, Helen %X

BACKGROUND: Female sex, subjective cognitive decline (SCD), and cardiovascular risk factors (CVRFs) are known risk factors for developing Alzheimer's disease (AD). We previously demonstrated that yoga improved depression, resilience, memory and executive functions, increased hippocampal choline concentrations, and modulated brain connectivity in older adults with mild cognitive impairment.

OBJECTIVE: In this study (NCT03503669), we investigated brain gray matter volume (GMV) changes in older women with SCD and CVRFs following three months of yoga compared to memory enhancement training (MET).

METHODS: Eleven women (mean age = 61.45, SD = 6.58) with CVRF and SCD completed twelve weeks of Kundalini Yoga and Kirtan Kriya (KY + KK) while eleven women (mean age = 64.55, SD = 6.41) underwent MET. Anxiety, resilience, stress, and depression were assessed at baseline and 12 weeks, as were T1-weighted MRI scans (Siemens 3T Prisma scanner). We used Freesurfer 6.0 and tested group differences in GMV change, applying Monte-Carlo simulations with alpha = 0.05. Region-of-interest analysis was performed for hippocampus and amygdala.

RESULTS: Compared to KY + KK, MET showed reductions in GMV in left prefrontal, pre- and post-central, supramarginal, superior temporal and pericalcarine cortices, right paracentral, postcentral, superior and inferior parietal cortices, the banks of the superior temporal sulcus, and the pars opercularis. Right hippocampal volume increased after yoga but did not survive corrections.

CONCLUSION: Yoga training may offer neuroprotective effects compared to MET in preventing neurodegenerative changes and cognitive decline, even over short time intervals. Future analyses will address changes in functional connectivity in both groups.

%B J Alzheimers Dis %V 87 %P 569-581 %8 2022 May 17 %G eng %N 2 %R 10.3233/JAD-215563 %0 Journal Article %J J Alzheimers Dis %D 2022 %T α-Lipoic Acid Has the Potential to Normalize Copper Metabolism, Which Is Dysregulated in Alzheimer's Disease. %A Metsla, Kristel %A Kirss, Sigrid %A Laks, Katrina %A Sildnik, Gertrud %A Palgi, Mari %A Palumaa, Teele %A Tõugu, Vello %A Palumaa, Peep %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Aspartic Acid Endopeptidases %K Brain %K Cell Line %K Copper %K Disease Models, Animal %K Drosophila melanogaster %K Humans %K Neurons %K Thioctic Acid %X

BACKGROUND: Alzheimer's disease (AD) is an age-dependent progressive neurodegenerative disorder and the most common cause of dementia. The treatment and prevention of AD present immense yet unmet needs. One of the hallmarks of AD is the formation of extracellular amyloid plaques in the brain, composed of amyloid-β (Aβ) peptides. Besides major amyloid-targeting approach there is the necessity to focus also on alternative therapeutic strategies. One factor contributing to the development of AD is dysregulated copper metabolism, reflected in the intracellular copper deficit and excess of extracellular copper.

OBJECTIVE: In the current study, we follow the widely accepted hypothesis that the normalization of copper metabolism leads to the prevention or slowing of the disease and search for new copper-regulating ligands.

METHODS: We used cell culture, ICP MS, and Drosophila melanogaster models of AD.

RESULTS: We demonstrate that the natural intracellular copper chelator, α-lipoic acid (LA) translocates copper from extracellular to intracellular space in an SH-SY5Y-based neuronal cell model and is thus suitable to alleviate the intracellular copper deficit characteristic of AD neurons. Furthermore, we show that supplementation with LA protects the Drosophila melanogaster models of AD from developing AD phenotype by improving locomotor activity of fruit fly with overexpression of human Aβ with Iowa mutation in the fly brain. In addition, LA slightly weakens copper-induced smooth eye phenotype when amyloid-β protein precursor (AβPP) and beta-site AβPP cleaving enzyme 1 (BACE1) are overexpressed in eye photoreceptor cells.

CONCLUSION: Collectively, these results provide evidence that LA has the potential to normalize copper metabolism in AD.

%B J Alzheimers Dis %V 85 %P 715-728 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864665?dopt=Abstract %R 10.3233/JAD-215026 %0 Journal Article %J J Alzheimers Dis %D 2021 %T 40 Hz Light Flicker Promotes Learning and Memory via Long Term Depression in Wild-Type Mice. %A Tian, Tian %A Qin, Xin %A Wang, Yali %A Shi, Yan %A Yang, Xin %X

BACKGROUND: 40 Hz light flicker is a well-known non-invasive treatment that is thought to be effective in treating Alzheimer's disease. However, the effects of 40 Hz visual stimulation on neural networks, synaptic plasticity, and learning and memory in wild-type animals remain unclear.

OBJECTIVE: We aimed to explore the impact of 40 Hz visual stimulation on synaptic plasticity, place cell, and learning and memory in wild-type mice.

METHODS: c-Fos+ cell distribution and in vivo electrophysiology was used to explore the effects of 40 Hz chronic visual stimulation on neural networks and neuroplasticity in wild-type mice. The character of c-Fos+ distribution in the brain and the changes of corticosterone levels in the blood were used to investigate the state of animal. Place cell analysis and novel location test were utilized to examine the effects of 40 Hz chronic visual stimulation on learning and memory in wild-type mice.

RESULTS: We found that 40 Hz light flicker significantly affected many brain regions that are related to stress. Also, 40 Hz induced gamma enrichment within 15 min after light flickers and impaired the expression of long-term potentiation (LTP), while facilitated the expression of long-term depression (LTD) in the hippocampal CA1. Furthermore, 40 Hz light flicker enhanced the expression of corticosterone, rendered well-formed place cells unstable and improved animal's learning and memory in novel local recognition test, which could be blocked by pre-treatment with the LTD specific blocker Glu2A-3Y.

CONCLUSION: These finding suggested that 40 Hz chronic light flicker contains stress effects, promoting learning and memory in wild-type mice via LTD.

%B J Alzheimers Dis %V 84 %P 983-993 %8 2021 Nov 23 %G eng %N 3 %R 10.3233/JAD-215212 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Accelerometer-Measured, Habitual Physical Activity and Circulating Brain-Derived Neurotrophic Factor: A Cross-Sectional Study. %A Spartano, Nicole L %A Himali, Jayandra J %A Trinquart, Ludovic %A Yang, Qiong %A Weinstein, Galit %A Satizabal, Claudia L %A Dukes, Kimberly A %A Beiser, Alexa S %A Murabito, Joanne M %A Vasan, Ramachandran S %A Seshadri, Sudha %X

BACKGROUND: One of the mechanisms suggested to link physical activity (PA) to favorable brain health is through stimulation of neural growth factors such as brain-derived neurotrophic factor (BDNF). Acute bouts of PA stimulate circulating BDNF levels.

OBJECTIVE: In this investigation, we assessed whether habitual, accelerometer-measured PA levels were related to circulating BDNF levels in a middle-aged cohort.

METHODS: In the Framingham Heart Study Third Generation cohort, 1,769 participants provided reliable accelerometry data and were not missing BDNF measurement and platelet counts. In a cross-sectional analysis, using multivariable regression, we related PA measures to serum BDNF levels, adjusting for age, sex, smoking status, platelet count, depression status, and accelerometer wear time.

RESULTS: Our study participants (mean age 47±9 years, 50.8% women) spent an average of 22.3 mins/day moderate-to-vigorous (MV)PA. Most PA variables (steps, MVPA, light activity, and sedentary time) were not related to BDNF levels (p > 0.05). We observed a non-linear trend, where 15-50 mins/week vigorous activity was associated with lower BDNF compared to those with 0 min vigorous activity (β= -0.049±0.024, p = 0.05), but with no significant associations at lower or higher vigorous activity levels. In smokers, MVPA was also associated with lower BDNF levels (β= -0.216±0.079, p = 0.01).

CONCLUSION: Our study reveals that circulating BDNF is not chronically elevated in individuals with higher levels of habitual PA in middle-aged adults from the community and may even be chronically suppressed with higher PA in subgroups, including current smokers. These results do not contradict previous studies demonstrating that circulating BDNF rises acutely after PA.

%B J Alzheimers Dis %V 85 %P 805-814 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-215109 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Is Acculturation Associated with the Cognitive Performance of Older Hispanics? %A Alam, Rifat B %A Singleton, Chelsea R %A Aguiñaga, Susan %A Chodzko-Zajko, Wojtek %A Jahan, Nilufer A %A Oke, Adeyosola %A Schwingel, Andiara %X

BACKGROUND: Hispanics in the United Statues are disproportionately affected by Alzheimer's disease and related dementias. Little is known about the impact of acculturation on cognitive performance.

OBJECTIVE: This study examined the association between acculturation and cognitive performance among older Hispanics.

METHODS: We analyzed cross-sectional data of 616 Hispanic participants in the National Health and Nutrition Examination Survey (NHANES) 2011-2014 [average age = 67.15 years, %Female = 51.46, %less than high-school graduate = 52.60]. Cognitive performance was measured by two neuropsychological tests: Animal Fluency Test (AFT) and Digit Symbol Substitution Test (DSST). We used two single-item proxy measures to quantify acculturation: nativity status (non-US-born residing <  15 years in the US (low acculturation), non-US-born residing ≥15 years in the US, and US-born (high acculturation)); and language acculturation (only/mostly Spanish (low acculturation), Spanish and English, only/mostly English (high acculturation)). We used adjusted linear regression to evaluate associations between acculturation and cognitive performance.

RESULTS: Results indicated poorer cognitive performance among the low-acculturated groups for both nativity and linguistic measures. Participants who were non-US-born living ≥15 years (p = 0.02) and speaking only/mostly Spanish or Spanish and English (p = 0.01 and 0.006 respectively) had significantly lower AFT scores compared to US-born and only/mostly English-speaking groups. Participants who were non-US-born living <  15 years (p <  0.0001) or non-US-born living ≥15 years (p <  0.0001) and speaking only/mostly Spanish (p = 0.0008) scored lower on the DSST than the US-born and only/mostly English-speaking participants.

CONCLUSION: In summary, low acculturation is associated with poorer cognitive performance among older Hispanics. Acculturation might be an important attribute to help understand cognitive decline and dementias among Hispanics.

%B J Alzheimers Dis %V 85 %P 535-544 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-210502 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Acute Exercise and Cognitive Function in Alzheimer's Disease. %A Ben Ayed, Ines %A Castor-Guyonvarch, Naomie %A Amimour, Souad %A Naija, Salma %A Aouichaoui, Chirine %A Ben Omor, Sana %A Tabka, Zouhair %A El Massioui, Farid %X

BACKGROUND: Many studies have shown the impact of acute aerobic exercises (AAE) on cognition in healthy adults or at a pre-dementia stage. Few studies, however, have explored the positive effects of AAE in moderate Alzheimer's disease (ADM) patients.

OBJECTIVE: Evaluating the effect of AAE on cognitive functions in ADM patients.

METHODS: Overall, 79 (age: 69.62±0.99) ADM patients were recruited. Participants were divided into three groups according to the task: aerobic exercises done alone or combined with cognitive games presented on a screen, and a control group who performed a reading task. The aerobic exercise protocol consisted of a 20-min cycling exercise of moderate intensity, corresponding to 60%of the individual target maximal heart rate recorded in a 6-minute walking test. The participants' cognition was monitored before and after the intervention using the Tower of Hanoi, Digit Span, and Stroop tasks.

RESULTS: After the exercise, the participants' attention in both the physical and combined groups improved for the Stroop, the forward and backward Digit Span tasks, as well as the time taken to solve the Tower of Hanoi, although no significant differences were found in the number of moves taken in the latter. By contrast, the control group did not show any significant improvement for most of the cognitive tasks after the reading session.

CONCLUSION: Current evidence suggests that AAE may help to improve cognitive functions in ADM patients. This improvement is enhanced when the exercise is combined with cognitive games. Safe and progressive types of exercises should be promoted among ADM patients.

%B J Alzheimers Dis %V 82 %P 749-760 %8 2021 Jul 20 %G eng %N 2 %R 10.3233/JAD-201317 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Alzheimer's Disease and Face Masks in Times of COVID-19. %A Gil, Roger %A Arroyo-Anlló, Eva M %K Alzheimer Disease %K Communicable Disease Control %K COVID-19 %K Emotions %K Facial Expression %K Humans %K Masks %X

Generalized lockdown caused by COVID-19, necessary yesterday, can no longer be that of tomorrow. It will no longer be possible to cram the humblest into cramped areas, but priority must be given to prevention (certainly with physical barriers, hydro-alcoholic gel, face masks), biological diagnosis, isolation, and also the care of any infected person. COVID-19 has hit the most vulnerable first in terms of biological inequality, such as Alzheimer's disease (AD) patients. Those with AD can have sensorial deficits and perception troubles, including visual difficulties and the inability to recognize faces and emotions. Face masks and physical distancing can disrupt facial familiarity and make it more difficult to recognize emotional facial expressions. It can provoke distress, which the visitor can perceive and feel obligated to take off the face mask. This gesture should not be considered as an act of indiscipline, but an act of empathy. Transparent face masks could improve the suffering of AD patients, distraught in the presence of their loved ones whose masks hide their faces. Wearing a mask should not be due to fear of punishment, but as an understanding of the responsibility of each individual in the control of the current pandemic. It may be necessary to convince more citizens of this civic duty, using clear and attractive messaging in order to standardize the wearing of face masks for the general public and to adapt them to the needs of patients.

%B J Alzheimers Dis %V 79 %P 9-14 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33252083?dopt=Abstract %R 10.3233/JAD-201233 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Alzheimer's Disease-Related Neuropathology Among Patients with Medication Treated Type 2 Diabetes in a Community-Based Autopsy Cohort. %A Barthold, Douglas %A Gibbons, Laura E %A Marcum, Zachary A %A Gray, Shelly L %A Dirk Keene, C %A Grabowski, Thomas J %A Postupna, Nadia %A Larson, Eric B %A Crane, Paul K %X

BACKGROUND: Diabetes is a risk factor for Alzheimer's disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC).

OBJECTIVE: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications.

METHODS: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N = 118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ 1-42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index.

RESULTS: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ 1-42 (-0.57 (CI: -1.12, -0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ 1-42 compared to nonusers (-0.15 (CI: -0.28, -0.02), -0.31 (CI: -0.54, -0.07), respectively).

CONCLUSION: Some evidence exists that diabetes medications are associated with lower levels of Aβ 1-42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.

%B J Alzheimers Dis %V 83 %P 1303-1312 %8 2021 Sep 28 %G eng %N 3 %R 10.3233/JAD-210059 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Amyloid Deposition Is Greater in Cerebral Gyri than in Cerebral Sulci with Worsening Clinical Diagnosis Across the Alzheimer's Disease Spectrum. %A Walden, Lucas M %A Hu, Song %A Madabhushi, Anant %A Prescott, Jeffrey W %X

BACKGROUND: Histopathologic studies have demonstrated differential amyloid-β (Aβ) burden between cortical sulci and gyri in Alzheimer's disease (AD), with sulci having a greater Aβ burden.

OBJECTIVE: To characterize Aβ deposition in the sulci and gyri of the cerebral cortex in vivo among subjects with normal cognition (NC), mild cognitive impairment (MCI), and AD, and to evaluate if these differences could improve discrimination between diagnostic groups.

METHODS: T1-weighted 3T MR and florbetapir (amyloid) positron emission tomography (PET) data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). T1 images were segmented and the cortex was separated into sulci/gyri based on pial surface curvature measurements. T1 images were registered to PET images and regional standardized uptake value ratios (SUVr) were calculated. A linear mixed effects model was used to analyze the relationship between clinical variables and amyloid PET SUVr measurements in the sulci/gyri. Receiver operating characteristic (ROC) analysis was performed to define amyloid positivity. Logistic models were used to evaluate predictive performance of clinical diagnosis using amyloid PET SUVr measurements in sulci/gyri.

RESULTS: 719 subjects were included: 272 NC, 315 MCI, and 132 AD. Gyral and sulcal Aβ increased with worsening cognition, however there was a greater increase in gyral Aβ. Females had a greater gyral and sulcal Aβ burden. Focusing on sulcal and gyral Aβ did not improve predictive power for diagnostic groups.

CONCLUSION: While there were significant differences in Aβ deposition in cerebral sulci and gyri across the AD spectrum, these differences did not translate into improved prediction of diagnosis. Females were found to have greater gyral and sulcal Aβ burden.

%B J Alzheimers Dis %V 83 %P 423-433 %8 2021 Aug 31 %G eng %N 1 %R 10.3233/JAD-210308 %0 Journal Article %J J Alzheimers Dis %D 2021 %T ANMerge: A Comprehensive and Accessible Alzheimer's Disease Patient-Level Dataset. %A Birkenbihl, Colin %A Westwood, Sarah %A Shi, Liu %A Nevado-Holgado, Alejo %A Westman, Eric %A Lovestone, Simon %A Hofmann-Apitius, Martin %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cohort Studies %K Datasets as Topic %K Female %K Gene Expression Profiling %K Genotype %K Humans %K Magnetic Resonance Imaging %K Male %K Proteomics %X

BACKGROUND: Accessible datasets are of fundamental importance to the advancement of Alzheimer's disease (AD) research. The AddNeuroMed consortium conducted a longitudinal observational cohort study with the aim to discover AD biomarkers. During this study, a broad selection of data modalities was measured including clinical assessments, magnetic resonance imaging, genotyping, transcriptomic profiling, and blood plasma proteomics. Some of the collected data were shared with third-party researchers. However, this data was incomplete, erroneous, and lacking in interoperability.

OBJECTIVE: To provide the research community with an accessible, multimodal, patient-level AD cohort dataset.

METHODS: We systematically addressed several limitations of the originally shared resources and provided additional unreleased data to enhance the dataset.

RESULTS: In this work, we publish and describe ANMerge, a new version of the AddNeuroMed dataset. ANMerge includes multimodal data from 1,702 study participants and is accessible to the research community via a centralized portal.

CONCLUSION: ANMerge is an information rich patient-level data resource that can serve as a discovery and validation cohort for data-driven AD research, such as, for example, machine learning and artificial intelligence approaches.

%B J Alzheimers Dis %V 79 %P 423-431 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33285634?dopt=Abstract %R 10.3233/JAD-200948 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Anti-Aβ Antibody Aducanumab Regulates the Proteome of Senile Plaques and Closely Surrounding Tissue in a Transgenic Mouse Model of Alzheimer's Disease. %A Bastrup, Joakim %A Hansen, Kathrine H %A Poulsen, Thomas B G %A Kastaniegaard, Kenneth %A Asuni, Ayodeji A %A Christensen, Søren %A Belling, Dorthe %A Helboe, Lone %A Stensballe, Allan %A Volbracht, Christiane %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Antibodies, Monoclonal, Humanized %K Brain %K Chromatography, Liquid %K Cytoskeletal Proteins %K Disease Models, Animal %K Humans %K Mice %K Mice, Transgenic %K Mitochondrial Proteins %K Plaque, Amyloid %K Presenilin-1 %K Protein Transport %K Proteome %K Proteomics %K Stress, Physiological %K Tandem Mass Spectrometry %X

BACKGROUND: Alzheimer's disease (AD) is characterized by accumulation of amyloid-β (Aβ) species and deposition of senile plaques (SPs). Clinical trials with the anti-Aβ antibody aducanumab have been completed recently.

OBJECTIVE: To characterize the proteomic profile of SPs and surrounding tissue in a mouse model of AD in 10-month-old tgAPPPS1-21 mice after chronic treatment with aducanumab for four months with weekly dosing (10 mg/kg).

METHODS: After observing significant reduction of SP numbers in hippocampi of aducanumab-treated mice, we applied a localized proteomic analysis by combining laser microdissection and liquid chromatography-tandem mass spectrometry (LC-MS/MS) of the remaining SPs in hippocampi. We microdissected three subregions, containing SPs, SP penumbra level 1, and an additional penumbra level 2 to follow the proteomic profile as gradient.

RESULTS: In the aducanumab-treated mice, we identified 17 significantly regulated proteins that were associated with 1) mitochondria and metabolism (ACAT2, ATP5J, ETFA, EXOG, HK1, NDUFA4, NDUFS7, PLCB1, PPP2R4), 2) cytoskeleton and axons (ADD1, CAPZB, DPYSL3, MAG), 3) stress response (HIST1H1C/HIST1H1D, HSPA12A), and 4) AβPP trafficking/processing (CD81, GDI2). These pathways and some of the identified proteins are implicated in AD pathogenesis. Proteins associated with mitochondria and metabolism were mainly upregulated while proteins associated with AβPP trafficking/processing and stress response pathways were mainly downregulated, suggesting that aducanumab could lead to a beneficial proteomic profile around SPs in tgAPPPS1-21 mice.

CONCLUSION: We identified novel proteomic patterns of SPs and surrounding tissue indicating that chronic treatment with aducanumab could inhibit Aβ toxicity and increase phagocytosis and cell viability.

%B J Alzheimers Dis %V 79 %P 249-265 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33252074?dopt=Abstract %R 10.3233/JAD-200715 %0 Journal Article %J J Alzheimers Dis %D 2021 %T APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid. %A Berger, Miles %A Cooter, Mary %A Roesler, Alexander S %A Chung, Stacey %A Park, John %A Modliszewski, Jennifer L %A VanDusen, Keith W %A Thompson, J Will %A Moseley, Arthur %A Devinney, Michael J %A Smani, Shayan %A Hall, Ashley %A Cai, Victor %A Browndyke, Jeffrey N %A Lutz, Michael W %A Corcoran, David L %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Biomarkers %K Chitinase-3-Like Protein 1 %K DNA Copy Number Variations %K Female %K Fructose-Bisphosphate Aldolase %K Humans %K Male %K Proteomics %K Receptors, Immunologic %X

BACKGROUND: APOE4 has been hypothesized to increase Alzheimer's disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear.

OBJECTIVE: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number.

METHODS: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction.

RESULTS: Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q < 0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q < 0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million.

CONCLUSION: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

%B J Alzheimers Dis %V 79 %P 511-530 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33337362?dopt=Abstract %R 10.3233/JAD-200747 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Apolipoprotein E ɛ4 (APOE ɛ4) Allele is Associated with Long Sleep Duration Among Elderly with Cognitive Impairment. %A Basta, Maria %A Zaganas, Ioannis %A Simos, Panagiotis %A Koutentaki, Eirini %A Dimovasili, Christina %A Mathioudakis, Lambros %A Bourbouli, Mara %A Panagiotakis, Symeon %A Kapetanaki, Stefania %A Vgontzas, Alexandros %X

BACKGROUND: Apolipoprotein E gene (APOE) ɛ4 allele increases the risk for Alzheimer's disease (AD). Furthermore, among patients with cognitive impairment, longer sleep duration is associated with worse cognitive performance. To date, literature examining the associations between APOE ɛ4 allele and objective sleep duration is limited.

OBJECTIVE: Our aim was to assess the association between APOE ɛ4 and objective sleep duration, among patients with mild cognitive impairment (MCI) and AD. A sub-sample of 89 patients with AD (n = 49) and MCI (n = 40) were recruited from a large, population-based cohort of 3,140 elders (>60 years) residing on Crete, Greece.

METHODS: All participants underwent medical history/physical examination, extensive neuropsychiatric and neuropsychological evaluation, 3-day 24 h actigraphy and APOE ɛ4 allele genotyping. Comparisons of sleep duration variables between APOE ɛ4 allele carriers and non-carriers were assessed using ANCOVA, controlling for confounders.

RESULTS: The sample included 18 APOE ɛ4 carriers and 71 non-carriers, aged 78.6±6.6 and 78.2±6.5 years, respectively. Comparisons between the APOE ɛ4 carriers and non-carriers revealed no significant differences in terms of demographic and clinical variables. In terms of objective sleep duration across the two groups, APOE ɛ4 carriers compared to non-carriers had significantly longer nighttime Total Sleep Time (nTST) (7.7±1.4 versus 7.2±1.3  h, respectively, p = 0.011), as well as 24 h TST (8.5±1.6 versus 7.8±1.5  h, respectively, p = 0.012).

CONCLUSION: Among patients with MCI and AD, APOE ɛ4 carriers have longer objective nighttime and 24 h sleep duration compared to non-carriers. These findings further support that objective long sleep duration is a genetically-driven pre-clinical marker associated with worse prognosis in elderly with cognitive impairment.

%B J Alzheimers Dis %V 79 %P 763-771 %8 2021 Jan 19 %G eng %N 2 %R 10.3233/JAD-200958 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Assessing the Progression of Alzheimer's Disease in Real-World Settings in Three European Countries. %A Lladó, Albert %A Froelich, Lutz %A Khandker, Rezaul K %A Roset, Montserrat %A Black, Christopher M %A Lara, Nuria %A Chekani, Farid %A Ambegaonkar, Baishali M %K Alzheimer Disease %K Cholinesterase Inhibitors %K Cognition Disorders %K Disease Progression %K Europe %K Germany %K Humans %K Institutionalization %K Neuropsychological Tests %K Spain %X

BACKGROUND: There exists considerable variation in disease progression rates among patients with Alzheimer's disease (AD).

OBJECTIVE: The primary objective of this observational study is to assess the progression of AD by characterizing cognitive, functional, and behavioral changes during the follow-up period between 6 and 24 months.

METHODS: A longitudinal prospective study with community-dwelling patients with an established clinical diagnosis of AD of mild to moderate severity was conducted in Germany, Spain and the UK. A sample of 616 patients from 69 sites was included.

RESULTS: Patients had a mean of 1.9 years (SD = 1.9) since AD diagnosis at study inclusion. Cognitive symptoms were reported to have first occurred a mean of 1.1 years (SD = 1.7) prior to AD diagnosis and 1.4 (SD = 1.8) years prior to AD treatment. Patients initially diagnosed with mild and moderate AD spent a median (95%CI) of 3.7 (2.8; 4.4) and 11.1 (6.1, 'not reached') years until progression to moderate and severe AD, respectively, according to the Mini-Mental State Examination (MMSE) scores. A mixed model developed for cognitive, functional, and neuropsychiatric scores, obtained from study patients at baseline and during follow-up period, showed progressive deterioration of AD patients over time.

CONCLUSION: The study showed a deterioration of cognitive, functional, and neuropsychiatric functions during the follow-up period. Cognitive deterioration was slightly faster in patients with moderate AD compared to mild AD. The duration of moderate AD can be overestimated due to the use of retrospective data, lack of availability of MMSE scores in clinical charts and exclusion of patients at time of institutionalization.

%B J Alzheimers Dis %V 80 %P 749-759 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33579841?dopt=Abstract %R 10.3233/JAD-201172 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Association Between Elevated Depressive Symptoms and Cognitive Function Moderated by APOE4 Status: Framingham Offspring Study. %A Piers, Ryan J %A Liu, Yulin %A Ang, Ting F A %A Tao, Qiushan %A Au, Rhoda %A Qiu, Wei Qiao %X

BACKGROUND: Depression and Apolipoprotein E4 (APOE4) are associated with decreased cognitive function and differences in brain structure.

OBJECTIVE: This study investigated whether APOE4 status moderates the association between elevated depressive symptoms, cognitive function, and brain structure.

METHODS: Stroke- and dementia-free participants (n = 1,968) underwent neuropsychological evaluation, brain MRI, and depression screening. Linear and logistic regression was used to examine all associations. Secondary analyses were performed using interaction terms to assess effect modification by APOE4 status.

RESULTS: Elevated depressive symptoms were associated with lower cognitive performance in several domains. In stratified analyses, elevated depressive symptoms were associated with poorer visual short- and long-term memory performance for APOE4 + participants. Elevated depressive symptoms were not associated with any brain structure in this study sample.

CONCLUSION: Elevated depressive symptoms impact cognitive function in non-demented individuals. Having the APOE4 allele may exacerbate the deleterious effects of elevated depressive symptoms on visual memory performance. Screening for elevated depressive symptoms in both research studies and clinical practice may be warranted to avoid false positive identification of neurodegeneration, particularly among those who are APOE4 + .

%B J Alzheimers Dis %V 80 %P 1269-1279 %8 2021 Apr 06 %G eng %N 3 %R 10.3233/JAD-200998 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Association Between Homocysteine and Memory in Older Adults. %A Nelson, Monica E %A Andel, Ross %A Nedelska, Zuzana %A Martinkova, Julie %A Cechova, Katerina %A Marková, Hana %A Matuskova, Veronika %A Nikolai, Tomas %A Lerch, Ondřej %A Pařízková, Martina %A Laczó, Jan %A Vyhnálek, Martin %A Hort, Jakub %X

BACKGROUND: Identifying modifiable risk factors for cognitive decline can reduce burden of dementia.

OBJECTIVE: We examined whether homocysteine was associated with memory performance, mediated by entorhinal volume, hippocampal volume, total gray matter volume, or white matter lesions, and moderated by APOE ɛ4 allele, B vitamins, creatinine, total cholesterol, or triglycerides.

METHODS: All 204 members of the Czech Brain Aging Study with subjective cognitive decline (SCD; n = 60) or amnestic mild cognitive impairment (aMCI; n = 144) who had valid data were included. Linear regression was used, followed by conditional process modeling to examine mediation and moderation.

RESULTS: Controlling for age, sex, and education, higher homocysteine was related to poorer memory performance overall (b = -0.03, SE = 0.01, p = 0.017) and in participants with SCD (b = -0.06, SE = 0.03, p = 0.029), but less so in aMCI (b = -0.03, SE = 0.02, p = 0.074); though sensitivity analyses revealed a significant association when sample was reduced to aMCI patients with more complete cognitive data (who were also better functioning; b = -0.04, SE = 0.02, p = 0.022). Results were unchanged in fully adjusted models. Neither mediation by markers of brain integrity nor moderation by APOE ɛ4, B vitamins, creatinine, and cardiovascular factors were significant. Memory sub-analyses revealed that results for SCD were likely driven by non-verbal memory. The homocysteine-memory relationship was significant when hippocampal volume was below the median (b = -0.04, SE = 0.02, p = 0.046), but not at/above the median (p = 0.247).

CONCLUSION: Higher homocysteine levels may adversely influence memory performance, particularly in those without cognitive impairment. Results appear to be independent of brain health, suggesting that homocysteine may represent a good target for intervention.

%B J Alzheimers Dis %V 81 %P 413-426 %8 2021 May 04 %G eng %N 1 %R 10.3233/JAD-201558 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Association Between the APOEɛ2/ɛ4 Genotype and Alzheimer's Disease and Mild Cognitive Impairment Among African Americans. %A Ren, Dianxu %A Lopez, Oscar L %A Lingler, Jennifer H %A Conley, Yvette %X

We examined the association between APOEɛ2/ɛ4 with incident Alzheimer's disease (AD) and mild cognitive impairment (MCI) among African Americans using the national dataset from the National Alzheimer's Coordinating Center (NACC) from 2005 to September 2019. Compared to ɛ3/ɛ3 carriers, ɛ2/ɛ4 carriers exhibited a similar risk of incident AD (adjusted hazard ratio [aHR] = 0.85, 95% CI [0.39, 1.84]) among the AD cohort and similar risk of incident MCI (aHR = 0.88, 95% CI [0.51, 1.50]) among the MCI cohort. Our findings suggest that, unlike the increased risk of AD and MCI in non-Latino whites, APOEɛ2/ɛ4 genotype is not associated with the incidence of AD and MCI among African Americans.

%B J Alzheimers Dis %V 81 %P 943-948 %8 2021 Jun 01 %G eng %N 3 %R 10.3233/JAD-201613 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Association of Amyloid-β Pathology with Decision Making and Scam Susceptibility. %A Kapasi, Alifiya %A Yu, Lei %A Stewart, Christopher %A Schneider, Julie A %A Bennett, David A %A Boyle, Patricia A %X

BACKGROUND: Recent findings suggest that poor decision making and increased scam susceptibility are harbingers of Alzheimer's disease (AD) dementia and may be among the earliest behavioral manifestations of pathologic cognitive aging. However, the degree to which poor decision making and scam susceptibility reflect accumulating Alzheimer's disease (AD) pathology remains unclear.

OBJECTIVE: To investigate the associations of AD pathology with decision making and scam susceptibility in older adults without dementia.

METHODS: Data came from 198 deceased participants without clinical dementia (mean age at death = 90 years; 69%women) from two ongoing studies of aging. All underwent annual clinical evaluations, completed assessments of healthcare and financial decision making and scam susceptibility, and brain donation. Neuropathologic evaluations quantified pathologic hallmarks of AD, amyloid-β and tau-tangles, Lewy body pathology, and TDP-43 proteinopathy.

RESULTS: In linear regression models adjusted for demographics, amyloid-β pathology was associated with lower decision making (estimate = -0.35; SE = 0.16, p = 0.03), particularly healthcare decision making (estimate = -0.20; SE = 0.09, p = 0.03), as well as greater scam susceptibility (estimate = 0.12; SE = 0.04, p = 0.003); tau-tangle pathology was not related. Further, TDP-43 pathology was associated with greater scam susceptibility (estimate = 0.10; SE = 0.04; p = 0.02).

CONCLUSION: Accumulating AD pathology, particularly amyloid-β, is associated with poor decision making and increased scam susceptibility among older persons without overt cognitive impairment. These findings provide compelling evidence that decision making and scam susceptibility are sensitive to the earliest pathological changes of AD.

%B J Alzheimers Dis %V 83 %P 879-887 %8 2021 Sep 21 %G eng %N 2 %R 10.3233/JAD-210356 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Association of Essential Metals with APOE Genotype in Alzheimer's Disease. %A Babić Leko, Mirjana %A Jurasović, Jasna %A Nikolac Perković, Matea %A Španić, Ena %A Sekovanić, Ankica %A Orct, Tatjana %A Lukinović Škudar, Vesna %A Bačić Baronica, Koraljka %A Kiđemet-Piskač, Spomenka %A Vogrinc, Željka %A Pivac, Nela %A Borovečki, Fran %A Hof, Patrick R %A Šimić, Goran %X

BACKGROUND: The major confirmed genetic risk factor for late-onset, sporadic Alzheimer's disease (AD) is variant ɛ4 of apolipoprotein E gene (APOE). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron, zinc, and calcium with ApoE4-mediated toxicity.

OBJECTIVE: To test the association of essential metals with APOE genotype.

METHODS: We compared plasma and cerebrospinal fluid (CSF) levels of copper, zinc, iron, sodium, magnesium, calcium, cobalt, molybdenum, manganese, boron, and chromium, and CSF ferritin levels among AD, mild cognitive impairment (MCI) patients, and healthy controls (HC) with different APOE genotype.

RESULTS: Sodium, copper, and magnesium levels were increased in carriers of ɛ4 allele. Additionally, the increase in sodium, calcium and cobalt plasma levels was observed in carriers of ɛ4/ɛx genotype. The decrease in boron plasma levels was observed in carriers of ɛ4 allele and ɛ4/ɛ4 genotype. Additionally, CSF zinc levels as well as plasma sodium levels were increased in AD patients compared to HC.

CONCLUSION: These results indicate that the molecular underpinnings of association of essential metals and metalloids with APOE should be further tested and clarified in vivo and in vitro.

%B J Alzheimers Dis %V 82 %P 661-672 %8 2021 Jul 20 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34057084?dopt=Abstract %R 10.3233/JAD-210158 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Association of Malnutrition with Functional and Cognitive Trajectories in People Living with Dementia: A Five-Year Follow-Up Study. %A Borda, Miguel Germán %A Ayala Copete, Ana María %A Tovar-Rios, Diego Alejandro %A Jaramillo-Jimenez, Alberto %A Giil, Lasse Melvær %A Soennesyn, Hogne %A Gómez-Arteaga, Camilo %A Venegas-Sanabria, Luis Carlos %A Kristiansen, Ida %A Chavarro-Carvajal, Diego Andrés %A Caicedo, Sandra %A Cano-Gutierrez, Carlos Alberto %A Vik-Mo, Audun %A Aarsland, Dag %X

BACKGROUND: In dementia, functional status depends on multiple factors in addition to cognition. Nutritional status is a potentially modifiable factor related to homeostasis and proper functioning of body systems and may contribute to cognitive and functional decline.

OBJECTIVE: This paper aims to analyze the association of malnutrition with the course of cognitive and functional decline in people living with dementia.

METHODS: This is an analysis of a longitudinal cohort study, the Dementia Study of Western Norway. Data of 202 patients diagnosed with mild dementia were analyzed; Alzheimer's disease (AD) (n = 103), Lewy body dementia (LBD) (n = 74), and other dementias (OD) (n = 25). Cognition was assessed with the Mini-Mental State Examination and functional decline through the activities of daily living included in the Rapid Disability Rating Scale. The Global Leadership Initiative on Malnutrition Index was used to determine nutritional status. Associations of nutritional status with cognitive and functional decline were evaluated through adjusted linear mixed models.

RESULTS: At baseline, the prevalence of general malnutrition was 28.7%; 17.32% were classified as moderate malnutrition and 11.38% as severe malnutrition (there were no significant differences between AD and LBD). Malnutrition at diagnosis and over follow-up was a significant predictor of functional-decline, but not of cognitive decline.

CONCLUSION: According to our results malnutrition was associated with faster functional loss but, not cognitive decline in older adults with dementia. A more comprehensive dementia approach including nutritional assessments could improve prognosis.

%B J Alzheimers Dis %V 79 %P 1713-1722 %8 2021 Feb 16 %G eng %N 4 %R 10.3233/JAD-200961 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Association of Midlife Depressive Symptoms with Regional Amyloid-β and Tau in the Framingham Heart Study. %A Gonzales, Mitzi M %A Samra, Jasmeet %A O'Donnell, Adrienne %A Mackin, R Scott %A Salinas, Joel %A Jacob, Mini %A Satizabal, Claudia L %A Aparicio, Hugo J %A Thibault, Emma G %A Sanchez, Justin S %A Finney, Rebecca %A Rubinstein, Zoe B %A Mayblyum, Danielle V %A Killiany, Ron J %A Decarli, Charlie S %A Johnson, Keith A %A Beiser, Alexa S %A Seshadri, Sudha %X

BACKGROUND: Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective.

OBJECTIVE: The study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator.

METHODS: Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored.

RESULTS: Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β= 0.446, SE = 0.155, p = 0.006) and amygdala (β= 0.350, SE = 0.133, p = 0.012).

CONCLUSION: Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.

%B J Alzheimers Dis %V 82 %P 249-260 %8 2021 Jun 29 %G eng %N 1 %R 10.3233/JAD-210232 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Association of White Matter Hyperintensity Progression with Cognitive Decline in Patients with Amnestic Mild Cognitive Impairment. %A Hirao, Kentaro %A Yamashita, Fumio %A Tsugawa, Akito %A Haime, Rieko %A Fukasawa, Raita %A Sato, Tomohiko %A Kanetaka, Hidekazu %A Umahara, Takahiko %A Sakurai, Hirofumi %A Hanyu, Haruo %A Shimizu, Soichiro %X

BACKGROUND: White matter hyperintensities (WMH) on MRI have been reported to increase the risk of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). However, effects of the progression of WMH on the cognition of patients with MCI remains unclear to date.

OBJECTIVE: To investigate the association between WMH progression and cognitive decline in amnestic MCI patients.

METHODS: Thirty-eight subjects with amnestic MCI were analyzed prospectively every year for 2 years. Fourteen MCI subjects dropped out on the final visit, and therefore 24 subjects with MCI were analyzed for the entire duration. The volumes of periventricular hyperintensities (PVH) and deep WMH (DWMH) were measured on T2 FLAIR using the 3D-slicer. The associations between PVH/DWMH progression and cognitive decline were investigated.

RESULTS: An increase in DWMH volume significantly correlated with changes in Mini-Mental State Examination and category verbal fluency scores, whereas an increase in PVH volume did not correlate with changes in any item.

CONCLUSION: DWMH progression was closely associated with a decline in frontal lobe function and semantic memory, suggesting that WMH progression might affect some AD pathophysiologies in amnestic MCI patients.

%B J Alzheimers Dis %V 80 %P 877-883 %8 2021 March 23 %G eng %N 2 %R 10.3233/JAD-201451 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Automatic Subtyping of Individuals with Primary Progressive Aphasia. %A Themistocleous, Charalambos %A Ficek, Bronte %A Webster, Kimberly %A den Ouden, Dirk-Bart %A Hillis, Argye E %A Tsapkini, Kyrana %K Acoustics %K Aged %K Aphasia, Primary Progressive %K Decision Trees %K Female %K Humans %K Linguistics %K Machine Learning %K Male %K Models, Theoretical %K Neural Networks, Computer %K Primary Progressive Nonfluent Aphasia %K Reproducibility of Results %K Support Vector Machine %X

BACKGROUND: The classification of patients with primary progressive aphasia (PPA) into variants is time-consuming, costly, and requires combined expertise by clinical neurologists, neuropsychologists, speech pathologists, and radiologists.

OBJECTIVE: The aim of the present study is to determine whether acoustic and linguistic variables provide accurate classification of PPA patients into one of three variants: nonfluent PPA, semantic PPA, and logopenic PPA.

METHODS: In this paper, we present a machine learning model based on deep neural networks (DNN) for the subtyping of patients with PPA into three main variants, using combined acoustic and linguistic information elicited automatically via acoustic and linguistic analysis. The performance of the DNN was compared to the classification accuracy of Random Forests, Support Vector Machines, and Decision Trees, as well as to expert clinicians' classifications.

RESULTS: The DNN model outperformed the other machine learning models as well as expert clinicians' classifications with 80% classification accuracy. Importantly, 90% of patients with nfvPPA and 95% of patients with lvPPA was identified correctly, providing reliable subtyping of these patients into their corresponding PPA variants.

CONCLUSION: We show that the combined speech and language markers from connected speech productions can inform variant subtyping in patients with PPA. The end-to-end automated machine learning approach we present can enable clinicians and researchers to provide an easy, quick, and inexpensive classification of patients with PPA.

%B J Alzheimers Dis %V 79 %P 1185-1194 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33427742?dopt=Abstract %R 10.3233/JAD-201101 %0 Journal Article %J J Alzheimers Dis %D 2021 %T B Vitamins Prevent Iron-Associated Brain Atrophy and Domain-Specific Effects of Iron, Copper, Aluminum, and Silicon on Cognition in Mild Cognitive Impairment. %A Jakubowski, Hieronim %A Zioła-Frankowska, Anetta %A Frankowski, Marcin %A Perła-Kaján, Joanna %A Refsum, Helga %A de Jager, Celeste A %A Smith, A David %B J Alzheimers Dis %V 84 %P 1039-1055 %8 2021 Nov 23 %G eng %N 3 %R 10.3233/JAD-215085 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Behavioral and Psychological Symptoms of Dementia in Down Syndrome Scale (BPSD-DS II): Optimization and Further Validation. %A Dekker, Alain D %A Ulgiati, Aurora M %A Groen, Henk %A Boxelaar, Vincent A %A Sacco, Silvia %A Falquero, Ségolène %A Carfi, Angelo %A di Paola, Antonella %A Benejam, Bessy %A Valldeneu, Silvia %A Fopma, Roelie %A Oosterik, Marjo %A Hermelink, Marloes %A Beugelsdijk, Gonny %A Schippers, Mieke %A Henstra, Hepie %A Scholten-Kuiper, Martine %A Willink-Vos, Judith %A de Ruiter, Lisa %A Willems, Liesbeth %A Loonstra-de Jong, Anneke %A Coppus, Antonia M W %A Tollenaere, Marleen %A Fortea, Juan %A Onder, Graziano %A Rebillat, Anne-Sophie %A Van Dam, Debby %A De Deyn, Peter P %K Adult %K Aged %K Anxiety %K Dementia %K Down Syndrome %K Female %K Humans %K Irritable Mood %K Male %K Middle Aged %K Reproducibility of Results %K Symptom Assessment %X

BACKGROUND: People with Down syndrome (DS) are at high risk to develop Alzheimer's disease dementia (AD). Behavioral and psychological symptoms of dementia (BPSD) are common and may also serve as early signals for dementia. However, comprehensive evaluation scales for BPSD, adapted to DS, are lacking. Therefore, we previously developed the BPSD-DS scale to identify behavioral changes between the last six months and pre-existing life-long characteristic behavior.

OBJECTIVE: To optimize and further study the scale (discriminative ability and reliability) in a large representative DS study population.

METHODS: Optimization was based on item irrelevance and clinical experiences obtained in the initial study. Using the shortened and refined BPSD-DS II, informant interviews were conducted to evaluate 524 individuals with DS grouped according to dementia status: no dementia (DS, N = 292), questionable dementia (DS + Q, N = 119), and clinically diagnosed dementia (DS + AD, N = 113).

RESULTS: Comparing item change scores between groups revealed prominent changes in frequency and severity for anxious, sleep-related, irritable, restless/stereotypic, apathetic, depressive, and eating/drinking behavior. For most items, the proportion of individuals displaying an increased frequency was highest in DS + AD, intermediate in DS + Q, and lowest in DS. For various items within sections about anxious, sleep-related, irritable, apathetic, and depressive behaviors, the proportion of individuals showing an increased frequency was already substantial in DS + Q, suggesting that these changes may serve as early signals of AD in DS. Reliability data were promising.

CONCLUSION: The optimized scale yields largely similar results as obtained with the initial version. Systematically evaluating BPSD in DS may increase understanding of changes among caregivers and (timely) adaptation of care/treatment.

%B J Alzheimers Dis %V 81 %P 1505-1527 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33967040?dopt=Abstract %R 10.3233/JAD-201427 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Bile Acids as Key Modulators of the Brain-Gut-Microbiota Axis in Alzheimer's Disease. %A Mulak, Agata %K Alzheimer Disease %K Bile Acids and Salts %K Brain-Gut Axis %K Humans %K Neuroprotection %K Signal Transduction %X

Recently, the concept of the brain-gut-microbiota (BGM) axis disturbances in the pathogenesis of Alzheimer's disease (AD) has been receiving growing attention. At the same time, accumulating data revealing complex interplay between bile acids (BAs), gut microbiota, and host metabolism have shed new light on a potential impact of BAs on the BGM axis. The crosstalk between BAs and gut microbiota is based on reciprocal interactions since microbiota determines BA metabolism, while BAs affect gut microbiota composition. Secondary BAs as microbe-derived neuroactive molecules may affect each of three main routes through which interactions within the BGM axis occur including neural, immune, and neuroendocrine pathways. BAs participate in the regulation of multiple gut-derived molecule release since their receptors are expressed on various cells. The presence of BAs and their receptors in the brain implies a direct effect of BAs on the regulation of neurological functions. Experimental and clinical data confirm that disturbances in BA signaling are present in the course of AD. Disturbed ratio of primary to secondary BAs as well as alterations in BA concertation in serum and brain samples have been reported. An age-related shift in the gut microbiota composition associated with its decreased diversity and stability observed in AD patients may significantly affect BA metabolism and signaling. Given recent evidence on BA neuroprotective and anti-inflammatory effects, new therapeutic targets have been explored including gut microbiota modulation by probiotics and dietary interventions, ursodeoxycholic acid supplementation, and use of BA receptor agonists.

%B J Alzheimers Dis %V 84 %P 461-477 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34569953?dopt=Abstract %R 10.3233/JAD-210608 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Bispecific Tau Antibodies with Additional Binding to C1q or Alpha-Synuclein. %A Quint, Wim Hendricus %A Matečko-Burmann, Irena %A Schilcher, Irene %A Löffler, Tina %A Schöll, Michael %A Burmann, Björn Marcus %A Vogels, Thomas %X

BACKGROUND: Alzheimer's disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinson's disease and Lewy body dementia also frequently occur together with tau pathology.

OBJECTIVE: Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes it desirable to simultaneously target more than one disease pathway.

METHODS: Herein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q.

RESULTS: Affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway.

CONCLUSION: Bispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.

%B J Alzheimers Dis %V 80 %P 813-829 %8 2021 Mar 23 %G eng %N 2 %R 10.3233/JAD-201334 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Blood-Based ATN Biomarkers of Alzheimer's Disease: A Meta-Analysis. %A Koychev, Ivan %A Jansen, Katrin %A Dette, Alina %A Shi, Liu %A Holling, Heinz %K Alzheimer Disease %K Amyloid beta-Peptides %K Humans %K Neurodegenerative Diseases %K Neurofibrillary Tangles %K Neurofilament Proteins %K Peptide Fragments %K Phosphorylation %K Plaque, Amyloid %K tau Proteins %X

BACKGROUND: The Amyloid Tau Neurodegeneration (ATN) framework was proposed to define the biological state underpinning Alzheimer's disease (AD). Blood-based biomarkers offer a scalable alternative to the costly and invasive currently available biomarkers.

OBJECTIVE: In this meta-analysis we sought to assess the diagnostic performance of plasma amyloid (Aβ40, Aβ42, Aβ42/40 ratio), tangle (p-tau181), and neurodegeneration (total tau [t-tau], neurofilament light [NfL]) biomarkers.

METHODS: Electronic databases were screened for studies reporting biomarker concentrations for AD and control cohorts. Biomarker performance was examined by random-effect meta-analyses based on the ratio between biomarker concentrations in patients and controls.

RESULTS: 83 studies published between 1996 and 2020 were included in the analyses. Aβ42/40 ratio as well as Aβ42 discriminated AD patients from controls when using novel platforms such as immunomagnetic reduction (IMR). We found significant differences in ptau-181 concentration for studies based on single molecule array (Simoa), but not for studies based on IMR or ELISA. T-tau was significantly different between AD patients and control in IMR and Simoa but not in ELISA-based studies. In contrast, NfL differentiated between groups across platforms. Exosome studies showed strong separation between patients and controls for Aβ42, t-tau, and p-tau181.

CONCLUSION: Currently available assays for sampling plasma ATN biomarkers appear to differentiate between AD patients and controls. Novel assay methodologies have given the field a significant boost for testing these biomarkers, such as IMR for Aβ, Simoa for p-tau181. Enriching samples through extracellular vesicles shows promise but requires further validation.

%B J Alzheimers Dis %V 79 %P 177-195 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33252080?dopt=Abstract %R 10.3233/JAD-200900 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Body Mass Index and Mild Cognitive Impairment Among Middle-Aged and Older Adults from Low- and Middle-Income Countries. %A Smith, Lee %A Shin, Jae Il %A Oh, Hans %A Carmichael, Christina %A Jacob, Louis %A Stefanac, Sinisa %A Lindsay, Rosie K %A Soysal, Pinar %A Veronese, Nicola %A Tully, Mark A %A Butler, Laurie %A Barnett, Yvonne %A Koyanagi, Ai %X

BACKGROUND: The effect of weight modification on future dementia risk is currently a subject of debate and may be modified by age.

OBJECTIVE: The aim of the present study was to investigate the association between body mass index (BMI) status with mild cognitive impairment (MCI) (a preclinical stage of dementia) in middle-aged and older adults residing in six low- and middle-income countries using nationally representative data.

METHODS: Cross-sectional data from the Study on Global Ageing and Adult Health (SAGE) were analyzed. MCI was defined using the National Institute on Aging-Alzheimer's Association criteria. BMI (kg/m2) was based on measured weight and height and categorized as: underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9), and obese (≥30.0). Multivariable logistic regression analysis and meta-analysis were conducted to assess associations.

RESULTS: Data on 32,715 individuals aged ≥50 years with preservation in functional abilities were analyzed [mean (SD) age 62.1 (15.6) years; 51.7% females]. Among those aged 50-64 years, compared to normal weight, underweight (OR = 1.44; 95% CI = 1.14-1.81), overweight (OR = 1.17; 95% CI = 1.002-1.37), and obesity (OR = 1.46; 95% CI = 1.09-1.94) were all significantly associated with higher odds for MCI. In those aged ≥65 years, underweight (OR = 0.71; 95% CI = 0.54-0.95) and overweight (OR = 0.72; 95% CI = 0.55-0.94) were associated with significantly lower odds for MCI, while obesity was not significantly associated with MCI.

CONCLUSION: The results of the study suggest that the association between BMI and MCI is likely moderated by age. Future longitudinal studies are required to confirm or refute the present findings before recommendations for policy and practice can be made.

%B J Alzheimers Dis %V 85 %P 1095-1105 %8 2022 Feb 01 %G eng %N 3 %R 10.3233/JAD-215345 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Borrelia burgdorferi Co-Localizing with Amyloid Markers in Alzheimer's Disease Brain Tissues. %A Senejani, Alireza G %A Maghsoudlou, Jasmin %A El-Zohiry, Dina %A Gaur, Gauri %A Wawrzeniak, Keith %A Caravaglia, Cristina %A Khatri, Vishwa A %A MacDonald, Alan %A Sapi, Eva %X

BACKGROUND: Infections by bacterial or viral agents have been hypothesized to influence the etiology of neurodegenerative diseases.

OBJECTIVE: This study examined the potential presence of Borrelia burgdorferi spirochete, the causative agent of Lyme disease, in brain autopsy tissue of patients diagnosed with either Alzheimer's (AD) or Parkinson's diseases.

METHODS: Brain tissue sections from patients with age-matched controls were evaluated for antigen and DNA presence of B. burgdorferi using various methods. Positive Borrelia structures were evaluated for co-localization with biofilm and AD markers such as amyloid and phospho-tau (p-Tau) using immunohistochemical methods.

RESULTS: The results showed the presence of B. burgdorferi antigen and DNA in patients with AD pathology and among those, one of them was previously diagnosed with Lyme disease. Interestingly, a significant number of Borrelia-positive aggregates with a known biofilm marker, alginate, were found along with the spirochetal structures. Our immunohistochemical data also showed that Borrelia-positive aggregates co-localized with amyloid and anti-phospho-tau markers. To further prove the potential relationship of B. burgdorferi and amyloids, we infected two mammalian cell lines with B. burgdorferi which resulted in a significant increase in the expression of amyloid-β and p-Tau proteins in both cells lines post-infection.

CONCLUSION: These results indicate that B. burgdorferi can be found in AD brain tissues, not just in spirochete but a known antibiotics resistant biofilm form, and its co-localized amyloid markers. In summary, this study provides evidence for a likely association between B. burgdorferi infections and biofilm formation, AD pathology, and chronic neurodegenerative diseases.

%B J Alzheimers Dis %V 85 %P 889-903 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-215398 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches. %A Clark, I A %A Vissel, B %K Alzheimer Disease %K Anti-Inflammatory Agents, Non-Steroidal %K Brain %K Brain Injuries %K COVID-19 %K Disease Progression %K Etanercept %K Heart Arrest %K Humans %K Locus Coeruleus %K Neurodegenerative Diseases %K Norepinephrine %K Parkinson Disease %K Risk Factors %K SARS-CoV-2 %K Stroke %K Survivors %K Tumor Necrosis Factor-alpha %X

Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post-traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer's disease and Parkinson's disease sufferers. In contrast, Alzheimer's disease and Parkinson's disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.

%B J Alzheimers Dis %V 79 %P 931-948 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33459706?dopt=Abstract %R 10.3233/JAD-201186 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cannabidiol Ameliorates Cognitive Function via Regulation of IL-33 and TREM2 Upregulation in a Murine Model of Alzheimer's Disease. %A Khodadadi, Hesam %A Salles, Évila Lopes %A Jarrahi, Abbas %A Costigliola, Vincenzo %A Khan, M B %A Yu, Jack C %A Morgan, John C %A Hess, David C %A Vaibhav, Kumar %A Dhandapani, Krishnan M %A Baban, Babak %K Alzheimer Disease %K Animals %K Cannabidiol %K Cognition %K Disease Models, Animal %K Humans %K Interleukin-33 %K Male %K Membrane Glycoproteins %K Mice %K Mice, Transgenic %K Receptors, Immunologic %K Up-Regulation %X

There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Behavioral tests and immunoassays were used to evaluate cognitive and motor outcomes. Our findings suggest that CBD treatment enhanced IL-33 and TREM2 expression, ameliorated the symptoms of AD, and retarded cognitive decline.

%B J Alzheimers Dis %V 80 %P 973-977 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33612548?dopt=Abstract %R 10.3233/JAD-210026 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Central Obesity, Cardiometabolic Risk, and Cognitive Change in the Study of Latinos: Investigation of Neurocognitive Aging. %A Stickel, Ariana M %A Tarraf, Wassim %A Gonzalez, Kevin A %A Isasi, Carmen R %A Kaplan, Robert %A Gallo, Linda C %A Zeng, Donglin %A Cai, Jianwen %A Pirzada, Amber %A Daviglus, Martha L %A Goodman, Zachary T %A Schneiderman, Neil %A González, Hector M %X

BACKGROUND: The relationships between obesity and cognitive decline in aging are mixed and understudied among Hispanics/Latinos.

OBJECTIVE: To understand associations between central obesity, cognitive aging, and the role of concomitant cardiometabolic abnormalities among Hispanics/Latinos.

METHODS: Participants included 6,377 diverse Hispanics/Latinos enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and SOL-Investigation for Neurocognitive Aging (SOL-INCA). Participants were 45 years and older at the first cognitive testing session (Visit 1). Cognitive outcomes (z-score units) included global composite and domain specific (learning, memory, executive functioning, processing speed) measures at a second visit (SOL-INCA, on average, 7 years later), and 7-year change. We used survey linear regression to examine associations between central obesity (waist circumference≥88 cm and≥102 cm for women and men, respectively) and cognition. We also tested whether the relationships between obesity and cognition differed by cardiometabolic status (indication of/treatment for 2 + of the following: high triglycerides, hypertension, hyperglycemia, low high-density lipoprotein cholesterol).

RESULTS: Central obesity was largely unassociated with cognitive outcomes, adjusting for covariates. However, among individuals with central obesity, cardiometabolic abnormality was linked to poorer cognitive function at SOL-INCA (ΔGlobalCognition =-0.165, p < 0.001) and to more pronounced cognitive declines over the average 7 years (ΔGlobalCognition = -0.109, p < 0.05); this was consistent across cognitive domains.

CONCLUSION: Central obesity alone was not associated with cognitive function. However, presence of both central obesity and cardiometabolic abnormalities was robustly predictive of cognition and 7-year cognitive declines, suggesting that in combination these factors may alter the cognitive trajectories of middle-aged and older Hispanics/Latinos.

%B J Alzheimers Dis %V 82 %P 1203-1218 %8 2021 Aug 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34151803?dopt=Abstract %R 10.3233/JAD-210314 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cerebrospinal Fluid Amyloid-β Oligomer Levels in Patients with Idiopathic Normal Pressure Hydrocephalus. %A Kawamura, Kaito %A Miyajima, Masakazu %A Nakajima, Madoka %A Kanai, Mitsuyasu %A Motoi, Yumiko %A Nojiri, Shuko %A Akiba, Chihiro %A Ogino, Ikuko %A Xu, Hanbing %A Kamohara, Chihiro %A Yamada, Shinya %A Karagiozov, Kostadin %A Ikeuchi, Takeshi %A Kondo, Akihide %A Arai, Hajime %X

BACKGROUND: The amyloid-β oligomers, consisting of 10-20 monomers (AβO10-20), have strong neurotoxicity and are associated with cognitive impairment in Alzheimer's disease (AD). However, their role in patients with idiopathic normal pressure hydrocephalus (iNPH) is poorly understood.

OBJECTIVE: We hypothesized that cerebrospinal fluid (CSF) AβO10-20 accumulates in patients with iNPH, and its clearance after CSF shunting contributes to neurological improvement. We measured CSF AβO10-20 levels before and after CSF shunting in iNPH patients evaluating their diagnostic and prognostic role.

METHODS: We evaluated two iNPH cohorts: "evaluation" (cohort-1) with 32 patients and "validation" (cohort-2) with 13 patients. Comparison cohorts included: 27 neurologically healthy controls (HCs), and 16 AD, 15 Parkinson's disease (PD), and 14 progressive supranuclear palsy (PSP) patients. We assessed for all cohorts CSF AβO10-20 levels and their comprehensive clinical data. iNPH cohort-1 pre-shunting data were compared with those of comparison cohorts, using cohort-2 for validation. Next, we compared cohort-1's clinical and CSF data: 1) before and after CSF shunting, and 2) increased versus decreased AβO10-20 levels at baseline, 1 and 3 years after shunting.

RESULTS: Cohort-1 had higher CSF AβO10-20 levels than the HCs, PD, and PSP cohorts. This result was validated with data from cohort-2. CSF AβO10-20 levels differentiated cohort-1 from the PD and PSP groups, with an area under receiver operating characteristic curve of 0.94. AβO10-20 levels in cohort-1 decreased after CSF shunting. Patients with AβO10-20 decrease showed better cognitive outcome than those without.

CONCLUSION: AβO10-20 accumulates in patients with iNPH and is eliminated by CSF shunting. AβO10-20 can be an applicable diagnostic and prognostic biomarker.

%B J Alzheimers Dis %V 83 %P 179-190 %8 2021 Aug 31 %G eng %N 1 %R 10.3233/JAD-210226 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction. %A VanDusen, Keith W %A Li, Yi-Ju %A Cai, Victor %A Hall, Ashley %A Hiles, Sarah %A Thompson, J Will %A Moseley, M Arthur %A Cooter, Mary %A Acker, Leah %A Levy, Jerrold H %A Ghadimi, Kamrouz %A Quiñones, Quintin J %A Devinney, Michael J %A Chung, Stacey %A Terrando, Niccolò %A Moretti, Eugene W %A Browndyke, Jeffrey N %A Mathew, Joseph P %A Berger, Miles %X

BACKGROUND: Postoperative cognitive dysfunction (POCD), a syndrome of cognitive deficits occurring 1-12 months after surgery primarily in older patients, is associated with poor postoperative outcomes. POCD is hypothesized to result from neuroinflammation; however, the pathways involved remain unclear. Unbiased proteomic analyses have been used to identify neuroinflammatory pathways in multiple neurologic diseases and syndromes but have not yet been applied to POCD.

OBJECTIVE: To utilize unbiased mass spectrometry-based proteomics to identify potential neuroinflammatory pathways underlying POCD.

METHODS: Unbiased LC-MS/MS proteomics was performed on immunodepleted cerebrospinal fluid (CSF) samples obtained before, 24 hours after, and 6 weeks after major non-cardiac surgery in older adults who did (n = 8) or did not develop POCD (n = 6). Linear mixed models were used to select peptides and proteins with intensity differences for pathway analysis.

RESULTS: Mass spectrometry quantified 8,258 peptides from 1,222 proteins in > 50%of patient samples at all three time points. Twelve peptides from 11 proteins showed differences in expression over time between patients with versus withoutPOCD (q < 0.05), including proteins previously implicated in neurodegenerative disease pathophysiology. Additionally, 283 peptides from 182 proteins were identified with trend-level differences (q < 0.25) in expression over time between these groups. Among these, pathway analysis revealed that 50 were from 17 proteins mapping to complement and coagulation pathways (q = 2.44*10-13).

CONCLUSION: These data demonstrate the feasibility of performing unbiased mass spectrometry on perioperative CSF samples to identify pathways associated with POCD. Additionally, they provide hypothesis-generating evidence for CSF complement and coagulation pathway changes in patients with POCD.

%B J Alzheimers Dis %V 80 %P 1281-1297 %8 2021 Apr 06 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33682719?dopt=Abstract %R 10.3233/JAD-201544 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cerebrospinal Fluid Sulfatide Levels Lack Diagnostic Utility in the Subcortical Small Vessel Type of Dementia. %A Svensson, Johan %A Blomqvist, Maria %A Kettunen, Petronella %A Eckerström, Carl %A Henricsson, Marcus %A Jonsson, Michael %A Bjerke, Maria %A Månsson, Jan-Eric %A Wallin, Anders %X

BACKGROUND: Sulfatides (STs) in cerebrospinal fluid (CSF), as well as magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMHs), may reflect demyelination. Here, we investigated the diagnostic utility of CSF ST levels in the subcortical small vessel type of dementia (SSVD), which is characterized by the presence of brain WMHs.

OBJECTIVE: To study the diagnostic utility of CSF ST levels in SSVD.

METHODS: This was a mono-center, cross-sectional study of SSVD (n = 16), Alzheimer's disease (n = 40), mixed dementia (n = 27), and healthy controls (n = 33). Totally, 20 ST species were measured in CSF by liquid chromatography-mass spectrometry (LC-MS/MS).

RESULTS: CSF total ST levels, as well as CSF levels of hydroxylated and nonhydroxylated ST species, did not differ across the study groups. In contrast, CSF neurofilament light chain (NFL) levels separated the patient groups from the controls. CSF total ST level correlated with CSF/serum albumin ratio in the total study population (r = 0.64, p <  0.001) and in all individual study groups. Furthermore, CSF total ST level correlated positively with MRI-estimated WMH volume in the total study population (r = 0.30, p <  0.05), but it did not correlate with CSF NFL level.

CONCLUSION: Although there was some relation between CSF total ST level and WMH volume, CSF ST levels were unaltered in all dementia groups compared to the controls. This suggests that CSF total ST level is a poor biomarker of demyelination in SSVD. Further studies are needed to investigate the mechanisms underlying the marked correlation between CSF total ST level and CSF/serum albumin ratio.

%B J Alzheimers Dis %V 82 %P 781-790 %8 2021 Jul 20 %G eng %N 2 %R 10.3233/JAD-201552 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cerebrovascular microRNA Expression Profile During Early Development of Alzheimer's Disease in a Mouse Model. %A Chum, Phoebe P %A Hakim, Md A %A Behringer, Erik J %X

BACKGROUND: Emerging evidence demonstrates association of Alzheimer's disease (AD) with impaired delivery of blood oxygen and nutrients to and throughout the brain. The cerebral circulation plays multiple roles underscoring optimal brain perfusion and cognition entailing moment-to-moment blood flow control, vascular permeability, and angiogenesis. With currently no effective treatment to prevent or delay the progression of AD, cerebrovascular microRNA (miRNA) markers corresponding to post-transcriptional regulation may distinguish phases of AD.

OBJECTIVE: We tested the hypothesis that cerebrovascular miRNA expression profiles indicate developmental stages of AD pathology.

METHODS: Total RNA was isolated from total brain vessel segments of male and female 3xTg-AD mice [young, 1-2 mo; cognitive impairment (CI), 4-5 mo; extracellular amyloid-β plaques (Aβ), 6-8 mo; plaques+neurofibrillary tangles (AβT), 12-15 mo]. NanoString technology nCounter miRNA Expression panel for mouse was used to screen for 599 miRNAs.

RESULTS: Significant (p < 0.05) downregulation of various miRNAs indicated transitions from young to CI (e.g., let-7g & miR-1944, males; miR-133a & miR-2140, females) and CI to Aβ (e.g., miR-99a, males) but not from Aβ to AβT. In addition, altered expression of select miRNAs from overall Pre-AD (young + CI) versus AD (Aβ+ AβT) were detected in both males (let-7d, let-7i, miR-23a, miR-34b-3p, miR-99a, miR-126-3p, miR-132, miR-150, miR-151-5p, miR-181a) and females (miR-150, miR-539). Altogether, at least 20 cerebrovascular miRNAs effectively delineate AD versus Pre-AD pathology.

CONCLUSION: Using the 3xTg-AD mouse model, these data demonstrate that cerebrovascular miRNAs pertaining to endothelial function, vascular permeability, angiogenesis, inflammation, and Aβ/tau metabolism can track early development of AD.

%B J Alzheimers Dis %V 85 %P 91-113 %8 2022 Jan 04 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34776451?dopt=Abstract %R 10.3233/JAD-215223 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Clinical Approach of Low-Dose Whole-Brain Ionizing Radiation Treatment in Alzheimer's Disease Dementia Patients. %A Chung, Mijoo %A Rhee, Hak Young %A Chung, Weon Kuu %K Alzheimer Disease %K Animals %K Brain %K Cranial Irradiation %K Humans %X

Our research team recently published two relevant papers. In one study, we have seen the acute effect of low-dose ionizing irradiation (LDIR) did not reduce the amyloid-β (Aβ) protein concentration in brain tissue, yet significantly improved synaptic degeneration and neuronal loss in the hippocampus and cerebral cortex. Surprisingly, in another study, we could see late effect that the LDIR-treated mice showed significantly improved learning and memory skills compared with those in the sham group. In addition, Aβ concentrations were significantly decreased in brain tissue. Furthermore, the pro-inflammatory cytokine tumor necrosis factor-α was decreased and the anti-inflammatory cytokine transforming growth factor-β was increased in the brain tissue of 5xFAD mice treated with LDIR. Definitive clinical results for the safety and efficacy of LDIR have not yet been published and, despite the promising outcomes reported during preclinical studies, LDIR can only be applied to patients with Alzheimer's disease dementia when clinical results are made available. In addition, in the case of LDIR, additional large-scale clinical studies are necessary to determine the severity of Alzheimer's disease dementia, indications for LDIR, the total dose to be irradiated, fraction size, and intervals of LDIR treatment. The purpose of this review is to summarize the mechanism of LDIR based on existing preclinical results in a way that is useful for conducting subsequent clinical research.

%B J Alzheimers Dis %V 80 %P 941-947 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33612549?dopt=Abstract %R 10.3233/JAD-210042 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Clinical Features and Outcomes of Patients with Dementia Compared to an Aging Cohort Hospitalized During the Initial New York City COVID-19 Wave. %A Harb, Amro A %A Chen, RuiJun %A Chase, Herbert S %A Natarajan, Karthik %A Noble, James M %X

BACKGROUND: Patients with dementia are vulnerable during the coronavirus disease 2019 (COVID-19) pandemic, yet few studies describe their hospital course and outcomes.

OBJECTIVE: To describe and compare the hospital course for COVID-19 patients with dementia to an aging cohort without dementia in a large New York City academic medical center.

METHODS: This was a single-center retrospective cohort study describing all consecutive patients age 65 or older with confirmed COVID-19 who presented to the emergency department or were hospitalized at New York-Presbyterian/Columbia University Irving Medical Center between March 6 and April 7, 2020.

RESULTS: A total of 531 patients were evaluated, including 116 (21.8%) with previously diagnosed dementia, and 415 without dementia. Patients with dementia had higher mortality (50.0%versus 35.4%, p = 0.006); despite similar comorbidities and complications, multivariate analysis indicated the association was dependent on age, sex, comorbidities, and code status. Patients with dementia more often presented with delirium (36.2%versus 11.6%, p <  0.001) but less often presented with multiple other COVID-19 symptoms, and these findings remained after adjusting for age and sex.

CONCLUSION: Hospitalized COVID-19 patients with dementia had higher mortality, but dementia was not an independent risk factor for death. These patients were approximately 3 times more likely to present with delirium but less often manifested or communicated other common COVID-19 symptoms. For this high-risk population in a worsening pandemic, understanding the unique manifestations and course in dementia and aging populations may help guide earlier diagnosis and optimize medical management.

%B J Alzheimers Dis %V 81 %P 679-690 %8 2021 May 18 %G eng %N 2 %R 10.3233/JAD-210050 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Cognition and Flow Study: A Feasibility Randomized Controlled Trial of the Effects of Cognitive Training on Cerebral Blood Flow. %A Beishon, Lucy C %A Panerai, Ronney B %A Budgeon, Charley %A Subramaniam, Hari %A Mukaetova-Ladinska, Elizabeta %A Robinson, Thompson G %A Haunton, Victoria J %X

BACKGROUND: Cognitive training (CT) has demonstrated benefits for healthy older adults (HG) and mild cognitive impairment (MCI), but the effects on vascular function are unknown.

OBJECTIVE: This is a feasibility trial investigating the effects of CT on cerebral blood flow velocity (CBFv).

METHODS: Twenty HG, 24 with Alzheimer's disease (AD), and 12 with MCI were randomized to 12 weeks of multi-domain CT or control. Outcomes included: cognition (Addenbrooke's Cognitive Examination III), mood, quality of life (QoL), physical, and neurovascular function (transcranial Doppler ultrasonography measured task activation of CBFv responses). Data are presented as mean difference (MD) and 95% confidence interval (CI).

RESULTS: 47 participants completed the trial. There were three dropouts from the training arm in the AD group, and one in the HG group. The intervention was acceptable and feasible to the majority of participants with a high completion rate (89%). The dropout rate was higher among participants with dementia. Few changes were identified on secondary analyses, but QoL was significantly improved in HG post-training (MD: 4.83 [95% CI: 1.13, 8.54]). CBFv response rate was not significantly different in HG (MD: 1.84 [95% CI: -4.81, 1.12]), but a significant increase was seen in the patient group (MD: 1.79 [95% CI: 0.005, 3.58]), requiring sample sizes of 56 and 84 participants respectively for a fully-powered trial.

CONCLUSION: A 12-week CT program was acceptable and feasible in HG, AD, and MCI. CT may be associated with alterations in vascular physiology which require further investigation in an appropriately powered randomized controlled trial.

%B J Alzheimers Dis %V 80 %P 1567-1581 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201444 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cognition at Each Stage of Lewy Body Disease with Co-occurring Alzheimer's Disease Pathology. %A Ryman, Sephira G %A Yutsis, Maya %A Tian, Lu %A Henderson, Victor W %A Montine, Thomas J %A Salmon, David P %A Galasko, Douglas %A Poston, Kathleen L %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Cognitive Dysfunction %K Female %K Humans %K Lewy Body Disease %K Male %X

BACKGROUND: Alzheimer's disease neuropathologic change (ADNC) may contribute to dementia in patients with Lewy body disease (LBD) pathology.

OBJECTIVE: To examine how co-occurring ADNC impacts domain specific cognitive impairments at each pathologic stage (brainstem, limbic, cerebral cortical) of LBD.

METHODS: 2,433 participants with antemortem longitudinal neuropsychological assessment and postmortem neuropathological assessment from the National Alzheimer's Coordinating Center's Uniform Data Set were characterized based on the evaluation of ADNC and LBD. Longitudinal mixed-models were used to derive measures of cumulative cognitive deficit for each cognitive domain at each pathologic stage of LBD (brainstem, limbic, and cerebral cortical).

RESULTS: 111 participants with a pathologic diagnosis of LBD, 741 participants with combined LBD and ADNC, 1,357 participants with ADNC only, and 224 with no pathology (healthy controls) were included in the analyses. In the executive/visuospatial domain, combined LBD and ADNC showed worse deficits than LBD only when Lewy bodies were confined to the brainstem, but no difference when Lewy bodies extended to the limbic or cerebral cortical regions. The cerebral cortical LBD only group exhibited greater executive/visuospatial deficits than the ADNC only group. By contrast, the ADNC only group and the combined pathology group both demonstrated significantly greater cumulative memory deficits relative to Lewy body disease only, regardless of stage.

CONCLUSION: The impact of co-occurring ADNC on antemortem cumulative cognitive deficits varies not only by domain but also on the pathological stage of Lewy bodies. Our findings stress the cognitive impact of different patterns of neuropathological progression in Lewy body diseases.

%B J Alzheimers Dis %V 80 %P 1243-1256 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646154?dopt=Abstract %R 10.3233/JAD-201187 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cognitive Effects of Aerobic Exercise in Alzheimer's Disease: A Pilot Randomized Controlled Trial. %A Yu, Fang %A Vock, David M %A Zhang, Lin %A Salisbury, Dereck %A Nelson, Nathaniel W %A Chow, Lisa S %A Smith, Glenn %A Barclay, Terry R %A Dysken, Maurice %A Wyman, Jean F %X

BACKGROUND: Aerobic exercise has shown inconsistent cognitive effects in older adults with Alzheimer's disease (AD) dementia.

OBJECTIVE: To examine the immediate and longitudinal effects of 6-month cycling on cognition in older adults with AD dementia.

METHODS: This randomized controlled trial randomized 96 participants (64 to cycling and 32 to stretching for six months) and followed them for another six months. The intervention was supervised, moderate-intensity cycling for 20-50 minutes, 3 times a week for six months. The control was light-intensity stretching. Cognition was assessed at baseline, 3, 6, 9, and 12 months using the AD Assessment Scale-Cognition (ADAS-Cog). Discrete cognitive domains were measured using the AD Uniform Data Set battery.

RESULTS: The participants were 77.4±6.8 years old with 15.6±2.9 years of education, and 55%were male. The 6-month change in ADAS-Cog was 1.0±4.6 (cycling) and 0.1±4.1 (stretching), which were both significantly less than the natural 3.2±6.3-point increase observed naturally with disease progression. The 12-month change was 2.4±5.2 (cycling) and 2.2±5.7 (control). ADAS-Cog did not differ between groups at 6 (p = 0.386) and 12 months (p = 0.856). There were no differences in the 12-month rate of change in ADAS-Cog (0.192 versus 0.197, p = 0.967), memory (-0.012 versus -0.019, p = 0.373), executive function (-0.020 versus -0.012, p = 0.383), attention (-0.035 versus -0.033, p = 0.908), or language (-0.028 versus -0.026, p = 0.756).

CONCLUSION: Exercise may reduce decline in global cognition in older adults with mild-to-moderate AD dementia. Aerobic exercise did not show superior cognitive effects to stretching in our pilot trial, possibly due to the lack of power.

%B J Alzheimers Dis %V 80 %P 233-244 %8 2021 Mar 9 %G eng %N 1 %R 10.3233/JAD-201100 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cognitive Effects of the BET Protein Inhibitor Apabetalone: A Prespecified Montreal Cognitive Assessment Analysis Nested in the BETonMACE Randomized Controlled Trial. %A Cummings, Jeffrey %A Schwartz, Gregory G %A Nicholls, Stephen J %A Khan, Aziz %A Halliday, Chris %A Toth, Peter P %A Sweeney, Michael %A Johansson, Jan O %A Wong, Norman C W %A Kulikowski, Ewelina %A Kalantar-Zadeh, Kamyar %A Lebioda, Kenneth %A Ginsberg, Henry N %A Winblad, Bengt %A Zetterberg, Henrik %A Ray, Kausik K %K Aged %K Cardiovascular Diseases %K Cognitive Dysfunction %K Epigenesis, Genetic %K Female %K Humans %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Quinazolinones %X

BACKGROUND: Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer's disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic "readers" that may distort normal gene expression and contribute to chronic disorders.

OBJECTIVE: To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE).

METHODS: The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. 464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score≥26 (normal performance), MoCA score 25-22 (mild cognitive impairment), and MoCA score≤21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group.

RESULTS: Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of≤21 (p = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%).

CONCLUSION: In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.

%B J Alzheimers Dis %V 83 %P 1703-1715 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/34459400?dopt=Abstract %R 10.3233/JAD-210570 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Combining Multimodal Behavioral Data of Gait, Speech, and Drawing for Classification of Alzheimer's Disease and Mild Cognitive Impairment. %A Yamada, Yasunori %A Shinkawa, Kaoru %A Kobayashi, Masatomo %A Caggiano, Vittorio %A Nemoto, Miyuki %A Nemoto, Kiyotaka %A Arai, Tetsuaki %K Aged %K Alzheimer Disease %K Cognitive Dysfunction %K Female %K Gait %K Humans %K Male %K Neuropsychological Tests %K Speech %X

BACKGROUND: Gait, speech, and drawing behaviors have been shown to be sensitive to the diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, previous studies focused on only analyzing individual behavioral modalities, although these studies suggested that each of these modalities may capture different profiles of cognitive impairments associated with AD.

OBJECTIVE: We aimed to investigate if combining behavioral data of gait, speech, and drawing can improve classification performance compared with the use of individual modality and if each of these behavioral data can be associated with different cognitive and clinical measures for the diagnosis of AD and MCI.

METHODS: Behavioral data of gait, speech, and drawing were acquired from 118 AD, MCI, and cognitively normal (CN) participants.

RESULTS: Combining all three behavioral modalities achieved 93.0% accuracy for classifying AD, MCI, and CN, and only 81.9% when using the best individual behavioral modality. Each of these behavioral modalities was statistically significantly associated with different cognitive and clinical measures for diagnosing AD and MCI.

CONCLUSION: Our findings indicate that these behaviors provide different and complementary information about cognitive impairments such that classification of AD and MCI is superior to using either in isolation.

%B J Alzheimers Dis %V 84 %P 315-327 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34542076?dopt=Abstract %R 10.3233/JAD-210684 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Copper Imbalance in Alzheimer's Disease and Its Link with the Amyloid Hypothesis: Towards a Combined Clinical, Chemical, and Genetic Etiology. %A Squitti, Rosanna %A Faller, Peter %A Hureau, Christelle %A Granzotto, Alberto %A White, Anthony R %A Kepp, Kasper P %X

The cause of Alzheimer's disease (AD) is incompletely defined. To date, no mono-causal treatment has so far reached its primary clinical endpoints, probably due to the complexity and diverse neuropathology contributing to the neurodegenerative process. In the present paper, we describe the plausible etiological role of copper (Cu) imbalance in the disease. Cu imbalance is strongly associated with neurodegeneration in dementia, but a complete biochemical etiology consistent with the clinical, chemical, and genetic data is required to support a causative association, rather than just correlation with disease. We hypothesize that a Cu imbalance in the aging human brain evolves as a gradual shift from bound metal ion pools, associated with both loss of energy production and antioxidant function, to pools of loosely bound metal ions, involved in gain-of-function oxidative stress, a shift that may be aggravated by chemical aging. We explain how this may cause mitochondrial deficits, energy depletion of high-energy demanding neurons, and aggravated protein misfolding/oligomerization to produce different clinical consequences shaped by the severity of risk factors, additional comorbidities, and combinations with other types of pathology. Cu imbalance should be viewed and integrated with concomitant genetic risk factors, aging, metabolic abnormalities, energetic deficits, neuroinflammation, and the relation to tau, prion proteins, α-synuclein, TAR DNA binding protein-43 (TDP-43) as well as systemic comorbidity. Specifically, the Amyloid Hypothesis is strongly intertwined with Cu imbalance because amyloid-β protein precursor (AβPP)/Aβ are probable Cu/Zn binding proteins with a potential role as natural Cu/Zn buffering proteins (loss of function), and via the plausible pathogenic role of Cu-Aβ.

%B J Alzheimers Dis %V 83 %P 23-41 %8 2021 Aug 31 %G eng %N 1 %R 10.3233/JAD-201556 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cortical Thickness and Its Association with Clinical Cognitive and Neuroimaging Markers in Cerebral Amyloid Angiopathy. %A Subotic, Arsenije %A McCreary, Cheryl R %A Saad, Feryal %A Nguyen, Amanda %A Alvarez-Veronesi, Ana %A Zwiers, Angela M %A Charlton, Anna %A Beaudin, Andrew E %A Ismail, Zahinoor %A Bruce Pike, G %A Smith, Eric E %X

BACKGROUND: Cerebral amyloid angiopathy (CAA) contributes to brain neurodegeneration and cognitive decline, but the relationship between these two processes is incompletely understood.

OBJECTIVE: The purpose of this study is to examine cortical thickness and its association with cognition and neurodegenerative biomarkers in CAA.

METHODS: Data were collected from the Functional Assessment of Vascular Reactivity study and the Calgary Normative Study. In total, 48 participants with probable CAA, 72 cognitively normal healthy controls, and 24 participants with mild dementia due to AD were included. Participants underwent an MRI scan, after which global and regional cortical thickness measurements were obtained using FreeSurfer. General linear models, adjusted for age and sex, were used to compare cortical thickness globally and in an AD signature region.

RESULTS: Global cortical thickness was lower in CAA compared to healthy controls (mean difference (MD) -0.047 mm, 95% confidence interval (CI) -0.088, -0.005, p = 0.03), and lower in AD compared to CAA (MD -0.104 mm, 95% CI -0.165, -0.043, p = 0.001). In the AD signature region, cortical thickness was lower in CAA compared to healthy controls (MD -0.07 mm, 95% CI -0.13 to -0.01, p = 0.02). Within the CAA group, lower cortical thickness was associated with lower memory scores (R2 = 0.10; p = 0.05) and higher white matter hyperintensity volume (R2 = 0.09, p = 0.04).

CONCLUSION: CAA contributes to neurodegeneration in the form of lower cortical thickness, and this could contribute to cognitive decline. Regional overlap with an AD cortical atrophy signature region suggests that co-existing AD pathology may contribute to lower cortical thickness observed in CAA.

%B J Alzheimers Dis %V 81 %P 1663-1671 %8 2021 Jun 15 %G eng %N 4 %R 10.3233/JAD-210138 %0 Journal Article %J J Alzheimers Dis %D 2021 %T A Cost-Consequence Analysis of Different Screening Procedures in Alzheimer's Disease: Results from the MOPEAD Project. %A Wimo, Anders %A Belger, Mark %A Bon, Jaka %A Jessen, Frank %A Dumas, Annette %A Kramberger, Milica G %A Jamilis, Laura %A Johansson, Gunilla %A Rodrigo Salas, Adrián %A Rodríguez Gómez, Octavio %A Sannemann, Lena %A Stoekenbroek, Malou %A Gurruchaga Telleria, Miren %A Valero, Sergi %A Vermunt, Lisa %A Waterink, Lisa %A Winblad, Bengt %A Visser, Peter Jelle %A Zwan, Marissa %A Boada, Merce %X

BACKGROUND: For care planning and support, under-detection and late diagnosis of Alzheimer's disease (AD) is a great challenge. Models of Patient-Engagement for Alzheimer's Disease (MOPEAD) is an EU-funded project aiming at testing different strategies to improve this situation.

OBJECTIVE: To make a cost-consequence analysis of MOPEAD.

METHODS: Four screening strategies were tested in five countries (Germany, the Netherlands, Slovenia, Spain, and Sweden): 1) a web-approach; 2) Open-House initiative; 3) in primary care; and 4) by diabetes specialists. Persons-at-risk of AD in all strategies were offered referral to a hospital-based specialist. The primary health-economic outcome was the cost per true-positive case (TP) of AD from the screened population.

RESULTS: Of 2,847 screened persons, 1,121 screened positive (39%), 402 were evaluated at memory clinics (14%), and 236 got an AD diagnosis (8%). The cost per TP of those screened was 3,115€ with the web-approach, 2,722€ with the Open-House, 1,530€ in primary care, and 1,190€ by diabetes specialists. Sensitivity analyses that more likely reflect the real-world situation confirmed the results. The number-needed-to-screen was 30 with the web-approach, 8 with the Open-House and primary care, and 6 with the diabetes specialists.There were country differences in terms of screening rates, referrals to memory clinics, staff-types involved, and costs per TP.

CONCLUSION: In primary care and by the diabetes specialist, the costs per TP/screened population were lowest, but the capacity of such settings to identify cases with AD-risk must be discussed. Hence new diagnostic strategies such as web-solutions and Open-House initiatives may be valuable after modifications.

%B J Alzheimers Dis %V 83 %P 1149-1159 %8 2021 Sep 28 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34420954?dopt=Abstract %R 10.3233/JAD-210303 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Could Altered Evoked Pain Responsiveness Be a Phenotypic Biomarker for Alzheimer's Disease Risk? A Cross-Sectional Analysis of Cognitively Healthy Individuals. %A Romano, Raymond R %A Carter, Michael A %A Dietrich, Mary S %A Cowan, Ronald L %A Bruehl, Stephen P %A Monroe, Todd B %K Adult %K Aged %K Aged, 80 and over %K Alleles %K Alzheimer Disease %K Apolipoprotein E4 %K Biomarkers %K Cross-Sectional Studies %K Female %K Genetic Association Studies %K Hot Temperature %K Humans %K Male %K Middle Aged %K Pain Perception %K Phenotype %K Risk Factors %X

BACKGROUND: This study evaluated whether the apolipoprotein ɛ4 (APOE4) allele, a genetic marker associated with increased risk of developing late-onset Alzheimer's disease (AD), was associated with differences in evoked pain responsiveness in cognitively healthy subjects.

OBJECTIVE: The aim was to determine whether individuals at increased risk of late-onset AD based on APOE allele genotype differ phenotypically in their response to experimentally-induced painful stimuli compared to those who do not have at least one copy of the ɛ4 allele.

METHODS: Forty-nine cognitively healthy subjects aged 30-89 years old with the APOE4 allele (n = 12) and without (n = 37) were assessed for group differences in pain thresholds and affective (unpleasantness) responses to experimentally-induced thermal pain stimuli.

RESULTS: Statistically significant main effects of APOE4 status were observed for both the temperature at which three different pain intensity percepts were reached (p = 0.040) and the level of unpleasantness associated with each (p = 0.014). APOE4 positive participants displayed lower overall pain sensitivity than those who were APOE4 negative and also greater overall levels of pain unpleasantness regardless of intensity level.

CONCLUSION: Cognitively healthy APOE4 carriers at increased risk of late-onset AD demonstrated reduced thermal pain sensitivity but greater unpleasantness to thermal pain stimuli relative to individuals at lower risk of late-onset AD. These results suggest that altered evoked pain perception could potentially be used as a phenotypic biomarker of late-onset AD risk prior to disease onset. Additional studies of this issue may be warranted.

%B J Alzheimers Dis %V 79 %P 1227-1233 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33337380?dopt=Abstract %R 10.3233/JAD-201293 %0 Journal Article %J J Alzheimers Dis %D 2021 %T COVID-19: Association Between Increase of Behavioral and Psychological Symptoms of Dementia During Lockdown and Caregivers' Poor Mental Health. %A Pongan, Elodie %A Dorey, Jean-Michel %A Borg, Céline %A Getenet, Jean Claude %A Bachelet, Romain %A Lourioux, Charles %A Laurent, Bernard %A Rey, Romain %A Rouch, Isabelle %K Aged %K Aged, 80 and over %K Caregivers %K Communicable Disease Control %K COVID-19 %K Cross-Sectional Studies %K Dementia %K Female %K France %K Humans %K Male %K Mental Disorders %K Mental Health %K Middle Aged %K Surveys and Questionnaires %X

BACKGROUND: From March 2020, the support and care systems for caregivers and people with dementia (PWD) were suspended or dramatically changed due to the lockdown during the world pandemic of COVID-19. Thus, these changes in living conditions have had deleterious consequences on the behavior of PWD and subsequently on their caregivers' mental health, the two being linked.

OBJECTIVE: Our study aimed to examine changes in behavior among PWD and to look for associations between the evolution of behavioral and psychological symptoms of dementia (BPSD) and caregivers' mental health in the context of COVID-19.

METHODS: The study was conducted among caregivers of PWD living at home in France. Caregivers were interviewed via an anonymous cross-sectional online survey during the first lockdown between April 15 and June 15, 2020.

RESULTS: Three hundred and eighty-nine caregivers accompanying a relative living at home participated in the study; 43.3%of the PWD presented a worsening of BPSD during the lockdown. With multivariate logistic regressions, a significant association was observed between "more BPSD" and burden, anxiety and depression, between "BPSD equivalent" and anxiety and depression, and between "emerging BPSD" and only depression.

CONCLUSION: The lockdown seems to have an impact on behavioral disorders in PWD and these disorders are associated with poorer mental health of caregivers. Our findings suggest attention should be given to caregivers of PWD who have BPSD before lockdown and the need for continued consultations and professional help in case of new lockdowns.

%B J Alzheimers Dis %V 80 %P 1713-1721 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646163?dopt=Abstract %R 10.3233/JAD-201396 %0 Journal Article %J J Alzheimers Dis %D 2021 %T COVID-19 Crisis Effects on Caregiver Distress in Neurocognitive Disorder. %A Alexopoulos, Panagiotis %A Soldatos, Rigas %A Kontogianni, Evangelia %A Frouda, Maria %A Loanna Aligianni, Souzana %A Skondra, Maria %A Passa, Maria %A Konstantopoulou, Georgia %A Stamouli, Evangelia %A Katirtzoglou, Evgenia %A Politis, Anastasios %A Economou, Polychronis %A Alexaki, Maria %A Siarkos, Kostas %A Politis, Antonios %K Aged %K Aged, 80 and over %K Caregivers %K COVID-19 %K Female %K Greece %K Humans %K Male %K Middle Aged %K Neurocognitive Disorders %K Quarantine %X

BACKGROUND: The outbreak of the COVID-19 pandemic seems to have mental health implications for both people with neurocognitive disorder and their caregivers.

OBJECTIVE: The study aimed to shed light on relations between caregiver mental reaction to the pandemic and caregiver distress related to neuropsychiatric symptoms, memory impairment progression, and functional impairment of people with neurocognitive disorder during the period of confinement in Greece.

METHODS: The study included caregivers of patients with mild (N = 13) and major (N = 54) neurocognitive disorder. The caregiver-based telephone interview was based on items of the neuropsychiatric inventory questionnaire, the AD8 Dementia Screening Instrument, and the Bristol Activities of Daily Living Scale. Regarding the mental impact of the COVID-19 crisis on caregivers, four single questions referring to their worries in the last seven days were posed, in addition to the scales Generalized Anxiety Disorder 7-Item (GAD-7) and the 22-item Impact of Event Scale-revised (IES-R). A stepwise linear regression model was employed for studying the relationship between caregiver distress and demographic and clinical data and caregiver mental reaction to COVID-19 pandemic outbreak.

RESULTS: Caregiver distress severity during the confinement period was influenced not only by memory deficits (p = 0.009) and neuropsychiatric symptoms (p < 0.001) of patients, but also by caregiver hyperarousal (p = 0.003) and avoidance symptoms (p = 0.033) and worries directly linked to the COVID-19 crisis (p = 0.022).

CONCLUSION: These observations provide further evidence for the urgent need for support of caregivers of patients with neurocognitive disorder during the COVID-19 pandemic.

%B J Alzheimers Dis %V 79 %P 459-466 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33185608?dopt=Abstract %R 10.3233/JAD-200991 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Current and Future Prevalence Estimates of Mild Cognitive Impairment, Dementia, and Its Subtypes in a Population-Based Sample of People 70 Years and Older in Norway: The HUNT Study. %A GjØra, Linda %A Strand, Bjørn Heine %A Bergh, Sverre %A Borza, Tom %A Brækhus, Anne %A Engedal, Knut %A Johannessen, Aud %A Kvello-Alme, Marte %A Krokstad, Steinar %A Livingston, Gill %A Matthews, Fiona E %A Myrstad, Christian %A Skjellegrind, Håvard %A Thingstad, Pernille %A Aakhus, Eivind %A Aam, Stina %A Selbæk, Geir %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Dementia %K Female %K Forecasting %K Humans %K Male %K Mental Status and Dementia Tests %K Neuropsychological Tests %K Norway %K Prevalence %K Sex Factors %K Surveys and Questionnaires %X

BACKGROUND: Having accurate, up-to-date information on the epidemiology of mild cognitive impairment (MCI) and dementia is imperative.

OBJECTIVE: To determine the prevalence of MCI and dementia in Norway using data from a large population-based study.

METHODS: All people 70 + years of age, n = 19,403, in the fourth wave of the Trøndelag Health Study (HUNT4) were invited to participate in the study HUNT4 70 + . Trained health personnel assessed participants using cognitive tests at a field station, at homes, or at their nursing home. Interviewers also completed a structured carer questionnaire in regard to participants suspected of having dementia. Clinical experts made diagnoses according to DSM-5 criteria. We calculated prevalence weighing the data to ensure population representativeness.

RESULTS: A total of 9,930 (51.2%) of the possible 19,403 people participated, and 9,663 of these had sufficient information for analysis. Standardized prevalence of dementia and MCI was 14.6% (95% confidence interval (CI) 13.9-15.4) and 35.3% (95% CI 34.3-36.4), respectively. Dementia was more prevalent in women and MCI more prevalent in men. The most prevalent dementia subtype was Alzheimer's disease (57%). By adding data collected from a study of persons < 70 years in the same region, we estimate that there are 101,118 persons with dementia in Norway in 2020, and this is projected to increase to 236,789 and 380,134 in 2050 and 2100, respectively.

CONCLUSION: We found a higher prevalence of dementia and MCI than most previous studies. The present prevalence and future projections are vital for preparing for future challenges to the healthcare system and the entire society.

%B J Alzheimers Dis %V 79 %P 1213-1226 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33427745?dopt=Abstract %R 10.3233/JAD-201275 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Current Status and Challenges of Stem Cell Treatment for Alzheimer's Disease. %A Pacheco-Herrero, Mar %A Soto-Rojas, Luis O %A Reyes-Sabater, Heidy %A Garcés-Ramirez, Linda %A de la Cruz López, Fidel %A Villanueva-Fierro, Ignacio %A Luna-Muñoz, José %K Alzheimer Disease %K Amyloid %K Government Regulation %K Hippocampus %K Humans %K Neocortex %K Neurofibrillary Tangles %K Plaque, Amyloid %K Stem Cells %K tau Proteins %X

Neurodegenerative diseases called tauopathies, such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease, among others, are characterized by the pathological processing and accumulation of tau protein. AD is the most prevalent neurodegenerative disease and is characterized by two lesions: neurofibrillary tangles (NFTs) and neuritic plaques. The presence of NFTs in the hippocampus and neocortex in early and advanced stages, respectively, correlates with the patient's cognitive deterioration. So far, no drugs can prevent, decrease, or limit neuronal death due to abnormal pathological tau accumulation. Among potential non-pharmacological treatments, physical exercise has been shown to stimulate the development of stem cells (SCs) and may be useful in early stages. However, this does not prevent neuronal death from the massive accumulation of NFTs. In recent years, SCs therapies have emerged as a promising tool to repopulate areas involved in cognition in neurodegenerative diseases. Unfortunately, protocols for SCs therapy are still being developed and the mechanism of action of such therapy remains unclear. In this review, we show the advances and limitations of SCs therapy. Finally, we provide a critical analysis of its clinical use for AD.

%B J Alzheimers Dis %V 84 %P 917-935 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34633316?dopt=Abstract %R 10.3233/JAD-200863 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Deaths with Dementia in Indigenous and Non-Indigenous Australians: A Nationwide Study. %A Waller, Michael %A Buckley, Rachel F %A Masters, Colin L %A Nona, Francis R %A Eades, Sandra %A Dobson, Annette J %X

BACKGROUND: The prevalence of dementia is generally reported to be higher among Indigenous peoples.

OBJECTIVE: The rates and coding of dementia mortality were compared between Indigenous and non-Indigenous Australians.

METHODS: De-identified individual records on causes of death for all people aged 40 years or more who died in Australia between 2006 and 2014 (n = 1,233,084) were used. There were 185,237 records with International Classification of Diseases, Tenth Revision, codes for dementia (Alzheimer's Disease, vascular dementia, or unspecified dementia) as the underlying cause of death or mentioned elsewhere on the death certificate. Death rates were compared using Poisson regression. Logistic regression was used to assess whether dementia was more likely to be classified as 'unspecified' type in Indigenous Australians.

RESULTS: The rates of death with dementia were 57% higher in Indigenous Australians, compared to non-Indigenous, relative rate (RR) 1.57, 95% confidence interval (CI) (1.48, 1.66), p <  0.0001. This excess of deaths was highest at ages below 75 (RRs >  2, test for interaction p <  0.0001), and among men (test for interaction p <  0.0001). When the underreporting of Indigenous status on the death certificate was taken into account the relative rate increased to 2.17, 95% CI (2.07, 2.29). Indigenous Australians were also more likely to have their dementia coded as 'unspecified' on their death certificate (Odds Ratio 1.92, 95% CI (1.66, 2.21), p <  0.0001), compared to the non-Indigenous group.

CONCLUSION: This epidemiological analysis based on population level mortality data demonstrates the higher dementia-related mortality rate for Indigenous Australians especially at younger ages.

%B J Alzheimers Dis %V 81 %P 1589-1599 %8 2021 Jun 15 %G eng %N 4 %R 10.3233/JAD-201175 %0 Journal Article %J J Alzheimers Dis %D 2021 %T A Decade of Decline in Serious Cognitive Problems Among Older Americans: A Population-Based Study of 5.4 Million Respondents. %A Fuller-Thomson, Esme %A Ahlin, Katherine Marie %X

BACKGROUND: Numerous studies suggest the prevalence of dementia has decreased over the past several decades in Western countries. Less is known about whether these trends differ by gender or age cohort, and if generational differences in educational attainment explain these trajectories.

OBJECTIVE: 1) To detect temporal trends in the age-sex-race adjusted prevalence of serious cognitive problems among Americans aged 65+; 2) To establish if these temporal trends differ by gender and age cohort; 3) To examine if these temporal trends are attenuated by generational differences in educational attainment.

METHODS: Secondary analysis of 10 years of annual nationally representative data from the American Community Survey with 5.4 million community-dwelling and institutionalized older adults aged 65+. The question on serious cognitive problems was, "Because of a physical, mental, or emotional condition, does this person have serious difficulty concentrating, remembering, or making decisions?"

RESULTS: The prevalence of serious cognitive problems in the US population aged 65 and older declined from 12.2%to 10.0%between 2008 and 2017. Had the prevalence remained at the 2008 levels, there would have been an additional 1.13 million older Americans with serious cognitive problems in 2017. The decline in memory problems across the decade was higher for women (23%) than for men (13%). Adjusting for education substantially attenuated the decline.

CONCLUSION: Between 2008 and 2017, the prevalence of serious cognitive impairment among older Americans declined significantly, although these declines were partially attributable to generational differences in educational attainment.

%B J Alzheimers Dis %V 85 %P 141-151 %8 2022 Jan 04 %G eng %N 1 %R 10.3233/JAD-210561 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Deciphering Alzheimer's Disease Pathogenic Pathway: Role of Chronic Brain Hypoperfusion on p-Tau and mTOR. %A de la Torre, Jack C %X

This review examines new biomolecular findings that lend support to the hemodynamic role played by chronic brain hypoperfusion (CBH) in driving a pathway to Alzheimer's disease (AD). CBH is a common clinical feature of AD and the current topic of intense investigation in AD models. CBH is also the basis for the vascular hypothesis of AD which we originally proposed in 1993. New biomolecular findings reveal the interplay of CBH in increasing tau phosphorylation (p-Tau) in the hippocampus and cortex of AD mice, damaging fast axonal transport, increasing signaling of mammalian target of rapamycin (mTOR), impairing learning-memory function, and promoting the formation of neurofibrillary tangles, a neuropathologic hallmark of AD. These pathologic elements have been singularly linked with neurodegeneration and AD but their abnormal, collective participation during brain aging have not been fully examined. The format for this review will provide a consolidated analysis of each pathologic phase contributing to cognitive decline and AD onset, summarized in nine chronological steps. These steps galvanize each factor's active participation and contribution in constructing a biomolecular pathway to AD onset generated by CBH.

%B J Alzheimers Dis %V 79 %P 1381-1396 %8 2021 Feb 16 %G eng %N 4 %R 10.3233/JAD-201165 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Dementia and COVID-19, a Bidirectional Liaison: Risk Factors, Biomarkers, and Optimal Health Care. %A Toniolo, Sofia %A Scarioni, Marta %A Di Lorenzo, Francesco %A Hort, Jakub %A Georges, Jean %A Tomic, Svetlana %A Nobili, Flavio %A Frederiksen, Kristian Steen %K Alzheimer Disease %K Biomarkers %K Brain %K Cognitive Dysfunction %K Comorbidity %K COVID-19 %K Humans %K Neuroimaging %K Neuroimmunomodulation %K Patient Care %K SARS-CoV-2 %X

Cognitive impairment following SARS-CoV-2 infection is being increasingly recognized as an acute and possibly also long-term sequela of the disease. Direct viral entry as well as systemic mechanisms such as cytokine storm are thought to contribute to neuroinflammation in these patients. Biomarkers of COVID-19-induced cognitive impairment are currently lacking, but there is some limited evidence that SARS-CoV-2 could preferentially target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET. Possible confounders include cognitive impairment due to hypoxia and mechanical ventilation and post-traumatic stress disorder. Conversely, patients already suffering from dementia, as well as their caregivers, have been greatly impacted by the disruption of their care caused by COVID-19. Patients with dementia have experienced worsening of cognitive, behavioral, and psychological symptoms, and the rate of COVID-19-related deaths is disproportionately high among cognitively impaired people. Multiple factors, such as difficulties in remembering and executing safeguarding procedures, age, comorbidities, residing in care homes, and poorer access to hospital standard of care play a role in the increased morbidity and mortality. Non-pharmacological interventions and new technologies have shown a potential for the management of patients with dementia, and for the support of their caregivers.

%B J Alzheimers Dis %V 82 %P 883-898 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34092646?dopt=Abstract %R 10.3233/JAD-210335 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Dementia and Parkinson's Disease: Risk Factors for 30-Day Mortality in Nursing Home Residents with COVID-19. %A Rutten, Jeanine J S %A van Kooten, Janine %A van Loon, Anouk M %A van Buul, Laura W %A Joling, Karlijn J %A Smalbrugge, Martin %A Hertogh, Cees M P M %X

BACKGROUND: The COVID-19 pandemic has led to high mortality rates in nursing homes (NHs) in Europe. For adequate risk management and good prognostications, it is essential to identify mortality risk factors.

OBJECTIVE: This study aimed to determine whether previously identified risk factors for 30-day mortality in Dutch NH residents with COVID-19 are unique to COVID-19.

METHODS: In this cohort study, we included 1,294 NH residents with COVID-19 (cases) and 17,999 NH residents without COVID-19 (controls, from the pre-COVID-19 period). We used descriptive statistics and Cox proportional hazard models to compare mortality rates in residents with and without COVID-19, categorized by risk factors.

RESULTS: Cases had a more than 18 times higher hazard of death within 30 days compared to controls (HR 18, 95%CI: 16-20). For residents with COVID-19, being male, having dementia, and having Parkinson's disease (PD) were all associated with a higher 30-day mortality (HR 1.8 versus 1.3 versus 1.7). Being male was also associated with a higher mortality (HR 1.7) in the control group, whereas having dementia and PD were not. COVID-19 symptomatology was very similar for residents with and without dementia or PD, except for delirium and malaise which was more frequent in residents with dementia.

CONCLUSION: Dementia and PD were significant additional risk factors for mortality in Dutch NH residents with COVID-19, whereas male gender was not unique to residents with COVID-19. The frailty of PD and dementia in NH residents with COVID-19 are relevant to consider in prognostication, communication, and care planning with residents and their families.

%B J Alzheimers Dis %V 84 %P 1173-1181 %8 2021 Nov 23 %G eng %N 3 %R 10.3233/JAD-210319 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Dementia-Friendly "Design": Impact on COVID-19 Death Rates in Long-Term Care Facilities Around the World. %A Olson, Nancy L %A Albensi, Benedict C %K COVID-19 %K Dementia %K Environment Design %K Health Services Needs and Demand %K Humans %K Long-Term Care %K Pandemics %K Quality of Life %X

Persons with dementia (PWD) make up a large portion of the long-term care (LTC) population the world over. Before a global pandemic swept the world, governments and healthcare providers struggled with how to best care for this unique population. One of the greatest challenges is a PWD's tendency to "walk with purpose" and exhibit unsafe wayfinding and elopement, which places them at risk of falls and injury. Past solutions included increased use of restraints and pharmacological interventions, but these have fallen out of favor over the years and are not optimal. These challenges put enormous strain on staff and caregivers, who are often poorly trained in dementia care, underpaid, overworked, and overstressed. PWD are impacted by these stresses, and unmet needs in LTC places an even greater stress on them and increases their risks of morbidity and mortality. The physical design of their environments contributes to the problem. Old, institutionalized buildings have poor lighting, poor ventilation, long dead-end hallways, poor visual cues, lack of home-like décor, shared bedrooms and bathrooms, and are often dense and overcrowded. These design elements contribute to the four 'A's' of dementia: apathy, anxiety, agitation, and aggression, and they also contributed to the rapid spread of COVID-19 in these facilities the world over. In this review, we present current "dementia friendly" design models in the home, community, and LTC, and argue how they could have saved lives during the pandemic and reduced the stresses on both the dementia resident and the caregiver/staff.

%B J Alzheimers Dis %V 81 %P 427-450 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33814449?dopt=Abstract %R 10.3233/JAD-210017 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Depression and Dementia: The Role of Cortisol and Vascular Brain Lesions. AGES-Reykjavik Study. %A Gerritsen, Lotte %A Twait, Emma L %A Jonsson, Palmi V %A Gudnason, Vilmundur %A Launer, Lenore J %A Geerlings, Mirjam I %X

BACKGROUND: Late-life depression (LLD) is related to an increased risk of developing dementia; however, the biological mechanisms explaining this relationship remain unclear.

OBJECTIVE: To determine whether the relationship between LLD and dementia can be best explained by the glucocorticoid cascade or vascular hypothesis.

METHODS: Data are from 4,354 persons (mean age 76±5 years) without dementia at baseline from the AGES-Reykjavik Study. LLD was assessed with the MINI diagnostic interview (current and remitted major depressive disorder [MDD]) and the Geriatric Depression Scale-15. Morning and evening salivary cortisol were collected (glucocorticoid cascade hypothesis). White matter hyperintensities (WMH; vascular hypothesis) volume was assessed using 1.5T brain MRI. Using Cox proportional hazard models, we estimated the associations of LLD, cortisol levels, and WMH volume with incident all-cause dementia, AD, and non-AD dementia.

RESULTS: During 8.8±3.2 years of follow-up, 843 persons developed dementia, including 397 with AD. Current MDD was associated with an increased risk of developing all-cause dementia (HR = 2.17; 95% CI 1.66-2.67), with risks similar for AD and non-AD, while remitted MDD was not (HR = 1.02; 95% CI 0.55-1.49). Depressive symptoms were also associated with increased risk of dementia, in particular non-AD dementias. Higher levels of evening cortisol increased risk of dementia, but this was independent of MDD. WMH partially explained the relation between current MDD and dementia risk but remained increased (HR = 1.71; 95% CI 1.34-2.08).

CONCLUSION: The current study highlights the importance of LLD in developing dementia. However, neither the glucocorticoid cascade nor the vascular hypotheses fully explained the relation between depression and dementia.

%B J Alzheimers Dis %V 85 %P 1677-1687 %8 2022 Feb 15 %G eng %N 4 %R 10.3233/JAD-215241 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Depressive Symptoms Imputed Across the Life Course Are Associated with Cognitive Impairment and Cognitive Decline. %A Brenowitz, Willa D %A Zeki Al Hazzouri, Adina %A Vittinghoff, Eric %A Golden, Sherita H %A Fitzpatrick, Annette L %A Yaffe, Kristine %X

BACKGROUND: Depressive symptoms may increase risk for dementia, but findings are controversial because late-life depression may be a prodromal dementia symptom. Life course data on depression and dementia risk may clarify this association; however, data is limited.

OBJECTIVE: To impute adult depressive symptoms trajectories across adult life stages and estimate the association with cognitive impairment and decline.

METHODS: Using a pooled study of 4 prospective cohorts (ages 20-89), we imputed adult life course depressive symptoms trajectories based on Center for Epidemiologic Studies Depression Scale-10 (CESD-10) and calculated time-weighted averages for early adulthood (ages 20-49), mid-life (ages 50-69), and late-life (ages 70-89) for 6,122 older participants. Adjusted pooled logistic and mixed-effects models estimated associations of imputed depressive symptoms with two cognitive outcomes: cognitive impairment defined by established criteria and a composite cognitive score.

RESULTS: In separate models, elevated depressive symptoms in each life stage were associated with cognitive outcomes: early adulthood OR for cognitive impairment = 1.59 (95%CI: 1.35,1.87); mid-life OR = 1.94 (95%CI:1.16, 3.26); and late-life OR = 1.77 (95%CI:1.42, 2.21). When adjusted for depressive symptoms in the other life-stages, elevated depressive symptoms in early adulthood (OR = 1.73; 95%CI: 1.42,2.11) and late-life (OR = 1.43; 95%CI: 1.08,1.89) remained associated with cognitive impairment and were also associated with faster rates of cognitive decline (p <  0.05).

CONCLUSION: Imputing depressive symptom trajectories from pooled cohorts may help expand data across the life course. Our findings suggest early adulthood depressive symptoms may be a risk factor for cognitive impairment independent of mid- or late-life depressive symptoms.

%B J Alzheimers Dis %V 83 %P 1379-1389 %8 2021 Sep 28 %G eng %N 3 %R 10.3233/JAD-210588 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Diagnosing Mild Cognitive Impairment Among Racially Diverse Older Adults: Comparison of Consensus, Actuarial, and Statistical Methods. %A Devlin, Kathryn N %A Brennan, Laura %A Saad, Laura %A Giovannetti, Tania %A Hamilton, Roy H %A Wolk, David A %A Xie, Sharon X %A Mechanic-Hamilton, Dawn %X

BACKGROUND: Actuarial and statistical methods have been proposed as alternatives to conventional methods of diagnosing mild cognitive impairment (MCI), with the aim of enhancing diagnostic and prognostic validity, but have not been compared in racially diverse samples.

OBJECTIVE: We compared the agreement of consensus, actuarial, and statistical MCI diagnostic methods, and their relationship to race and prognostic indicators among diverse older adults.

METHODS: Participants (N = 354; M age = 71; 68% White, 29% Black) were diagnosed with MCI or normal cognition (NC) according to clinical consensus, actuarial neuropsychological criteria (Jak/Bondi), and latent class analysis (LCA). We examined associations with race/ethnicity, longitudinal cognitive and functional change, and incident dementia.

RESULTS: MCI rates by consensus, actuarial criteria, and LCA were 44%, 53%, and 41%, respectively. LCA identified three MCI subtypes (memory; memory/language; memory/executive) and two NC classes (low normal; high normal). Diagnostic agreement was substantial, but agreement of the actuarial method with consensus and LCA was weaker than the agreement between consensus and LCA. Among cases classified as MCI by actuarial criteria only, Black participants were over-represented, and outcomes were generally similar to those of NC participants. Consensus diagnoses best predicted longitudinal outcomes overall, whereas actuarial diagnoses best predicted longitudinal functional change among Black participants.

CONCLUSION: Consensus diagnoses optimize specificity in predicting dementia, but among Black older adults, actuarial diagnoses may be more sensitive to early signs of decline. Results highlight the need for cross-cultural validity in MCI diagnosis and should be explored in community- and population-based samples.

%B J Alzheimers Dis %V 85 %P 627-644 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-210455 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Diet May Moderate the Relationship Between Arterial Stiffness and Cognitive Performance in Older Adults. %A Gauci, Sarah %A Young, Lauren M %A White, David J %A Reddan, Jeffery M %A Lassemillante, Annie-Claude %A Meyer, Denny %A Pipingas, Andrew %A Scholey, Andrew %X

BACKGROUND: Cognitive decline is influenced by various factors including diet, cardiovascular disease, and glucose control. However, the combined effect of these risk factors on cognitive performance is yet to be fully understood.

OBJECTIVE: The current study aimed to explore the inter-relationship between these risk factors and cognitive performance in older adults at risk of future cognitive decline.

METHODS: The sample comprised 163 (Age: M = 65.23 years, SD = 6.50) participants. Food Frequency Questionnaire data was used to score diet quality and adherence to the Western Style Diet (WSD) and Prudent Style Diet (PSD). Glucose control was gauged by serum levels of glycated hemoglobin (HbA1c) and arterial stiffness was measured using carotid to femoral pulse wave velocity. Cognitive performance was assessed using two subtests of the Swinburne University Computerized Cognitive Assessment Battery (SUCCAB) and Rey's Verbal Learning Test (RVLT).

RESULTS: Diet quality, adherence to the WSD or PSD, and glucose control were not significantly related to cognitive outcomes. However, a significant negative association was found between arterial stiffness and the spatial working memory subtest of SUCCAB (β= -0.21, p <  0.05). Arterial stiffness also significantly interacted with the PSD to impact total recall (F change (1,134) = 5.37, p <  0.05) and the composite score of RVLT (F change (1,134) = 4.03, p <  0.05).

CONCLUSION: In this sample of older adults at risk of cognitive decline, diet alone was not found to predict cognitive performance; however, it was found to moderate the relationship between arterial stiffness and cognition.

%B J Alzheimers Dis %V 85 %P 815-828 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-210567 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid. %A Boström, Gustaf %A Freyhult, Eva %A Virhammar, Johan %A Alcolea, Daniel %A Tumani, Hayrettin %A Otto, Markus %A Brundin, Rose-Marie %A Kilander, Lena %A Löwenmark, Malin %A Giedraitis, Vilmantas %A Lleo, Alberto %A von Arnim, Christine A F %A Kultima, Kim %A Ingelsson, Martin %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Cross-Sectional Studies %K Female %K Frontotemporal Dementia %K Humans %K Inflammation %K Male %K Middle Aged %K Peptide Fragments %K tau Proteins %X

BACKGROUND: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases.

OBJECTIVE: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD.

METHODS: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing.

RESULTS: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14-1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20-1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10-1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05).

CONCLUSION: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.

%B J Alzheimers Dis %V 81 %P 629-640 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33814444?dopt=Abstract %R 10.3233/JAD-201565 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Droplet Degeneration of Hippocampal and Cortical Neurons Signifies the Beginning of Neuritic Plaque Formation. %A Streit, Wolfgang J %A Rotter, Jonas %A Winter, Karsten %A Müller, Wolf %A Khoshbouei, Habibeh %A Bechmann, Ingo %X

BACKGROUND: Neuritic plaques contain neural and microglial elements, and amyloid-β protein (Aβ), but their pathogenesis remains unknown.

OBJECTIVE: Elucidate neuritic plaque pathogenesis.

METHODS: Histochemical visualization of hyperphosphorylated-tau positive (p-tau+) structures, microglia, Aβ, and iron.

RESULTS: Disintegration of large projection neurons in human hippocampus and neocortex presents as droplet degeneration: pretangle neurons break up into spheres of numerous p-tau+ droplets of various sizes, which marks the beginning of neuritic plaques. These droplet spheres develop in the absence of colocalized Aβ deposits but once formed become encased in diffuse Aβ with great specificity. In contrast, neurofibrillary tangles often do not colocalize with Aβ. Double-labelling for p-tau and microglia showed a lack of microglial activation or phagocytosis of p-tau+ degeneration droplets but revealed massive upregulation of ferritin in microglia suggesting presence of high levels of free iron. Perl's Prussian blue produced positive staining of microglia, droplet spheres, and Aβ plaque cores supporting the suggestion that droplet degeneration of pretangle neurons in the hippocampus and cortex represents ferroptosis, which is accompanied by the release of neuronal iron extracellularly.

CONCLUSION: Age-related iron accumulation and ferroptosis in the CNS likely trigger at least two endogenous mechanisms of neuroprotective iron sequestration and chelation, microglial ferritin expression and Aβ deposition, respectively, both contributing to the formation of neuritic plaques. Since neurofibrillary tangles and Aβ deposits colocalize infrequently, tangle formation likely does not involve release of neuronal iron extracellularly. In human brain, targeted deposition of Aβ occurs specifically in response to ongoing ferroptotic droplet degeneration thereby producing neuritic plaques.

%B J Alzheimers Dis %V 85 %P 1701-1720 %8 2022 Feb 15 %G eng %N 4 %R 10.3233/JAD-215334 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Economic Burden of Alzheimer's Disease Dementia in Japan. %A Ikeda, Shunya %A Mimura, Masaru %A Ikeda, Manabu %A Wada-Isoe, Kenji %A Azuma, Mie %A Inoue, Sachie %A Tomita, Kiyoyuki %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Caregivers %K Female %K Health Care Costs %K Humans %K Japan %K Long-Term Care %K Male %X

BACKGROUND: Alzheimer's disease dementia (ADD) is the leading cause of long-term care in Japan.

OBJECTIVE: This study estimates the annual healthcare and long-term care costs in fiscal year 2018 for adults over 65 years of age with ADD in Japan and the informal care costs and productivity loss for their families.

METHODS: Healthcare and long-term care costs for ADD were estimated according to the disease severity classified by the clinical dementia rating (CDR) score, using reports from a literature review. For the costs of time spent on caregiving activities, productivity loss for ADD family caregivers aged 20-69 and informal care costs for all ADD family caregivers were estimated.

RESULTS: The total healthcare cost of ADD was JPY 1,073 billion, of which 86% (JPY 923 billion) was attributed to healthcare costs other than ADD drug costs (JPY 151 billion). The healthcare costs other than ADD drug costs by severity were less than JPY 200 billion for CDR 0.5, CDR 1, and CDR 2, respectively, but increased to JPY 447 billion (48%) for CDR 3. The public long-term care costs were estimated to be JPY 4,783 billion, which increased according to the severity. Total productivity loss for ADD family caregivers aged 20-69 was JPY 1,547 billion and the informal care cost for all ADD family caregivers was JPY 6,772 billion.

CONCLUSION: ADD costs have a significant impact on public-funded healthcare, long-term care systems, and families in Japan. To minimize the economic burden of ADD, prolonging healthy life expectancy is the key factor to address.

%B J Alzheimers Dis %V 81 %P 309-319 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33780371?dopt=Abstract %R 10.3233/JAD-210075 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Effects of COVID-19 Home Confinement on Mental Health in Individuals with Increased Risk of Alzheimer's Disease. %A Soldevila-Domenech, Natalia %A Forcano, Laura %A Boronat, Anna %A Lorenzo, Thais %A Piera, Iris %A Puig-Pijoan, Albert %A Mateus, Julian %A González de Echevarri Gómez, José María %A Knezevic, Iva %A Soteras, Anna %A Fauria, Karine %A Pizarro, Nieves %A Molinuevo, José Luis %A de la Torre, Rafael %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Anxiety Disorders %K Apolipoprotein E3 %K Apolipoprotein E4 %K Cognition Disorders %K Cognitive Dysfunction %K COVID-19 %K Depressive Disorder %K Female %K Humans %K Male %K Mental Health %K Middle Aged %K Psychological Distress %K Quarantine %K Risk %K Spain %X

We explored the impact of the Spanish COVID-19 strict home confinement on mental health and cognition in non-infected subjects (N = 16, 60-80 years) diagnosed with subjective cognitive decline and APOEɛ3/ɛ4 carriers. Mental health was monitored for 2 months on a daily, weekly, or monthly basis, and compared to pre-confinement values. Emotional distress, anxiety, and depression scores increased to pathological threshold values during and after confinement. Those with lower mood during confinement experienced a decline in their mood after confinement. Cognition did not change. These preliminary results suggest that mental health consequences of corona measures in preclinical stages of Alzheimer's disease should be further evaluated.

%B J Alzheimers Dis %V 79 %P 1015-1021 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33386809?dopt=Abstract %R 10.3233/JAD-201408 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Effects of High Definition-Transcranial Direct Current Stimulation on Local GABA and Glutamate Levels Among Older Adults with and without Mild Cognitive Impairment: An Exploratory Study. %A Lengu, Ketrin %A Ryan, Shannon %A Peltier, Scott J %A Tyszkowski, Troy %A Kairys, Anson %A Giordani, Bruno %A Hampstead, Benjamin M %X

BACKGROUND: Prior research, primarily with young adults, suggests transcranial direct current stimulation (tDCS) effects are driven by the primary excitatory and/or inhibitory neurotransmitters, glutamate, and gamma-aminobutyric acid (GABA), respectively.

OBJECTIVE: We examined the neurometabolic mechanisms of tDCS in older adults with and without mild cognitive impairment (MCI).

METHODS: We used data from a double-blind, cross-over, randomized controlled trial (NCT01958437) in 32 older adults to evaluate high definition (HD)-tDCS-induced changes in glutamate and GABA via magnetic resonance spectroscopy (MRS). Participants underwent MRS following two counterbalanced HD-tDCS sessions (one active, one sham) that targeted the right superior parietal cortex (center anode at P2) and delivered 2mA for 20 minutes.

RESULTS: Relative to sham, and when co-varying for MRS voxel overlap and right superior parietal volume, active HD-tDCS significantly increased GABA and decreased the ratio of glutamate to GABA. No changes were observed in a left prefrontal control MRS voxel. Although we did not find a significant correlation between strength of delivered current (measured via MRI-based computational modeling) and neurometabolite change, there was a robust positive relationship between the volume of right superior parietal cortex and neurometabolite change.

CONCLUSION: Our preliminary findings of increased GABA and reduced glutamate/GABA ratio raise the possibility that (HD-)tDCS effects differ by age. Moreover, age- and disease-related regional brain volume loss may be especially important to consider when planning future studies. Replication would emphasize the importance of developing population-specific tDCS parameters that consider structural and physiologic changes associated with "normal" and pathological aging.

%B J Alzheimers Dis %V 84 %P 1091-1102 %8 2021 Nov 23 %G eng %N 3 %R 10.3233/JAD-201091 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Effects of Peroral Omega-3 Fatty Acid Supplementation on Cerebrospinal Fluid Biomarkers in Patients with Alzheimer's Disease: A Randomized Controlled Trial-The OmegAD Study. %A Tofiq, Avin %A Zetterberg, Henrik %A Blennow, Kaj %A Basun, Hans %A Cederholm, Tommy %A Eriksdotter, Maria %A Faxen-Irving, Gerd %A Hjorth, Erik %A Jernerén, Fredrik %A Schultzberg, Marianne %A Wahlund, Lars-Olof %A Palmblad, Jan %A Freund-Levi, Yvonne %X

BACKGROUND: Studies have suggested a connection between a decrease in the levels of polyunsaturated fatty acids (PUFAs) and Alzheimer's disease (AD). We aimed to assess the effect of supplementation with omega-3 fatty acids (n-3 FAs) on biomarkers analyzed in the cerebrospinal fluid (CSF) of patients diagnosed with AD.

OBJECTIVE: To investigate the effects of daily supplementation with 2.3 g of PUFAs in AD patients on the biomarkers in CSF described below. We also explored the possible correlation between these biomarkers and the performance in the cognitive test Mini-Mental State Examination (MMSE).

METHODS: Thirty-three patients diagnosed with AD were randomized to either treatment with a daily intake of 2.3 g of n-3 FAs (n  =  18) or placebo (n  =  15). CSF samples were collected at baseline and after six months of treatment, and the following biomarkers were analyzed: Aβ 38, Aβ 40, Aβ 42, t-tau, p-tau, neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), soluble IL-1 receptor type II (sIL-1RII), and IL-6.

RESULTS: There were no significant differences between the groups concerning the level of the different biomarkers in the CSF at baseline. Within the treatment group, there was a small but significant increase in both YKL-40 (p = 0.04) and NfL (p = 0.03), while the other CSF biomarkers remained stable.

CONCLUSION: Supplementation with n-3 FAs had a statistically significant effect on NfL and YKL-40, resulting in an increase of both biomarkers, indicating a possible increase of inflammatory response and axonal damage. This increase in biomarkers did not correlate with MMSE score.

%B J Alzheimers Dis %V 83 %P 1291-1301 %8 2021 Sep 28 %G eng %N 3 %R 10.3233/JAD-210007 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Egocentric and Allocentric Spatial Memory in Mild Cognitive Impairment with Real-World and Virtual Navigation Tasks: A Systematic Review. %A Tuena, Cosimo %A Mancuso, Valentina %A Stramba-Badiale, Chiara %A Pedroli, Elisa %A Stramba-Badiale, Marco %A Riva, Giuseppe %A Repetto, Claudia %K Alzheimer Disease %K Cognitive Dysfunction %K Humans %K Spatial Memory %K Spatial Navigation %X

BACKGROUND: Spatial navigation is the ability to estimate one's position on the basis of environmental and self-motion cues. Spatial memory is the cognitive substrate underlying navigation and relies on two different reference frames: egocentric and allocentric. These spatial frames are prone to decline with aging and impairment is even more pronounced in Alzheimer's disease (AD) or in mild cognitive impairment (MCI).

OBJECTIVE: To conduct a systematic review of experimental studies investigating which MCI population and tasks are used to evaluate spatial memory and how allocentric and egocentric deficits are impaired in MCI after navigation.

METHODS: PRISMA and PICO guidelines were applied to carry out the systematic search. Down and Black checklist was used to assess methodological quality.

RESULTS: Our results showed that amnestic MCI and AD pathology are the most investigated typologies; both egocentric and allocentric memory are impaired in MCI individuals, and MCI due to AD biomarkers has specific encoding and retrieval impairments; secondly, spatial navigation is principally investigated with the hidden goal task (virtual and real-world version), and among studies involving virtual reality, the privileged setting consists of non-immersive technology; thirdly, despite subtle differences, real-world and virtual versions showed good overlap for the assessment of MCI spatial memory.

CONCLUSION: Considering that MCI is a subclinical entity with potential risk for conversion to dementia, investigating spatial memory deficits with navigation tasks might be crucial to make accurate diagnosis and rehabilitation.

%B J Alzheimers Dis %V 79 %P 95-116 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33216034?dopt=Abstract %R 10.3233/JAD-201017 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Elevated Norepinephrine Metabolism Gauges Alzheimer's Disease-Related Pathology and Memory Decline. %A Riphagen, Joost M %A van Egroo, Maxime %A Jacobs, Heidi I L %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Cohort Studies %K Disease Progression %K Female %K Humans %K Learning %K Locus Coeruleus %K Male %K Memory Disorders %K Methoxyhydroxyphenylglycol %K Middle Aged %K Neuropsychological Tests %K Norepinephrine %K Predictive Value of Tests %K tau Proteins %X

The noradrenergic (NE) locus coeruleus (LC) is vulnerable to hyperphosphorylated tau, and dysregulated NE-metabolism is linked to greater tau and disease progression. We investigated whether elevated NE-metabolism alone predicts memory decline or whether concomitant presence of tau and amyloid-β is required. Among 114 memory clinic participants, time trends (max. six years) showed dose-response declines in learning across groups with elevated NE-metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) with no, one, or two Alzheimer's disease biomarkers; and no decline in the low MHPG group. Elevated MHPG is required and sufficient to detect learning declines, supporting a pathophysiologic model including the LC-NE system contributing to initial Alzheimer's disease-related processes.

%B J Alzheimers Dis %V 80 %P 521-526 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554915?dopt=Abstract %R 10.3233/JAD-201411 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Is Engagement in Intellectual and Social Leisure Activities Protective Against Dementia Risk? Evidence from the English Longitudinal Study of Ageing. %A Almeida-Meza, Pamela %A Steptoe, Andrew %A Cadar, Dorina %K Aged %K Aged, 80 and over %K Aging %K Dementia %K Female %K Humans %K Incidence %K Leisure Activities %K Life Style %K Longitudinal Studies %K Male %K Marital Status %K Middle Aged %K Proportional Hazards Models %K Sex Factors %K Social Behavior %K Surveys and Questionnaires %K Survival Analysis %K United Kingdom %X

BACKGROUND: Studies have suggested that mentally stimulating activities and socially engaged lifestyles may reduce dementia risk; however, it is unclear which activities are more beneficial.

OBJECTIVE: We investigated intellectual and social leisure activities in relation to dementia incidence and explored the modifying role of sex and marital status in these associations.

METHODS: The sample was comprised of 8,030 participants aged 50+ from the English Longitudinal Study of Ageing, who joined at wave 1 (2002-2003), or waves 3 (2006-2007), or 4 (2008-2009). The end of the study period was wave 8 (2016-2017). Subdistribution hazard models investigated the role of leisure activities grouped into intellectual and social domains in relation to dementia while accounting for the risk of death. Subsequent analyses were conducted with individual leisure activities.

RESULTS: During the study period of up to 15 years, 412 participants developed dementia, and 2,192 died. We found that increased engagement in the intellectual activities' domain was associated with a decreased dementia incidence (SHR 0.85, 95% CI 0.76-0.96, p = 0.007), independent of the risk of death in married individuals, but not in those who were single, divorced, or widowed. Individual analyses for each leisure activity showed independent associations for reading newspapers in females (SHR 0.65, 95% CI 0.49-0.84, p = 0.001), mobile phone usage in males (SHR 0.61, 95% CI 0.45-0.84, p = 0.002), and having hobbies for married individuals (SHR 0.70, 95% CI 0.51-0.95, p = 0.02).

CONCLUSION: We found that intellectual leisure activities contribute to lower dementia risk in a representative population of English adults, suggesting intervention opportunities.

%B J Alzheimers Dis %V 80 %P 555-565 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554903?dopt=Abstract %R 10.3233/JAD-200952 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Enhancing the Sensitivity of Memory Tests: Reference Data for the Free and Cued Selective Reminding Test and the Logical Memory Task from Cognitively Healthy Subjects with Normal Alzheimer's Disease Cerebrospinal Fluid Biomarker Levels. %A Brugulat-Serrat, Anna %A Cañas, Alba %A Canals, Lidia %A Marne, Paula %A Gramunt, Nina %A Milà-Alomà, Marta %A Suárez-Calvet, Marc %A Arenaza-Urquijo, Eider M %A Grau-Rivera, Oriol %A González-de-Echávarri, José María %A Minguillon, Carolina %A Fauria, Karine %A Kollmorgen, Gwendlyn %A Suridjan, Ivonne %A Zetterberg, Henrik %A Blennow, Kaj %A Gispert, Juan Domingo %A Molinuevo, José Luis %A Sánchez-Benavides, Gonzalo %X

BACKGROUND: Cognitive performance of a given individual should be interpreted in the context of reference standards obtained in cognitively healthy populations. Recent evidence has shown that removing asymptomatic individuals with biomarker evidence of Alzheimer's disease (AD) pathology from normative samples increases the sensitivity of norms to detect memory impairments. These kind of norms may be useful for defining subtle cognitive decline, the transitional cognitive decline between normal cognition and mild cognitive impairment.

OBJECTIVE: The present study aims to provide norms for the Free and Cued Selective Reminding Test (FCSRT) and the Logical Memory subtest of the Wechsler Memory Scale-IV in a sample of individuals aged 50-70 years with normal levels of amyloid (A) and tau (T) cerebrospinal fluid (CSF) biomarkers.

METHODS: The sample was composed of 248 individuals from the ALFA+ study with negative amyloid-β and tau CSF biomarker levels. Regression-based norms were developed, including adjustments for age, education, and sex when applicable.

RESULTS: We found that education was associated with the performance in all the variables of both tests while age had a marginal effect only in the delayed free recall of the FCSRT. Sex was also related to the performance in the FCSRT, with women outperforming men. Equations to calculate z-scores and normative percentile tables were created. As compared with previously published norms the reference data presented were more sensitive but less specific, as expected.

CONCLUSION: The use of the norms provided in this work, in combination with the already published conventional norms, may contribute to detecting subtle memory impairment.

%B J Alzheimers Dis %V 84 %P 119-128 %8 2021 Oct 26 %G eng %N 1 %R 10.3233/JAD-210640 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Entorhinal Perfusion Predicts Future Memory Decline, Neurodegeneration, and White Matter Hyperintensity Progression in Older Adults. %A Bangen, Katherine J %A Thomas, Kelsey R %A Sanchez, Danielle L %A Edmonds, Emily C %A Weigand, Alexandra J %A Delano-Wood, Lisa %A Bondi, Mark W %X

BACKGROUND: Altered cerebral blood flow (CBF) has been linked to increased risk for Alzheimer's disease (AD). However, whether altered CBF contributes to AD risk by accelerating cognitive decline remains unclear. It also remains unclear whether reductions in CBF accelerate neurodegeneration and development of small vessel cerebrovascular disease.

OBJECTIVE: To examine associations between CBF and trajectories of memory performance, regional brain atrophy, and global white matter hyperintensity (WMH) volume.

METHOD: 147 Alzheimer's Disease Neuroimaging Initiative participants free of dementia underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure CBF and serial neuropsychological and structural MRI examinations. Linear mixed effects models examined 5-year rate of change in memory and 4-year rate of change in regional brain atrophy and global WMH volumes as a function of baseline regional CBF. Entorhinal and hippocampal CBF were examined in separate models.

RESULTS: Adjusting for demographic characteristics, pulse pressure, apolipoprotein E ɛ4 positivity, cerebrospinal fluid p-tau/Aβ ratio, and neuronal metabolism (i.e., fluorodeoxyglucose standardized uptake value ratio), lower baseline entorhinal CBF predicted faster rates of decline in memory as well as faster entorhinal thinning and WMH progression. Hippocampal CBF did not predict cognitive or brain structure trajectories.

CONCLUSION: Findings highlight the importance of early cerebrovascular dysfunction in AD risk and suggest that entorhinal CBF as measured by noninvasive ASL MRI is a useful biomarker predictive of future cognitive decline and of risk of both.

%B J Alzheimers Dis %V 81 %P 1711-1725 %8 2021 Jun 15 %G eng %N 4 %R 10.3233/JAD-201474 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Ethnic Differences in Dementia Risk: A Systematic Review and Meta-Analysis. %A Shiekh, Suhail Ismail %A Cadogan, Sharon Louise %A Lin, Liang-Yu %A Mathur, Rohini %A Smeeth, Liam %A Warren-Gash, Charlotte %X

BACKGROUND: Globally around 50 million people have dementia. Risk factors for dementia such as hypertension and diabetes are more common in Black, Asian, and other ethnic minorities. There are also marked ethnic inequalities in care seeking, likelihood of diagnosis, and uptake of treatments for dementia. Nevertheless, ethnic differences in dementia incidence and prevalence remain under-explored.

OBJECTIVE: To examine published peer-reviewed observational studies comparing age-specific or age-adjusted incidence or prevalence rates of dementia between at least two ethnic groups.

METHODS: We searched seven databases on 1 September 2019 using search terms for ethnicity, dementia, and incidence or prevalence. We included population-based studies comparing incidence or prevalence of dementia after accounting for age of at least two ethnic groups in adults aged 18 or more. Meta-analysis was conducted for eligible ethnic comparisons.

RESULTS: We included 12 cohort studies and seven cross-sectional studies. Thirteen were from the US, and two studies each from the UK, Singapore, and Xinjiang Uyghur Autonomous Region in China. The pooled risk ratio for dementia incidence obtained from four studies comparing Black and White ethnic groups was 1.33 (95% CI 1.07-1.65; I-squared = 58.0%). The pooled risk ratio for dementia incidence comparing the Asian and White ethnic groups was 0.86 (95% CI 0.728-1.01; I-squared = 43.9%). There was no difference in the incidence of dementia for Latino ethnic group compared to the White ethnic group.

CONCLUSION: Evidence to date suggest there are ethnic differences in risk of dementia. Better understanding of the drivers of these differences may inform efforts to prevent or treat dementia.

%B J Alzheimers Dis %V 80 %P 337-355 %8 2021 Mar 9 %G eng %N 1 %R 10.3233/JAD-201209 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Event-Related Potentials, Inhibition, and Risk for Alzheimer's Disease Among Cognitively Intact Elders. %A Elverman, Kathleen H %A Paitel, Elizabeth R %A Figueroa, Christina M %A McKindles, Ryan J %A Nielson, Kristy A %X

BACKGROUND: Despite advances in understanding Alzheimer's disease (AD), prediction of AD prior to symptom onset remains severely limited, even when primary risk factors such as the apolipoprotein E (APOE) ɛ4 allele are known.

OBJECTIVE: Although executive dysfunction is highly prevalent and is a primary contributor to loss of independence in those with AD, few studies have examined neural differences underlying executive functioning as indicators of risk for AD prior to symptom onset, when intervention might be effective.

METHODS: This study examined event-related potential (ERP) differences during inhibitory control in 44 cognitively intact older adults (20 ɛ4+, 24 ɛ4-), relative to 41 young adults. All participants completed go/no-go and stop-signal tasks.

RESULTS: Overall, both older adult groups exhibited slower reaction times and longer ERP latencies compared to young adults. Older adults also had generally smaller N200 and P300 amplitudes, except at frontal electrodes and for N200 stop-signal amplitudes, which were larger in older adults. Considered with intact task accuracy, these findings suggest age-related neural compensation. Although ɛ4 did not distinguish elders during go or no-go tasks, this study uniquely showed that the more demanding stop-signal task was sensitive to ɛ4 differences, despite comparable task and neuropsychological performance with non-carriers. Specifically, ɛ4+ elders had slower frontal N200 latency and larger N200 amplitude, which was most robust at frontal sites, compared with ɛ4-.

CONCLUSION: N200 during a stop-signal task is sensitive to AD risk, prior to any evidence of cognitive dysfunction, suggesting that stop-signal ERPs may be an important protocol addition to neuropsychological testing.

%B J Alzheimers Dis %V 80 %P 1413-1428 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201559 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Five-Year Change in Body Mass Index Predicts Conversion to Mild Cognitive Impairment or Dementia Only in APOE ɛ4 Allele Carriers. %A Kadey, Kylie R %A Woodard, John L %A Moll, Allison C %A Nielson, Kristy A %A Smith, J Carson %A Durgerian, Sally %A Rao, Stephen M %X

BACKGROUND: Body mass index (BMI) has been identified as an important modifiable lifestyle risk factor for dementia, but less is known about how BMI might interact with Apolipoprotein E ɛ4 (APOE ɛ4) carrier status to predict conversion to mild cognitive impairment (MCI) and dementia.

OBJECTIVE: The aim of this study was to investigate the interaction between APOE ɛ4 status and baseline (bBMI) and five-year BMI change (ΔBMI) on conversion to MCI or dementia in initially cognitively healthy older adults.

METHODS: The associations between bBMI, ΔBMI, APOE ɛ4 status, and conversion to MCI or dementia were investigated among 1,289 cognitively healthy elders from the National Alzheimer's Coordinating Center (NACC) database.

RESULTS: After five years, significantly more carriers (30.6%) converted to MCI or dementia than noncarriers (17.6%), p <  0.001, OR = 2.06. Neither bBMI (OR = 0.99, 95%CI = 0.96-1.02) nor the bBMI by APOE interaction (OR = 1.02, 95%CI = 0.96-1.08) predicted conversion. Although ΔBMI also did not significantly predict conversion (OR = 0.90, 95%CI = 0.78-1.04), the interaction between ΔBMI and carrier status was significant (OR = 0.72, 95%CI = 0.53-0.98). For carriers only, each one-unit decline in BMI over five years was associated with a 27%increase in the odds of conversion (OR = 0.73, 95%CI = 0.57-0.94).

CONCLUSION: A decline in BMI over five years, but not bBMI, was strongly associated with conversion to MCI or dementia only for APOE ɛ4 carriers. Interventions and behaviors aimed at maintaining body mass may be important for long term cognitive health in older adults at genetic risk for AD.

%B J Alzheimers Dis %V 81 %P 189-199 %8 2021 May 04 %G eng %N 1 %R 10.3233/JAD-201360 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Is the Frontal Lobe the Primary Target of SARS-CoV-2? %A Toniolo, Sofia %A Di Lorenzo, Francesco %A Scarioni, Marta %A Frederiksen, Kristian Steen %A Nobili, Flavio %K Acute Febrile Encephalopathy %K Biomarkers %K COVID-19 %K Delirium %K Electroencephalography %K Frontal Lobe %K Humans %K Magnetic Resonance Imaging %K Nerve Net %K SARS-CoV-2 %K Virulence %X

Acute delirium and other neuropsychiatric symptoms have frequently been reported in COVID-19 patients and are variably referred to as acute encephalopathy, COVID-19 encephalopathy, SARS-CoV-2 encephalitis, or steroid-responsive encephalitis. COVID-19 specific biomarkers of cognitive impairment are currently lacking, but there is some evidence that SARS-CoV-2 could preferentially and directly target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET imaging. We suggest that an inflammatory parainfectious process targeting preferentially the frontal lobes (and/or frontal networks) could be the underlying cause of these shared clinical, neurophysiological, and imaging findings in COVID-19 patients. We explore the biological mechanisms and the clinical biomarkers that might underlie such disruption of frontal circuits and highlight the need of standardized diagnostic procedures to be applied when investigating patients with these clinical findings. We also suggest the use of a unique label, to increase comparability across studies.

%B J Alzheimers Dis %V 81 %P 75-81 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33720900?dopt=Abstract %R 10.3233/JAD-210008 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Gut Microbiome Features of Chinese Patients Newly Diagnosed with Alzheimer's Disease or Mild Cognitive Impairment. %A Guo, Mingyan %A Peng, Jun %A Huang, Xiaoyan %A Xiao, Lingjun %A Huang, Fenyan %A Zuo, Zhiyi %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Asians %K Biodiversity %K China %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Feces %K Female %K Gastrointestinal Microbiome %K Humans %K Male %K Middle Aged %K RNA, Ribosomal, 16S %X

BACKGROUND: Patients with Alzheimer's disease (AD) have gut microbiome alterations compared with healthy controls. However, previous studies often assess AD patients who have been on medications or other interventions for the disease. Also, simultaneous determination of gut microbiome in patients with mild cognitive impairment (MCI) or AD in a study is rare.

OBJECTIVE: To determine whether there was a gut microbiome alteration in patients newly diagnosed with AD or MCI and whether the degree of gut microbiome alteration was more severe in patients with AD than patients with MCI.

METHODS: Fecal samples of 18 patients with AD, 20 patients with MCI, and 18 age-matched healthy controls were collected in the morning for 16S ribosomal RNA sequencing. No patient had medications or interventions for AD or MCI before the samples were collected.

RESULTS: Although there was no difference in the microbial α-diversity among the three groups, patients with AD or MCI had increased β-diversity compared with healthy controls. Patients with AD had decreased Bacteroides, Lachnospira, and Ruminiclostridium_9 and increased Prevotella at the genus level compared with healthy controls. The changing direction of these genera in patients with MCI was the same as patients with AD. However, Lachnospira was the only genus whose abundance in patients with MCI was statistically significantly lower than healthy controls. Bacteroides, Lachnospira, and Ruminiclostridium_9 were positively associated with better cognitive functions whereas Prevotella was on the contrary when subjects of all three groups were considered. The negative correlation of Prevotella with cognitive functions remained among patients with MCI.

CONCLUSION: Patients newly diagnosed with AD or MCI have gut dysbiosis that includes the decrease of potentially protective microbiome, such as Bacteroides, and the increase of microbiome that can promote inflammation, such as Prevotella. Our results support a novel idea that the degree of gut dysbiosis is worsened with the disease stage from MCI to AD.

%B J Alzheimers Dis %V 80 %P 299-310 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33523001?dopt=Abstract %R 10.3233/JAD-201040 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Gut Microbiota Alterations and Cognitive Impairment Are Sexually Dissociated in a Transgenic Mice Model of Alzheimer's Disease. %A Cuervo-Zanatta, Daniel %A Garcia-Mena, Jaime %A Perez-Cruz, Claudia %K Alzheimer Disease %K Animals %K Cognitive Dysfunction %K Female %K Gastrointestinal Microbiome %K Humans %K Male %K Mice %K Mice, Transgenic %K Sex Characteristics %K Spatial Memory %X

BACKGROUND: Normal aging is accompanied by cognitive deficiencies, affecting women and men equally. Aging is the main risk factor for Alzheimer's disease (AD), with women having a higher risk. The higher prevalence of AD in women is associated with the abrupt hormonal decline seen after menopause. However, other factors may be involved in this sex-related cognitive decline. Alterations in gut microbiota (GM) and its bioproducts have been reported in AD subjects and transgenic (Tg) mice, having a direct impact on brain amyloid-β pathology in male (M), but not in female (F) mice.

OBJECTIVE: The aim of this work was to determine GM composition and cognitive dysfunction in M and F wildtype (WT) and Tg mice, in a sex/genotype segregation design.

METHODS: Anxiety, short term working-memory, spatial learning, and long-term spatial memory were evaluated in 6-month-old WT and Tg male mice. Fecal short chain fatty acids were determined by chromatography, and DNA sequencing and bioinformatic analyses were used to determine GM differences.

RESULTS: We observed sex-dependent differences in cognitive skills in WT mice, favoring F mice. However, the cognitive advantage of females was lost in Tg mice. GM composition showed few sex-related differences in WT mice. Contrary, Tg-M mice presented a more severe dysbiosis than Tg-F mice. A decreased abundance of Ruminococcaceae was associated with cognitive deficits in Tg-F mice, while butyrate levels were positively associated with better working- and object recognition-memory in WT-F mice.

CONCLUSION: This report describes a sex-dependent association between GM alterations and cognitive impairment in a mice model of AD.

%B J Alzheimers Dis %V 82 %P S195-S214 %8 2021 %G eng %N s1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33492296?dopt=Abstract %R 10.3233/JAD-201367 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Gut Microbiota Changes and Their Correlation with Cognitive and Neuropsychiatric Symptoms in Alzheimer's Disease. %A Zhou, Yunzhe %A Wang, Yan %A Quan, Meina %A Zhao, Huiying %A Jia, Jianping %X

BACKGROUND: Gut microbiota can influence human brain function and behavior. Recent studies showed that gut microbiota might play an important role in the pathogenesis of Alzheimer's disease (AD).

OBJECTIVE: To investigate the composition of gut microbiota in AD patients and their association with cognitive function and neuropsychiatric symptoms (NPS).

METHODS: The fecal samples from 60 AD patients (30 with NPS and 30 without NPS) and 32 healthy control subjects (HC) were collected and analyzed by 16S ribosomal RNA sequencing. The functional variations of gut microbiota were predicted using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States. The correlation between different bacterial taxa and cognitive (Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR)), and NPS measures were analyzed.

RESULTS: The fecal microbial composition of AD patients was quite distinct from HC. Bifidobacterium, Sphingomonas, Lactobacillus, and Blautia were enriched, while Odoribacter, Anaerobacterium, and Papillibacter were reduced. AD patients with NPS showed decreased Chitinophagaceae, Taibaiella, and Anaerobacterium compared with those without NPS. Functional pathways were different between AD and HC, and between AD patients with and without NPS. Correlation analysis showed that Sphingomonas correlated negatively with MMSE; Anaerobacterium and Papillibacter correlated positively with MMSE and negatively with CDR. Cytophagia, Rhodospirillaceae, and Cellvibrio correlated positively with NPS, while Chitinophagaceae, Taibaiella, and Anaerobacterium correlated negatively with NPS.

CONCLUSION: AD patients have gut microbiota alterations related to cognition, and differential taxa between AD patients with and without NPS associated differently with NPS domains, which helps further understand the pathogenesis of AD and explore potential therapeutic targets.

%B J Alzheimers Dis %V 81 %P 583-595 %8 2021 May 18 %G eng %N 2 %R 10.3233/JAD-201497 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Hemochromatosis Mutations, Brain Iron Imaging, and Dementia in the UK Biobank Cohort. %A Atkins, Janice L %A Pilling, Luke C %A Heales, Christine J %A Savage, Sharon %A Kuo, Chia-Ling %A Kuchel, George A %A Steffens, David C %A Melzer, David %X

BACKGROUND: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males.

OBJECTIVE: To estimated p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort.

METHODS: UK Biobank participants with follow-up hospitalization records (mean 10.5 years). MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2 * measures (lower values indicating more iron).

RESULTS: European ancestry participants included 2,890 p.C282Y homozygotes. Male p.C282Y homozygotes had lower T2 * measures in areas including the putamen, thalamus, and hippocampus, compared to no HFE mutations. Incident dementia was more common in p.C282Y homozygous men (Hazard Ratio HR = 1.83; 95% CI 1.23 to 2.72, p = 0.003), as was delirium. There were no associations in homozygote women or in heterozygotes.

CONCLUSION: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes.

%B J Alzheimers Dis %V 79 %P 1203-1211 %8 2021 Feb 2 %G eng %N 3 %R 10.3233/JAD-201080 %0 Journal Article %J J Alzheimers Dis %D 2021 %T High Fat Diet Mediates Amyloid-β Cleaving Enzyme 1 Phosphorylation and SUMOylation, Enhancing Cognitive Impairment in APP/PS1 Mice. %A Bao, Jian %A Liang, Zheng %A Gong, Xiaokang %A Yu, Jing %A Xiao, Yifan %A Liu, Wei %A Wang, Xiaochuan %A Wang, Jian-Zhi %A Shu, Xiji %X

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in older adults and extracellular accumulation of amyloid-β (Aβ) is one of the two characterized pathologies of AD. Obesity is significantly associated with AD developing factors. Several studies have reported that high fat diet (HFD) influenced Aβ accumulation and cognitive performance during AD pathology. However, the underlying neurobiological mechanisms have not yet been elucidated.

OBJECTIVE: The objective of this study was to explore the underlying neurobiological mechanisms of HFD influenced Aβ accumulation and cognitive performance during AD pathology.

METHODS: 2.5-month-old male APP/PS1 mice were randomly separated into two groups: 1) the normal diet (ND) group, fed a standard diet (10 kcal%fat); and 2) the HFD group, fed a high fat diet (40 kcal%fat, D12492; Research Diets). After 4 months of HFD or ND feeding, mice in the two groups were subjected for further ethological, morphological, and biochemical analyses.

RESULTS: A long-term HFD diet significantly increased perirenal fat and impaired dendritic integrity and aggravated neurodegeneration, and augmented learning and memory deficits in APP/PS1 mice. Furthermore, the HFD increased beta amyloid cleaving enzyme 1 (BACE1) dephosphorylation and SUMOylation, resulting in enhanced enzyme activity and stability, which exacerbated the deposition of amyloid plaques.

CONCLUSION: Our study demonstrates that long-term HFD consumption aggravates amyloid-β accumulation and cognitive impairments, and that modifiable lifestyle factors, such as obesity, can induce BACE1 post-modifications which may contribute to AD pathogenesis.

%B J Alzheimers Dis %V 85 %P 863-876 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-215299 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Hippocampal Functional Connectivity and Memory Performance After Exercise Intervention in Older Adults with Mild Cognitive Impairment. %A Won, Junyeon %A Callow, Daniel D %A S Pena, Gabriel %A Jordan, Leslie S %A Arnold-Nedimala, Naomi A %A Nielson, Kristy A %A Smith, J Carson %X

BACKGROUND: Exercise training (ET) has neuroprotective effects in the hippocampus, a key brain region for memory that is vulnerable to age-related dysfunction.

OBJECTIVE: We investigated the effects of ET on functional connectivity (FC) of the hippocampus in older adults with mild cognitive impairment (MCI) and a cognitively normal (CN) control group. We also assessed whether the ET-induced changes in hippocampal FC (Δhippocampal-FC) are associated with changes in memory task performance (Δmemory performance).

METHODS: 32 older adults (77.0±7.6 years; 16 MCI and 16 CN) participated in the present study. Cardiorespiratory fitness tests, memory tasks (Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory Test (LM)), and resting-state fMRI were administered before and after a 12-week walking ET intervention. We utilized a seed-based correlation analysis using the bilateral anterior and posterior hippocampi as priori seed regions of interest. The associations of residualized ET-induced Δhippocampal-FC and Δmemory performance were assessed using linear regression.

RESULTS: There were significant improvements in RAVLT Trial 1 and LM test performance after ET across participants. At baseline, MCI, compared to CN, demonstrated significantly lower posterior hippocampal FC. ET was associated with increased hippocampal FC across groups. Greater ET-related anterior and posterior hippocampal FC with right posterior cingulate were associated with improved LM recognition performance in MCI participants.

CONCLUSION: Our findings indicate that hippocampal FC is significantly increased following 12-weeks of ET in older adults and, moreover, suggest that increased hippocampal FC may reflect neural network plasticity associated with ET-related improvements in memory performance in individuals diagnosed with MCI.

%B J Alzheimers Dis %V 82 %P 1015-1031 %8 2021 Aug 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34151792?dopt=Abstract %R 10.3233/JAD-210051 %0 Journal Article %J J Alzheimers Dis %D 2021 %T How Do Persons with Young and Late Onset Dementia Die? %A Roβmeier, Carola %A Hartmann, Julia %A Riedl, Lina %A Dorn, Bianca %A Fischer, Julia %A Hartmann, Florentine %A Egert-Schwender, Silvia %A Kehl, Victoria %A Schneider-Schelte, Helga %A Jox, Ralf J %A Dinkel, Andreas %A Diehl-Schmid, Janine %K Advance Care Planning %K Age of Onset %K Aged %K Aged, 80 and over %K Caregivers %K Dementia %K Female %K Humans %K Long-Term Care %K Male %K Palliative Care %K Quality of Life %X

BACKGROUND: End of life symptoms and symptom management as well as the quality of dying (QoD) of persons with advanced dementia (PWAD) have not yet been systematically studied in Germany.

OBJECTIVE: 1) To investigate symptoms, treatment and care at the end of life, advance care planning, and circumstances of death of recently deceased PWAD; 2) To determine whether there are differences between young and late onset dementia (YOD and LOD).

METHODS: The study was performed in the context of the project EPYLOGE (IssuEs in Palliative care for persons in advanced and terminal stages of Young-onset and Late-Onset dementia in Germany). Closest relatives of recently deceased patients with advanced YOD (N = 46) and LOD (N = 54) living at home or in long term care were interviewed.

RESULTS: Circumstances of death, symptoms, and treatment appeared to be similar between YOD and LOD, except that persons with LOD had significantly more somatic comorbidities and were admitted to hospital in the last three months of life more often than persons with LOD. At end of life, 60% of PWAD appeared to be "at peace". Difficulty swallowing, gurgling, shortness of breath, and discomfort were observed most frequently. Large interindividual differences in suffering and QoD were present. Determinants of QoD were not identified.

CONCLUSION: Our findings suggest that low QoD was caused by inadequate recognition and/or insufficient treatment of burdensome physical and emotional symptoms. PWADs' needs should be assessed regularly, and strategies focusing on treatment and implementing support for both the patient and caregiver must be established.

%B J Alzheimers Dis %V 81 %P 843-852 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33843681?dopt=Abstract %R 10.3233/JAD-210046 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Hypertension and Hypercholesterolemia Modify Dementia Risk in Relation to APOEɛ4 Status. %A Pillai, Jagan A %A Lei, Kou %A Bena, James %A Penn, Lisa %A Leverenz, James B %X

BACKGROUND: There is significant interest in understanding the role of modifiable vascular risk factors contributing to dementia risk across age groups.

OBJECTIVE: Risk of dementia onset was assessed in relation to vascular risk factors of hypertension and hypercholesterolemia among cognitively normal APOEɛ4 carriers and non-carriers.

METHODS: In a sample of prospectively characterized longitudinal cohort from the National Alzheimer's Coordinating Center database, 9,349 participants met criteria for normal cognition at baseline, had a CDR-Global (CDR-G) score of zero, and had concomitant data on APOEɛ4 status and medical co-morbidities including histories of hypertension and hypercholesterolemia. Multivariable Cox proportional hazards models adjusted for well-known potential confounders were used to compare dementia onset among APOEɛ4 carriers and non-carriers by young (≤65 years) and old (>  65 year) age groups.

RESULTS: 519 participants converted to dementia within an average follow up of 5.97 years. Among older APOEɛ4 carriers, hypercholesterolemia was related to lower risk of dementia (HR (95% CI), 0.68 (0.49-0.94), p = 0.02). Among older APOEɛ4 non-carriers, hypertension was related to higher risk of dementia (HR (95% CI), 1.44 (1.13-1.82), p = 0.003). These results were corroborated among a subset with autopsy data characterizing underlying neuropathology. Among younger participants, vascular risk factors did not impact dementia risk, likely from a lower frequency of vascular and Alzheimer's as etiologies of dementia among this cohort.

CONCLUSION: A history of hypercholesterolemia related to a lower risk of dementia among older APOEɛ4 carriers, while hypertension related to a higher risk of dementia among older APOEɛ4 non-carriers.

%B J Alzheimers Dis %V 81 %P 1493-1504 %8 2021 Jun 15 %G eng %N 4 %R 10.3233/JAD-201609 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases. %A Merelli, Amalia %A Repetto, Marisa %A Lazarowski, Alberto %A Auzmendi, Jerónimo %K Animals %K Apoptosis %K Brain %K Erythropoietin %K Humans %K Hypoxia %K Inflammation Mediators %K Neurodegenerative Diseases %K Oxidative Stress %X

The cerebral hypoxia-ischemia can induce a wide spectrum of biologic responses that include depolarization, excitotoxicity, oxidative stress, inflammation, and apoptosis, and result in neurodegeneration. Several adaptive and survival endogenous mechanisms can also be activated giving an opportunity for the affected cells to remain alive, waiting for helper signals that avoid apoptosis. These signals appear to help cells, depending on intensity, chronicity, and proximity to the central hypoxic area of the affected tissue. These mechanisms are present not only in a large list of brain pathologies affecting commonly older individuals, but also in other pathologies such as refractory epilepsies, encephalopathies, or brain trauma, where neurodegenerative features such as cognitive and/or motor deficits sequelae can be developed. The hypoxia inducible factor 1α (HIF-1α) is a master transcription factor driving a wide spectrum cellular response. HIF-1α may induce erythropoietin (EPO) receptor overexpression, which provides the therapeutic opportunity to administer pharmacological doses of EPO to rescue and/or repair affected brain tissue. Intranasal administration of EPO combined with other antioxidant and anti-inflammatory compounds could become an effective therapeutic alternative, to avoid and/or slow down neurodegenerative deterioration without producing adverse peripheral effects.

%B J Alzheimers Dis %V 82 %P S109-S126 %8 2021 %G eng %N s1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33325385?dopt=Abstract %R 10.3233/JAD-201074 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Impact of 40 Hz Transcranial Alternating Current Stimulation on Cerebral Tau Burden in Patients with Alzheimer's Disease: A Case Series. %A Dhaynaut, Maeva %A Sprugnoli, Giulia %A Cappon, Davide %A Macone, Joanna %A Sanchez, Justin S %A Normandin, Marc %A Guehl, Nicolas %A Koch, Giacomo %A Paciorek, Rachel %A Connor, Ann %A Press, Daniel %A Johnson, Keith %A Pascual-Leone, Alvaro %A El-Fakhri, Georges %A Santarnecchi, Emiliano %X

BACKGROUND: Alzheimer's disease (AD) is characterized by diffuse amyloid-β (Aβ) and phosphorylated Tau (p-Tau) aggregates as well as neuroinflammation. Exogenously-induced 40 Hz gamma oscillations have been showing to reduce Aβ and p-Tau deposition presumably via microglia activation in AD mouse models.

OBJECTIVE: We aimed to translate preclinical data on gamma-induction in AD patients by means of transcranial alternating current stimulation (tACS).

METHODS: Four participants with mild-to-moderate AD received 1 h of daily 40 Hz (gamma) tACS for 4 weeks (Monday to Friday) targeting the bitemporal lobes (20 h treatment duration). Participant underwent Aβ, p-Tau, and microglia PET imaging with [11C]-PiB, [18F]-FTP, and [11C]-PBR28 respectively, before and after the intervention along with electrophysiological assessment.

RESULTS: No adverse events were reported, and an increase in gamma spectral power on EEG was observed after the treatment. [18F]-FTP PET revealed a significant decrease over 2% of p-Tau burden in 3/4 patients following the tACS treatment, primarily involving the temporal lobe regions targeted by tACS and especially mesial regions (e.g., entorhinal cortex). The amount of intracerebral Aβ as measured by [11C]-PiB was not significantly influenced by tACS, whereas 1/4 reported a significant decrease of microglia activation as measured by [11C]-PBR28.

CONCLUSION: tACS seems to represent a safe and feasible option for gamma induction in AD patients, with preliminary evidence of a possible effect on protein clearance partially mimicking what is observed in animal models. Longer interventions and placebo control conditions are needed to fully evaluate the potential for tACS to slow disease progression.

%B J Alzheimers Dis %V 85 %P 1667-1676 %8 2022 Feb 15 %G eng %N 4 %R 10.3233/JAD-215072 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Impact of a Global Pandemic on People Living with Dementia and Their Care Partners: Analysis of 417 Lived Experience Reports. %A Tam, Mallorie T %A Dosso, Jill A %A Robillard, Julie M %K Adaptation, Psychological %K Aged %K Alzheimer Disease %K British Columbia %K Caregivers %K COVID-19 %K Disabled Persons %K Female %K Humans %K Loneliness %K Male %K Needs Assessment %K Psychosocial Support Systems %K Social Isolation %K Social Support %K Stress, Psychological %K Surveys and Questionnaires %X

BACKGROUND: The COVID-19 pandemic is impacting the physical and emotional health of older adults living with dementia and their care partners.

OBJECTIVE: Using a patient-centered approach, we explored the experiences and needs of people living with dementia and their care partners during the COVID-19 pandemic as part of an ongoing evaluation of dementia support services in British Columbia, Canada.

METHODS: A survey instrument was developed around the priorities identified in the context of the COVID-19 and Dementia Task Force convened by the Alzheimer Society of Canada.

RESULTS: A total of 417 surveys were analyzed. Overall, respondents were able to access information that was helpful for maintaining their own health and managing a period of social distancing. Care partners reported a number of serious concerns, including the inability to visit the person that they care for in long-term or palliative care. Participants also reported that the pandemic increased their levels of stress overall and that they felt lonelier and more isolated than they did before the pandemic. The use of technology was reported as a way to connect socially with their loved ones, with the majority of participants connecting with others at least twice per week.

CONCLUSION: Looking at the complex effects of a global pandemic through the experiences of people living with dementia and their care partners is vital to inform healthcare priorities to restore their quality of life and health and better prepare for the future.

%B J Alzheimers Dis %V 80 %P 865-875 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554905?dopt=Abstract %R 10.3233/JAD-201114 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Impact of Social Isolation on People with Dementia and Their Family Caregivers. %A Azevedo, Lílian Viana Dos Santos %A Calandri, Ismael Luis %A Slachevsky, Andrea %A Graviotto, Héctor Gastón %A Vieira, Maria Carolina Santos %A Andrade, Caíssa Bezerra de %A Rossetti, Adriana Peredo %A Generoso, Alana Barroso %A Carmona, Karoline Carvalho %A Pinto, Ludmilla Aparecida Cardoso %A Sorbara, Marcos %A Pinto, Alejandra %A Guajardo, Tania %A Olavarria, Loreto %A Thumala, Daniela %A Crivelli, Lucía %A Vivas, Ludmila %A Allegri, Ricardo Francisco %A Barbosa, Maira Tonidandel %A Serrano, Cecilia M %A Miranda-Castillo, Claudia %A Caramelli, Paulo %K Activities of Daily Living %K Adult %K Aged %K Aged, 80 and over %K Argentina %K Brazil %K Caregivers %K Chile %K COVID-19 %K Dementia %K Female %K Humans %K Male %K Middle Aged %K Pandemics %K Physical Distancing %K Social Isolation %K Surveys and Questionnaires %X

BACKGROUND: People with dementia and their family caregivers may face a great burden through social isolation due to the COVID-19 pandemic, which can be manifested as various behavioral and clinical symptoms.

OBJECTIVE: To investigate the impacts of social isolation due to the COVID-19 pandemic on individuals with dementia and their family caregivers.

METHODS: Two semi-structured questionnaires were applied via telephone to family caregivers of people diagnosed with dementia in three cities in Argentina, Brazil, and Chile, in order to assess clinical and behavioral changes in people with dementia and in their caregivers.

RESULTS: In general, 321 interviews were conducted. A significant decline in memory function has been reported among 53.0%of people with dementia. In addition, 31.2%of individuals with dementia felt sadder and 37.4%had increased anxiety symptoms. These symptoms of anxiety were greater in individuals with mild to moderate dementia, while symptoms of agitation were greater in individuals with severe dementia. Moreover, compulsive-obsessive behavior, hallucinations, increased forgetfulness, altered appetite, and increased difficulty in activities of daily living were reported more frequently among individuals with moderate to severe dementia. Caregivers reported feeling more tired and overwhelmed during this period and these symptoms were also influenced by the severity of dementia.

CONCLUSION: Social isolation during the COVID-19 pandemic triggered a series of negative behavioral repercussions, both for people with dementia and for their family caregivers in these three South American countries.

%B J Alzheimers Dis %V 81 %P 607-617 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33814446?dopt=Abstract %R 10.3233/JAD-201580 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Impacts of Iron Metabolism Dysregulation on Alzheimer's Disease. %A Jouini, Najla %A Saied, Zakaria %A Ben Sassi, Samia %A Nebli, Fatma %A Messaoud, Taieb %A Hentati, Faycel %A Belal, Samir %X

BACKGROUND: Iron plays an important role in maintaining cell survival, with normal iron trafficking known to be regulated by the ceruloplasmin-transferrin (Cp-Tf) antioxidant system. Disruption to this system is thought to be detrimental to normal brain function.

OBJECTIVE: To determine whether an imbalance of iron and the proteins involved in its metabolism (ceruloplasmin and transferrin) are linked to Alzheimer's disease (AD) and to the expression of amyloid-beta (Aβ) peptide 1-42 (Aβ 1-42), which is a major species of Aβ, and the most toxic.

METHODS: We evaluated the concentrations of iron, calcium, magnesium, and Aβ 1-42 in the cerebrospinal fluid (CSF) of patients with AD and cognitively normal controls. Correlations between the components of the Cp-Tf antioxidant system in plasma were studied to determine the role of peripheral blood in the onset and/or development of AD. We used commercial ELISA immunoassays to measure Aβ 1-42, immunoturbidimetry to quantify ceruloplasmin and transferrin, and colorimetry to quantify iron, calcium, and magnesium.

RESULTS: We found that the AD group had lower CSF concentrations of Aβ 1-42 (p <  0.001) and calcium (p <  0.001), but a higher CSF concentration of iron (p <  0.001). Significantly lower plasma concentrations of ceruloplasmin (p = 0.003), transferrin (mean, p <  0.001), and iron (p <  0.001) were observed in the AD group than in cognitively normal adults. Moreover, we found a strong interdependence between most of these components.

CONCLUSION: Iron dyshomeostasis has a crucial role in the onset of AD and/or its development. Correcting metal misdistribution is an appealing therapeutic strategy for AD.

%B J Alzheimers Dis %V 80 %P 1439-1450 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201250 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Implementing Delirium Prevention in the Era of COVID-19. %A Radhakrishnan, Nila S %A Mufti, Mariam %A Ortiz, Daniel %A Maye, Suzanne T %A Melara, Jennifer %A Lim, Duke %A Rosenberg, Eric I %A Price, Catherine C %K Aged %K Alzheimer Disease %K COVID-19 %K Delirium %K Humans %K Male %X

Patients admitted with COVID-19 can develop delirium due to predisposing factors, isolation, and the illness itself. Standard delirium prevention methods focus on interaction and stimulation. It can be challenging to deliver these methods of care in COVID settings where it is necessary to increase patient isolation. This paper presents a typical clinical vignette of representative patients in a tertiary care hospital and how a medical team modified an evidence-based delirium prevention model to deliver high-quality care to COVID-19 patients. The implemented model focuses on four areas of delirium-prevention: Mobility, Sleep, Cognitive Stimulation, and Nutrition. Future studies will be needed to track quantitative outcome measures.

%B J Alzheimers Dis %V 79 %P 31-36 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33252073?dopt=Abstract %R 10.3233/JAD-200696 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Improving the Diagnosis of the Frontal Variant of Alzheimer's Disease with the DAPHNE Scale. %A Lehingue, Elsa %A Gueniat, Julien %A Jourdaa, Sandra %A Hardouin, Jean BenoÎt %A Pallardy, Amandine %A Courtemanche, Hélène %A Rocher, Laetitia %A Etcharry-Bouyx, Frédérique %A Auriacombe, Sophie %A Mollion, Hélène %A Formaglio, Maıté %A Rouaud, Olivier %A Bretonnière, Cédric %A Thomas-Antérion, Catherine %A Boutoleau-Bretonnière, Claire %K Aged %K Alzheimer Disease %K Cohort Studies %K Diagnosis, Differential %K Female %K Frontal Lobe %K Frontotemporal Dementia %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %X

BACKGROUND: The frontal variant of Alzheimer's disease (fAD) is poorly understood and poorly defined. The diagnosis remains challenging. The main differential diagnosis is the behavioral variant of frontotemporal degeneration (bvFTD). For fAD, there is some dissociation between the clinical frontal presentation and imaging and neuropathological studies, which do not always find a specific involvement of the frontal lobes. DAPHNE is a behavioral scale, which demonstrated excellent performance to distinguish between bvFTD and AD.

OBJECTIVE: The aim of the present study was to assess the reliability of this new tool to improve the clinical diagnosis of fAD.

METHODS: Twenty fAD patients and their caregivers were prospectively included and were compared with 36 bvFTD and 22 AD patients.

RESULTS: The three main behavioral disorders in the fAD patients were apathy, loss of empathy, and disinhibition. Three disorders were discriminant because they were less frequent and less severe in the fAD patients than in the bvFTD patients, namely hyperorality, neglect, and perseverations. This specific pattern of behavioral disorders was corroborated by SPECT or 18FDG PET-CT scan that showed that patients with fAD could have a medial frontal hypoperfusion, whereas in bvFTD patients the orbitofrontal cortex was the main involved region, with more diffuse hypoperfusion.

CONCLUSION: We demonstrated that DAPHNE had good sensitivity and good specificity to discriminate between the three groups and in particular between fAD and bvFTD patients. DAPHNE is a quick tool that could help clinicians in memory clinics not only to differentiate bvFTD from typical AD but also from fAD.

%B J Alzheimers Dis %V 79 %P 1735-1745 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33459637?dopt=Abstract %R 10.3233/JAD-201088 %0 Journal Article %J J Alzheimers Dis %D 2021 %T In Vivo Amyloid, Neurodegeneration, and Verbal Learning in Late Middle-Aged Hispanics. %A Tahmi, Mouna %A Rippon, Brady %A Palta, Priya %A Sherwood, Greysi %A Hernandez, Gabriela %A Soto, Luisa %A Ceballos, Fernando %A Pardo, Michelle %A Laing, Krystal %A Igwe, Kay %A He, Hengda %A Teresi, Jeanne A %A Moreno, Herman %A Razlighi, Qolamreza %A Brickman, Adam M %A Luchsinger, JosA %X

BACKGROUND: The National Institute on Aging (NIA)/Alzheimer's Association (AA) 2018 framework conceptualizes Alzheimer's disease (AD) biologically. Evidence of brain amyloid by biomarkers defines AD pathologic change and the Alzheimer's continuum. The presence of tau or neurodegeneration in the absence of amyloid defines non-AD pathologic change.

OBJECTIVE: To examine the relation of in vivo amyloid and neurodegeneration with verbal learning, one of the cognitive abilities affected early in AD, in late middle age.

METHODS: This was a cross-sectional study of amyloid and neurodegeneration biomarkers in a community-based cohort of 350 late-middle aged Hispanics without dementia (mean age: 64.15±3.34; 72.0%women). Amyloid (A) was measured as global standardized uptake value ratio (SUVR) with 18F-Florbetaben positron emission tomography (PET). Neurodegeneration (N) was ascertained as cortical thickness (CT) in AD signature areas using brain magnetic resonance imaging. We examined A/N continuously, categorically, by A/N profiles, and profile categories. The amyloid threshold for positivity was defined using the K means method. The CT threshold was defined as 2 standard deviations below the mean CT. Verbal learning was ascertained using total recall and delayed recall in the Buschke Selective Reminding test (SRT).

RESULTS: Higher cortical thickness was associated with higher performance in SRT delayed recall. Amyloid SUVR was not related to SRT performance. The low CT category was associated with lower performance in SRT delayed recall, while Amyloid categories were not related to any SRT score. The non-AD pathologic change group (A-N+) performed worse in SRT delayed recall compared to the Normal A/N profile group (A-N-).

CONCLUSION: In late middle-aged Hispanics without dementia, non-AD pathologic change, but not the Alzheimer's continuum, was related to verbal learning.

%B J Alzheimers Dis %V 82 %P 317-325 %8 2021 Jun 29 %G eng %N 1 %R 10.3233/JAD-201304 %0 Journal Article %J J Alzheimers Dis %D 2021 %T In vivo Characterization of Biochemical Variants of Amyloid-β in Subjects with Idiopathic Normal Pressure Hydrocephalus and Alzheimer's Disease Neuropathological Change. %A Libard, Sylwia %A Walter, Jochen %A Alafuzoff, Irina %X

BACKGROUND: Stepwise occurrence of biochemically modified amyloid-β (Aβ) in the brain of subjects with Alzheimer's disease (AD) has been suggested to be of significance for cognitive impairment. Our previous reports have shown that Aβ is observed in 63% of all subjects with idiopathic normal pressure hydrocephalus (iNPH) suggesting that the majority of iNPH subjects with Aβ are indeed also suffering from AD.

OBJECTIVE: We assessed the occurrence of biochemically modified Aβ variants, in vivo, in subjects with iNPH and in a cohort of postmortem brain samples from patients with dementia.

METHODS: We assessed Aβ proteins in 127 diagnostic brain biopsies obtained from subjects with iNPH and in a cohort of subjects with dementia by means of immunohistochemistry.

RESULTS: The pyroglutamylated Aβ (pyAβ) precedes the aggregation of phosphorylated Aβ (pAβ) during the AD neuropathological change progression; moreover, these modified variants of Aβ correlate with hyperphosphorylated tau in the frontal cortical area of human brain. Our results confirm the existence of the suggested biochemical stages of Aβ aggregation that might be of significance for neurodegeneration leading to cognitive impairment.

CONCLUSION: The observation that both pyAβ and pAβ are seen in vivo in iNPH subjects is intriguing. It has been reported that most of the iNPH subjects with Aβ in the brain biopsy indeed develop AD with time. Based on our current and previous results, it is clinically merited to obtain a diagnostic biopsy from a subject with iNPH. When Aβ is observed in the biopsy, the biochemical characterization is of interest.

%B J Alzheimers Dis %V 80 %P 1003-1012 %8 2021 Apr 06 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33612546?dopt=Abstract %R 10.3233/JAD-201469 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Incremental Healthcare Utilization and Cost Burden of Comorbid Insomnia in Alzheimer's Disease Patients. %A Qureshi, Zaina P %A Thiel, Ellen %A Nelson, James %A Khandker, Rezaul %K Aged, 80 and over %K Alzheimer Disease %K Comorbidity %K Databases, Factual %K Female %K Health Care Costs %K Humans %K Male %K Medicare %K Patient Acceptance of Health Care %K Retrospective Studies %K Sleep Initiation and Maintenance Disorders %K United States %X

BACKGROUND: Insomnia is associated with worsened clinical outcomes among Alzheimer's disease dementia (AD) patients, increased caregiver burden, and healthcare utilization.

OBJECTIVE: This study aimed to characterize the incremental healthcare burden of insomnia in AD using real-world data.

METHODS: A retrospective observational study was conducted on AD patients selected from the IBM® MarketScan Commercial and Medicare Supplemental Databases. AD patients with claims-based evidence of insomnia were direct matched to a non-insomnia cohort based on demographic factors. Healthcare utilization and associated costs were assessed for a 12-month follow-up period.

RESULTS: A total of 3,500 insomnia AD patients and 9,884 non-insomnia AD patients were analyzed. The insomnia cohort had a higher comorbidity burden at baseline (mean score on Charlson Comorbidity Index 2.5 versus 2.2, p < 0.001) and higher proportions of patients with baseline diagnoses for other conditions including depression: 40%, insomnia cohort versus 25%, non-insomnia (p < 0.001). AD patients with insomnia were more likely to have a claim for inpatient hospitalizations (39.8%versus 32.3%), emergency room services (56.4%versus 48.0%), and skilled-nursing services (42.6%versus 31.9%) (all p < 0.05). Mean total annual healthcare costs during the 12-month follow-up period were significantly higher among AD patients with insomnia as compared to those without. (Mean costs: $37,356 versus $27,990, p < 0.001).

CONCLUSION: AD patients with comorbid insomnia are more likely to use higher-cost healthcare services such as inpatient hospitalization, and skilled nursing, and have higher total healthcare costs. This real-world analysis provides evidence that AD disease management should consider proper treatment of comorbid insomnia due to the incremental burden and cost implications.

%B J Alzheimers Dis %V 83 %P 1679-1690 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/34420974?dopt=Abstract %R 10.3233/JAD-210713 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Infectious Disease Burden and the Risk of Alzheimer's Disease: A Population-Based Study. %A Douros, Antonios %A Santella, Christina %A Dell'Aniello, Sophie %A Azoulay, Laurent %A Renoux, Christel %A Suissa, Samy %A Brassard, Paul %X

BACKGROUND: Previous studies suggested a link between various infectious pathogens and the development of Alzheimer's disease (AD), posing the question whether infectious disease could present a novel modifiable risk factor.

OBJECTIVE: To assess whether infectious disease burden due to clinically apparent infections is associated with an increased risk of AD.

METHODS: We conducted a population-based nested case-control study using the United Kingdom Clinical Practice Research Datalink. We included all dementia-free subjects ≥50 years of age enrolling in the database between January 1988 and December 2017. Each case of AD identified during follow-up was matched with up to 40 controls. Conditional logistic regression estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of AD associated with ≥1 infection diagnosed >  2 years before the index date compared with no infection during the study period. We further stratified by time since first infection and cumulative number of infections.

RESULTS: The cohort included overall 4,262,092 individuals (mean age at cohort entry 60.4 years; 52% female). During a median follow-up of 10.5 years, 40,455 cases of AD were matched to 1,610,502 controls. Compared with having no burden of infectious disease, having a burden of infectious disease was associated with an increase in the risk of AD (OR, 1.05; 95% CI, 1.02 to 1.08). The risk increased with longer time since first infection, peaking after 12-30 years (OR, 1.11; 95% CI, 1.05-1.17). The risk did not increase with cumulative number of infections.

CONCLUSION: The overall risk of AD associated with infectious disease burden was small but increased gradually with longer time since first infection.

%B J Alzheimers Dis %V 81 %P 329-338 %8 2021 May 04 %G eng %N 1 %R 10.3233/JAD-201534 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Inhibitory Fcγ Receptor and Paired Immunoglobulin Type 2 Receptor Alpha Genotypes in Alzheimer's Disease. %A Pandey, Janardan P %A Namboodiri, Aryan M %A Nietert, Paul J %A Barnes, Lisa L %A Bennett, David A %X

We investigated whether FCGRIIB (rs1050501 C/T) and PILRA (rs1859788 A/G) genotypes contributed to the development of Alzheimer's disease (AD). We genotyped 209 African American (AA) and 638 European American participants for the FCGRIIB and PILRA alleles. In the AA cohort, subjects homozygous for the C allele of FCGRIIB were more than 4 times as likely to develop AD as those homozygous for the alternative T allele. This SNP also interacted with PILRA: participants who were the carriers of the FCGRIIB C allele and PILRA A allele were 3 times as likely to develop AD as those who lacked these alleles.

%B J Alzheimers Dis %V 84 %P 965-968 %8 2021 Nov 23 %G eng %N 3 %R 10.3233/JAD-215174 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Internal Jugular Vein Velocity and Spontaneous Echo Contrast Correlate with Alzheimer's Disease and Cognitive Function. %A Matsuzono, Kosuke %A Suzuki, Masayuki %A Miura, Kumiko %A Ozawa, Tadashi %A Mashiko, Takafumi %A Koide, Reiji %A Tanaka, Ryota %A Fujimoto, Shigeru %X

BACKGROUND: Many issues persist in the today's Alzheimer's disease (AD) screening and the breakthrough method is desired.

OBJECTIVE: We aim to validate the association between venous reflux and AD, and to develop a new method for AD screening.

METHODS: We examined spontaneous echo contrast, area, diameter, retrograde velocity, and anterograde velocity of the bilateral cervical internal jugular vein (IJV) using carotid ultrasonography.

RESULTS: A total of 112 patients participated in this study, with 26 diagnosed as AD. The proportion of both or either IJV spontaneous echo contrast (+) occupied 25 of total 26 AD patients, which showed 96.2%of sensitivity and 98.5%negative predictive value. The IJV velocities also showed significant correlation with AD diagnosis, although the IJV area or diameter did not.

CONCLUSION: Our results indicate that the validation of the spontaneous echo contrast or velocities of the IJV are convenient AD diagnosis screening methods and that the venous reflux disturbance correlates with AD development.

%B J Alzheimers Dis %V 84 %P 787-796 %8 2021 Nov 09 %G eng %N 2 %R 10.3233/JAD-210490 %0 Journal Article %J J Alzheimers Dis %D 2021 %T An Introduction to Ultrasensitive Assays for Plasma Tau Detection. %A Ding, Xu-Long %A Tuo, Qing-Zhang %A Lei, Peng %K Alzheimer Disease %K Biological Assay %K Biomarkers %K Enzyme-Linked Immunosorbent Assay %K Humans %K Phosphorylation %K tau Proteins %X

The detection of plasma tau and its phosphorylation is technically challenging due to the relatively low sensitivity. However, in Alzheimer's disease and other tauopathies, it is hypothesized that tau in the biofluid may serve as a biomarker. In recent years, several ultrasensitive assays have been developed, which can successfully detect tau and its phosphorylation in various biofluids, and collectively demonstrated the prognostic and diagnostic value of plasma tau/phosphorylated tau. Here we have summarized the principle of four ultrasensitive assays newly developed suitable for plasma tau detection, namely single-molecule array, immunomagnetic reduction assay, enhanced immunoassay using multi-arrayed fiber optics, and meso scale discovery assay, with their advantages and applications. We have also compared these assays with traditional enzyme-linked-immunosorbent serologic assay, hoping to facilitate future tau-based biomarker discovery for Alzheimer's disease and other neurodegenerative diseases.

%B J Alzheimers Dis %V 80 %P 1353-1362 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33682718?dopt=Abstract %R 10.3233/JAD-201499 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Iron Responsive Element-Mediated Responses to Iron Dyshomeostasis in Alzheimer's Disease. %A Hin, Nhi %A Newman, Morgan %A Pederson, Stephen %A Lardelli, Michael %X

BACKGROUND: Iron trafficking and accumulation is associated with Alzheimer's disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterized, making it difficult to explore these in existing datasets.

OBJECTIVE: To identify sets of genes predicted to contain iron responsive elements (IREs) and use these to explore possible iron dyshomeostasis-associated gene expression responses in AD.

METHODS: Comprehensive sets of genes containing predicted IRE or IRE-like motifs in their 3' or 5' untranslated regions (UTRs) were identified in human, mouse, and zebrafish reference transcriptomes. Further analyses focusing on these genes were applied to a range of cultured cell, human, mouse, and zebrafish gene expression datasets.

RESULTS: IRE gene sets are sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, changes in IRE transcript abundance are among the earliest observable changes in zebrafish familial AD (fAD)-like brains, preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some IREs in the 3' untranslated regions of transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead display decreased stability, indicating that this is not a generalizable paradigm.

CONCLUSION: Our results reveal IRE gene expression changes as early markers of the pathogenic process in fAD and are consistent with iron dyshomeostasis as an important driver of this disease. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis-associated gene expression responses across different species, tissues, and conditions.

%B J Alzheimers Dis %V 84 %P 1597-1630 %8 2021 Dec 07 %G eng %N 4 %R 10.3233/JAD-210200 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Latent Cognitive Class at Enrollment Predicts Future Cognitive Trajectories of Decline in a Community Sample of Older Adults. %A Zammit, Andrea R %A Yang, Jingyun %A Buchman, Aron S %A Leurgans, Sue E %A Muniz-Terrera, Graciela %A Lipton, Richard B %A Hall, Charles B %A Boyle, Patricia %A Bennett, David A %X

BACKGROUND: Methods that can identify subgroups with different trajectories of cognitive decline are crucial for isolating the biologic mechanisms which underlie these groupings.

OBJECTIVE: This study grouped older adults based on their baseline cognitive profiles using a latent variable approach and tested the hypothesis that these groups would differ in their subsequent trajectories of cognitive change.

METHODS: In this study we applied time-varying effects models (TVEMs) to examine the longitudinal trajectories of cognitive decline across different subgroups of older adults in the Rush Memory and Aging Project.

RESULTS: A total of 1,662 individuals (mean age = 79.6 years, SD = 7.4, 75.4%female) participated in the study; these were categorized into five previously identified classes of older adults differing in their baseline cognitive profiles: Superior Cognition (n = 328, 19.7%), Average Cognition (n = 767, 46.1%), Mixed-Domains Impairment (n = 71, 4.3%), Memory-Specific Impairment (n = 274, 16.5%), and Frontal Impairment (n = 222, 13.4%). Differences in the trajectories of cognition for these five classes persisted during 8 years of follow-up. Compared with the Average Cognition class, The Mixed-Domains and Memory-Specific Impairment classes showed steeper rates of decline, while other classes showed moderate declines.

CONCLUSION: Baseline cognitive classes of older adults derived through the use of latent variable methods were associated with distinct longitudinal trajectories of cognitive decline that did not converge during an average of 8 years of follow-up.

%B J Alzheimers Dis %V 83 %P 641-652 %8 2021 Sep 21 %G eng %N 2 %R 10.3233/JAD-210484 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Life Course Air Pollution Exposure and Cognitive Decline: Modelled Historical Air Pollution Data and the Lothian Birth Cohort 1936. %A Russ, Tom C %A Cherrie, Mark P C %A Dibben, Chris %A Tomlinson, Sam %A Reis, Stefan %A Dragosits, Ulrike %A Vieno, Massimo %A Beck, Rachel %A Carnell, Ed %A Shortt, Niamh K %A Muniz-Terrera, Graciela %A Redmond, Paul %A Taylor, Adele M %A Clemens, Tom %A van Tongeren, Martie %A Agius, Raymond M %A Starr, John M %A Deary, Ian J %A Pearce, Jamie R %K Adolescent %K Adult %K Aged %K Air Pollution %K Child %K Cognitive Dysfunction %K Environmental Exposure %K Female %K History, 20th Century %K Humans %K Linear Models %K Male %K Middle Aged %K Particulate Matter %K Scotland %K Young Adult %X

BACKGROUND: Air pollution has been consistently linked with dementia and cognitive decline. However, it is unclear whether risk is accumulated through long-term exposure or whether there are sensitive/critical periods. A key barrier to clarifying this relationship is the dearth of historical air pollution data.

OBJECTIVE: To demonstrate the feasibility of modelling historical air pollution data and using them in epidemiologicalmodels.

METHODS: Using the EMEP4UK atmospheric chemistry transport model, we modelled historical fine particulate matter (PM2.5) concentrations for the years 1935, 1950, 1970, 1980, and 1990 and combined these with contemporary modelled data from 2001 to estimate life course exposure in 572 participants in the Lothian Birth Cohort 1936 with lifetime residential history recorded. Linear regression and latent growth models were constructed using cognitive ability (IQ) measured by the Moray House Test at the ages of 11, 70, 76, and 79 years to explore the effects of historical air pollution exposure. Covariates included sex, IQ at age 11 years, social class, and smoking.

RESULTS: Higher air pollution modelled for 1935 (when participants would have been in utero) was associated with worse change in IQ from age 11-70 years (β = -0.006, SE = 0.002, p = 0.03) but not cognitive trajectories from age 70-79 years (p > 0.05). There was no support for other critical/sensitive periods of exposure or an accumulation of risk (all p > 0.05).

CONCLUSION: The life course paradigm is essential in understanding cognitive decline and this is the first study to examine life course air pollution exposure in relation to cognitive health.

%B J Alzheimers Dis %V 79 %P 1063-1074 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33427734?dopt=Abstract %R 10.3233/JAD-200910 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Lipidomic Network of Mild Cognitive Impairment from the Mayo Clinic Study of Aging. %A Wang, Xuewei %A Bui, Hai %A Vemuri, Prashanthi %A Graff-Radford, Jonathan %A Jack, Clifford R %A Petersen, Ronald C %A Mielke, Michelle M %X

BACKGROUND: Lipid alterations contribute to Alzheimer's disease (AD) pathogenesis. Lipidomics studies could help systematically characterize such alterations and identify potential biomarkers.

OBJECTIVE: To identify lipids associated with mild cognitive impairment and amyloid-β deposition, and to examine lipid correlation patterns within phenotype groupsMethods:Eighty plasma lipids were measured using mass spectrometry for 1,255 non-demented participants enrolled in the Mayo Clinic Study of Aging. Individual lipids associated with mild cognitive impairment (MCI) were first identified. Correlation network analysis was then performed to identify lipid species with stable correlations across conditions. Finally, differential correlation network analysis was used to determine lipids with altered correlations between phenotype groups, specifically cognitively unimpaired versus MCI, and with elevated brain amyloid versus without.

RESULTS: Seven lipids were associated with MCI after adjustment for age, sex, and APOE4. Lipid correlation network analysis revealed that lipids from a few species correlated well with each other, demonstrated by subnetworks of these lipids. 177 lipid pairs differently correlated between cognitively unimpaired and MCI patients, whereas 337 pairs of lipids exhibited altered correlation between patients with and without elevated brain amyloid. In particular, 51 lipid pairs showed correlation alterations by both cognitive status and brain amyloid. Interestingly, the lipids central to the network of these 51 lipid pairs were not significantly associated with either MCI or amyloid, suggesting network-based approaches could provide biological insights complementary to traditional association analyses.

CONCLUSION: Our attempt to characterize the alterations of lipids at network-level provides additional insights beyond individual lipids, as shown by differential correlations in our study.

%B J Alzheimers Dis %V 81 %P 533-543 %8 2021 May 18 %G eng %N 2 %R 10.3233/JAD-201347 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Locus Coeruleus in Aging and Alzheimer's Disease: A Postmortem and Brain Imaging Review. %A Beardmore, Rebecca %A Hou, Ruihua %A Darekar, Angela %A Holmes, Clive %A Boche, Delphine %K Aging %K Alzheimer Disease %K Animals %K Autopsy %K Brain Stem %K Humans %K Locus Coeruleus %K Magnetic Resonance Imaging %K Melanins %K Mice %K Norepinephrine %K Rats %K tau Proteins %X

The locus coeruleus (LC), a tiny nucleus in the brainstem and the principal site of noradrenaline synthesis, has a major role in regulating autonomic function, arousal, attention, and neuroinflammation. LC dysfunction has been linked to a range of disorders; however particular interest is given to the role it plays in Alzheimer's disease (AD). The LC undergoes significant neuronal loss in AD, thought to occur early in the disease process. While neuronal loss in the LC has also been suggested to occur in aging, this relationship is less clear as the findings have been contradictory. LC density has been suggested to be indicative of cognitive reserve and the evidence for these claims will be discussed. Recent imaging techniques allowing visualization of the LC in vivo using neuromelanin-sensitive MRI are developing our understanding of the role of LC in aging and AD. Tau pathology within the LC is evident at an early age in most individuals; however, the relationship between tau accumulation and neuronal loss and why some individuals then develop AD is not understood. Neuromelanin pigment accumulates within LC cells with age and is proposed to be toxic and inflammatory when released into the extracellular environment. This review will explore our current knowledge of the LC changes in both aging and AD from postmortem, imaging, and experimental studies. We will discuss the reasons behind the susceptibility of the LC to neuronal loss, with a focus on the role of extracellular neuromelanin and neuroinflammation caused by the dysfunction of the LC-noradrenaline pathway.

%B J Alzheimers Dis %V 83 %P 5-22 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34219717?dopt=Abstract %R 10.3233/JAD-210191 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Loneliness, Not Social Support, Is Associated with Cognitive Decline and Dementia Across Two Longitudinal Population-Based Cohorts. %A Freak-Poli, Rosanne %A Wagemaker, Nina %A Wang, Rui %A Lysen, Thom S %A Ikram, M Arfan %A Vernooij, Meike W %A Dintica, Christina S %A Vernooij-Dassen, Myrra %A Melis, Rene J M %A Laukka, Erica J %A Fratiglioni, Laura %A Xu, Weili %A Tiemeier, Henning %X

BACKGROUND: Poor social health is likely associated with cognitive decline and risk of dementia; however, studies show inconsistent results. Additionally, few studies separate social health components or control for mental health.

OBJECTIVE: To investigate whether loneliness and social support are independently associated with cognitive decline and risk of dementia, and whether depressive symptoms confound the association.

METHODS: We included 4,514 participants from the population-based Rotterdam Study (RS; aged 71±7SD years) followed up to 14 years (median 10.8, interquartile range 7.4-11.6), and 2,112 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K; aged 72±10SD years) followed up to 10 years (mean 5.9±1.6SD). At baseline, participants were free of major depression and scored on the Mini-Mental State Examination (MMSE) ≥26 for RS and ≥25 for SNAC-K. We investigated loneliness, perceived social support, and structural social support (specifically marital status and number of children). In both cohorts, dementia was diagnosed and cognitive function was repeatedly assessed with MMSE and a global cognitive factor (g-factor).

RESULTS: Loneliness was prospectively associated with a decline in the MMSE in both cohorts. Consistently, persons who were lonely had an increased risk of developing dementia (RS: HR 1.34, 95%CI 1.08-1.67; SNAC-K: HR 2.16, 95%CI 1.12-4.17). Adjustment for depressive symptoms and exclusion of the first 5 years of follow-up did not alter results. Neither perceived or structural social support was associated with cognitive decline or dementia risk.

CONCLUSION: Loneliness, not social support, predicted cognitive decline and incident dementia independently of depressive symptoms.

%B J Alzheimers Dis %V 85 %P 295-308 %8 2022 Jan 04 %G eng %N 1 %R 10.3233/JAD-210330 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Longitudinal Body Weight Change, Visit-To-Visit Body Weight Fluctuation, and Cognitive Decline Among Older Adults. %A Lan, Yu-Tung %A Blacker, Deborah %A Yuan, Changzheng %A Chibnik, Lori B %A Hofman, Albert %A Ma, Yuan %X

BACKGROUND: The evidence regarding dementia and late-life weight change is inconsistent, and data on body weight fluctuation and dementia are limited.

OBJECTIVE: To test the hypothesis that weight loss and substantial weight fluctuation predict cognitive decline independent of body weight and traditional risk factors of dementia.

METHODS: This study utilized longitudinal data from the National Alzheimer's Coordinating Center for 10,639 stroke- and dementia-free older adults (60.9%female, mean age 71.6 years, median follow-up 5.5 years). Trends in weight change and weight fluctuation were estimated for each individual by regressing repeated body weight measurements on time. Cognitive decline was examined as diagnostic progression from normal to mild cognitive impairment (MCI) or dementia and from MCI to dementia.

RESULTS: Compared to participants with stable weight, those with weight loss had increased odds of diagnostic progression (adjusted OR = 1.35, 95%CI [1.21, 1.51]). Also, large weight fluctuation was associated with increased odds of diagnostic progression (OR comparing the extreme quartiles = 1.20, 95%CI [1.04, 1.39]) after adjusting for traditional risk factors for dementia and body weight change. The magnitude of the association appeared larger among those older than 80 and those with 3 or more cardiometabolic risk factors at baseline (both p for interaction <  0.05).

CONCLUSION: Weight loss and substantial weight fluctuation during late-life were associated with increased odds of cognitive decline independent of body weight and traditional risk factors of dementia. Our results suggested the linkage between late-life body weight instability and cognitive decline especially among those with greater age or higher cardiometabolic risk.

%B J Alzheimers Dis %V 84 %P 777-786 %8 2021 Nov 09 %G eng %N 2 %R 10.3233/JAD-210625 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Longitudinal Trajectories in Cortical Thickness and Volume Atrophy: Superior Cognitive Performance Does Not Protect Against Brain Atrophy in Older Adults. %A Gardener, Samantha L %A Weinborn, Michael %A Sohrabi, Hamid R %A Doecke, James D %A Bourgeat, Pierrick %A Rainey-Smith, Stephanie R %A Shen, Kai-Kai %A Fripp, Jurgen %A Taddei, Kevin %A Maruff, Paul %A Salvado, Olivier %A Savage, Greg %A Ames, David %A Masters, Colin L %A Rowe, Christopher C %A Martins, Ralph N %X

BACKGROUND: Previous research has identified a small subgroup of older adults that maintain a high level of cognitive functioning well into advanced age. Investigation of those with superior cognitive performance (SCP) for their age is important, as age-related decline has previously been thought to be inevitable.

OBJECTIVE: Preservation of cortical thickness and volume was evaluated in 76 older adults with SCP and 100 typical older adults (TOAs) assessed up to five times over six years.

METHODS: Regions of interest (ROIs) found to have been associated with super-aging status (a construct similar to SCP status) in previous literature were investigated, followed by a discovery phase analyses of additional regions. SCPs were aged 70 + at baseline, scoring at/above normative memory (CVLT-II) levels for demographically similar individuals aged 30-44 years old, and in the unimpaired range for all other cognitive domains over the course of the study.

RESULTS: In linear mixed models, following adjustment for multiple comparisons, there were no significant differences between rates of thinning or volume atrophy between SCPs and TOAs in previously identified ROIs, or the discovery phase analyses. With only amyloid-β negative individuals in the analyses, again there were no significant differences between SCPs and TOAs.

CONCLUSION: The increased methodological rigor in classifying groups, together with the influence of cognitive reserve, are discussed as potential factors accounting for our findings as compared to the extant literature on those with superior cognitive performance for their age.

%B J Alzheimers Dis %V 81 %P 1039-1052 %8 2021 Jun 01 %G eng %N 3 %R 10.3233/JAD-201243 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Longitudinally Increasing Elevated Asymmetric Flortaucipir Binding in a Cognitively Unimpaired Amyloid-Negative Older Individual. %A Schwarz, Christopher G %A Knopman, David S %A Ramanan, Vijay K %A Lowe, Val J %A Wiste, Heather J %A Cogswell, Petrice M %A Utianski, Rene L %A Senjem, Matthew L %A Gunter, Jeffrey R %A Vemuri, Prashanthi %A Petersen, Ronald C %A Jack, Clifford R %X

We present the case of a cognitively unimpaired 77-year-old man with elevated, asymmetric, and longitudinally increasing Flortaucipir tau PET despite normal (visually negative) amyloid PET. His atypical tau PET signal persisted and globally increased in a follow-up scan five years later. Across eight years of observations, temporoparietal atrophy was observed consistent with tau PET patterns, but he retained the cognitively unimpaired classification. Altogether, his atypical tau PET signal is not explained by any known risk factors or alternative pathologies, and other imaging findings were not remarkable. He remains enrolled for further observation.

%B J Alzheimers Dis %V 85 %P 59-64 %8 2022 Jan 04 %G eng %N 1 %R 10.3233/JAD-215052 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Low Doses of Ionizing Radiation as a Treatment for Alzheimer's Disease: A Pilot Study. %A Cuttler, Jerry M %A Abdellah, Eslam %A Goldberg, Yael %A Al-Shamaa, Sarmad %A Symons, Sean P %A Black, Sandra E %A Freedman, Morris %K Aged, 80 and over %K Alzheimer Disease %K Cranial Irradiation %K Female %K Humans %K Male %K Pilot Projects %K Radiation, Ionizing %X

BACKGROUND: In 2015, a patient in hospice with Alzheimer's disease (AD) was treated with ionizing radiation to her brain using repeated CT scans. Improvement in cognition, speech, movement, and appetite was observed. These improvements were so momentous that she was discharged from the hospice to a long-term care home. Based on this case, we conducted a pilot clinical trial to examine the effect of low-dose ionizing radiation (LDIR) in severe AD.

OBJECTIVE: To determine whether the previously reported benefits of LDIR in a single case with AD could be observed again in other cases with AD when the same treatments are given.

METHODS: In this single-arm study, four patients were treated with three consecutive treatments of LDIR, each spaced two weeks apart. Qualitative changes in communication and behavior with close relatives were observed and recorded. Quantitative measures of cognition and behavior were administered pre and post LDIR treatments.

RESULTS: Minor improvements on quantitative measures were noted in three of the four patients following treatment. However, the qualitative observations of cognition and behavior suggested remarkable improvements within days post-treatment, including greater overall alertness. One patient showed no change.

CONCLUSION: LDIR may be a promising, albeit controversial therapy for AD. Trials of patients with less severe AD, double-blind and placebo-controlled, should be carried out to determine the benefits of LDIR. Quantitative measures are needed that are sensitive to the remarkable changes induced by LDIR, such as biological markers of oxidative stress that are associated with AD.

%B J Alzheimers Dis %V 80 %P 1119-1128 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646146?dopt=Abstract %R 10.3233/JAD-200620 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Lung Function Impairment and the Risk of Incident Dementia: The Rotterdam Study. %A Xiao, Tian %A Wijnant, Sara R A %A Licher, Silvan %A Terzikhan, Natalie %A Lahousse, Lies %A Ikram, M Kamran %A Brusselle, Guy G %A Ikram, M Arfan %X

BACKGROUND: The etiology of dementia may partly be underpinned by impaired lung function via systemic inflammation and hypoxia.

OBJECTIVE: To prospectively examine the association between chronic obstructive pulmonary disease (COPD) and subclinical impairments in lung function and the risk of dementia.

METHODS: In the Rotterdam Study, we assessed the risk of incident dementia in participants with Preserved Ratio Impaired Spirometry (PRISm; FEV1/FVC≥0.7, FEV1 < 80% predicted) and in participants with COPD (FEV1/FVC < 0.7) compared to those with normal spirometry (controls; FEV1/FVC≥0.7, FEV1≥80% predicted). Hazard ratios (HRs) with 95% confidence intervals (CI) for dementia were adjusted for age, sex, education attainment, smoking status, systolic blood pressure, body mass index, triglycerides, comorbidities and Apolipoprotein E (APOE) genotype.

RESULTS: Of 4,765 participants, 110 (2.3%) developed dementia after 3.3 years. Compared to controls, participants with PRISm, but not COPD, had an increased risk for all-type dementia (adjusted HRPRISm 2.70; 95% CI, 1.53-4.75; adjusted HRCOPD 1.03; 95% CI, 0.61-1.74). These findings were primarily driven by men and smokers. Similarly, participants with FVC% predicted values in the lowest quartile compared to those in the highest quartile were at increased risk of all-type dementia (adjusted HR 2.28; 95% CI, 1.31-3.98), as well as Alzheimer's disease (AD; adjusted HR 2.13; 95% CI, 1.13-4.02).

CONCLUSION: Participants with PRISm or a low FVC% predicted lung function were at increased risk of dementia, compared to those with normal spirometry or a higher FVC% predicted, respectively. Further research is needed to elucidate whether this association is causal and how PRISm might contribute to dementia pathogenesis.

%B J Alzheimers Dis %V 82 %P 621-630 %8 2021 Jul 20 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34057085?dopt=Abstract %R 10.3233/JAD-210162 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Medical and Social Determinants of Brain Health and Dementia in a Multicultural Community Cohort of Older Adults. %A Galvin, James E %A Chrisphonte, Stephanie %A Chang, Lun-Ching %X

BACKGROUND: Socioeconomic status (SES), race, ethnicity, and medical comorbidities may contribute to Alzheimer's disease and related disorders (ADRD) health disparities.

OBJECTIVE: Analyze effects of social and medical determinants on cognition in 374 multicultural older adults participating in a community-based dementia screening program.

METHODS: We used the Montreal Cognitive Assessment (MoCA) and AD8 as measures of cognition, and a 3-way race/ethnicity variable (White, African American, Hispanic) and SES (Hollingshead index) as predictors. Potential contributors to health disparities included: age, sex, education, total medical comorbidities, health self-ratings, and depression. We applied K-means cluster analyses to study medical and social dimension effects on cognitive outcomes.

RESULTS: African Americans and Hispanics had lower SES status and cognitive performance compared with similarly aged Whites. We defined three clusters based on age and SES. Cluster #1 and #3 differed by SES but not age, while cluster #2 was younger with midlevel. Cluster #1 experienced the worse health outcomes while cluster #3 had the best health outcomes. Within each cluster, White participants had higher SES and better health outcomes, African Americans had the worst physical performance, and Hispanics had the most depressive symptoms. In cross-cluster comparisons, higher SES led to better health outcomes for all participants.

CONCLUSION: SES may contribute to disparities in access to healthcare services, while race and ethnicity may contribute to disparities in the quality and extent of services received. Our study highlights the need to critically address potential interactions between race, ethnicity, and SES which may better explain disparities in ADRD health outcomes.

%B J Alzheimers Dis %V 84 %P 1563-1576 %8 2021 Dec 07 %G eng %N 4 %R 10.3233/JAD-215020 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Memory-Related Frontal Brainwaves Predict Transition to Mild Cognitive Impairment in Healthy Older Individuals Five Years Before Diagnosis. %A Jiang, Yang %A Li, Juan %A Schmitt, Frederick A %A Jicha, Gregory A %A Munro, Nancy B %A Zhao, Xiaopeng %A Smith, Charles D %A Kryscio, Richard J %A Abner, Erin L %K Aged %K Brain Waves %K Cognition %K Cognitive Dysfunction %K Electroencephalography %K Female %K Humans %K Longitudinal Studies %K Male %K Memory, Short-Term %K Neuropsychological Tests %K Prodromal Symptoms %X

BACKGROUND: Early prognosis of high-risk older adults for amnestic mild cognitive impairment (aMCI), using noninvasive and sensitive neuromarkers, is key for early prevention of Alzheimer's disease. We have developed individualized measures in electrophysiological brain signals during working memory that distinguish patients with aMCI from age-matched cognitively intact older individuals.

OBJECTIVE: Here we test longitudinally the prognosis of the baseline neuromarkers for aMCI risk. We hypothesized that the older individuals diagnosed with incident aMCI already have aMCI-like brain signatures years before diagnosis.

METHODS: Electroencephalogram (EEG) and memory performance were recorded during a working memory task at baseline. The individualized baseline neuromarkers, annual cognitive status, and longitudinal changes in memory recall scores up to 10 years were analyzed.

RESULTS: Seven of the 19 cognitively normal older adults were diagnosed with incident aMCI for a median 5.2 years later. The seven converters' frontal brainwaves were statistically identical to those patients with diagnosed aMCI (n = 14) at baseline. Importantly, the converters' baseline memory-related brainwaves (reduced mean frontal responses to memory targets) were significantly different from those who remained normal. Furthermore, differentiation pattern of left frontal memory-related responses (targets versus nontargets) was associated with an increased risk hazard of aMCI (HR = 1.47, 95% CI 1.03, 2.08).

CONCLUSION: The memory-related neuromarkers detect MCI-like brain signatures about five years before diagnosis. The individualized frontal neuromarkers index increased MCI risk at baseline. These noninvasive neuromarkers during our Bluegrass memory task have great potential to be used repeatedly for individualized prognosis of MCI risk and progression before clinical diagnosis.

%B J Alzheimers Dis %V 79 %P 531-541 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33337367?dopt=Abstract %R 10.3233/JAD-200931 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Metabolites Associated with Early Cognitive Changes Implicated in Alzheimer's Disease. %A Darst, Burcu F %A Huo, Zhiguang %A Jonaitis, Erin M %A Koscik, Rebecca L %A Clark, Lindsay R %A Lu, Qiongshi %A Kremen, William S %A Franz, Carol E %A Rana, Brinda %A Lyons, Michael J %A Hogan, Kirk J %A Zhao, Jinying %A Johnson, Sterling C %A Engelman, Corinne D %B J Alzheimers Dis %V 79 %P 1041-1054 %8 2021 Feb 2 %G eng %N 3 %R 10.3233/JAD-200176 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Mild Behavioral Impairment and Subjective Cognitive Decline Predict Cognitive and Functional Decline. %A Ismail, Zahinoor %A McGirr, Alexander %A Gill, Sascha %A Hu, Sophie %A Forkert, Nils D %A Smith, Eric E %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Disease Progression %K Executive Function %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Odds Ratio %K Risk Assessment %X

BACKGROUND: Mild behavioral impairment (MBI) and subjective cognitive decline (SCD) are dementia risk states, and potentially represent neurobehavioral and neurocognitive manifestations, respectively, of early stage neurodegeneration. Both MBI and SCD predict incident cognitive decline and dementia, are associated with known dementia biomarkers, and are both represented in the NIA-AA research framework for AD in Stage 2 (preclinical disease).

OBJECTIVE: To assess the associations of MBI and SCD, alone and in combination, with incident cognitive and functional decline in a population of older adults. We tested the hypothesis that MBI and SCD confer additive risk for decline.

METHODS: Cognitively normal participants were followed up annually at Alzheimer's Disease Centers. Logistic regression assessed the relationship between baseline classification (MBI-SCD-, MBI-SCD+, MBI+SCD-, or MBI+SCD+) and 3-year outcome.

RESULTS: Of 2,769 participants (mean age=76), 1,536 were MBI-SCD-, 254 MBI-SCD+, 743 MBI+SCD-, and 236 MBI+SCD+. At 3 years, 349 (12.6%) declined to CDR >0, including 23.1% of the MBI+group, 23.5% of the SCD+group, and 30.9% of the intersection group of both MBI+and SCD+participants. Compared to SCD-MBI-, we observed an ordinal progression in risk (ORs [95% CI]): 3.61 [2.42-5.38] for MBI-SCD+ (16.5% progression), 4.76 [3.57-6.34] for MBI+SCD- (20.7%), and 8.15 [5.71-11.64] for MBI+SCD+(30.9%).

CONCLUSION: MBI and SCD together were associated with the greatest risk of decline. These complementary dementia risk syndromes can be used as simple and scalable methods to identify high-risk patients for workup or for clinical trial enrichment.

%B J Alzheimers Dis %V 80 %P 459-469 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554909?dopt=Abstract %R 10.3233/JAD-201184 %0 Journal Article %J J Alzheimers Dis %D 2021 %T MIND Diet, Common Brain Pathologies, and Cognition in Community-Dwelling Older Adults. %A Dhana, Klodian %A James, Bryan D %A Agarwal, Puja %A Aggarwal, Neelum T %A Cherian, Laurel J %A Leurgans, Sue E %A Barnes, Lisa L %A Bennett, David A %A Schneider, Julie A %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid %K Autopsy %K Brain %K Chicago %K Cognition %K Diet, Mediterranean %K Female %K Humans %K Independent Living %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Surveys and Questionnaires %X

BACKGROUND: MIND diet, a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet, is associated with a slower cognitive decline and lower risk of Alzheimer's disease (AD) dementia in older adults.

OBJECTIVE: We aim to examine whether the association of the MIND diet with cognition is independent of common brain pathologies.

METHODS: Utilizing data from the Rush Memory and Aging Project (MAP), a longitudinal clinical-pathologic study, we studied 569 decedents with valid dietary data, cognitive testing proximate to death, and complete autopsy data at the time of these analyses. A series of regression analyses were used to examine associations of the MIND diet, dementia-related brain pathologies, and global cognition proximate to death adjusting for age, sex, education, APOEɛ4, late-life cognitive activities, and total energy intake.

RESULTS: A higher MIND diet score was associated with better global cognitive functioning proximate to death (β= 0.119, SE = 0.040, p = 0.003), and neither the strength nor the significance of association changed substantially when AD pathology and other brain pathologies were included in the model. The β-estimate after controlling for global AD pathology was 0.111 (SE = 0.037, p = 0.003). The MIND diet-cognition relationship remained significant when we restricted our analysis to individuals without mild cognitive impairment at the baseline (β= 0.121, SE = 0.042, p = 0.005) or in people diagnosed with postmortem diagnosis of AD based on NIA-Reagan consensus recommendations (β= 0.114, SE = 0.050, p = 0.023).

CONCLUSION: MIND diet is associated with better cognitive functioning independently of common brain pathology, suggesting that the MIND diet may contribute to cognitive resilience in the elderly.

%B J Alzheimers Dis %V 83 %P 683-692 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34334393?dopt=Abstract %R 10.3233/JAD-210107 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Mitochondrial Membrane Potential Influences Amyloid-β Protein Precursor Localization and Amyloid-β Secretion. %A Wilkins, Heather M %A Troutwine, Benjamin R %A Menta, Blaise W %A Manley, Sharon J %A Strope, Taylor A %A Lysaker, Colton R %A Swerdlow, Russell H %X

BACKGROUND: Amyloid-β (Aβ), which derives from the amyloid-β protein precursor (AβPP), forms plaques and serves as a fluid biomarker in Alzheimer's disease (AD). How Aβ forms from AβPP is known, but questions relating to AβPP and Aβ biology remain unanswered. AD patients show mitochondrial dysfunction, and an Aβ/AβPP mitochondria relationship exists.

OBJECTIVE: We considered how mitochondrial biology may impact AβPP and Aβ biology.

METHODS: SH-SY5Y cells were transfected AβPP constructs. After treatment with FCCP (uncoupler), Oligomycin (ATP synthase inhibitor), or starvation Aβ levels were measured. β-secretase (BACE1) expression was measured. Mitochondrial localized full-length AβPP was also measured. All parameters listed were measured in ρ0 cells on an SH-SY5Y background. iPSC derived neurons were also used to verify key results.

RESULTS: We showed that mitochondrial depolarization routes AβPP to, while hyperpolarization routes AβPP away from, the organelle. Mitochondrial AβPP and cell Aβ secretion inversely correlate, as cells with more mitochondrial AβPP secrete less Aβ, and cells with less mitochondrial AβPP secrete more Aβ. An inverse relationship between secreted/extracellular Aβ and intracellular Aβ was observed.

CONCLUSION: Our findings indicate mitochondrial function alters AβPP localization and suggest enhanced mitochondrial activity promote Aβ secretion while depressed mitochondrial activity minimize Aβ secretion. Our data complement other studies that indicate a mitochondrial, AβPP, and Aβ nexus, and could help explain why cerebrospinal fluid Aβ is lower in those with AD. Our data further suggest Aβ secretion could serve as a biomarker of cell or tissue mitochondrial function.

%B J Alzheimers Dis %V 85 %P 381-394 %8 2022 Jan 04 %G eng %N 1 %R 10.3233/JAD-215280 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Modifiable Barriers for Recruitment and Retention of Older Adults Participants from Underrepresented Minorities in Alzheimer's Disease Research. %A Indorewalla, Khushnoo K %A O'Connor, Maureen K %A Budson, Andrew E %A Guess DiTerlizzi, Christina %A Jackson, Jonathan %K Alzheimer Disease %K Clinical Trials as Topic %K Humans %K Minority Groups %K Patient Selection %X

Clinical Alzheimer's disease (AD) trials currently face a critical shortfall of thousands of eligible participants, which inflates the duration and cost of the clinical study as well as threatens the scientific merit of promising clinical interventions. This recruitment crisis is further compounded by the fact that underrepresented and marginalized populations-particularly those identifying as a racial or ethnic minority, those with low socioeconomic status, or living in rural areas-have been historically underrepresented in ongoing AD clinical trials despite overwhelming evidence that such populations are at increased risk for developing dementia. As a result of various recruitment barriers, current AD clinical studies frequently reflect a decreasingly representative segment of the US population, which threatens the overall generalizability of these findings. The current narrative review provides an updated examination and critique of common recruitment barriers and potential solutions, as well as a discussion of theoretical approaches that may address barriers disproportionately experienced by underrepresented communities. AD clinical researchers are encouraged to take purposive action aimed at increasing diversity of enrolled AD clinical trial cohorts by actively identifying and quantifying barriers to research participation-especially recruitment barriers and health disparities that disproportionately prevent underrepresented and marginalized populations from participating in research. Furthermore, researchers are encouraged to closely track which individuals who express interest in AD research ultimately enroll in research studies to examine whether AD research participation is appropriately representative of the intended population for whom these new and novel AD interventions are being designed.

%B J Alzheimers Dis %V 80 %P 927-940 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33612540?dopt=Abstract %R 10.3233/JAD-201081 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Mortality After Ischemic Stroke in Patients with Alzheimer's Disease Dementia and Other Dementia Disorders. %A Zupanic, Eva %A von Euler, Mia %A Winblad, Bengt %A Xu, Hong %A Secnik, Juraj %A Kramberger, Milica Gregoric %A Religa, Dorota %A Norrving, Bo %A Garcia-Ptacek, Sara %K Aged %K Aged, 80 and over %K Comorbidity %K Dementia %K Female %K Fibrinolytic Agents %K Humans %K Incidence %K Ischemic Stroke %K Male %K Registries %K Survival Rate %K Sweden %K Thrombolytic Therapy %X

BACKGROUND: Stroke and dementia are interrelated diseases and risk for both increases with age. Even though stroke incidence and age-standardized death rates have decreased due to prevention of stroke risk factors, increased utilization of reperfusion therapies, and other changes in healthcare, the absolute numbers are increasing due to population growth and aging.

OBJECTIVE: To analyze predictors of death after stroke in patients with dementia and investigate possible time and treatment trends.

METHODS: A national longitudinal cohort study 2007-2017 using Swedish national registries. We compared 12,629 ischemic stroke events in patients with dementia with matched 57,954 stroke events in non-dementia controls in different aspects of patient care and mortality. Relationship between dementia status and dementia type (Alzheimer's disease and mixed dementia, vascular dementia, other dementias) and death was analyzed using Cox regressions.

RESULTS: Differences in receiving intravenous thrombolysis between patients with and without dementia disappeared after the year 2015 (administered to 11.1% dementia versus 12.3% non-dementia patients, p = 0.117). One year after stroke, nearly 50% dementia and 30% non-dementia patients had died. After adjustment for demographics, mobility, nursing home placement, and comorbidity index, dementia was an independent predictor of death compared with non-dementia patients (HR 1.26 [1.23-1.29]).

CONCLUSION: Dementia before ischemic stroke is an independent predictor of death. Over time, early and delayed mortality in patients with dementia remained increased, regardless of dementia type. Patients with≤80 years with prior Alzheimer's disease or mixed dementia had higher mortality rates after stroke compared to patients with prior vascular dementia.

%B J Alzheimers Dis %V 81 %P 1253-1261 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33935077?dopt=Abstract %R 10.3233/JAD-201459 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Multiple Neurodegenerative Pathologies in an Alzheimer's Disease Patient Treated with Fornical Deep Brain Stimulation. %A White, Bartholomew %A Lyketsos, Constantine G %A Rosenberg, Paul B %A Oh, Esther S %A Chen, Liam %X

As an established treatment for movement disorders, deep brain stimulation (DBS) has been adapted for the treatment of Alzheimer's disease (AD) by modulating fornix activity. Although it is generally regarded as a safe intervention in patients over 65 years of age, the complex neurophysiology and interconnection within circuits connected to the fornix warrants a careful ongoing evaluation of the true benefit and risk potential of DBS on slowing cognitive decline in AD patients. Here we report on a patient who died long after being implanted with a DBS device who donated her brain for neuropathologic study. The autopsy confirmed multiple proteinopathies including AD-related change, diffuse neocortical Lewy body disease, TDP-43 proteinopathy, and a nonspecific tauopathy. We discuss the possible mechanisms of these overlapping neurodegenerative disorders and caution that future studies of DBS for AD will need to take these findings into consideration.

%B J Alzheimers Dis %V 80 %P 1383-1387 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201415 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Mutations in the Amyloid-β Protein Precursor Reduce Mitochondrial Function and Alter Gene Expression Independent of 42-Residue Amyloid-β Peptide. %A Pope, Chad A %A Wilkins, Heather M %A Swerdlow, Russell H %A Wolfe, Michael S %X

BACKGROUND: Dominant missense mutations in the amyloid-β protein precursor (AβPP) cause early-onset familial Alzheimer's disease (FAD) and are associated with changes in the production or properties of the amyloid-β peptide (Aβ), particularly of the 42-residue variant (Aβ 42) that deposits in the Alzheimer's disease (AD) brain. Recent findings, however, show that FAD mutations in AβPP also lead to increased production of longer Aβ variants of 45-49 residues in length.

OBJECTIVE: We aimed to test neurotoxicity of Aβ 42 vis-á-vis longer variants, focusing specifically on mitochondrial function, as dysfunctional mitochondria are implicated in the pathogenesis of AD.

METHODS: We generated SH-SY5Y human neuroblastoma cells stably expressing AβPP mutations that lead to increased production of long Aβ peptides with or without Aβ 42. These AβPP-expressing cells were tested for oxygen consumption rates (OCR) under different conditions designed to interrogate mitochondrial function. These cell lines were also examined for expression of genes important for mitochondrial or neuronal structure and function.

RESULTS: The mutant AβPP-expressing cells showed decreased basal OCRs as well as decreased OCRs associated with mitochondrial ATP production, even more so in the absence of Aβ 42 production. Moreover, mutant AβPP-expressing cells producing longer forms of Aβ displayed altered expression of certain mitochondrial- and neuronal-associated genes, whether or not Aβ 42 was produced.

CONCLUSION: These findings suggest that mutant AβPP can cause mitochondrial dysfunction that is associated with long Aβ but not with Aβ 42.

%B J Alzheimers Dis %V 83 %P 1039-1049 %8 2021 Sep 28 %G eng %N 3 %R 10.3233/JAD-210366 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Near-Infrared Optical Spectroscopy In Vivo Distinguishes Subjects with Alzheimer's Disease from Age-Matched Controls. %A Greco, Frank A %A McKee, Ann C %A Kowall, Neil W %A Hanlon, Eugene B %X

BACKGROUND: Medical imaging methods such as PET and MRI aid clinical assessment of Alzheimer's disease (AD). Less expensive, less technically demanding, and more widely deployable technologies are needed to expand objective screening for diagnosis, treatment, and research. We previously reported brain tissue near-infrared optical spectroscopy (NIR) in vitro indicating the potential to meet this need.

OBJECTIVE: To determine whether completely non-invasive, clinical, NIR in vivo can distinguish AD patients from age-matched controls and to show the potential of NIR as a clinical screen and monitor of therapeutic efficacy.

METHODS: NIR spectra were acquired in vivo. Three groups were studied: autopsy-confirmed AD, control and mild cognitive impairment (MCI). A feature selection approach using the first derivative of the intensity normalized spectra was used to discover spectral regions that best distinguished "AD-alone" (i.e., without other significant neuropathology) from controls. The approach was then applied to other autopsy-confirmed AD cases and to clinically diagnosed MCI cases.

RESULTS: Two regions about 860 and 895 nm completely separate AD patients from controls and differentiate MCI subjects according to the degree of impairment. The 895 nm feature is more important in separating MCI subjects from controls (ratio-of-weights: 1.3); the 860 nm feature is more important for distinguishing MCI from AD (ratio-of-weights: 8.2).

CONCLUSION: These results form a proof of the concept that near-infrared spectroscopy can detect and classify diseased and normal human brain in vivo. A clinical trial is needed to determine whether the two features can track disease progression and monitor potential therapeutic interventions.

%B J Alzheimers Dis %V 82 %P 791-802 %8 2021 Jul 20 %G eng %N 2 %R 10.3233/JAD-201021 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Needs of Dementia Family Caregivers in Spain During the COVID-19 Pandemic. %A Carcavilla, Nuria %A Pozo, Ana Sofía %A González, Belén %A Moral-Cuesta, Débora %A Roldán, José Joaquín %A Erice, Victoria %A Remírez, Ana de Ganuza %K Adaptation, Psychological %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Anxiety Disorders %K Caregivers %K COVID-19 %K Feeding and Eating Disorders %K Female %K Humans %K Male %K Middle Aged %K Mood Disorders %K Needs Assessment %K Sleep Wake Disorders %K Social Isolation %K Social Support %K Spain %X

We explored the experience from caregivers of people with dementia (PwD) during mandatory confinement due to the COVID-19 pandemic in Spain. An online survey, which studied the perceptions of the main problems and consequences experienced during confinement, was answered by 106 family caregivers of PwD. Results showed that family caregivers of PwD experienced psychological problems, like anxiety, mood, sleep, or eating disorders during confinement and felt less supported when they had to handle challenging behaviors or offer meaningful activities. An innovative multi-tiered supportive approach is needed which considers a post-pandemic reality and ensures the continuity of quality care for PwD and their family careers.

%B J Alzheimers Dis %V 80 %P 533-537 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554916?dopt=Abstract %R 10.3233/JAD-201430 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Neuropsychiatric Symptoms in Patients with Dementia Associated with Increased Psychological Distress in Caregivers During the COVID-19 Pandemic. %A Borelli, Wyllians Vendramini %A Augustin, Marina Coutinho %A de Oliveira, Paola Bell Felix %A Reggiani, Lorenzo Casagrande %A Bandeira-de-Mello, Renato Gorga %A Schumacher-Schuh, Artur Francisco %A Chaves, Marcia Lorena Fagundes %A Castilhos, Raphael Machado %K Adult %K Aged %K Aged, 80 and over %K Brazil %K Caregivers %K COVID-19 %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Male %K Mental Disorders %K Middle Aged %K Outpatient Clinics, Hospital %K Pandemics %K Psychological Distress %K Social Isolation %K Young Adult %X

BACKGROUND: The social isolation imposed by COVID-19 pandemic can have a major impact on the mental health of dementia patients and their caregivers.

OBJECTIVE: We aim to evaluate the neurological decline of patients with dementia and the caregivers' burden during the pandemic.

METHODS: We performed a cross-sectional study. Caregivers of dementia patients following in the outpatient clinic were included. A structured telephone interview composed of the Neuropsychiatric Inventory Questionnaire (NPI-Q), Zarit Burden Interview (ZBI), Beck Depression (BDI) and Anxiety (BAI) Inventories to address cognitive, behavioral, and functional changes associated with social distancing during the Sars-Cov-2 outbreak. Patients were divided in two groups according to caregivers' report: with perceived Altered Cognition (AC) and Stable Cognition (SC).

RESULTS: A total of 58 patients (median age: 57 years [21-87], 58.6%females) and caregivers (median age: 76.5 years [55-89], 79.3%females) were included. Cognitive decline was shown by most patients (53.4%), as well as behavioral symptoms (48.3%), especially apathy/depression (24.1%), and functional decline (34.5%). The AC group (n = 31) presented increased behavioral (67.7%versus 25.9%, p = 0.002) and functional (61.3%versus 3.7%, p < 0.001) changes when compared to the SC group. In the AC group, ZBI, BDI, NPI-Q caregiver distress, and NPI-Q patient's severity of symptoms scores were worse than the SC group (p < 0.005 for all).

CONCLUSION: Patients' neuropsychiatric worsening and caregiver burden were frequent during the pandemic. Worsening of cognition was associated with increased caregivers' psychological distress.

%B J Alzheimers Dis %V 80 %P 1705-1712 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646168?dopt=Abstract %R 10.3233/JAD-201513 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Neuropsychiatric Symptoms in Patients with Neurocognitive Disorder and Their Performance Between Mild and Major Stages. %A Botero-Rodríguez, Felipe %A Córdoba Sastoque, Ana Melisa %A Escudero, José Manuel Santacruz %A Santamaría-García, Hernando %X

BACKGROUND: The neuropsychiatric symptoms (NPS) in patients with neurocognitive disorders (NCD) increases the risk of exhibiting significant cognitive and functional decline. However, to the best of our knowledge, few studies have evaluated to what extent the presence of chronic and early NPS impacts cognition and functionality in patients with minor or major stages of NCD.

OBJECTIVE: We aimed to assess the interplay between early and chronic NPS and cognitive and functional presentation of patients with mild and major forms of NCD.

METHODS: We used two NPS tools tracking early and late NPS and assessed to what extent they determine cognitive and functional outcomes in patients with mild and major forms of NCD.

RESULTS: We found an inverse relationship between the presence of NPS, as measured by the Neuropsychiatric Inventory and Mild Behavioral Impairment Checklist (MBI-C), and cognitive and functional variables in major forms of NCD. In contrast, the minor stage of NCD was associated with increased MBI-C scores.

CONCLUSION: Our results revealed that NPS are associated with cognitive and functional outcomes in mild and chronic forms of NCD. Crucially our results suggest that NPS could be considered as a pathological marker of the clinical course of dementia. Additionally, our study calls to study early and late forms of NPS as both impact cognition and functionality of NCD.

%B J Alzheimers Dis %V 85 %P 1735-1744 %8 2022 Feb 15 %G eng %N 4 %R 10.3233/JAD-215283 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic Dysfunction. %A Wei, Wei %A Liu, Yinghua %A Dai, Chunling %A Baazaoui, Narjes %A Tung, Yunn-Chyn %A Liu, Fei %A Iqbal, Khalid %X

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Cognitive dysfunction and loss of neuronal plasticity are known to begin decades before the clinical diagnosis of the disease. The important influence of congenital genetic mutations on the early development of AD provides a novel opportunity to initiate treatment during early development to prevent the Alzheimer-like behavior and synaptic dysfunction.

OBJECTIVE: To explore strategies for early intervention to prevent Alzheimer's disease.

METHODS: In the present study, we investigated the effect of treatment during early development with a ciliary neurotrophic factor (CNTF) derived peptidergic compound, P021 (Ac-DGGLAG-NH2) on cognitive function and synaptic plasticity in 3xTg-AD transgenic mouse model of AD. 3xTg-AD and genetic background-matched wild type female mice were treated from birth to postnatal day 120 with P021 in diet or as a control with vehicle diet, and cognitive function and molecular markers of neuroplasticity were evaluated.

RESULTS: P021 treatment during early development prevented cognitive impairment and increased expressions of pCREB and BDNF that activated downstream various signaling cascades such as PLC/PKC, MEK/ERK and PI3K/Akt, and ameliorated synaptic protein deficit in 4-month-old 3xTg-AD mice.

CONCLUSION: These findings indicate that treatment with the neurotrophic peptide mimetic such as P021 during early development can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial AD and related tauopathies.

%B J Alzheimers Dis %V 82 %P 631-646 %8 2021 Jul 20 %G eng %N 2 %R 10.3233/JAD-201599 %0 Journal Article %J J Alzheimers Dis %D 2021 %T New Frontiers in the Prevention, Diagnosis, and Treatment of Alzheimer's Disease. %A Guzmán-Martínez, Leonardo %A Calfío, Camila %A Farías, Gonzalo A %A Vilches, Cristian %A Prieto, Raul %A Maccioni, Ricardo B %K Acupuncture Therapy %K Aging %K Alzheimer Disease %K Biomarkers %K Dietary Supplements %K Early Diagnosis %K Humans %K Medicine, Chinese Traditional %K Meditation %K Quality of Life %K Treatment Outcome %X

One of the major puzzles in medical research and public health systems worldwide is Alzheimer's disease (AD), reaching nowadays a prevalence near 50 million people. This is a multifactorial brain disorder characterized by progressive cognitive impairment, apathy, and mood and neuropsychiatric disorders. The main risk of AD is aging; a normal biological process associated with a continuum dynamic involving a gradual loss of people's physical capacities, but with a sound experienced view of life. Studies suggest that AD is a break from normal aging with changes in the powerful functional capacities of neurons as well as in the mechanisms of neuronal protection. In this context, an important path has been opened toward AD prevention considering that there are elements of nutrition, daily exercise, avoidance of toxic substances and drugs, an active social life, meditation, and control of stress, to achieve healthy aging. Here, we analyze the involvement of such factors and how to control environmental risk factors for a better quality of life. Prevention as well as innovative screening programs for early detection of the disease using reliable biomarkers are becoming critical to control the disease. In addition, the failure of traditional pharmacological treatments and search for new drugs has stimulated the emergence of nutraceutical compounds in the context of a "multitarget" therapy, as well as mindfulness approaches shown to be effective in the aging, and applied to the control of AD. An integrated approach involving all these preventive factors combined with novel pharmacological approaches should pave the way for the future control of the disease.

%B J Alzheimers Dis %V 82 %P S51-S63 %8 2021 %G eng %N s1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33523002?dopt=Abstract %R 10.3233/JAD-201059 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Niemann-Pick Type C 1 (NPC1) and NPC2 Gene Variability in Demented Patients with Evidence of Brain Amyloid Deposition. %A Sorrentino, Federica %A Arighi, Andrea %A Serpente, Maria %A Arosio, Beatrice %A Arcaro, Marina %A Visconte, Caterina %A Rotondo, Emanuela %A Vimercati, Roberto %A Ferri, Evelyn %A Fumagalli, Giorgio G %A Pietroboni, Anna M %A Carandini, Tiziana %A Scarpini, Elio %A Fenoglio, Chiara %A Galimberti, Daniela %X

BACKGROUND: Variants in Niemann-Pick Type C genes (NPC1 and NPC2) have been suggested to play a role as risk or disease modifying factors for Alzheimer's disease (AD).

OBJECTIVE: The aim of this study was to analyze NPC1 and NPC2 variability in demented patients with evidence of brain amyloid-β 1-42 (Aβ) deposition and to correlate genetic data with clinical phenotypes.

METHODS: A targeted Next Generation Sequencing panel was customized to screen NPC1, NPC2, and main genes related to neurodegenerative dementias in a cohort of 136 demented patients with cerebrospinal fluid (CSF) low Aβ levels or positive PET with Aβ tracer and 200 non-demented geriatric subjects.

RESULTS: Seven patients were carriers of NPC variants in heterozygosis. Four of them displayed pathogenic variants previously found in NPC patients and one AD patient had a novel variant. The latter was absent in 200 non-demented elderly subjects. Five of seven patients (70%) exhibited psychiatric symptoms at onset or later as compared with 43%in non-carriers (p >  0.05).

CONCLUSION: The frequency of NPC1 and NPC2 heterozygous variants in patients with CSF evidence of Aβ deposition is higher than in the general population.

%B J Alzheimers Dis %V 83 %P 1313-1323 %8 2021 Sep 28 %G eng %N 3 %R 10.3233/JAD-210453 %0 Journal Article %J J Alzheimers Dis %D 2021 %T NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer's Disease. %A Van Zeller, Mariana %A Dias, Diogo %A Sebastião, Ana M %A Valente, Cláudia A %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Astrocytes %K Humans %K Inflammasomes %K Inflammation %K Microglia %K NLR Family, Pyrin Domain-Containing 3 Protein %K Tauopathies %X

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.

%B J Alzheimers Dis %V 83 %P 939-961 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34366341?dopt=Abstract %R 10.3233/JAD-210268 %0 Journal Article %J J Alzheimers Dis %D 2021 %T A Novel Approach to the Treatment and Prevention of Alzheimer's Disease Based on the Pathology and Microbiology. %A Allen, Herbert B %K Alzheimer Disease %K Biofilms %K Borrelia burgdorferi %K Brain %K Humans %K Inflammation %K Neurons %K Penicillins %K Plaque, Amyloid %K tau Proteins %K Treponema denticola %X

Utilizing the pathology and microbiology found in tissue from patients with documented Alzheimer's disease (AD), the pathogenesis of this fateful disorder has been made clear. Borrelia burgdorferi and Treponema denticola spirochetes enter the brain, mostly via neuronal pathways and the entorhinal circulation. These organisms easily pass through the blood-brain barrier and have an affinity for neural tissue. Once in the brain, the spirochetes make intra- and extracellular biofilms, and it is the biofilms that create the pathology. Specifically, it is the intracellular biofilms that are ultimately responsible for neurofibrillary tangles and dendritic disintegration. The extracellular biofilms are responsible for the inflammation that initially is generated by the first responder, Toll-like receptor 2. The hypothesis that arises from this work is two-pronged: one is related to prevention; the other to treatment. Regarding prevention, it is very likely possible that AD could be prevented by periodic administration of penicillin (PCN), which would kill the spirochetes before they made biofilms; this would prevent the disease and would not allow any of the above deleterious changes generated by the biofilms to occur. As regards treatment, it may be possible to slow or prevent further decline in early AD by administration of PCN together with a biofilm disperser. The disperser would disrupt the biofilm coating and enable the PCN to kill the spirochetes. This protocol could be administered in a trial with the control arm utilizing the current treatment. The progress of the treatment could be evaluated by one of the current blood tests that is semi-quantitative. The specific protocols are listed.

%B J Alzheimers Dis %V 84 %P 61-67 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34542071?dopt=Abstract %R 10.3233/JAD-210429 %0 Journal Article %J J Alzheimers Dis %D 2021 %T A Novel Cognitive Function Scale Using Functional Near-Infrared Spectroscopy for Evaluating Cognitive Dysfunction. %A Nakamura, Shin %A Yomota, Satoshi %A Ito, Hitomi %A Akinaga, Nobuyuki %A Hori, Ayaka %A Chinomi, Kenta %A Suzuki, Hideaki %A Uchida, Kazuhiko %A Asada, Takashi %X

BACKGROUND: Maintaining cognitive function is integral to a healthy social life in the aged. Although neuropsychological tests and brain imaging methods can assess cognitive dysfunction, these techniques are subjective, psychologically burdensome, and cannot be conducted easily.

OBJECTIVE: We sought to develop an objective, low-burden novel cognitive function scale based on functional near-infrared spectroscopy (fNIRS) of hemodynamic changes in the cerebral cortex during daily task performance.

METHODS: A total of 63 participants (aged 60-80 years) identified as non-dementia controls (NDC) or with mild cognitive impairment (MCI) were recruited and randomly assigned to training and test data sets. Explanatory variables were hemodynamic responses during low-burden sensory and simple tasks without higher-order brain functioning.

RESULTS: A logistic regression analysis of the fNIRS index in NDCs and MCI patients revealed area under the curve, sensitivity, specificity, and holdout results of 0.98, 94%, 88%, and 62% respectively. Correlation between fNIRS index and MCI odds showed positive linearity (R2 = 0.96).

CONCLUSION: Positive correlation between the fNIRS index and MCI odds indicated effectiveness of this fNIRS measurement. Although additional experiments are necessary, the fNIRS index representing degree of cognitive decline can be an onsite monitoring tool to assess cognitive status.

%B J Alzheimers Dis %V 81 %P 1579-1588 %8 2021 Jun 15 %G eng %N 4 %R 10.3233/JAD-210072 %0 Journal Article %J J Alzheimers Dis %D 2021 %T One-Year Aerobic Exercise Reduced Carotid Arterial Stiffness and Increased Cerebral Blood Flow in Amnestic Mild Cognitive Impairment. %A Tomoto, Tsubasa %A Liu, Jie %A Tseng, Benjamin Y %A Pasha, Evan P %A Cardim, Danilo %A Tarumi, Takashi %A Hynan, Linda S %A Munro Cullum, C %A Zhang, Rong %K Aged %K Brain %K Cardiorespiratory Fitness %K Carotid Arteries %K Cerebrovascular Circulation %K Cognitive Dysfunction %K Exercise %K Humans %K Magnetic Resonance Imaging %K Neuropsychological Tests %K Vascular Stiffness %X

BACKGROUND: Central arterial stiffness and brain hypoperfusion are emerging risk factors of Alzheimer's disease (AD). Aerobic exercise training (AET) may improve central arterial stiffness and brain perfusion.

OBJECTIVE: To investigate the effects of AET on central arterial stiffness and cerebral blood flow (CBF) in patients with amnestic mild cognitive impairment (MCI), a prodromal stage of AD.

METHODS: This is a proof-of-concept, randomized controlled trial that assigned 70 amnestic MCI patients into a 12-month program of moderate-to-vigorous AET or stretching-and-toning (SAT) intervention. Carotid β-stiffness index and CBF were measured by color-coded duplex ultrasonography and applanation tonometry. Total CBF was measured as the sum of CBF from both the internal carotid and vertebral arteries, and divided by total brain tissue mass assessed with MRI to obtain normalized CBF (nCBF). Episodic memory and executive function were assessed using standard neuropsychological tests (CVLT-II and D-KEFS). Changes in cardiorespiratory fitness were measured by peak oxygen uptake (VO2peak).

RESULTS: Total 48 patients (29 in SAT and 19 in AET) were completed one-year training. AET improved VO2peak, decreased carotid β-stiffness index and CBF pulsatility, and increased nCBF. Changes in VO2peak were associated positively with changes in nCBF (r = 0.388, p = 0.034) and negatively with carotid β-stiffness index (r = -0.418, p = 0.007) and CBF pulsatility (r = -0.400, p = 0.014). Decreases in carotid β-stiffness were associated with increases in cerebral perfusion (r = -0.494, p = 0.003). AET effects on cognitive performance were minimal compared with SAT.

CONCLUSION: AET reduced central arterial stiffness and increased CBF which may precede its effects on neurocognitive function in patients with MCI.

%B J Alzheimers Dis %V 80 %P 841-853 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33579857?dopt=Abstract %R 10.3233/JAD-201456 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Paraoxonase 1, B Vitamins Supplementation, and Mild Cognitive Impairment. %A Perła-Kaján, Joanna %A Włoczkowska, Olga %A Zioła-Frankowska, Anetta %A Frankowski, Marcin %A David Smith, A %A de Jager, Celeste A %A Refsum, Helga %A Jakubowski, Hieronim %X

BACKGROUND: Identification of modifiable risk factors that affect cognitive decline is important for the development of preventive and treatment strategies. Status of paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme, may play a role in the development of neurological diseases, including Alzheimer's disease.

OBJECTIVE: We tested a hypothesis that PON1 status predicts cognition in individuals with mild cognitive impairment (MCI).

METHODS: Individuals with MCI (n = 196, 76.8-years-old, 60% women) participating in a randomized, double-blind placebo-controlled trial (VITACOG) were assigned to receive a daily dose of folic acid (0.8 mg), vitamin B12 (0.5 mg) and B6 (20 mg) (n = 95) or placebo (n = 101) for 2 years. Cognition was analyzed by neuropsychological tests. Brain atrophy was quantified in a subset of participants (n = 168) by MRI. PON1 status, including PON1 Q192R genotype, was determined by quantifying enzymatic activity of PON1 using paraoxon and phenyl acetate as substrates.

RESULTS: In the placebo group, baseline phenylacetate hydrolase (PhAcase) activity of PON1 (but not paraoxonase activity or PON1 Q192R genotype) was significantly associated with global cognition (Mini-Mental State Examination, MMSE; Telephone Inventory for Cognitive Status-modified, TICS-m), verbal episodic memory (Hopkins Verbal Learning Test-revised: Total Recall, HVLT-TR; Delayed Recall, HVLT-DR), and attention/processing speed (Trail Making A and Symbol Digits Modalities Test, SDMT) at the end of study. In addition to PhAcase, baseline iron and triglycerides predicted MMSE, baseline fatty acids predicted SDMT, baseline anti-N-Hcy-protein autoantibodies predicted TICS-m, SDMT, Trail Making A, while BDNF V66M genotype predicted HVLT-TR and HVLT-DR scores at the end of study. B-vitamins abrogated associations of PON1 and other variables with cognition.

CONCLUSION: PON1 is a new factor associated with impaired cognition that can be ameliorated by B-vitamins in individuals with MCI.

%B J Alzheimers Dis %V 81 %P 1211-1229 %8 2021 Jun 01 %G eng %N 3 %R 10.3233/JAD-210137 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Periodontal Disease and Risk of Dementia in Medicare Patients with Hepatitis C Virus. %A Malone, Joseph %A Jung, Jeah %A Tran, Linh %A Zhao, Chen %X

BACKGROUND: Periodontal disease and hepatitis C virus (HCV) represent chronic infectious states that are common in elderly adults. Both conditions have independently been associated with an increased risk for dementia. Chronic infections are thought to lead to neurodegenerative changes in the central nervous system possibly by promoting a proinflammatory state. This is consistent with growing literature on the etiological role of infections in dementia. Few studies have previously evaluated the association of periodontal disease with dementia in HCV patients.

OBJECTIVE: To examine whether periodontal disease increases the risk of developing Alzheimer's disease and related dementias (ADRD) among HCV patients in Medicare claims data.

METHODS: We used Medicare claims data for HCV patients to assess the incidence rate of ADRD with and without exposure to periodontal disease between 2014 and 2017. Cox multivariate regression was used to estimate the association between periodontal disease and development of ADRD, controlling for age, gender, race, ZIP-level income and education, and medical comorbidities.

RESULTS: Of 439,760 HCV patients, the incidence rate of ADRD was higher in patients with periodontal diseases compared to those without (10.84% versus 9.26%, p <  0.001), and those with periodontal disease developed ADRD earlier compared to those without periodontal disease (13.99 versus 21.60 months, p <  0.001). The hazard of developing ADRD was 1.35 times higher in those with periodontal disease (95% CI, 1.30 to 1.40, p <  0.001) after adjusting for all covariates, including age.

CONCLUSION: Periodontal disease increased the risk of developing ADRD among HCV patients in a national Medicare claims dataset.

%B J Alzheimers Dis %V 85 %P 1301-1308 %8 2022 Feb 01 %G eng %N 3 %R 10.3233/JAD-210666 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Pharmacological Strategies to Improve Dendritic Spines in Alzheimer's Disease. %A Ettcheto, Miren %A Busquets, Oriol %A Cano, Amanda %A Sánchez-López, Elena %A Manzine, Patricia R %A Espinosa-Jimenez, Triana %A Verdaguer, Ester %A Sureda, Francesc X %A Olloquequi, Jordi %A Castro-Torres, Ruben D %A Auladell, Carme %A Folch, Jaume %A Casadesus, Gemma %A Camins, Antoni %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Dendritic Spines %K Diet, Healthy %K Exercise %K Gastrointestinal Microbiome %K Humans %K Mannose %K Oligosaccharides %K Synapses %X

To deeply understand late onset Alzheimer's disease (LOAD), it may be necessary to change the concept that it is a disease exclusively driven by aging processes. The onset of LOAD could be associated with a previous peripheral stress at the level of the gut (changes in the gut microbiota), obesity (metabolic stress), and infections, among other systemic/environmental stressors. The onset of LOAD, then, may result from the generation of mild peripheral inflammatory processes involving cytokine production associated with peripheral stressors that in a second step enter the brain and spread out the process causing a neuroinflammatory brain disease. This hypothesis could explain the potential efficacy of Sodium Oligomannate (GV-971), a mixture of acidic linear oligosaccharides that have shown to remodel gut microbiota and slowdown LOAD. However, regardless of the origin of the disease, the end goal of LOAD-related preventative or disease modifying therapies is to preserve dendritic spines and synaptic plasticity that underlay and support healthy cognition. Here we discuss how systemic/environmental stressors impact pathways associated with the regulation of spine morphogenesis and synaptic maintenance, including insulin receptor and the brain derived neurotrophic factor signaling. Spine structure remodeling is a plausible mechanism to maintain synapses and provide cognitive resilience in LOAD patients. Importantly, we also propose a combination of drugs targeting such stressors that may be able to modify the course of LOAD by acting on preventing dendritic spines and synapsis loss.

%B J Alzheimers Dis %V 82 %P S91-S107 %8 2021 %G eng %N s1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33325386?dopt=Abstract %R 10.3233/JAD-201106 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Physical Activity and Trajectory of Cognitive Change in Older Persons: Mayo Clinic Study of Aging. %A Krell-Roesch, Janina %A Syrjanen, Jeremy A %A Bezold, Jelena %A Trautwein, Sandra %A Barisch-Fritz, Bettina %A Boes, Klaus %A Woll, Alexander %A Forzani, Erica %A Kremers, Walter K %A Machulda, Mary M %A Mielke, Michelle M %A Knopman, David S %A Petersen, Ronald C %A Vassilaki, Maria %A Geda, Yonas E %X

BACKGROUND: Little is known about the association between physical activity (PA) and cognitive trajectories in older adults.

OBJECTIVE: To examine the association between PA and change in memory, language, attention, visuospatial skills, and global cognition, and a potential impact of sex or Apolipoprotein E (APOE) ɛ4 status.

METHODS: Longitudinal study derived from the population-based Mayo Clinic Study of Aging, including 2,060 cognitively unimpaired males and females aged ≥70 years. Engagement in midlife (ages 50-65) and late-life (last year) PA was assessed using a questionnaire. Neuropsychological testing was done every 15 months (mean follow-up 5.8 years). We ran linear mixed-effect models to examine whether mid- or late-life PA at three intensities (mild, moderate, vigorous) was associated with cognitive z-scores.

RESULTS: Light intensity midlife PA was associated with less decline in memory function compared to the no-PA reference group (time x light PA; estimate [standard error] 0.047 [0.016], p = 0.004). Vigorous late-life PA was associated with less decline in language (0.033 [0.015], p = 0.030), attention (0.032 [0.017], p = 0.050), and global cognition (0.039 [0.016], p = 0.012). Females who were physically inactive in midlife experienced more pronounced cognitive decline than females physically active in midlife and males regardless of PA (p-values for time interaction terms with midlife PA levels and sex were all p <  0.05 for global cognition). APOE ɛ4 carriership did not moderate the association between PA and cognition.

CONCLUSION: Engaging in PA, particularly of vigorous intensity in late-life, was associated with less pronounced decline in global and domain-specific cognition. This association may differ by sex.

%B J Alzheimers Dis %V 79 %P 377-388 %8 2021 Jan 5 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33216032?dopt=Abstract %R 10.3233/JAD-200959 %0 Journal Article %J J Alzheimers Dis %D 2021 %T PINK1 Activation Attenuates Impaired Neuronal-Like Differentiation and Synaptogenesis and Mitochondrial Dysfunction in Alzheimer's Disease Trans-Mitochondrial Cybrid Cells. %A Du, Fang %A Yu, Qing %A Yan, Shirley ShiDu %X

BACKGROUND: Mitochondrial dysfunction, bioenergetic deficit, and extensive oxidative stress underlie neuronal perturbation during the early stage of Alzheimer's disease (AD). Previously, we demonstrated that decreased PTEN-induced putative kinase 1 (PINK1) expression is associated with AD pathology in AD-affected human brains and AD mice.

OBJECTIVE: In the present study, we highlight the essential role of PINK1 in AD-relevant mitochondrial perturbation and neuronal malfunction.

METHODS: Using trans-mitochondrial "cybrid" (cytoplasmic hybrid) neuronal cells, whose mitochondria are transferred from platelets of patients with sporadic AD, we observed the effect of PINK1 in neuronal-like differentiation and synaptogenesis and mitochondrial functions.

RESULTS: In AD cybrid cells, the downregulation of PINK1 is correlated to the alterations in mitochondrial morphology and function and deficit in neuronal-like differentiation. Restoring/increasing PINK1 by lentivirus transduction of PINK1 robustly attenuate mitochondrial defects and rescue neurite-like outgrowth. Importantly, defective PINK1 kinase activity fails to reverse these detrimental effects. Mechanistically, AD cybrid cells reveal a significant decrease in PINK1-dependent phosphorylated mitofusin (Mfn) 2, a key mitochondrial membrane protein that participates in mitochondrial fusion, and an insufficient autophagic activity for clearance of dysfunctional mitochondria. Overexpression of PINK1, but not mutant PINK1 elevates phosphorylation of Mfn2 and autophagy signaling LC3-II. Accordingly, PINK1-overexpressed AD cybrids exhibit increases in mitochondrial length and density and suppressed reactive oxygen species. These results imply that activation of PINK1 protects against AD-affected mitochondrial dysfunction and impairment in neuronal maturation and differentiation.

CONCLUSION: PINK1-mediated mitophagy is important for maintaining mitochondrial health by clearance of dysfunctional mitochondria and therefore, improves energy homeostasis in AD.

%B J Alzheimers Dis %V 81 %P 1749-1761 %8 2021 Jun 15 %G eng %N 4 %R 10.3233/JAD-210095 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Plasma Biomarkers of Alzheimer's Disease in African Americans. %A Deniz, Kaancan %A Ho, Charlotte C G %A Malphrus, Kimberly G %A Reddy, Joseph S %A Nguyen, Thuy %A Carnwath, Troy P %A Crook, Julia E %A Lucas, John A %A Graff-Radford, Neill R %A Carrasquillo, Minerva M %A Ertekin-Taner, Nilufer %K African Americans %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Case-Control Studies %K Female %K Humans %K Interleukin-10 %K Interleukin-6 %K Male %K Middle Aged %K Peptide Fragments %K tau Proteins %K Tumor Necrosis Factor-alpha %X

BACKGROUND/OBJECTIVE: The aim of this study was to determine if plasma concentrations of 5 surrogate markers of Alzheimer's disease (AD) pathology and neuroinflammation are associated with disease status in African Americans.

METHODS: We evaluated 321 African Americans (159 AD, 162 controls) from the Florida Consortium for African-American Alzheimer's Disease Studies (FCA3DS). Five plasma proteins reflecting AD neuropathology or inflammation (Aβ42, tau, IL6, IL10, TNFα) were tested for associations with AD, age, sex, APOE and MAPT genotypes, and for pairwise correlations.

RESULTS: Plasma tau levels were higher in AD when adjusted for biological and technical covariates. APOEɛ4 was associated with lower plasma Aβ42 and tau levels. Older age was associated with higher plasma Aβ42, tau, and TNFα. Females had lower IL10 levels. Inflammatory proteins had strong pairwise correlations amongst themselves and with Aβ42.

CONCLUSION: We identified effects of demographic and genetic variants on five potential plasma biomarkers in African Americans. Plasma inflammatory biomarkers and Aβ42 may reflect correlated pathologies and elevated plasma tau may be a biomarker of AD in this population.

%B J Alzheimers Dis %V 79 %P 323-334 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33252078?dopt=Abstract %R 10.3233/JAD-200828 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Plasma EFEMP1 Is Associated with Brain Aging and Dementia: The Framingham Heart Study. %A McGrath, Emer R %A Himali, Jayandra J %A Levy, Daniel %A Yang, Qiong %A DeCarli, Charles S %A Courchesne, Paul %A Satizabal, Claudia L %A Finney, Rebecca %A Vasan, Ramachandran S %A Beiser, Alexa S %A Seshadri, Sudha %X

BACKGROUND: Epidermal growth factor containing fibulin extracellular matrix protein-1 (EFEMP1) has been associated with increased white matter hyperintensities (WMH) burden and disorders of premature aging and may have a shared pathophysiological role in the development of WMH and dementia.

OBJECTIVE: To determine the association between plasma EFEMP1 levels and MRI markers of vascular brain injury and incident all-cause and Alzheimer's disease (AD) dementia.

METHODS: We measured plasma EFEMP1 levels in 1597 [53% women, mean age 68.7 (SD 5.7) years] dementia-free Framingham Offspring cohort participants between 1998-2001 and subsequently followed them for incident dementia. Secondary outcomes included stroke, structural MRI brain measures and neurocognitive test performance.

RESULTS: During a median 11.8 [Q1, Q3 : 7.1, 13.3] year follow-up, 131 participants developed dementia. The highest quintile of plasma EFEMP1, compared to the bottom four quintiles, was associated with an increased risk of time to incident all-cause dementia (HR 1.77, 95% CI 1.18-2.64) and AD dementia (HR 1.76, 95% CI 1.11-2.81) but not with markers of vascular brain injury (WMH, covert brain infarcts or stroke). Higher circulating EFEMP1 concentrations were also cross-sectionally associated with lower total brain (β±SE, -0.28±0.11, p = 0.01) and hippocampal volumes (-0.006±0.003, p = 0.04) and impaired abstract reasoning (Similarities test, -0.18±0.08, p = 0.018 per standard deviation increment in EFEMP1).

CONCLUSION: Elevated circulating EFEMP1 is associated with an increased risk of all-cause and AD dementia, smaller hippocampal and total brain volumes, and poorer cognitive performance. EFEMP1 may play an important biological role in the development of AD dementia. Further studies to validate these findings are warranted.

%B J Alzheimers Dis %V 85 %P 1657-1666 %8 2022 Feb 15 %G eng %N 4 %R 10.3233/JAD-215053 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Plasma Neurofilament Light Chain Predicts Cognitive Progression in Prodromal and Clinical Dementia with Lewy Bodies. %A Pilotto, Andrea %A Imarisio, Alberto %A Carrarini, Claudia %A Russo, Mirella %A Masciocchi, Stefano %A Gipponi, Stefano %A Cottini, Elisabetta %A Aarsland, Dag %A Zetterberg, Henrik %A Ashton, Nicholas J %A Hye, Abdul %A Bonanni, Laura %A Padovani, Alessandro %X

Plasma neurofilament light chain (NfL) is a marker of neuronal damage in different neurological disorders and might predict disease progression in dementia with Lewy bodies (DLB). The study enrolled 45 controls and 44 DLB patients (including 17 prodromal cases) who underwent an extensive assessment at baseline and at 2 years follow-up. At baseline, plasma NfL levels were higher in both probable DLB and prodromal cases compared to controls. Plasma NfL emerged as the best predictor of cognitive decline compared to age, sex, and baseline severity variables. The study supports the role of plasma NfL as a useful prognostic biomarker from the early stages of DLB.

%B J Alzheimers Dis %V 82 %P 913-919 %8 2021 Aug 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34151807?dopt=Abstract %R 10.3233/JAD-210342 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Plasma Total-Tau and Neurofilament Light Chain as Diagnostic Biomarkers of Alzheimer's Disease Dementia and Mild Cognitive Impairment in Adults with Down Syndrome. %A Petersen, Melissa E %A Rafii, Michael S %A Zhang, Fan %A Hall, James %A Julovich, David %A Ances, Beau M %A Schupf, Nicole %A Krinsky-McHale, Sharon J %A Mapstone, Mark %A Silverman, Wayne %A Lott, Ira %A Klunk, William %A Head, Elizabeth %A Christian, Brad %A Foroud, Tatiana %A Lai, Florence %A Diana Rosas, H %A Zaman, Shahid %A Wang, Mei-Cheng %A Tycko, Benjamin %A Lee, Joseph %A Handen, Benjamin %A Hartley, Sigan %A Fortea, Juan %A O'Bryant, Sid %X

BACKGROUND: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, the application of such biomarkers has been limited among the DS population.

OBJECTIVE: This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults.

METHODS: Plasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS-AD) participants enrolled in the Alzheimer's Biomarker Consortium -Down Syndrome.

RESULTS: In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS.

CONCLUSION: Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.

%B J Alzheimers Dis %V 79 %P 671-681 %8 2021 Jan 19 %G eng %N 2 %& 671 %R 10.3233/JAD-201167 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Polyphenols as Potential Metal Chelation Compounds Against Alzheimer's Disease. %A Lakey-Beitia, Johant %A Burillo, Andrea M %A La Penna, Giovanni %A Hegde, Muralidhar L %A Rao, K S %K Alzheimer Disease %K Amyloid beta-Peptides %K Antioxidants %K Chelating Agents %K Copper %K Humans %K Oxidative Stress %K Polyphenols %K Zinc %X

Alzheimer's disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide. The pathology of this multifactorial disease is primarily characterized by the formation of amyloid-β (Aβ) aggregates; however, other etiological factors including metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), play critical role in disease progression. Because these transition metal ions are important for cellular function, their imbalance can cause oxidative stress that leads to cellular death and eventual cognitive decay. Importantly, these transition metal ions can interact with the amyloid-β protein precursor (AβPP) and Aβ42 peptide, affecting Aβ aggregation and increasing its neurotoxicity. Considering how metal dyshomeostasis may substantially contribute to AD, this review discusses polyphenols and the underlying chemical principles that may enable them to act as natural chelators. Furthermore, polyphenols have various therapeutic effects, including antioxidant activity, metal chelation, mitochondrial function, and anti-amyloidogenic activity. These combined therapeutic effects of polyphenols make them strong candidates for a moderate chelation-based therapy for AD.

%B J Alzheimers Dis %V 82 %P S335-S357 %8 2021 Jun 22 %G eng %N s1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32568200?dopt=Abstract %R 10.3233/JAD-200185 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Porphyromonas Gingivalis Infection Induces Synaptic Failure via Increased IL-1β Production in Leptomeningeal Cells. %A Huang, Wanyi %A Zeng, Fan %A Gu, Yebo %A Jiang, Muzhou %A Zhang, Xinwen %A Yan, Xu %A Kadowaki, Tomoko %A Mizutani, Shinsuke %A Kashiwazaki, Haruhiko %A Ni, Junjun %A Wu, Zhou %X

BACKGROUND: Studies have reported that synaptic failure occurs before the Alzheimer's disease (AD) onset. The systemic Porphyromonas gingivalis (P. gingivalis) infection is involved in memory decline. We previously showed that leptomeningeal cells, covering the brain, activate glial cells by releasing IL-1β in response to systemic inflammation.

OBJECTIVE: In the present study, we focused on the impact of leptomeningeal cells on neurons during systemic P. gingivalis infection.

METHODS: The responses of leptomeningeal cells and cortical neurons to systemic P. gingivalis infection were examined in 15-month-old mice. The mechanism of IL-1β production by P. gingivalis infected leptomeningeal cells was examined, and primary cortical neurons were treated with P. gingivalis infected leptomeningeal cells condition medium (Pg LCM).

RESULTS: Systemic P. gingivalis infection increased the expression of IL-1β in leptomeninges and reduced the synaptophysin (SYP) expression in leptomeninges proximity cortex in mice. Leptomeningeal cells phagocytosed P. gingivalis resulting in lysosomal rupture and Cathepsin B (CatB) leakage. Leaked CatB mediated NLRP3 inflammasome activation inducing IL-1β secretion in leptomeningeal cells. Pg LCM decreased the expression of synaptic molecules, including SYP, which was inhibited by an IL-1 receptor antagonist pre-treatment.

CONCLUSION: These observations demonstrate that P. gingivalis infection is involved in synaptic failure by inducing CatB/NLRP3 inflammasome-mediated IL-1β production in leptomeningeal cells. The periodontal bacteria-induced synaptic damage may accelerate the onset and cognitive decline of AD.

%B J Alzheimers Dis %V 83 %P 665-681 %8 2021 Sep 21 %G eng %N 2 %R 10.3233/JAD-210031 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Porphyromonas gingivalis Outer Membrane Vesicles as the Major Driver of and Explanation for Neuropathogenesis, the Cholinergic Hypothesis, Iron Dyshomeostasis, and Salivary Lactoferrin in Alzheimer's Disease. %A Nara, Peter L %A Sindelar, Daniel %A Penn, Marc S %A Potempa, Jan %A Griffin, W Sue T %K Alzheimer Disease %K Anti-Infective Agents %K Bacterial Outer Membrane Proteins %K Bacteroidaceae Infections %K Brain %K Cholinergic Agents %K Extremophiles %K Humans %K Iron %K Lactoferrin %K Porphyromonas gingivalis %K Saliva %X

Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced "chronic" multi-systems inflammatory disease(s) including Alzheimer's disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria's direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the "infection hypothesis" of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of "Pg bacteria" residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the "Gingipains Hypothesis", AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.

%B J Alzheimers Dis %V 82 %P 1417-1450 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/34275903?dopt=Abstract %R 10.3233/JAD-210448 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Porphyromonas gingivalis (W83) Infection Induces Alzheimer's Disease-Like Pathophysiology in Obese and Diabetic Mice. %A Bahar, Bojlul %A Kanagasingam, Shalini %A Tambuwala, Murtaza M %A Aljabali, Alaa A A %A Dillon, Stephanie A %A Doaei, Saeid %A Welbury, Richard %A Chukkapalli, Sasanka S %A Singhrao, Sim K %X

BACKGROUND: Periodontal disease(s) and metabolic illnesses negatively impact the quality of life and, eventually mental health.

OBJECTIVE: This study investigated the effect of Porphyromonas gingivalis (W83) oral infection on the development of Alzheimer's disease (AD) pathophysiology in a wild-type obese, diabetic (db/db) mouse model.

METHODS: The db/db mice were either orally infected with P. gingivalis and Fusobacterium nucleatum or sham infected for 16 weeks. The presence of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) were assessed using a silver impregnation technique and subsequently by immunohistochemistry for tau and neuroinflammation. The mRNA abundance of a panel of 184 genes was performed using quantitative real-time PCR, and the differentially expressed genes were analyzed by Ingenuity Pathway Analysis.

RESULTS: While no Aβ plaques and NFTs were evident by silver impregnation, immunohistochemistry (glial cell markers) of the P. gingivalis-infected mice tissue sections exhibited neuroinflammation in the form of reactive microglia and astrocytes. Anti-tau immunopositivity, in addition to cells, was prominent in thickened axons of hippocampal CA neurons. The mRNA abundance of crucial genes in the insulin signaling pathway (INSR, IGF1, IRS, IDE, PIK3R, SGK1, GYS, GSK3B, AKT1) were upregulated, potentially exacerbating insulin resistance in the brain by P. gingivalis oral infection. Increased mRNA abundance of several kinases, membrane receptors, transcription factors, and pro-inflammatory mediators indicated hyperactivation of intracellular cascades with potential for tau phosphorylation and Aβ release in the same infection group.

CONCLUSION: P. gingivalis W83 infection of db/db mice provides a disease co-morbidity model with the potential to reproduce AD pathophysiology with induced periodontal disease.

%B J Alzheimers Dis %V 82 %P 1259-1275 %8 2021 Aug 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34151813?dopt=Abstract %R 10.3233/JAD-210465 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Possible Role of Activin in the Adiponectin Paradox-Induced Progress of Alzheimer's Disease. %A Hashimoto, Makoto %A Ho, Gilbert %A Sugama, Shuei %A Takenouchi, Takato %A Waragai, Masaaki %A Sugino, Hiromu %A Inoue, Satoshi %A Masliah, Eliezer %X

Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer's disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-β (Aβ) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor β (TGFβ) superfamily of peptides, to antagonistic pleiotropy effects of APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFβ increases during aging. Also, activin/TGFβ signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aβ 42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFβ receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target.

%B J Alzheimers Dis %V 81 %P 451-458 %8 2021 May 18 %G eng %N 2 %R 10.3233/JAD-210206 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Potential Role of Ferroptosis in Alzheimer's Disease. %A Zhang, Guimei %A Zhang, Yaru %A Shen, Yanxin %A Wang, Yongchun %A Zhao, Meng %A Sun, Li %K Alzheimer Disease %K Animals %K Ferroptosis %K Humans %X

Alzheimer's disease (AD) is the most prevalent cause of dementia, accounting for approximately 60%-80%of all cases. Although much effort has been made over the years, the precise mechanism of AD has not been completely elucidated. Recently, great attention has shifted to the roles of iron metabolism, lipid peroxidation, and oxidative stress in AD pathogenesis. We also note that these pathological events are the vital regulators of a novel regulatory cell death, termed ferroptosis-an iron-dependent, oxidative, non-apoptotic cell death. Ferroptosis differs from apoptosis, necrosis, and autophagy with respect to morphology, biochemistry, and genetics. Mounting evidence suggests that ferroptosis may be involved in neurological disorders, including AD. Here, we review the underlying mechanisms of ferroptosis; discuss the potential interaction between AD and ferroptosis in terms of iron metabolism, lipid peroxidation, and the glutathione/glutathione peroxidase 4 axis; and describe some associated studies that have explored the implication of ferroptosis in AD.

%B J Alzheimers Dis %V 80 %P 907-925 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646161?dopt=Abstract %R 10.3233/JAD-201369 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Predictors of Mild Cognitive Impairment Stability, Progression, or Reversion in the Lothian Birth Cohort 1936. %A Welstead, Miles %A Luciano, Michelle %A Muniz-Terrera, Graciela %A Saunders, Stina %A Mullin, Donncha S %A Russ, Tom C %X

BACKGROUND: Mild cognitive impairment (MCI) describes a borderland between healthy cognition and dementia. Progression to and reversion from MCI is relatively common but more research is required to understand the factors affecting this fluidity and improve clinical care interventions.

OBJECTIVE: We explore these transitions in MCI status and their predictive factors over a six-year period in a highly-phenotyped longitudinal study, the Lothian Birth Cohort 1936.

METHODS: MCI status was derived in the LBC1936 at ages 76 (n = 567) and 82 years (n = 341) using NIA-AA diagnostic guidelines. Progressions and reversions between healthy cognition and MCI over the follow-up period were assessed. Multinomial logistic regression assessed the effect of various predictors on the likelihood of progressing, reverting, or maintaining cognitive status.

RESULTS: Of the 292 participants who completed both time points, 41 (14%) participants had MCI at T1 and 56 (19%) at T2. Over the follow-up period, 74%remained cognitively healthy, 12%transitioned to MCI, 7%reverted to healthy cognition, and 7%maintained their baseline MCI status. Findings indicated that membership of these transition groups was affected by age, cardiovascular disease, and number of depressive symptoms.

CONCLUSION: Findings that higher baseline depressive symptoms increase the likelihood of reverting from MCI to healthy cognition indicate that there may be an important role for the treatment of depression for those with MCI. However, further research is required to identify prevention strategies for those at high risk of MCI and inform effective interventions that increase the likelihood of reversion to, and maintenance of healthy cognition.

%B J Alzheimers Dis %V 80 %P 225-232 %8 2021 Mar 9 %G eng %N 1 %R 10.3233/JAD-201282 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Preventing Delirium and Promoting Long-Term Brain Health: A Clinical Trial Design for the Perioperative Cognitive Enhancement (PROTECT) Trial. %A Atkins, Kelly J %A Scott, David %A Silbert, Brendan %A Pike, Kerryn E %A Evered, Lis %X

BACKGROUND: Perioperative neurocognitive disorders (PND), including postoperative delirium (POD), are common in older adults and, for many, precipitate functional decline and/or dementia.

OBJECTIVE: In this protocol, we describe a novel multidisciplinary, multicomponent perioperative intervention that seeks to prevent or reduce POD and associated cognitive decline.

METHODS: We will conduct a prospective, single-blind, pragmatic, randomized-controlled trial to compare our tailored multi-disciplinary perioperative pathway against current standard of care practices. We will recruit a total of 692 elective surgical patients aged 65 years or more and randomize them in a 1:1 design. Our perioperative intervention targets delirium risk reduction strategies by emphasizing the importance of early mobilization, nutrition, hydration, cognitive orientation, sensory aids, and avoiding polypharmacy. To promote healthy behavior change, we will provide a tailored psychoeducation program both pre- and postoperatively, focusing on cardiovascular and psychosocial risks for cognitive and functional decline.

RESULTS: Our primary outcome is the incidence of any PND (encapsulating POD and mild or major postoperative neurocognitive disorder) at three months postoperative. Secondary outcomes include any incidence of POD or neurocognitive disorder at 12 months. A specialized delirium screening instrument, the Confusion Assessment Method (3D-CAM), and a neuropsychological test battery, will inform our primary and secondary outcomes.

CONCLUSION: Delirium is a common and debilitating postoperative complication that contributes to the cognitive and functional decline of older adults. By adopting a multicomponent, multidisciplinary approach to perioperative delirium prevention, we seek to reduce the burden of delirium and subsequent dementia in older adults.

%B J Alzheimers Dis %V 83 %P 1637-1649 %8 2021 Oct 12 %G eng %N 4 %R 10.3233/JAD-210438 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Primary Prevention of Dementia: An Ethical Review. %A Horstkötter, Dorothee %A Deckers, Kay %A Köhler, Sebastian %K Dementia %K Ethical Review %K Humans %K Life Style %K Primary Prevention %X

Dementia poses important medical and societal challenges, and of all health risks people face in life, dementia is one of the most feared. Recent research indicates that up to about 40% of all cases of dementia might be preventable. A series of environmental, social, and medical risk-factors have been identified that should be targeted from midlife onwards when people are still cognitively healthy. At first glance, this seems not merely advisable, but even imperative. However, these new developments trigger a series of new ethical questions and concerns which have hardly been addressed to date. Pro-active ethical reflection, however, is crucial to ensure that the interests and well-being of those affected, ultimately all of us, are adequately respected. This is the goal of the current contribution. Against the background of a concrete case in primary dementia prevention, it provides a systematic overview of the current ethical literature and sketches an ethical research agenda. First, possible benefits of increased well-being must be balanced with the burdens of being engaged in particularly long-term interventions for which it is unclear whether they will ever pay out on a personal level. Second, while knowledge about one's options to maintain brain health might empower people, it might also undermine autonomy, put high social pressure on people, medicalize healthy adults, and stigmatize those who still develop dementia. Third, while synergistic effects might occur, the ideals of dementia prevention might also conflict with other health and non-health related values people hold in life.

%B J Alzheimers Dis %V 79 %P 467-476 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33337375?dopt=Abstract %R 10.3233/JAD-201104 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Promoting Successful Cognitive Aging: A Ten-Year Update. %A Krivanek, Taylor J %A Gale, Seth A %A McFeeley, Brittany M %A Nicastri, Casey M %A Daffner, Kirk R %K Cognition %K Cognitive Aging %K Diet, Healthy %K Exercise %K Healthy Aging %K Healthy Lifestyle %K Humans %X

A decade has passed since we published a comprehensive review in this journal addressing the topic of promoting successful cognitive aging, making this a good time to take stock of the field. Because there have been limited large-scale, randomized controlled trials, especially following individuals from middle age to late life, some experts have questioned whether recommendations can be legitimately offered about reducing the risk of cognitive decline and dementia. Despite uncertainties, clinicians often need to at least make provisional recommendations to patients based on the highest quality data available. Converging lines of evidence from epidemiological/cohort studies, animal/basic science studies, human proof-of-concept studies, and human intervention studies can provide guidance, highlighting strategies for enhancing cognitive reserve and preventing loss of cognitive capacity. Many of the suggestions made in 2010 have been supported by additional research. Importantly, there is a growing consensus among major health organizations about recommendations to mitigate cognitive decline and promote healthy cognitive aging. Regular physical activity and treatment of cardiovascular risk factors have been supported by all of these organizations. Most organizations have also embraced cognitively stimulating activities, a heart-healthy diet, smoking cessation, and countering metabolic syndrome. Other behaviors like regular social engagement, limiting alcohol use, stress management, getting adequate sleep, avoiding anticholinergic medications, addressing sensory deficits, and protecting the brain against physical and toxic damage also have been endorsed, although less consistently. In this update, we review the evidence for each of these recommendations and offer practical advice about behavior-change techniques to help patients adopt brain-healthy behaviors.

%B J Alzheimers Dis %V 81 %P 871-920 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33935078?dopt=Abstract %R 10.3233/JAD-201462 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Proteome Profiling Identified Amyloid-β Protein Precursor as a Novel Binding Partner and Modulator of VGLUT1. %A Zhou, Jin-Wu %A Zhao, Man %A Rang, Wen-Liang %A Zhang, Xiao-Yan %A Liu, Zhen-Ming %A Zhang, Liang-Ren %A Wang, Tong-Xing %A Wu, Chu-Tse %A Cheng, Xiao-Rui %A Zhou, Wen-Xia %X

BACKGROUND: The toxicity of excessive glutamate release has been implicated in various acute and chronic neurodegenerative conditions. Vesicular glutamate transporters (VGLUTs) are the major mediators for the uptake of glutamate into synaptic vesicles. However, the dynamics and mechanism of this process in glutamatergic neurons are still largely unknown.

OBJECTIVE: This study aimed to investigate the candidate protein partners of VGLUT1 and their regulatory roles in the vesicles in rat brain.

METHODS: Pull down assay, co-immunoprecipitation assay, or split-ubiquitin membrane yeast two hybrid screening coupled with nanoRPLC-MS/MS were used to identify the candidate protein partners of VGLUT1 in the vesicles in rat brain. The in vitro and in vivo models were used to test effects of AβPP, Atp6ap2, Gja1, and Synataxin on VGLUT1 expression.

RESULTS: A total of 255 and 225 proteins and 172 known genes were identified in the pull down assay, co-immunoprecipitation assay, or split-ubiquitin yeast two-hybrid screening respectively. The physiological interactions of SV2A, Syntaxin 12, Gja1, AβPP, and Atp6ap2 to VGLUT1 were further confirmed. Knockdown of Atp6ap2, Gja1, and Synataxin increased VGLUT1 mRNA expression and only knockdown of AβPP increased both mRNA and protein levels of VGLUT1 in PC12 cells. The regulatory function of AβPP on VGLUT1 expression was further confirmed in the in vitro and in vivo models.

CONCLUSION: These results elucidate that the AβPP and VGLUT1 interacts at vesicular level and AβPP plays a role in the regulation of VGLUT1 expression which is essential for maintaining vesicular activities.

%B J Alzheimers Dis %V 81 %P 981-1038 %8 2021 Jun 01 %G eng %N 3 %R 10.3233/JAD-210117 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Proton Stimulation Targeting Plaque Magnetite Reduces Amyloid-β Plaque and Iron Redox Toxicity and Improves Memory in an Alzheimer's Disease Mouse Model. %A Seo, Seung-Jun %A Chang, Won-Seok %A Jeon, Jae-Geun %A Choi, Younshick %A Kim, EunHo %A Kim, Jong-Ki %X

BACKGROUND: The coexistence of magnetite within protein aggregates in the brain is a typical pathologic feature of Alzheimer's disease (AD), and the formation of amyloid-β (Aβ) plaques induces critical impairment of cognitive function.

OBJECTIVE: This study aimed to investigate the therapeutic effect of proton stimulation (PS) targeting plaque magnetite in the transgenic AD mouse brain.

METHODS: A proton transmission beam was applied to the whole mouse brain at a single entrance dose of 2 or 4 Gy to test the effect of disruption of magnetite-containing Aβ plaques by electron emission from magnetite. The reduction in Aβ plaque burden and the cognitive function of the PS-treated mouse group were assayed by histochemical analysis and memory tests, respectively. Aβ-magnetite and Aβ fibrils were treated with PS to investigate the breakdown of the amyloid protein matrix.

RESULTS: Single PS induced a 48-87%reduction in both the amyloid plaque burden and ferrous-containing magnetite level in the early-onset AD mouse brain while saving normal tissue. The overall Aβ plaque burden (68-82%) and (94-97%) hippocampal magnetite levels were reduced in late onset AD mice that showed improvements in cognitive function after PS compared with untreated AD mice (p <  0.001). Analysis of amyloid fibrils after exposure to a single 2 or 4 Gy proton transmission beam demonstrated that the protein matrix was broken down only in magnetite-associated Aβ fibrils.

CONCLUSION: Single PS targeting plaque magnetite effectively decreases the amyloid plaque burden and the ferrous-containing magnetite level, and this effect is useful for memory recovery.

%B J Alzheimers Dis %V 84 %P 377-392 %8 2021 Oct 26 %G eng %N 1 %R 10.3233/JAD-210739 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Psychological Distress in Caregivers for People with Dementia: A Population-Based Analysis of a National Cross-Sectional Study. %A Sugawara, Norio %A Yasui-Furukori, Norio %A Maruo, Kazushi %A Shimoda, Kazutaka %A Sumiyoshi, Tomiki %X

BACKGROUND: Taking care of patients with dementia is often stressful and exhausting. The burden placed on caregivers (CGs) for care recipients with dementia (CRDs) has been reported to cause psychological distress.

OBJECTIVE: The aim of this study was to evaluate the psychological distress experienced by CGs for CRDs and identify the sociodemographic factors affecting that distress.

METHODS: We utilized the 2013 Comprehensive Survey of the Living Conditions for CRDs and CGs. Linked data from 643 pairs of CRDs and CGs were extracted. Serious psychological distress experienced by CGs was measured by Kessler's Psychological Distress scale (K6) with a cutoff point of 13. Factors predictive of psychological distress were evaluated using multivariable logistic regression analysis with the forward selection method.

RESULTS: Overall, the mean age of the CGs was 63.5±11.6 years, and 5.3%(34/643) experienced serious psychological distress. Male sex of CRDs, knowing how to access consulting services, spending almost all day for nursing care, and having subjective symptoms within a few days of completing the survey were associated with having serious psychological distress, while older age, participating in shopping as part of the nursing activities, and having their own house were related to freedom from serious psychological distress.

CONCLUSION: Clinicians should be aware of the risk factors for psychological distress in CGs and consider providing support to reduce the distress imposed by modifiable factors. Further studies are warranted to examine whether such efforts would improve the mental health of CGs for CRDs.

%B J Alzheimers Dis %V 85 %P 667-674 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-210680 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Putative Blood Somatic Mutations in Post-Traumatic Stress Disorder-Symptomatic Soldiers: High Impact of Cytoskeletal and Inflammatory Proteins. %A Sragovich, Shlomo %A Gershovits, Michael %A Lam, Jacqueline C K %A Li, Victor O K %A Gozes, Illana %X

BACKGROUND: We recently discovered autism/intellectual disability somatic mutations in postmortem brains, presenting higher frequency in Alzheimer's disease subjects, compared with the controls. We further revealed high impact cytoskeletal gene mutations, coupled with potential cytoskeleton-targeted repair mechanisms.

OBJECTIVE: The current study was aimed at further discerning if somatic mutations in brain diseases are presented only in the most affected tissue (the brain), or if blood samples phenocopy the brain, toward potential diagnostics.

METHODS: Variant calling analyses on an RNA-seq database including peripheral blood samples from 85 soldiers (58 controls and 27 with symptoms of post-traumatic stress disorder, PTSD) was performed.

RESULTS: High (e.g., protein truncating) as well as moderate impact (e.g., single amino acid change) germline and putative somatic mutations in thousands of genes were found. Further crossing the mutated genes with autism, intellectual disability, cytoskeleton, inflammation, and DNA repair databases, identified the highest number of cytoskeletal-mutated genes (187 high and 442 moderate impact). Most of the mutated genes were shared and only when crossed with the inflammation database, more putative high impact mutated genes specific to the PTSD-symptom cohorts versus the controls (14 versus 13) were revealed, highlighting tumor necrosis factor specifically in the PTSD-symptom cohorts.

CONCLUSION: With microtubules and neuro-immune interactions playing essential roles in brain neuroprotection and Alzheimer-related neurodegeneration, the current mutation discoveries contribute to mechanistic understanding of PTSD and brain protection, as well as provide future diagnostics toward personalized military deployment strategies and drug design.

%B J Alzheimers Dis %V 79 %P 1723-1734 %8 2021 Feb 16 %G eng %N 4 %R 10.3233/JAD-201158 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Quality of Life in Advanced Dementia with Late Onset, Young Onset, and Very Young Onset. %A Hartmann, Julia %A Roßmeier, Carola %A Riedl, Lina %A Dorn, Bianca %A Fischer, Julia %A Slawik, Till %A Fleischhaker, Mareike %A Hartmann, Florentine %A Egert-Schwender, Silvia %A Kehl, Victoria %A Haller, Bernhard %A Schneider-Schelte, Helga %A Dinkel, Andreas %A Jox, Ralf J %A Diehl-Schmid, Janine %K Adult %K Age of Onset %K Aged %K Aged, 80 and over %K Antipsychotic Agents %K Behavioral Symptoms %K Caregivers %K Dementia %K Disease Progression %K Female %K Germany %K Home Care Services %K Humans %K Individuality %K Male %K Middle Aged %K Pain %K Palliative Care %K Psychotropic Drugs %K Quality of Life %X

BACKGROUND: Advanced stages of dementia are characterized by severe cognitive and physical impairment. It has not yet been investigated whether persons with young onset dementia (YOD) and late onset dementia (LOD) differ in advanced disease stages.

OBJECTIVES: To compare quality of life (QoL) between persons with advanced YOD and LOD; to explore the determinants of QoL; to investigate whether YOD and LOD differ with regard to symptoms and care.

METHODS: The study was performed in the context of EPYLOGE (IssuEs in Palliative care for persons in advanced and terminal stages of YOD and LOD in Germany). Persons with advanced dementia (PWAD) were assessed and caregivers were interviewed. QoL was measured with the proxy rating Quality of Life in Late Stage Dementia (QUALID) scale.

RESULTS: 93 persons with YOD and 98 with LOD were included. No significant differences in QoL were detected. Determinants of QoL were similar in YOD and LOD. Behavioral and psychological symptoms of dementia (BPSD), suffering and other distressing symptoms were associated with a lower QoL. In YOD but not in LOD antipsychotic treatment was associated with low QoL. The group of persons who were younger than 65 years at the time of the study visit experienced significantly more distressing symptoms than older PWAD.

CONCLUSION: Overall, persons with advanced YOD do not appear to be disadvantaged compared to old and oldest PWAD. Special attention, however, must be paid to the group of the very young persons who seem to be particularly vulnerable.

%B J Alzheimers Dis %V 80 %P 283-297 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33523011?dopt=Abstract %R 10.3233/JAD-201302 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Quantifying and Examining Reserve in Symptomatic Former National Football League Players. %A Foley, Éimear M %A Tripodis, Yorghos %A Yhang, Eukyung %A Koerte, Inga K %A Martin, Brett M %A Palmisano, Joseph %A Makris, Nikos %A Schultz, Vivian %A Lepage, Chris %A Muehlmann, Marc %A Wróbel, Paweł P %A Guenette, Jeffrey P %A Cantu, Robert C %A Lin, Alexander P %A Coleman, Michael %A Mez, Jesse %A Bouix, Sylvain %A Shenton, Martha E %A Stern, Robert A %A Alosco, Michael L %X

BACKGROUND: Repetitive head impacts (RHI) from contact sports have been associated with cognitive and neuropsychiatric disorders. However, not all individuals exposed to RHI develop such disorders. This may be explained by the reserve hypothesis. It remains unclear if the reserve hypothesis accounts for the heterogenous symptom presentation in RHI-exposed individuals. Moreover, optimal measurement of reserve in this population is unclear and likely unique from non-athlete populations.

OBJECTIVE: We examined the association between metrics of reserve and cognitive and neuropsychiatric functioning in 89 symptomatic former National Football League players.

METHODS: Individual-level proxies (e.g., education) defined reserve. We additionally quantified reserve as remaining residual variance in 1) episodic memory and 2) executive functioning performance, after accounting for demographics and brain pathology. Associations between reserve metrics and cognitive and neuropsychiatric functioning were examined.

RESULTS: Higher reading ability was associated with better attention/information processing (β=0.25; 95% CI, 0.05-0.46), episodic memory (β=0.27; 95% CI, 0.06-0.48), semantic and phonemic fluency (β=0.24; 95% CI, 0.02-0.46; β=0.38; 95% CI, 0.17-0.59), and behavioral regulation (β=-0.26; 95% CI, -0.48, -0.03) performance. There were no effects for other individual-level proxies. Residual episodic memory variance was associated with better attention/information processing (β=0.45; 95% CI, 0.25, 0.65), executive functioning (β=0.36; 95% CI, 0.15, 0.57), and semantic fluency (β=0.38; 95% CI, 0.17, 0.59) performance. Residual executive functioning variance was associated with better attention/information processing (β=0.44; 95% CI, 0.24, 0.64) and episodic memory (β=0.37; 95% CI, 0.16, 0.58) performance.

CONCLUSION: Traditional reserve proxies (e.g., years of education, occupational attainment) have limitations and may be unsuitable for use in elite athlete samples. Alternative approaches of reserve quantification may prove more suitable for this population.

%B J Alzheimers Dis %V 85 %P 675-689 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-210379 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Race/Ethnic Disparities in Mild Cognitive Impairment and Dementia: The Northern Manhattan Study. %A Wright, Clinton B %A DeRosa, Janet T %A Moon, Michelle P %A Strobino, Kevin %A DeCarli, Charles %A Cheung, Ying Kuen %A Assuras, Stephanie %A Levin, Bonnie %A Stern, Yaakov %A Sun, Xiaoyan %A Rundek, Tatjana %A Elkind, Mitchell S V %A Sacco, Ralph L %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Cohort Studies %K Cross-Sectional Studies %K Dementia %K Ethnicity %K Female %K Humans %K Male %K Middle Aged %K New York City %K Prevalence %X

BACKGROUND: Variability in dementia rates across racial and ethnic groups has been estimated at 60%. Studies suggest disparities in Caribbean Hispanic and Black populations, but community-based data are limited.

OBJECTIVE: Estimate the prevalence of mild cognitive impairment (MCI) and dementia in the racially and ethnically diverse community-based Northern Manhattan Study cohort and examine sociodemographic, vascular risk factor, and brain imaging correlates.

METHODS: Cases of MCI and dementia were adjudicated by a team of neuropsychologists and neurologists and prevalence was estimated across race/ethnic groups. Ordinal proportional odds models were used to estimate race/ethnic differences in the prevalence of MCI or dementia adjusting for sociodemographic variables (model 1), model 1 plus potentially modifiable vascular risk factors (model 2), and model 1 plus structural imaging markers of brain integrity (model 3).

RESULTS: There were 989 participants with cognitive outcome determinations (mean age 69±9 years; 68% Hispanic, 16% Black, 14% White; 62% women; mean (±SD) follow-up five (±0.6) years). Hispanic and Black participants had greater likelihood of MCI (20%) and dementia (5%) than White participants accounting for age and education differences. Hispanic participants had greater odds of MCI or dementia than both White and Black participants adjusting for sociodemographic variables, vascular risk factors, and brain imaging factors. White matter hyperintensity burden was significantly associated with greater odds of MCI or dementia (OR = 1.3, 1.1 to 1.6), but there was no significant interaction by race/ethnicity.

CONCLUSION: In this diverse community-based cohort, cross-sectional data revealed significant race/ethnic disparities in the prevalence of MCI and dementia. Longer follow-up and incidence data are needed to further clarify these relationships.

%B J Alzheimers Dis %V 80 %P 1129-1138 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646162?dopt=Abstract %R 10.3233/JAD-201370 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Race-Related Association between APOE Genotype and Alzheimer's Disease: A Systematic Review and Meta-Analysis. %A Qin, Wei %A Li, Wenwen %A Wang, Qi %A Gong, Min %A Li, Tingting %A Shi, Yuqing %A Song, Yang %A Li, Ying %A Li, Fangyu %A Jia, Jianping %K Alleles %K Alzheimer Disease %K Apolipoprotein E2 %K Apolipoprotein E4 %K Apolipoproteins E %K Genotype %K Humans %K Racial Groups %X

BACKGROUND: The global race-dependent association of Alzheimer's disease (AD) and apolipoprotein E (APOE) genotype is not well understood. Transethnic analysis of APOE could clarify the role of genetics in AD risk across populations.

OBJECTIVE: This study aims to determine how race and APOE genotype affect the risks for AD.

METHODS: We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library since 1993 to Aug 25, 2020. A total of 10,395 reports were identified, and 133 were eligible for analysis with data on 77,402 participants. Studies contained AD clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses. Odds ratios and 95% confidence intervals for developing AD were calculated for populations of different races and APOE genotypes.

RESULTS: The proportion of APOE genotypes and alleles differed between populations of different races. Results showed that APOEɛ4 was a risk factor for AD, whereas APOEɛ2 protected against it. The effects of APOEɛ4 and ɛ2 on AD risk were distinct in various races, and they were substantially attenuated among Black people. Sub-group analysis found a higher frequency of APOEɛ4/ɛ4 and lower frequency of APOEɛ3/ɛ3 among early-onset AD than late-onset AD in a combined group and different races.

CONCLUSION: Our meta-analysis suggests that the association of APOE genotypes and AD differ among races. These results enhance our understanding of APOE-related risk for AD across race backgrounds and provide new insights into precision medicine for AD.

%B J Alzheimers Dis %V 83 %P 897-906 %8 2021 %G eng %N 2 %R 10.3233/JAD-210549 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Rats Display Sexual Dimorphism in Phosphorylation of Brain Tau with Age. %A Niu, Jiahui %A Iqbal, Khalid %A Liu, Fei %A Hu, Wen %X

BACKGROUND: Women have a two-fold higher risk than men to Alzheimer's disease (AD) at midlife. Larger brain tau burden was consistently shown in older women than age-matched men. The biological basis for this gender disparity remains elusive.

OBJECTIVE: We sought to know whether tau expression and phosphorylation physiologically differ between males and females.

METHODS: We used western blots and immunohistochemistry to compare the levels of total tau and phosphorylated tau in the hippocampus and entorhinal cortex (EC) between sexes in Wistar rats at 40 days, and 8 and 20 months of age.

RESULTS: We detected no statistically significant difference in total tau, 3R-tau, and 4R-tau between sexes. However, female rats exhibited lower levels of tau unphosphorylated at the Tau-1 site at 40 days of age. At 8 months of age, females showed higher levels of tau phosphorylated at Ser190, Ser387, and Ser395 (Ser199, Ser396, and Ser404 of human tau, respectively) than males in EC. At 20 months of age, both brain regions of female rats consistently showed higher levels than males of tau phosphorylated at Ser253, Ser387, PHF-1 (Ser387/395), and Ser413 sites, which correspond to Ser262, Ser396, Ser396/404, and Ser422 of human tau, respectively.

CONCLUSION: Rats of both sexes have comparable levels of total tau, 3R-tau, and 4R-tau, whereas females exhibit higher levels of tau phosphorylated at multiple sites that are implicated in AD tau pathology, indicating a sexual dimorphism of tau phosphorylation that may potentially underlie the disparity in brain tau burden and risk for AD between sexes.

%B J Alzheimers Dis %V 82 %P 855-869 %8 2021 Jul 20 %G eng %N 2 %R 10.3233/JAD-210341 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Relation of a Socioeconomic Index with Cognitive Function and Neuroimaging in Hypertensive Individuals. %A Paradela, Regina Silva %A Ferreira, Naomi Vidal %A Nucci, Mariana Penteado %A Cabella, Brenno %A Martino, Luiza Menoni %A Torres, Laura Aló %A Costa, Danielle Irigoyen da %A Consolim-Colombo, Fernanda Marciano %A Suemoto, Claudia Kimie %A Irigoyen, Maria Claudia %X

BACKGROUND: Socioeconomic factors are important contributors to brain health. However, data from developing countries (where social inequalities are the most prominent) are still scarce, particularly about hypertensive individuals.

OBJECTIVE: To evaluate the relationship between socioeconomic index, cognitive function, and cortical brain volume, as well as determine whether white matter hyperintensities are mediators of the association of the socioeconomic index with cognitive function in hypertensive individuals.

METHODS: We assessed 92 hypertensive participants (mean age = 58±8.6 years, 65.2%female). Cognitive evaluation and neuroimaging were performed and clinical and sociodemographic data were collected using questionnaires. A socioeconomic index was created using education, income, occupation (manual or non-manual work), and race. The associations of the socioeconomic index with cognitive performance and brain volume were investigated using linear regression models adjusted for age, sex, time of hypertension since diagnosis, and comorbidities. A causal mediation analysis was also conducted.

RESULTS: Better socioeconomic status was associated with better visuospatial ability, executive function, and global cognition. We found associations between a better socioeconomic index and a higher parietal lobe volume. White matter hyperintensities were also not mediators in the relationship between the socioeconomic index and cognitive performance.

CONCLUSION: Socioeconomic disadvantages are associated with worse cognitive performance and brain volume in individuals with hypertension.

%B J Alzheimers Dis %V 82 %P 815-826 %8 2021 Jul 20 %G eng %N 2 %R 10.3233/JAD-210143 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Relation of Literacy and Music Literacy to Dementia in Older Black and White Brazilians. %A Capuano, Ana W %A Wilson, Robert S %A Leurgans, Sue E %A Sampaio, Carolina %A Farfel, Jose M %A Barnes, Lisa L %A Bennett, David A %X

BACKGROUND: Literacy is more consistently reported than education as protective against dementia in developing regions.

OBJECTIVE: To study the association of verbal literacy, numeracy, and music literacy with dementia in older Black and White Brazilians with a broad spectrum of education.

METHODS: We studied 1,818 Black, Mixed-race, and White deceased Brazilians 65 years or older at death (mean = 79.64). Data were retrospectively obtained within 36 hours after death in a face-to-face interview with an informant, usually a family member. Dementia was classified using the Clinical Dementia Rating (CDR) scale. Three forms of literacy were ascertained: verbal literacy (10 questions: reading and writing), numeracy (3 questions: multiplication, percentages, and use of a calculator), and music literacy (1 question: reading music). Black (11%) and Mixed-race (23%) older adults were combined in analyses. Models adjusted for age and sex.

RESULTS: Dementia was identified in 531 people. Participants had 0 to 25 years of education (median = 4). More literacy was associated with lower odds of dementia (all p≤0.039). Participants that read music had about half the odds of having dementia. Participants in the highest quartile of numeracy and verbal literacy had respectively 27%and 15%lower odds of having dementia compared to the lowest quartile. Literacy was lower in Blacks (p <  0.001, except music p = 0.894) but the effect of literacy on dementia was similar (interaction p >  0.237). In secondary analyses, playing instruments without reading music was not associated with dementia (p = 0.887).

CONCLUSION: In a large sample of Brazilians, verbal literacy, numeracy, and music literacy were associated with lower odds of dementia. The effect was similar across races.

%B J Alzheimers Dis %V 84 %P 737-744 %8 2021 Nov 09 %G eng %N 2 %R 10.3233/JAD-210601 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Relationship Between Cardiovascular Health and Rate of Cognitive Decline in Young-Old and Old-Old Adults: A Population-Based Study. %A Speh, Andreja %A Wang, Rui %A Winblad, Bengt %A Kramberger, Milica G %A Bäckman, Lars %A Qiu, Chengxuan %A Laukka, Erika J %X

BACKGROUND: Modifiable vascular risk factors have been associated with late-life cognitive impairment. The Life Simple 7 (LS7) score comprises seven cardiovascular health metrics: smoking, diet, physical activity, body mass index, plasma glucose, total serum cholesterol, and blood pressure.

OBJECTIVE: To investigate the association between individual and composite LS7 metrics and rate of cognitive decline, and potential differences in these associations between young-old and old-old individuals.

METHODS: This cohort study included 1,950 participants aged≥60 years (M = 70.7 years) from the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K), who underwent repeated neuropsychological testing (episodic and semantic memory, verbal fluency, processing speed, global cognition) across 12 years. The LS7 score was assessed at baseline and categorized as poor, intermediate, or optimal. Level and change in cognitive performance as a function LS7 categories were estimated using linear mixed-effects models.

RESULTS: Having an optimal LS7 total score was associated with better performance (expressed in standard deviation units) at baseline for perceptual speed (β= 0.21, 95%CI 0.12-0.29), verbal fluency (β= 0.08, 0.00-0.16), and global cognition (β= 0.06, 0.00-0.12) compared to the poor group. Age-stratified analyses revealed associations for cognitive level and change only in the young-old (<  78 years) group. For the specific metrics, diverging patterns were observed for young-old and old-old individuals.

CONCLUSION: Meeting the LS7 criteria for ideal cardiovascular health in younger old age is associated with slower rate of cognitive decline. However, the LS7 criteria may have a different meaning for cognitive function in very old adults.

%B J Alzheimers Dis %V 84 %P 1523-1537 %8 2021 Dec 07 %G eng %N 4 %R 10.3233/JAD-210280 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Relationships Between Cognition and Neuropathological Tau in Alzheimer's Disease Assessed by 18F Flortaucipir PET. %A Devous, Michael D %A Fleisher, Adam S %A Pontecorvo, Michael J %A Lu, Ming %A Siderowf, Andrew %A Navitsky, Michael %A Kennedy, Ian %A Southekal, Sudeepti %A Harris, Thomas S %A Mintun, Mark A %X

BACKGROUND: Tau neurofibrillary tangle burden increases with Alzheimer's disease (AD) stage and correlates with degree of cognitive impairment. Tau PET imaging could facilitate understanding the relationship between tau pathology and cognitive impairment.

OBJECTIVE: Evaluate the relationship between 18F flortaucipir uptake patterns and cognition across multiple cognitive domains.

METHODS: We acquired flortaucipir PET scans in 84 amyloid-positive control, mild cognitive impairment (MCI), and AD subjects. Flortaucipir standardized uptake value ratio (SUVr) values were obtained from a neocortical volume of interest (VOI), a precuneus VOI, and VOIs defined by the correlation between flortaucipir SUVr images and domain-specific cognitive tests. Cognitive assessments included Mini-Mental State Exam (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and a neuropsychological test battery (i.e., Wechsler Memory Scale-Revised Logical Memory (WMS-R), Trail Making Test, Boston Naming Test, Digit Symbol Substitution Test, Animal List Generation, WMS-R Digit Span, American National Adult Reading Test, Clock Drawing Test, Judgment of Line Orientation, and WMS-R Logical Memory II (Delayed Recall)) and the Functional Activities Questionnaire (FAQ). Correlation analyses compared regional and voxel-wise VOIs to cognitive scores.

RESULTS: Subjects included 5 controls, 47 MCI, and 32 AD subjects. Significant correlations were seen between both flortaucipir and florbetapir SUVrs and MMSE, ADAS-Cog, and FAQ. Cognitive impairment was associated with increased flortaucipir uptake in regionally specific patterns consistent with the neuroanatomy underlying specific cognitive tests.

CONCLUSION: Flortaucipir SUVr values demonstrated significant inverse correlations with cognitive scores in domain-specific patterns. Findings support the hypothesis that PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD.

%B J Alzheimers Dis %V 80 %P 1091-1104 %8 2021 Apr 06 %G eng %N 3 %R 10.3233/JAD-200808 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Relevance of a Truncated PRESENILIN 2 Transcript to Alzheimer's Disease and Neurodegeneration. %A Moussavi Nik, Seyyed Hani %A Porter, Tenielle %A Newman, Morgan %A Bartlett, Benjamin %A Khan, Imran %A Sabale, Miheer %A Eccles, Melissa %A Woodfield, Amy %A Groth, David %A Doré, Vincent %A Villemagne, Victor L %A Masters, Colin L %A Martins, Ralph N %A Laws, Simon M %A Lardelli, Michael %A Verdile, Giuseppe %X

BACKGROUND: The PRESENILIN genes (PSEN1, PSEN2) encoding for their respective proteins have critical roles in many aspects of Alzheimer's disease (AD) pathogenesis. The PS2V transcript of PSEN2 encodes a truncated protein and is upregulated in AD brains; however, its relevance to AD and disease progression remains to be determined.

OBJECTIVE: Assess transcript levels in postmortem AD and non-AD brain tissue and in lymphocytes collected under the Australian Imaging Biomarker and Lifestyle (AIBL) study.

METHODS: Full length PSEN2 and PS2V transcript levels were assessed by quantitative digital PCR in postmortem brain tissue (frontal cortex and hippocampus) from control, AD, frontotemporal dementia (FTD), and Lewy body dementia (LBD). Transcript levels were also assessed in lymphocytes obtained from the Perth subset of the AIBL study (n = 160). Linear regression analysis was used to assess correlations between transcript copy number and brain volume and neocortical amyloid load.

RESULTS: PS2V levels increased in AD postmortem brain but PS2V was also present at significant levels in FTD and LBD brains. PS2V transcript was detected in lymphocytes and PS2V/PSEN2 ratios were increased in mild cognitive impairment (p = 0.024) and AD (p = 0.019) groups compared to control group. Increased ratios were significantly correlated with hippocampal volumes only (n = 62, β= -0.269, p = 0.03).

CONCLUSION: Taken together, these results suggest that PS2V may be a marker of overall neurodegeneration.

%B J Alzheimers Dis %V 80 %P 1479-1489 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201133 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Reliability of Telephone and Videoconference Methods of Cognitive Assessment in Older Adults with and without Dementia. %A Hunter, Matthew B %A Jenkins, Natalie %A Dolan, Clare %A Pullen, Hannah %A Ritchie, Craig %A Muniz-Terrera, Graciela %K Aged %K Aged, 80 and over %K Cognition %K Cognitive Dysfunction %K Dementia %K Geriatric Assessment %K Humans %K Neuropsychological Tests %K Remote Consultation %K Reproducibility of Results %K Telephone %K Videoconferencing %X

BACKGROUND: Telephone and videoconference administration of cognitive tests introduce additional sources of variance compared to in-person testing. Reviews of test-retest reliability have included mixed neurocognitive and psychiatric populations with limited consideration of methodological and statistical contributions.

OBJECTIVE: We reviewed reliability estimates from comparison studies of older adults with and without dementia, considering test-retest analyses and study methods.

METHODS: Medline, Embase, PsycINFO, and Web of Science were systematically searched from 1 January 2000 to 9 June 2020 for original articles comparing telephone or videoconference administered cognitive instruments to in-person administration in older adults with and without dementia or mild cognitive impairment.

RESULTS: Of 4,125 articles, 23 were included: 11 telephone (N = 2 dementia cohorts) and 12 videoconference (N = 4 dementia cohorts). Telephone administered subtest scores trended in the same direction as in-person with comparable means. Person-level data were scarce. Data on dementia was only available for MMSE, with resulting subtle modality bias. MMSE, SMMSE, Letter Fluency, and HVLT-R in healthy to mild-moderate Alzheimer's disease were particularly reliable for videoconference administration. Other tests show promise but require more observations and comprehensive analyses. Most studies used high-speed stable videoconferencing hardware resulting in a lack of ecological validity for home administration.

CONCLUSION: Remote administration is often consistent with in-person administration but variable and limited at the person/test level. Improved statistical design and inclusion of dementia related cohorts in telephone studies is recommended. Reliability evidence is stronger for videoconferencing but with limited applicability to home administration and severe dementia. Improved reporting of administrative procedures is recommended.

%B J Alzheimers Dis %V 81 %P 1625-1647 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33967052?dopt=Abstract %R 10.3233/JAD-210088 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Research Attitudes and Interest Among Elderly Latinxs: The Impact of a Collaborative Video and Community Peers. %A Sewell, Margaret C %A Neugroschl, Judith %A Umpierre, Mari %A Chin, Shehan %A Zhu, Carolyn W %A Velasco, Nelly %A Gonzalez, Sabrina %A Acabá-Berrocal, Alexandra %A Bianchetti, Luca %A Silva, Gabriela %A Collazo, Alma %A Sano, Mary %X

BACKGROUND: Latinx elders are underrepresented in dementia research. In a previous study we assessed research attitudes in urban minority elders and found a significant minority expressed neutral to negative attitudes relating to trust, safety, and personal responsibility to help research.

OBJECTIVE: To assess the impact of a composite intervention on attitudes toward research and research participation among elderly Latinx. The intervention was a collaboratively produced research participation video shown during presentations with our elderly community advisory board (CAB) as co-presenters.

METHODS: The video was created by the ADRC and CAB. All senior center attendees were eligible to participate. Afterwards, the Research Attitudes Questionnaire (RAQ) and a brief questionnaire on the impact of the video were administered. Using Wilcoxon Rank Sum Tests, Chi Square, and OLS regressions, RAQ responses were compared to those from a historical cohort from similar centers.

RESULTS: 74 in the "Historical Cohort 1" and 104 in "Intervention Cohort 2" were included. RAQ total score was higher in Cohort 2 than Cohort 1 (28.5 versus 26.1, p <  0.05) after controlling for age, education, and country of origin. In response to the question "Has the video influenced your willingness and interest to participate in research", 88.7%of the participants in Cohort 2 reported being "more" or "much more" interested in research.

CONCLUSION: Tailoring community research recruitment programs to include relatable peers using novel recruitment techniques may have positive implications for improving enrollment of diverse elderly individuals in research.

%B J Alzheimers Dis %V 82 %P 771-779 %8 2021 Jul 20 %G eng %N 2 %R 10.3233/JAD-210027 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Retinal Vessel Density Can Reflect Cognitive Function in Patients with Alzheimer's Disease: Evidence from Optical Coherence Tomography Angiography. %A Yan, Yibing %A Wu, Xingqi %A Wang, Xiaojing %A Geng, Zhi %A Wang, Lu %A Xiao, Guixian %A Wu, Yue %A Zhou, Shanshan %A Liao, Rongfeng %A Wei, Ling %A Tian, Yanghua %A Wang, Kai %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cognition %K Female %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Retinal Vessels %K Tomography, Optical Coherence %X

BACKGROUND: There is increasing evidence that Alzheimer's disease (AD) patients may present decreased cerebral blood perfusion before pathological brain changes. Using the retina as a window to the brain, we can study disorders of the central nervous system through the eyes.

OBJECTIVE: This study aimed to investigate differences in retinal structure and vessel density (VD) between patients with mild AD and healthy controls (HCs). Furthermore, we explored the relationship between retinal VD and cognitive function.

METHODS: We enrolled 37 patients with AD and 29 age-matched HCs who underwent standard ophthalmic optical coherence tomography angiography (OCTA) for evaluation of the retinal layer thickness and VD parameters. Cognitive function was evaluated using a battery of neuropsychological assessments. Finally, the correlations among retinal layer thickness, VD parameters, and cognitive function were evaluated.

RESULTS: The retinal fiber layer thickness and retinal VD of patients with AD were significantly reduced compared with HCs. The retinal VD was significantly correlated with overall cognition, memory, executive, and visual-spatial perception functions. However, there was no significant between-group difference in the macular thickness.

CONCLUSION: Our findings indicate a positive correlation between retinal VD and some, but not all, cognitive function domains. Most importantly, we demonstrated the role of OCTA in detecting early capillary changes, which could be a noninvasive biomarker for early AD.

%B J Alzheimers Dis %V 79 %P 1307-1316 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33427738?dopt=Abstract %R 10.3233/JAD-200971 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Right Temporal Variant of Frontotemporal Dementia Is Not Genetically Sporadic: A Case Series. %A Ulugut Erkoyun, Hulya %A van der Lee, Sven J %A Nijmeijer, Bas %A van Spaendonk, Rosalina %A Nelissen, Anne %A Scarioni, Marta %A Dijkstra, Anke %A Samancı, Bedia %A Gürvit, Hakan %A Yıldırım, Zerrin %A Tepgeç, Fatih %A Bilgic, Basar %A Barkhof, Frederik %A Rozemuller, Annemieke %A van der Flier, Wiesje M %A Scheltens, Philip %A Cohn-Hokke, Petra %A Pijnenburg, Yolande %K Aphasia, Primary Progressive %K DNA-Binding Proteins %K Female %K Frontotemporal Dementia %K Functional Laterality %K Genetic Testing %K Genetic Variation %K Gyrus Cinguli %K Humans %K Male %K Middle Aged %K Progranulins %K tau Proteins %X

BACKGROUND: Right temporal variant frontotemporal dementia (rtvFTD) has been generally considered as a right sided variant of semantic variant primary progressive aphasia (svPPA), which is a genetically sporadic disorder. Recently, we have shown that rtvFTD has a unique clinical syndrome compared to svPPA and behavioral variant frontotemporal dementia.

OBJECTIVE: We challenge the assumption that rtvFTD is a sporadic, non-familial variant of FTD by identifying potential autosomal dominant inheritance and related genes in rtvFTD.

METHODS: We collected all subjects with a diagnosis of FTD or primary progressive aphasia who had undergone genetic screening (n = 284) and subsequently who had a genetic variant (n = 48) with a diagnosis of rtvFTD (n = 6) in 2 specialized memory clinics.

RESULTS: Genetic variants in FTD related genes were found in 33% of genetically screened rtvFTD cases; including MAPT (n = 4), GRN (n = 1), and TARDBP (n = 1) genes, whereas only one svPPA case had a genetic variant in our combined cohorts. Additionally, 4 out of 6 rtvFTD subjects had a strong family history for dementia.

CONCLUSION: Our results demonstrate that rtvFTD, unlike svPPA, is not a pure sporadic, but a heterogeneous potential genetic variant of FTD, and screening for genetic causes for FTD should be performed in patients with rtvFTD.

%B J Alzheimers Dis %V 79 %P 1195-1201 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33427744?dopt=Abstract %R 10.3233/JAD-201191 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Risk Variants in Three Alzheimer's Disease Genes Show Association with EEG Endophenotypes. %A Macedo, Ana %A Gómez, Carlos %A Rebelo, Miguel Ângelo %A Poza, Jesús %A Gomes, Iva %A Martins, Sandra %A Maturana-Candelas, Aarón %A Pablo, Víctor Gutiérrez-de %A Durães, Luis %A Sousa, Patrícia %A Figueruelo, Manuel %A Rodriguez, Maria %A Pita, Carmen %A Arenas, Miguel %A Alvarez, Luís %A Hornero, Roberto %A Lopes, Alexandra M %A Pinto, Nádia %X

BACKGROUND: Dementia due to Alzheimer's disease (AD) is a complex neurodegenerative disorder, which much of heritability remains unexplained. At the clinical level, one of the most common physiological alterations is the slowing of oscillatory brain activity, measurable by electroencephalography (EEG). Relative power (RP) at the conventional frequency bands (i.e., delta, theta, alpha, beta-1, and beta-2) can be considered as AD endophenotypes.

OBJECTIVE: The aim of this work is to analyze the association between sixteen genes previously related with AD: APOE, PICALM, CLU, BCHE, CETP, CR1, SLC6A3, GRIN2 β, SORL1, TOMM40, GSK3 β, UNC5C, OPRD1, NAV2, HOMER2, and IL1RAP, and the slowing of the brain activity, assessed by means of RP at the aforementioned frequency bands.

METHODS: An Iberian cohort of 45 elderly controls, 45 individuals with mild cognitive impairment, and 109 AD patients in the three stages of the disease was considered. Genomic information and brain activity of each subject were analyzed.

RESULTS: The slowing of brain activity was observed in carriers of risk alleles in IL1RAP (rs10212109, rs9823517, rs4687150), UNC5C (rs17024131), and NAV2 (rs1425227, rs862785) genes, regardless of the disease status and situation towards the strongest risk factors: age, sex, and APOE ɛ4 presence.

CONCLUSION: Endophenotypes reduce the complexity of the general phenotype and genetic variants with a major effect on those specific traits may be then identified. The found associations in this work are novel and may contribute to the comprehension of AD pathogenesis, each with a different biological role, and influencing multiple factors involved in brain physiology.

%B J Alzheimers Dis %V 80 %P 209-223 %8 2021 Mar 9 %G eng %N 1 %R 10.3233/JAD-200963 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Role of Microglia in Sporadic Alzheimer's Disease. %A Streit, Wolfgang J %A Khoshbouei, Habibeh %A Bechmann, Ingo %K Aging %K Alzheimer Disease %K Humans %K Microglia %X

Microglia constitute the brain's immune system and their involvement in Alzheimer's disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer's disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea.

%B J Alzheimers Dis %V 79 %P 961-968 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33361603?dopt=Abstract %R 10.3233/JAD-201248 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Segmented Linear Mixed Model Analysis Reveals Association of the APOEɛ4 Allele with Faster Rate of Alzheimer's Disease Dementia Progression. %A Chen, X Richard %A Shao, Yongzhao %A Sadowski, Martin J %X

BACKGROUND: APOEɛ4 allele carriers present with an increased risk for late-onset Alzheimer's disease (AD), show cognitive symptoms at an earlier age, and are more likely to transition from mild cognitive impairment (MCI) to dementia but despite this, it remains unclear whether or not the ɛ4 allele controls the rate of disease progression.

OBJECTIVE: To determine the effects of the ɛ4 allele on rates of cognitive decline and brain atrophy during MCI and dementia stages of AD.

METHODS: A segmented linear mixed model was chosen for longitudinal modeling of cognitive and brain volumetric data of 73 ɛ3/ɛ3, 99 ɛ3/ɛ4, and 39 ɛ4/ɛ4 Alzheimer's Disease Neuroimaging Initiative participants who transitioned during the study from MCI to AD dementia.

RESULTS: ɛ4 carriers showed faster decline on MMSE, ADAS-11, CDR-SB, and MoCA scales, with the last two measures showing significant ɛ4 allele-dose effects after dementia transition but not during MCI. The ɛ4 effect was more prevalent in younger participants and in females. ɛ4 carriers also demonstrated faster rates of atrophy of the whole brain, the hippocampus, the entorhinal cortex, the middle temporal gyrus, and expansion of the ventricles after transitioning to dementia but not during MCI.

CONCLUSION: Possession of the ɛ4 allele is associated with a faster progression of dementia due to AD. Our observations support the notion that APOE genotype not only controls AD risk but also differentially regulates mechanisms of neurodegeneration underlying disease advancement. Furthermore, our findings carry significance for AD clinical trial design.

%B J Alzheimers Dis %V 82 %P 921-937 %8 2021 Aug 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34120907?dopt=Abstract %R 10.3233/JAD-210434 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Selective Impairment of Long-Range Default Mode Network Functional Connectivity as a Biomarker for Preclinical Alzheimer's Disease in People with Down Syndrome. %A DiProspero, Natalie D %A Keator, David B %A Phelan, Michael %A van Erp, Theo G M %A Doran, Eric %A Powell, David K %A Van Pelt, Kathryn L %A Schmitt, Frederick A %A Head, Elizabeth %A Lott, Ira T %A Yassa, Michael A %X

BACKGROUND: Down syndrome (DS) is associated with increased risk for Alzheimer's disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS.

OBJECTIVE: Does lower DMN functional connectivity predict clinical onset of AD and cognitive decline in people with DS?

METHODS: Resting state functional MRI (rsfMRI), longitudinal neuropsychological, and clinical assessment data were collected on 15 nondemented people with DS (mean age = 51.66 years, SD = 5.34 years, range = 42-59 years) over four years, during which 4 transitioned to dementia. Amyloid-β (Aβ) PET data were acquired on 13 of the 15 participants. Resting state fMRI, neuropsychological, and clinical assessment data were also acquired on an independent, slightly younger unimpaired sample of 14 nondemented people with DS (mean age = 44.63 years, SD = 7.99 years, range = 38-61 years).

RESULTS: Lower functional connectivity between long-range but not short-range DMN regions predicts AD diagnosis and cognitive decline in people with DS. Aβ accumulation in the inferior parietal cortex is associated with lower regional DMN functional connectivity.

CONCLUSION: Reduction of long-range DMN connectivity is a potential biomarker for AD in people with DS that precedes and predicts clinical conversion.

%B J Alzheimers Dis %V 85 %P 153-165 %8 2022 Jan 04 %G eng %N 1 %R 10.3233/JAD-210572 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Serum Uric Acid May Aggravate Alzheimer's Disease Risk by Affecting Amyloidosis in Cognitively Intact Older Adults: The CABLE Study. %A Li, Lin-Lin %A Ma, Ya-Hui %A Bi, Yan-Lin %A Sun, Fu-Rong %A Hu, Hao %A Hou, Xiao-He %A Xu, Wei %A Shen, Xue-Ning %A Dong, Qiang %A Tan, Lan %A Yang, Jiu-Long %A Yu, Jin-Tai %X

BACKGROUND: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear.

OBJECTIVE: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD.

METHODS: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-β [Aβ], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models.

RESULTS: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aβ1 - 42 (p = 0.019) and Aβ1 - 42/Aβ1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aβ1 - 42 (p = 0.009) and t-Tau/Aβ1 - 42 (p = 0.043) were increased with the highest (>  75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them.

CONCLUSION: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA.

%B J Alzheimers Dis %V 81 %P 389-401 %8 2021 May 04 %G eng %N 1 %R 10.3233/JAD-201192 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Site-Specific Cerebrospinal Fluid Tau Hyperphosphorylation in Response to Alzheimer's Disease Brain Pathology: Not All Tau Phospho-Sites are Hyperphosphorylated. %A Barthélemy, Nicolas R %A Toth, Balazs %A Manser, Paul T %A Sanabria-Bohórquez, Sandra %A Teng, Edmond %A Keeley, Michael %A Bateman, Randall J %A Weimer, Robby M %A Wildsmith, Kristin R %X

BACKGROUND: Understanding patterns of association between CSF phosphorylated tau (p-tau) species and clinical disease severity will aid Alzheimer's disease (AD) diagnosis and treatment.

OBJECTIVE: To evaluate changes in tau phosphorylation ratios to brain imaging (amyloid PET, [18F]GTP1 PET, and MRI) and cognition across clinical stages of AD in two different cohorts.

METHODS: A mass spectrometry (MS)-based method was used to evaluate the relationship between p-tau/tau phosphorylation ratios on 11 sites in CSF and AD pathology measured by tau PET ([18F]GTP1) and amyloid PET ([18F]florbetapir or [18F]florbetaben). Cohort A included cognitively normal-amyloid negative (n = 6) and positive (n = 5) individuals, and amyloid positive prodromal (n = 13), mild (n = 12), and moderate AD patients (n = 10); and Cohort B included amyloid positive prodromal (n = 24) and mild (n = 40) AD patients.

RESULTS: In this cross-sectional analysis, we identified clusters of phosphosites with different profiles of phosphorylation ratios across stages of disease. Eight of 11 investigated sites were hyperphosphorylated and associated with the SUVR measures from [18F]GTP1 and amyloid PET. Novel sites 111, 153, and 208 may be relevant biomarkers for AD diagnosis to complement tau hyperphosphorylation measures on previously established sites 181, 205, 217, and 231. Hypophosphorylation was detected on residues 175, 199, and 202, and was inversely associated with [18F]GTP1 and amyloid PET.

CONCLUSION: Hyperphosphorylated and hypophosphorylated forms of tau are associated with AD pathologies, and due to their different site-specific profiles, they may be used in combination to assist with staging of disease.

%B J Alzheimers Dis %V 85 %P 415-429 %8 2022 Jan 04 %G eng %N 1 %R 10.3233/JAD-210677 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Sleep Deprivation, a Link Between Post-Traumatic Stress Disorder and Alzheimer's Disease. %A Delic, Vedad %A Ratliff, Whitney A %A Citron, Bruce A %K Alzheimer Disease %K Animals %K Humans %K Sleep Deprivation %K Stress Disorders, Post-Traumatic %X

An estimated 5 million Americans are living with Alzheimer's disease (AD), and there is also a significant impact on caregivers, with an additional 16 million Americans providing unpaid care for individuals with AD and other dementias. These numbers are projected to increase in the coming years. While AD is still without a cure, continued research efforts have led to better understanding of pathology and potential risk factors that could be exploited to slow disease progression. A bidirectional relationship between sleep deprivation and AD has been suggested and is well supported by both human and animal studies. Even brief episodes of inadequate sleep have been shown to cause an increase in amyloidβ and tau proteins, both well-established contributors toAD pathology. Sleep deprivation is also the most common consequence of post-traumatic stress disorder (PTSD). Patients with PTSD frequently present with sleep disturbances and also develop dementia at twice the rate of the general population accounting for a disproportionate representation of AD among U.S. Veterans. The goal of this review is to highlight the relationship triad between sleep deprivation, AD, and PTSD as well as their impact on molecular mechanisms driving AD pathology.

%B J Alzheimers Dis %V 79 %P 1443-1449 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33459652?dopt=Abstract %R 10.3233/JAD-201378 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Social Robot Interventions for People with Dementia: A Systematic Review on Effects and Quality of Reporting. %A Hirt, Julian %A Ballhausen, Nicola %A Hering, Alexandra %A Kliegel, Matthias %A Beer, Thomas %A Meyer, Gabriele %K Dementia %K Humans %K Research %K Robotics %K Social Behavior %X

BACKGROUND: Using non-pharmacological interventions is a current approach in dementia care to manage responsive behaviors, to maintain functional capacity, and to reduce emotional stress. Novel technologies such as social robot interventions might be useful to engage people with dementia in activities and interactions as well as to improve their cognitive, emotional, and physical status.

OBJECTIVE: Assessing the effects and the quality of reporting of social robot interventions for people with dementia.

METHODS: In our systematic review, we included quasi-experimental and experimental studies published in English, French, or German, irrespective of publication year. Searching CINAHL, Cochrane Library, MEDLINE, PsycINFO, and Web of Science Core Collection was supplemented by citation tracking and free web searching. To assess the methodological quality of included studies, we used tools provided by the Joanna Briggs Institute. To assess the reporting of the interventions, we applied CReDECI 2 and TIDieR.

RESULTS: We identified sixteen studies published between 2012 and 2018, including two to 415 participants with mostly non-defined type of dementia. Eight studies had an experimental design. The predominant robot types were pet robots (i.e., PARO). Most studies addressed behavioral, emotion-related, and functional outcomes with beneficial, non-beneficial, and mixed results. Predominantly, cognitive outcomes were not improved. Overall, studies were of moderate methodological quality.

CONCLUSION: Heterogeneous populations, intervention characteristics, and measured outcomes make it difficult to generalize the results with regard to clinical practice. The impact of social robot interventions on behavioral, emotion-related, and functional outcomes should therefore be assessed considering the severity of dementia and intervention characteristics.

%B J Alzheimers Dis %V 79 %P 773-792 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33361589?dopt=Abstract %R 10.3233/JAD-200347 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Soluble Amyloid-β Consumption in Alzheimer's Disease. %A Espay, Alberto J %A Sturchio, Andrea %A Schneider, Lon S %A Ezzat, Kariem %X

Brain proteins function in their soluble, native conformation and cease to function when transformed into insoluble aggregates, also known as amyloids. Biophysically, the soluble-to-insoluble phase transformation represents a process of polymerization, similar to crystallization, dependent on such extrinsic factors as concentration, pH, and a nucleation surface. The resulting cross-β conformation of the insoluble amyloid is markedly stable, making it an unlikely source of toxicity. The spread of brain amyloidosis can be fully explained by mechanisms of spontaneous or catalyzed polymerization and phase transformation instead of active replication, which is an enzyme- and energy-requiring process dependent on a specific nucleic acid code for the transfer of biological information with high fidelity. Early neuronal toxicity in Alzheimer's disease may therefore be mediated to a greater extent by a reduction in the pool of soluble, normal-functioning protein than its accumulation in the polymerized state. This alternative loss-of-function hypothesis of pathogenicity can be examined by assessing the clinical and neuroimaging effects of administering non-aggregating peptide analogs to replace soluble amyloid-β levels above the threshold below which neuronal toxicity may occur. Correcting the depletion of soluble amyloid-β, however, would only exemplify 'rescue medicine.' Precision medicine will necessitate identifying the pathogenic factors catalyzing the protein aggregation in each affected individual. Only then can we stratify patients for etiology-specific treatments and launch precision medicine for Alzheimer's disease and other neurodegenerative disorders.

%B J Alzheimers Dis %V 82 %P 1403-1415 %8 2021 Aug 17 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/34151810?dopt=Abstract %R 10.3233/JAD-210415 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Spiritual Fitness: A New Dimension in Alzheimer's Disease Prevention. %A Khalsa, Dharma Singh %A Newberg, Andrew B %K Alzheimer Disease %K Humans %K Life Style %K Love %K Meditation %K Spirituality %X

BACKGROUND: Religious and spiritual interventions may have an effect on Alzheimer's disease prevention. Kirtan Kriya meditation has been shown to mitigate the deleterious effects of chronic stress on cognition, reverse memory loss, and create psychological and spiritual wellbeing, which may reduce multiple drivers of Alzheimer's disease risk.

OBJECTIVE: To detail a new concept in medicine called Spiritual Fitness, a merging of stress reduction, basic wellbeing, and psycho/spiritual wellbeing to prevent Alzheimer's disease.

METHODS: The literature on the topics mentioned above is described, including an in-depth discussion on why and how each are critical to advancing the future of Alzheimer's disease prevention. The many negative effects of chronic stress, and the benefits of Kirtan Kriya, are reviewed. The four pillars of basic wellbeing, six practical aspects of psychological wellbeing, and the four new non-sectarian features of spiritual fitness are then disclosed. Moreover, instructions on practicing Kirtan Kriya are offered in the Supplementary Material.

CONCLUSION: Religious and spiritual practices, including Kirtan Kriya, are crucial components in the development of enhanced cognition and well-being, which may help prevent and, in some cases, reverse cognitive decline. The key point of this review is that making a commitment to live a brain longevity lifestyle including spiritual fitness is a critically important way for aging Alzheimer's disease free. We hope that this article will inspire scientists, clinicians, and patients to embrace this new concept of spiritual fitness and make it a part of every multidomain program for the prevention of cognitive disability.

%B J Alzheimers Dis %V 80 %P 505-519 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554917?dopt=Abstract %R 10.3233/JAD-201433 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Stages of Objective Memory Impairment Predict Alzheimer's Disease Neuropathology: Comparison with the Clinical Dementia Rating Scale-Sum of Boxes. %A Grober, Ellen %A Qi, Qi %A Kuo, Lynn %A Hassenstab, Jason %A Perrin, Richard J %A Lipton, Richard B %X

BACKGROUND: The ultimate validation of a clinical marker for Alzheimer's disease (AD) is its association with AD neuropathology.

OBJECTIVE: To examine how well the Stages of Objective Memory Impairment (SOMI) system predicts intermediate/high AD neuropathologic change and extent of neurofibrillary tangle (NFT) pathology defined by Braak stage, in comparison to the Clinical Dementia Rating (CDR) Scale sum of boxes (CDR-SB).

METHODS: 251 well-characterized participants from the Knight ADRC clinicopathologic series were classified into SOMI stage at their last assessment prior to death using the free recall and total recall scores from the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT + IR). Logistic regression models assessed the predictive validity of SOMI and CDR-SB for intermediate/high AD neuropathologic change. Receiver operating characteristics (ROC) analysis evaluated the discriminative validity of SOMI and CDR-SB for AD pathology. Ordinal logistic regression was used to predict Braak stage using SOMI and CDR-SB in separate and joint models.

RESULTS: The diagnostic accuracy of SOMI for AD diagnosis was similar to that of the CDR-SB (AUC: 85%versus 83%). In separate models, both SOMI and CDR-SB predicted Braak stage. In a joint model SOMI remained a significant predictor of Braak stage but CDR-SB did not.

CONCLUSION: SOMI provides a neuropathologically validated staging system for episodic memory impairment in the AD continuum and should be useful in predicting tau positivity based on its association with Braak stage.

%B J Alzheimers Dis %V 80 %P 185-195 %8 2021 Mar 9 %G eng %N 1 %R 10.3233/JAD-200946 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Substance Use-Related Cognitive Decline in Families with Autosomal Dominant Alzheimer's Disease: A Cohort Study. %A Ramos, Claudia %A Villalba, Camilo %A García, Jenny %A Lanata, Serggio %A López, Hugo %A Aguillón, David %A Cordano, Christian %A Madrigal, Lucía %A Aguirre-Acevedo, Daniel C %A Lopera, Francisco %X

BACKGROUND: Cigarette smoking is a known risk factor for Alzheimer's disease (AD). However, the association between neurodegeneration and other substances has not been fully determined. It is of vital importance to evaluate this relationship in populations at high risk of dementia. Since substance use possibly modifies the progression rate of cognitive decline, we studied this association in a unique and well-phenotyped cohort from the University of Antioquia: carriers of the PSEN1-E280A genetic variant.

OBJECTIVE: To determine the association between substance use and cognitive decline in carriers of the PSEN1-E280A genetic variant.

METHODS: A retrospective cohort study was conducted with 94 carriers and 69 noncarriers recruited between January 2019 and April 2020. A psychiatrist interviewed the participants using the Consumption of Alcohol, Cigarettes and other Substances questionnaire. The participants were also submitted to cognitive evaluation. The relationship between cognitive decline and substance use was explored through a mixed effects regression model.

RESULTS: There was an association between cigarettes and better performance on tasks related to perceptual organization, verbal fluency, and memory in carriers. Alcohol had a positive or negative effect on memory according to the type of alcoholic beverage. Results on marijuana use were no conclusive. Coffee was associated with progressive improvements in executive function and verbal fluency.

CONCLUSION: Cigarette and alcohol were associated with an improvement of some cognitive assessments, possibly by a survival bias. In addition, coffee was related to improvements in executive function and language; therefore, its short-term neuroprotective potential should be studied.

%B J Alzheimers Dis %V 85 %P 423-1439 %8 2022 Feb 15 %G eng %N 4 %R 10.3233/JAD-215169 %0 Journal Article %J J Alzheimers Dis %D 2021 %T A Super-Resolved View of the Alzheimer's Disease-Related Amyloidogenic Pathway in Hippocampal Neurons. %A Yu, Yang %A Gao, Yang %A Winblad, Bengt %A Tjernberg, Lars O %A Schedin-Weiss, Sophia %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Amyloidogenic Proteins %K Animals %K Cells, Cultured %K Hippocampus %K Humans %K Mice %K Mice, Inbred C57BL %K Microscopy %K Neurons %K Peptide Fragments %K Protein Transport %X

BACKGROUND: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ42), which is a key player in Alzheimer's disease.

OBJECTIVE: Our aim was to clarify the subcellular locations of the fragments involved in the amyloidogenic pathway in primary neurons with a focus on Aβ42 and its immediate substrate AβPP C-terminal fragment (APP-CTF). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy.

METHODS: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional three-channel imaging, and quantitative image analyses.

RESULTS: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes in soma, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes. Lack of colocalization of Aβ42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ42 were localized in different compartments.

CONCLUSION: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons.

%B J Alzheimers Dis %V 83 %P 833-852 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34366358?dopt=Abstract %R 10.3233/JAD-215008 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Sustained Hippocampal Neural Plasticity Questions the Reproducibility of an Amyloid-β-Induced Alzheimer's Disease Model. %A Paulo, Sara L %A Ribeiro-Rodrigues, Leonor %A Rodrigues, Rui S %A Mateus, Joana M %A Fonseca-Gomes, João %A Soares, Rita %A Diógenes, Maria J %A Solá, Susana %A Sebastião, Ana M %A Ribeiro, Filipa F %A Xapelli, Sara %X

BACKGROUND: The use of Alzheimer's disease (AD) models obtained by intracerebral infusion of amyloid-β (Aβ) has been increasingly reported in recent years. Nonetheless, these models may present important challenges.

OBJECTIVE: We have focused on canonical mechanisms of hippocampal-related neural plasticity to characterize a rat model obtained by an intracerebroventricular (icv) injection of soluble amyloid-β42 (Aβ42).

METHODS: Animal behavior was evaluated in the elevated plus maze, Y-Maze spontaneous or forced alternation, Morris water maze, and open field, starting 2 weeks post-Aβ42 infusion. Hippocampal neurogenesis was assessed 3 weeks after Aβ42 injection. Aβ deposition, tropomyosin receptor kinase B levels, and neuroinflammation were appraised at 3 and 14 days post-Aβ42 administration.

RESULTS: We found that immature neuronal dendritic morphology was abnormally enhanced, but proliferation and neuronal differentiation in the dentate gyrus was conserved one month after Aβ42 injection. Surprisingly, animal behavior did not reveal changes in cognitive performance nor in locomotor and anxious-related activity. Brain-derived neurotrophic factor related-signaling was also unchanged at 3 and 14 days post-Aβ icv injection. Likewise, astrocytic and microglial markers of neuroinflammation in the hippocampus were unaltered in these time points.

CONCLUSION: Taken together, our data emphasize a high variability and lack of behavioral reproducibility associated with these Aβ injection-based models, as well as the need for its further optimization, aiming at addressing the gap between preclinical AD models and the human disorder.

%B J Alzheimers Dis %V 82 %P 1183-1202 %8 2021 Aug 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34151790?dopt=Abstract %R 10.3233/JAD-201567 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Synaptic Molecular and Neurophysiological Markers Are Independent Predictors of Progression in Alzheimer's Disease. %A Smailovic, Una %A Kåreholt, Ingemar %A Koenig, Thomas %A Ashton, Nicholas J %A Winblad, Bengt %A Höglund, Kina %A Nilsson, Per %A Zetterberg, Henrik %A Blennow, Kaj %A Jelic, Vesna %X

BACKGROUND: Cerebrospinal fluid (CSF) neurogranin and quantitative electroencephalography (qEEG) are potential molecular and functional markers of synaptic pathology in Alzheimer's disease (AD). Synaptic markers have emerged as candidate prognostic indicators of AD since synaptic degeneration was shown to be an early event and the best correlate of cognitive deficits in patients along the disease continuum.

OBJECTIVE: The present study investigated the association between CSF neurogranin and qEEG measures as well as their potential to predict clinical deterioration in mild cognitive impairment (MCI) patients.

METHODS: Patients diagnosed with MCI (n = 99) underwent CSF conventional AD biomarkers and neurogranin analysis and resting-state EEG recordings. The study population was further stratified into stable (n = 41) and progressive MCI (n = 31), based on the progression to AD dementia during two years follow-up. qEEG analysis included computation of global field power and global field synchronization in four conventional frequency bands.

RESULTS: CSF neurogranin levels were associated with theta power and synchronization in the progressive MCI group. CSF neurogranin and qEEG measures were significant predictors of progression to AD dementia, independent of baseline amyloid status in MCI patients. A combination of CSF neurogranin with global EEG power in theta and global EEG synchronization in beta band exhibited the highest classification accuracy as compared to either of these markers alone.

CONCLUSION: qEEG and CSF neurogranin are independent predictors of progression to AD dementia in MCI patients. Molecular and neurophysiological synaptic markers may have additive value in a multimodal diagnostic and prognostic approach to dementia.

%B J Alzheimers Dis %V 83 %P 355-366 %8 2021 Aug 31 %G eng %N 1 %R 10.3233/JAD-201234 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Taking the A Train? Limited Consistency of Aβ42 and the Aβ42/40 Ratio in the AT(N) Classification. %A Gouilly, Dominique %A Tisserand, Camille %A Nogueira, Leonor %A Saint-Lary, Laura %A Rousseau, Vanessa %A Benaiteau, Marie %A Rafiq, Marie %A Carlier, Jasmine %A Milongo-Rigal, Emilie %A Pagès, Jean-Christophe %A Pariente, Jérémie %X

The consistency of cerebrospinal fluid amyloid-β (Aβ)42/40 ratio and Aβ 42 has not been assessed in the AT(N) classification system. We analyzed the classification changes of the dichotomized amyloid status (A+/A-) in 363 patients tested for Alzheimer's disease biomarkers after Aβ 42 was superseded by the Aβ 42/40 ratio. The consistency of Aβ 42 and the Aβ 42/40 ratio was very low. Notably, the proportions of "false" A+T-patients were considerable (74-91%) and corresponded mostly to patients not clinically diagnosed with Alzheimer's disease. Our results suggest that the interchangeability of Aβ 42/40 ratio and Aβ 42 is limited for classifying patients in clinical setting using the AT(N) scheme.

%B J Alzheimers Dis %V 83 %P 1033-1038 %8 2021 Sep 28 %G eng %N 3 %R 10.3233/JAD-210236 %0 Journal Article %J J Alzheimers Dis %D 2021 %T TAR DNA-Binding Protein 43 Is Associated with Rate of Memory and Functional and Global Cognitive Decline in the Decade Prior to Death. %A Buciuc, Marina %A Tosakulwong, Nirubol %A Machulda, Mary M %A Whitwell, Jennifer L %A Weigand, Stephen D %A Murray, Melissa E %A Ross Reichard, R %A Parisi, Joseph E %A Dickson, Dennis W %A Boeve, Bradley F %A Knopman, David S %A Petersen, Ronald C %A Josephs, Keith A %X

BACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline.

OBJECTIVE: To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain.

METHODS: Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-β (Aβ), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal decline.

RESULTS: Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) TDP-43 limited to amygdala, and 93 (24%) TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aβ burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations.

CONCLUSION: The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis.

%B J Alzheimers Dis %V 80 %P 683-693 %8 2021 Mar 23 %G eng %N 2 %R 10.3233/JAD-201166 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Thrombin Signaling Contributes to High Glucose-Induced Injury of Human Brain Microvascular Endothelial Cells. %A Rao, Haripriya V %A Bihaqi, Syed W %A Iannucci, Jaclyn %A Sen, Abhik %A Grammas, Paula %X

BACKGROUND: Diabetes is one of the strongest disease-related risk factors for Alzheimer's disease (AD). In diabetics, hyperglycemia-induced microvascular complications are the major cause of end-organ injury, contributing to morbidity and mortality. Microvascular pathology is also an important and early feature of AD. The cerebral microvasculature may be a point of convergence of both diseases. Several lines of evidence also implicate thrombin in AD as well as in diabetes.

OBJECTIVE: Our objective was to investigate the role of thrombin in glucose-induced brain microvascular endothelial injury.

METHODS: Cultured Human brain microvascular endothelial cells (HBMVECs) were treated with 30 mM glucose±100 nM thrombin and±250 nM Dabigatran or inhibitors of PAR1, p38MAPK, MMP2, or MMP9. Cytotoxicity and thrombin activity assays on supernatants and western blotting for protein expression in lysates were performed.

RESULTS: reatment of HBMVECs with 30 mM glucose increased thrombin activity and expression of inflammatory proteins TNFα, IL-6, and MMPs 2 and 9; this elevation was reduced by the thrombin inhibitor dabigatran. Direct treatment of brain endothelial cells with thrombin upregulated p38MAPK and CREB, and induced TNFα, IL6, MMP2, and MMP9 as well as oxidative stress proteins NOX4 and iNOS. Inhibition of thrombin, thrombin receptor PAR1 or p38MAPK decrease expression of inflammatory and oxidative stress proteins, implying that thrombin may play a central role in glucose-induced endothelial injury.

CONCLUSION: Since preventing brain endothelial injury would preserve blood-brain barrier integrity, prevent neuroinflammation, and retain intact functioning of the neurovascular unit, inhibiting thrombin, or its downstream signaling effectors, could be a therapeutic strategy for mitigating diabetes-induced dementia.

%B J Alzheimers Dis %V 79 %P 211-224 %8 2021 Jan 5 %G eng %N 1 %R 10.3233/JAD-200658 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus. %A Lukkarinen, Heikki %A Tesseur, Ina %A Pemberton, Darrel %A van der Ark, Peter %A Timmers, Maarten %A Slemmon, Randy %A Janssens, Luc %A Streffer, Johannes %A Van Nueten, Luc %A Bottelbergs, Astrid %A Rauramaa, Tuomas %A Koivisto, Anne M %A Herukka, Sanna-Kaisa %A Korhonen, Ville E %A Junkkari, Antti %A Hiltunen, Mikko %A Engelborghs, Sebastiaan %A Blennow, Kaj %A Zetterberg, Henrik %A Kolb, Hartmuth C %A Leinonen, Ville %X

BACKGROUND: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.

OBJECTIVE: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared.

METHODS: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs.

RESULTS: All biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p <  0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4.

CONCLUSION: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

%B J Alzheimers Dis %V 80 %P 1629-1642 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201361 %0 Journal Article %J J Alzheimers Dis %D 2021 %T TREM2 Deficiency Disrupts Network Oscillations Leading to Epileptic Activity and Aggravates Amyloid-β-Related Hippocampal Pathophysiology in Mice. %A Stoiljkovic, Milan %A Gutierrez, Karel Otero %A Kelley, Craig %A Horvath, Tamas L %A Hajós, Mihály %X

BACKGROUND: Genetic mutations in triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with increased risk of developing Alzheimer's disease (AD) and other progressive dementias. In the brain, TREM2 protein is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology. However, mechanisms by which TREM2 contributes to increased predisposition to clinical AD and influences its progression still remain largely unknown.

OBJECTIVE: Our aim was to elucidate the potential contribution of TREM2 on specific oscillatory dynamic changes associated with AD pathophysiology.

METHODS: Spontaneous and brainstem nucleus pontis oralis stimulation-induced hippocampal oscillation paradigm was used to investigate the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal network function in wild-type and Aβ overproducing Tg2576 mice under urethane anesthesia.

RESULTS: Partial (TREM2(Het)) or total (TREM2(Hom)) deletion of TREM2 led to increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Importantly, deficiency of TREM2 in Tg2576 mice significantly diminished power of theta oscillation in the hippocampus elicited by brainstem-stimulation compared to wild-type mice. However, it did not affect hippocampal theta-phase gamma-amplitude coupling significantly, since over a 60%reduction was found in coupling in Tg2576 mice regardless of TREM2 function.

CONCLUSION: Our findings indicate a role for TREM2-dependent microglial function in the hippocampal neuronal excitability in both wild type and Aβ overproducing mice, whereas deficiency in TREM2 function exacerbates disruptive effects of Aβ on hippocampal network oscillations.

%B J Alzheimers Dis %8 2021 Jun 08 %G eng %R 10.3233/JAD-210041 %0 Journal Article %J J Alzheimers Dis %D 2021 %T tRNA-Derived Fragments in Alzheimer's Disease: Implications for New Disease Biomarkers and Neuropathological Mechanisms. %A Wu, Wenzhe %A Lee, Inhan %A Spratt, Heidi %A Fang, Xiang %A Bao, Xiaoyong %K Aged %K Alzheimer Disease %K Biomarkers %K Blotting, Northern %K Case-Control Studies %K Hippocampus %K Humans %K Polymerase Chain Reaction %K RNA, Small Untranslated %K RNA, Transfer %X

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia caused by irreversible neurodegeneration, with the onset mechanisms elusive. tRNA-derived RNA fragments (tRFs), a recently discovered family of small non-coding RNAs (sncRNAs), have been found to associate with many human diseases, including infectious, metabolic, and neurological diseases. However, whether tRFs play a role in human AD development is not known.

OBJECTIVE: This study aimed to explore whether tRFs are involved in human AD.

METHODS: Thirty-four postmortem human hippocampus samples were used. The expression of Drosha, Dicer, and angiogenin (ANG), three ribonucleases responsible for the biogenesis of sncRNAs, was determined by qRT-PCR and western blot. The tRFs in the hippocampus was detected by qRT-PCR or northern blot. We also used qRT-PCR to quantify NOP2/Sun RNA methyltransferase 2 (NSun2) and polyadenylation factor I subunit 1 (CLP1), two tRNA modification enzymes.

RESULTS: tRFs derived from a subset of tRNAs are significantly altered in the hippocampus of AD patients. The expression change of some tRFs showed age- and disease stage-dependent. ANG is significantly enhanced in AD, suggesting its role in inducing tRFs in AD. The expression of NSun2 in AD patients younger than 65 was significantly decreased. According to a previous report supporting NSun2-mediated tRNA methylation modification making tRNA less susceptible to ANG-mediated cleavage, our results suggested that the decrease in NSun2 may make tRNAs less methylated and subsequently enhanced tRF production from ANG-mediated tRNA cleavage.

CONCLUSION: Our studies demonstrated for the first time the involvement of tRFs in human AD.

%B J Alzheimers Dis %V 79 %P 793-806 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33337366?dopt=Abstract %R 10.3233/JAD-200917 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Upregulation of Cortical A2A Adenosine Receptors Is Reflected in Platelets of Patients with Alzheimer's Disease. %A Merighi, Stefania %A Battistello, Enrica %A Casetta, Ilaria %A Gragnaniello, Daniela %A Poloni, Tino Emanuele %A Medici, Valentina %A Cirrincione, Alice %A Varani, Katia %A Vincenzi, Fabrizio %A Borea, Pier Andrea %A Gessi, Stefania %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Blood Platelets %K Cerebral Cortex %K Female %K Humans %K Male %K Receptor, Adenosine A2A %K Up-Regulation %X

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative pathology covering about 70%of all cases of dementia. Adenosine, a ubiquitous nucleoside, plays a key role in neurodegeneration, through interaction with four receptor subtypes. The A2A receptor is upregulated in peripheral blood cells of patients affected by Parkinson's and Huntington's diseases, reflecting the same alteration found in brain tissues. However, whether these changes are also present in AD pathology has not been determined.

OBJECTIVE: In this study we verified any significant difference between AD cases and controls in both brain and platelets and we evaluated whether peripheral A2A receptors may reflect the status of neuronal A2A receptors.

METHODS: We evaluated the expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, in postmortem AD patients and control subjects, through [3H]ZM 241385 binding experiments. The same analysis was performed in peripheral platelets from AD patients versus controls.

RESULTS: The expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, revealed a density (Bmax) of 174±29, 219±33, and 358±84 fmol/mg of proteins, respectively, in postmortem AD patients in comparison to 104±16, 103±19, and 121±20 fmol/mg of proteins in controls (p < 0.01). The same trend was observed in peripheral platelets from AD patients versus controls (Bmax of 214±17 versus 95±4 fmol/mg of proteins, respectively, p < 0.01).

CONCLUSION: AD subjects show significantly higher A2A receptor density than controls. Values on platelets seem to correlate with those in the brain supporting a role for A2A receptor as a possible marker of AD pathology and drug target for novel therapies able to modify the progression of dementia.

%B J Alzheimers Dis %V 80 %P 1105-1117 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646165?dopt=Abstract %R 10.3233/JAD-201437 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Upregulation of Local Hepcidin Contributes to Iron Accumulation in Alzheimer's Disease Brains. %A Chaudhary, Suman %A Ashok, Ajay %A McDonald, Dallas %A Wise, Aaron S %A Kritikos, Alexander E %A Rana, Neil A %A Harding, Clifford V %A Singh, Neena %X

BACKGROUND: Accumulation of iron is a consistent feature of Alzheimer's disease (AD) brains. The underlying cause, however, remains debatable.

OBJECTIVE: To explore whether local hepcidin synthesized by brain cells contributes to iron accumulation in AD brains.

METHODS: Brain tissue from the cingulate cortex of 33 cases of AD pre-assigned to Braak stage I-VI, 6 cases of non-dementia, and 15 cases of non-AD dementia were analyzed for transcriptional upregulation of hepcidin by RT-qPCR and RT-PCR. Change in the expression of ferritin, ferroportin (Fpn), microglial activation marker Iba1, IL-6, and TGFβ2 was determined by western blotting. Total tissue iron was determined by colorimetry.

RESULTS: Significant transcriptional upregulation of hepcidin was observed in Braak stage III-VI relative to Braak stage I and II, non-AD dementia, and non-dementia samples. Ferritin was increased in Braak stage V, and a significant increase in tissue iron was evident in Braak stage III-VI. The expression of Iba1 and IL-6 was also increased in Braak stage III-VI relative to Braak stage I and II and non-AD dementia samples. Amyloid-β plaques were absent in most Braak stage I and II samples, and present in Braak stage III-VI samples with few exceptions.

CONCLUSION: These observations suggest that upregulation of brain hepcidin is mediated by IL-6, a known transcriptional activator of hepcidin. The consequent downregulation of Fpn on neuronal and other cells results in accumulation of iron in AD brains. The increase in hepcidin is disease-specific, and increases with disease progression, implicating AD-specific pathology in the accumulation of iron.

%B J Alzheimers Dis %V 82 %8 2021 Aug 17 %G eng %N 4 %R 10.3233/JAD-210221 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Urban Air Pollution Nanoparticles from Los Angeles: Recently Decreased Neurotoxicity. %A Zhang, Hongqiao %A D'Agostino, Carla %A Forman, Henry Jay %A Cacciottolo, Mafalda %A Thorwald, Max %A Mack, William J %A Liu, Qinghai %A Shkirkova, Kristina %A Lamorie-Foote, Krista %A Sioutas, Constantinos %A Pirhadi, Milad %A Mack, Wendy Jean %A Morgan, Todd E %A Finch, Caleb E %X

BACKGROUND: Air pollution is widely associated with accelerated cognitive decline at later ages and risk of Alzheimer's disease (AD). Correspondingly, rodent models demonstrate the neurotoxicity of ambient air pollution and its components. Our studies with nano-sized particulate matter (nPM) from urban Los Angeles collected since 2009 have shown pro-amyloidogenic and pro-inflammatory responses. However, recent batches of nPM have diminished induction of the glutamate receptor GluA1 subunit, Iba1, TNFα, Aβ42 peptide, and white matter damage. The same methods, materials, and mouse genotypes were used throughout.

OBJECTIVE: Expand the nPM batch comparisons and evaluate archived brain samples to identify the earliest change in nPM potency.

METHODS: Batches of nPM were analyzed by in vitro cell assays for NF-κB and Nrf2 induction for comparison with in vivo responses of mouse brain regions from mice exposed to these batches, analyzed by PCR and western blot.

RESULTS: Five older nPM batches (2009-2017) and four recent nPM batches (2018, 2019) for NF-κB and Nrf2 induction showed declines in nPM potency after 2017 that paralleled declines of in vivo activity from independent exposures in different years.

CONCLUSION: Transcription-based in vitro assays of nPM corresponded to the loss of in vivo potency for inflammatory and oxidative responses. These recent decreases of nPM neurotoxicity give a rationale for evaluating possible benefits to the risk of dementia and stroke in Los Angeles populations.

%B J Alzheimers Dis %V 82 %P 307-316 %8 2021 Jun 29 %G eng %N 1 %R 10.3233/JAD-201577 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Visual Memory Deficits in Middle-Aged APOEɛ4 Homozygotes Detected Using Unsupervised Cognitive Assessments. %A Lim, Yen Ying %A Pase, Matthew P %A Buckley, Rachel F %A Yassi, Nawaf %A Bransby, Lisa %A Fowler, Christopher %A Laws, Simon M %A Masters, Colin L %A Maruff, Paul %X

BACKGROUND: The apolipoprotein E (APOE) ɛ4 allele is associated with dose-response effects on cognitive dysfunction and dementia risk in older adults. However, its effects on cognition in middle-aged adults remains unclear.

OBJECTIVE: We examined effects of ɛ4 heterozygosity and homozygosity on objective and subjective cognition in middle-aged adults enrolled in the Healthy Brain Project (HBP) and in older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.

METHODS: HBP participants (1,000 non-carriers; 450 ɛ4 heterozygotes; 50 ɛ4 homozygotes) completed unsupervised assessments of the Cogstate Brief Battery (CBB), ratings of subjective cognitive function and provided a saliva sample. AIBL cognitively normal participants (650 non-carriers; 204 ɛ4 heterozygotes; 31 ɛ4 homozygotes) completed in-person assessments of the CBB, ratings of subjective cognitive function and provided a blood sample.

RESULTS: Greater memory impairment was observed in middle-aged ɛ4 homozygotes compared with ɛ4 heterozygotes and non-carriers. When data from middle-aged (HBP) and older (AIBL) adults were pooled, the effect of ɛ4 homozygosity and memory impairment increased with age. In both middle-aged and older adults, ɛ4 heterozygotes did not differ from non-carriers on any measure of objective or subjective cognition.

CONCLUSION: Memory impairment in ɛ4 homozygotes is evident in adults aged 50-60 years, and this can be detected through unsupervised cognitive assessments. The effect of ɛ4 homozygosity increases with older age. APOEɛ4 homozygosity has a negative impact on memory as early as midlife, but due to the subtle magnitude of effect, our findings support the necessity of online platforms in large cohorts to assess these complex relationships.

%B J Alzheimers Dis %V 79 %P 1563-1573 %8 2021 Feb 16 %G eng %N 4 %R 10.3233/JAD-201281 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Vitamin D Levels, APOE Allele, and MRI Volumetry Assessed by NeuroQuant in Norwegian Adults with Cognitive Symptoms. %A Soares, Jelena Z %A Pettersen, Renate %A Benth, Jūratė Š %A Persson, Karin %A Strobel, Carsten %A Selbæk, Geir %A Bogdanovic, Nenad %X

BACKGROUND: Allele ɛ4 of the apolipoprotein (APOE∈4) gene is the strongest known genetic risk factor for late-onset sporadic Alzheimer's disease. A possible relationship between vitamin D and APOE is not yet clear.

OBJECTIVE: In this exploratory, cross-sectional study, we examined the association between serum levels of 25-hydroxyvitamin D [25(OH)D] and brain volumes and the associations of both serum levels of 25(OH)D and APOE polymorphism to brain volumes in 127 persons (mean age 66 years) with cognitive symptoms.

METHODS: All subjects were examined with fully automated software for MRI volumetry, NeuroQuant.

RESULTS: After adjustment for relevant covariates, higher serum 25(OH)D levels were associated with greater volumes of cortical gray matter on both left (p = 0.02) and right (p = 0.04) sides. When both 25(OH)D levels and APOE genotype were used as the main covariates, no significant associations were found between vitamin D level and brain volume in any of the 11 brain regions. In adjusted models, only homozygous but not heterozygous APOE∈4 allele carriers had significantly larger inferior lateral ventricles (p = 0.003) and smaller hippocampal volume (p = 0.035) than those without ɛ4. Homozygous APOE∈4 carriers also had significantly higher vitamin D levels (p = 0.009) compared to persons without the APOE∈4 allele.

CONCLUSION: Higher vitamin D levels might have a preserving effect on cortical grey matter volume.

%B J Alzheimers Dis %V 79 %P 311-321 %8 2021 Jan 5 %G eng %N 1 %R 10.3233/JAD-201018 %0 Journal Article %J J Alzheimers Dis %D 2021 %T White Matter Connectivity in Incident Mild Cognitive Impairment: A Diffusion Spectrum Imaging Study of World Trade Center Responders at Midlife. %A Huang, Chuan %A Kritikos, Minos %A Clouston, Sean A P %A Deri, Yael %A Serrano-Sosa, Mario %A Bangiyev, Lev %A Santiago-Michels, Stephanie %A Gandy, Sam %A Sano, Mary %A Bromet, Evelyn J %A Luft, Benjamin J %K Brain %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Emergency Responders %K Female %K Humans %K Incidence %K Male %K Middle Aged %K September 11 Terrorist Attacks %K White Matter %X

BACKGROUND: Individuals who participated in response efforts at the World Trade Center (WTC) following 9/11/2001 are experiencing elevated incidence of mild cognitive impairment (MCI) at midlife.

OBJECTIVE: We hypothesized that white matter connectivity measured using diffusion spectrum imaging (DSI) would be restructured in WTC responders with MCI versus cognitively unimpaired responders.

METHODS: Twenty responders (mean age 56; 10 MCI/10 unimpaired) recruited from an epidemiological study were characterized using NIA-AA criteria alongside controls matched on demographics (age/sex/occupation/race/education). Axial DSI was acquired on a 3T Siemen's Biograph mMR scanner (12-channel head coil) using a multi-band diffusion sequence. Connectometry examined whole-brain tract-level differences in white matter integrity. Fractional anisotropy (FA), mean diffusivity (MD), and quantified anisotropy were extracted for region of interest (ROI) analyses using the Desikan-Killiany atlas.

RESULTS: Connectometry identified both increased and decreased connectivity within regions of the brains of responders with MCI identified in the corticothalamic pathway and cortico-striatal pathway that survived adjustment for multiple comparisons. MCI was also associated with higher FA values in five ROIs including in the rostral anterior cingulate; lower MD values in four ROIs including the left rostral anterior cingulate; and higher MD values in the right inferior circular insula. Analyses by cognitive domain revealed nominal associations in domains of response speed, verbal learning, verbal retention, and visuospatial learning.

CONCLUSIONS: WTC responders with MCI at midlife showed early signs of neurodegeneration characterized by both increased and decreased white matter diffusivity in regions commonly affected by early-onset Alzheimer's disease.

%B J Alzheimers Dis %V 80 %P 1209-1219 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646156?dopt=Abstract %R 10.3233/JAD-201237 %0 Journal Article %J J Alzheimers Dis %D 2020 %T ABCA7 Genotype Moderates the Effect of Aerobic Exercise Intervention on Generalization of Prior Learning in Healthy Older African Americans. %A Sinha, Neha %A Berg, Chelsie N %A Shaw, Ashlee %A Gluck, Mark A %X

African Americans are at elevated risk for age-related cognitive decline, with double the prevalence of Alzheimer's disease (AD) compared to Caucasians Americans. Various behavioral, biological, and lifestyle factors may underlie this health disparity, but little is known about the relative importance and interactions among these different risk factors in African Americans. While the neuroprotective effects of aerobic exercise on biomarkers are well established, few studies have examined the differential benefits of exercise based on genetic risk for AD. Furthermore, evidence is limited regarding the potential moderating effects of ABCA7, a gene known to confer significantly greater AD risk in African Americans. In a case-control matched sample of 56 healthy older African Americans, we investigated the effect of an aerobic exercise intervention on a hippocampus-related assessment of generalization following rule learning, in individuals who were carriers of the ABCA7 rs3764650 non-risk (TT) or high-risk (GG) genotypes. Following the exercise-intervention, the non-risk group made significantly fewer generalization errors, while there was no improvement in generalization for the high-risk group. For the controls, no changes in generalization scores were observed regardless of genotype status. Our results indicate that the ongoing adverse effects of ABCA7 high-risk genotype may diminish the benefits associated with aerobic exercise. As such, the potential disease-modifying effects of aerobic exercise on AD-related neuropathology may be limited to carriers of the ABCA7 rs3764650 non-risk genotype.

%B J Alzheimers Dis %V 74 %P 309-318 %8 2020 Mar 10 %G eng %N 1 %R 10.3233/JAD-190723 %0 Journal Article %J J Alzheimers Dis %D 2020 %T An Active Lifestyle Is Associated with Better Cognitive Function Over Time in APOE ɛ4 Non-Carriers. %A Fernández-Matarrubia, Marta %A Goni, Leticia %A Rognoni, Teresa %A Razquin, Cristina %A Fernández-Lázaro, César Ignacio %A Bes-Rastrollo, Maira %A Martínez-González, Miguel Ángel %A Toledo, Estefanía %X

BACKGROUND: Available evidence on the association of physical activity (PA) or sedentary behavior with cognitive decline is inconclusive.

OBJECTIVE: To assess the association between an active lifestyle score and leisure-time physical activity (LTPA) and changes in cognitive function in the Seguimiento Universidad de Navarra (SUN) prospective cohort.

METHODS: Cognitive function was evaluated in a subsample of 806 participants of the SUN cohort study using the validated Telephone Interview for Cognitive Status-modified (STICS-m) questionnaire at baseline and after 6 years. LTPA was evaluated with a previously validated 17-item self-administered questionnaire and with information on sedentary lifestyles. We also calculated a multidimensional 8-item PA score. Multivariable linear regression analysis evaluated the association between PA and changes in cognitive function and its interaction by APOE genotype.

RESULTS: Mean age of participants was 66 (SD 5.3) years and 69.7% were male. When stratifying by APOE variants, no significant associations between the active lifestyle score or LTPA and changes in cognitive performance over time were found among APOE ɛ4 carriers. However, we observed that a higher adherence to an active lifestyle (high versus low PA score β= 0.76 95% CI 0.15,1.36; p trend = 0.011) and a high LTPA (Q4 versus Q1 β= 0.63; 95% CI -0.01,1.26; p trend = 0.030) were associated with more favorable changes in cognitive function over time among APOE ɛ4 non-carriers with statistically significant interactions in both cases (p for interaction = 0.042 for PA score, and p = 0.039 for LTPA).

CONCLUSION: The results of the present study suggest that an active lifestyle is associated with a better status of cognitive function over time only among APOE ɛ4 non-carriers.

%B J Alzheimers Dis %V 79 %P 1257-1268 %8 2021 Feb 2 %G eng %N 3 %R 10.3233/JAD-201090 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Adiponectin Paradox as a Therapeutic Target in Alzheimer's Disease. %A Waragai, Masaaki %A Ho, Gilbert %A Takamatsu, Yoshiki %A Wada, Ryoko %A Sugama, Shuei %A Takenouchi, Takato %A Masliah, Eliezer %A Hashimoto, Makoto %X

Despite the apparent neurotoxicity of amyloid-β (Aβ), recent clinical trials of Aβ immunotherapy have not shown any clinical benefit in Alzheimer's disease (AD). Given this, clarification of the next generation therapeutic strategy in AD is warranted. Hypothetically, adiponectin might be involved in promoting amyloidogenic evolvability in reproduction, which may result in the adiponectin paradox through antagonistic pleiotropy mechanism in aging, leading to AD. Accordingly, preventing the adiponectin paradox by suppressing adiponectin signaling might prove therapeutic in AD.

%B J Alzheimers Dis %V 76 %P 1249-1253 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32623396?dopt=Abstract %R 10.3233/JAD-200416 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Age of Migration and Cognitive Function Among Older Latinos in the United States. %A Garcia, Marc A %A Ortiz, Kasim %A Arévalo, Sandra P %A Diminich, Erica D %A Briceño, Emily %A Vega, Irving E %A Tarraf, Wassim %X

BACKGROUND: Age of migration has been shown to have a robust association with Latino immigrant health outcomes; however, the relationship between timing of migration and cognition is less understood.

OBJECTIVE: To examine associations between race/ethnicity, nativity, age of migration, and cognitive aging among US-born (USB) non-Latino Whites (NLW) and USB and foreign-born Latinos 50 years and older.

METHODS: We used longitudinal biennial data from the Health and Retirement Study (HRS; 2006-2014) to fit generalized linear and linear latent growth curve models for: 1) global cognition (Modified Telephone Interview for Cognitive Status; TICS-M); 2) memory and attention subdomains of TICS-M; and 3) cognitive dysfunction. We also tested for sex modifications.

RESULTS: In age and sex adjusted models, all Latino subgroups, independent of nativity and age of migration, had lower global and domain-specific cognitive scores and higher propensity of cognitive impairment classification compared to USB-NLWs. Differences between USB Latinos, but not other Latino subgroups, and USB-NLWs remained after full covariate adjustment. Latinas, independent of nativity or age of migration, had poorer cognitive scores relative to NLW females. Differences between all Latinos and USB-NLWs were principally expressed at baseline. Racial/ethnic, nativity, and age of migration grouping was not associated with slope (nor explained variance) of cognitive decline.

CONCLUSION: Older US-born Latinos, regardless of sex exhibit poorer cognitive function than older USB-NLWs and foreign-born Latinos. Social determinants that differentially affect cognitive function, particularly those that compensate for education and sex differences among US-born Latinos and foreign-born Latinos, require further exploration.

%B J Alzheimers Dis %V 76 %P 1493-1511 %8 2020 Aug 18 %G eng %N 4 %R 10.3233/JAD-191296 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes. %A Brewer, Gregory J %A Herrera, Robert A %A Philipp, Stephan %A Sosna, Justyna %A Reyes-Ruiz, Jorge Mauricio %A Glabe, Charles G %X

 This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iAβ), and the mechanism of an age-related increase in iAβ in adult AD-model mouse neurons. A new end-specific antibody for Aβ45 and another for aggregated forms of Aβ provide new insight into the composition of iAβ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAβ levels containing aggregates of Aβ45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iAβ was 8 times more abundant in 3xTg-AD than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iAβ and rapidly increased following a brief metabolic stress with glutamate. AβPP-CTF, Aβ45, and aggregated Aβ colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iAβ by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long Aβs by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iAβ processing may lead to application of countermeasures to prolong dementia-free health span.

%B J Alzheimers Dis %V 73 %P 229-246 %8 2020 Jan 07 %G eng %N 1 %R 10.3233/JAD-190835 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Age-Specific Retinal and Cerebral Immunodetection of Amyloid-β Plaques and Oligomers in a Rodent Model of Alzheimer's Disease. %A Habiba, Umma %A Merlin, Sam %A Lim, Jeremiah K H %A Wong, Vickie H Y %A Nguyen, Christine T O %A Morley, John W %A Bui, Bang V %A Tayebi, Mourad %X

BACKGROUND: Amyloid-β soluble oligomers (Aβo) are believed to be the cause of the pathophysiology underlying Alzheimer's disease (AD) and are normally detected some two decades before clinical onset of the disease. Retinal pathology associated with AD pathogenesis has previously been reported, including ganglion cell loss, accumulation of Aβ deposits in the retina, and reduction of nerve fiber layer thickness as well as abnormalities of the microvasculature.

OBJECTIVE: This study's aim is to better understand the relationship between brain and retinal Aβo deposition and in particular to quantify levels of the toxic Aβo as a function of age in the retina of a rodent model of AD.

METHODS: Retinas and brain tissue from 5×FAD mice were stained with Congo red, Thioflavin-T (Th-T), and Aβ plaque-specific and Aβo-specific antibodies.

RESULTS: We show that retinas displayed an age-dependent increase of Th-T-specific amyloid fibrils. Staining with anti-Aβ antibody confirmed the presence of the Aβ plaques in all 5×FAD retinas tested. In contrast, staining with anti-Aβo antibody showed an age-dependent decrease of retinal Aβo. Of note, Aβo was observed mainly in the retinal nuclear layers. Finally, we confirmed the localization of Aβo to neurons, typically accumulating in late endosomes, indicating possible impairment of the endocytic pathway.

CONCLUSION: Our results demonstrate the presence of intraneuronal Aβo in the retina and its accumulation inversely correlated with retinal Aβ plaque deposition, indicating an age-related conversion in this animal model. These results support the development of an early AD diagnostic test targeting Aβo in the eye.

%B J Alzheimers Dis %V 76 %P 1135-1150 %8 2020 Aug 04 %G eng %N 3 %R 10.3233/JAD-191346 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Aggregates of RNA Binding Proteins and ER Chaperones Linked to Exosomes in Granulovacuolar Degeneration of the Alzheimer's Disease Brain. %A Yamoah, Alfred %A Tripathi, Priyanka %A Sechi, Antonio %A Köhler, Christoph %A Guo, Haihong %A Chandrasekar, Akila %A Nolte, Kay Wilhelm %A Wruck, Christoph Jan %A Katona, Istvan %A Anink, Jasper %A Troost, Dirk %A Aronica, Eleonora %A Steinbusch, Harry %A Weis, Joachim %A Goswami, Anand %X

Granulovacuolar degeneration (GVD) occurs in Alzheimer's disease (AD) brain due to compromised autophagy. Endoplasmic reticulum (ER) function and RNA binding protein (RBP) homeostasis regulate autophagy. We observed that the ER chaperones GRP78/BiP, Sigma receptor 1 (SigR1), and VAPB were elevated in many AD patients' subicular neurons. However, those neurons which were affected by GVD showed lower chaperone levels, and there was only minor co-localization of chaperones with GVD bodies (GVBs), suggesting that neurons lacking sufficient chaperone-mediated proteostasis enter the GVD pathway. Consistent with this notion, granular, incipient pTau aggregates in human AD and pR5 tau transgenic mouse neurons were regularly co-localized with increased chaperone immunoreactivity, whereas neurons with mature neurofibrillary tangles lacked both the chaperone buildup and significant GVD. On the other hand, APP/PS1 (APPswe/PSEN1dE9) transgenic mouse hippocampal neurons that are devoid of pTau accumulation displayed only few GVBs-like vesicles, which were still accompanied by prominent chaperone buildup. Identifying a potential trigger for GVD, we found cytoplasmic accumulations of RBPs including Matrin 3 and FUS as well as stress granules in GVBs of AD patient and pR5 mouse neurons. Interestingly, we observed that GVBs containing aggregated pTau and pTDP-43 were consistently co-localized with the exosomal marker Flotillin 1 in both AD and pR5 mice. In contrast, intraneuronal 82E1-immunoreactive amyloid-β in human AD and APP/PS1 mice only rarely co-localized with Flotillin 1-positive exosomal vesicles. We conclude that altered chaperone-mediated ER protein homeostasis and impaired autophagy manifesting in GVD are linked to both pTau and RBP accumulation and that some GVBs might be targeted to exocytosis.

%B J Alzheimers Dis %V 75 %P 139-156 %8 2020 May 05 %G eng %N 1 %R 10.3233/JAD-190722 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Aluminum and Amyloid-β in Familial Alzheimer's Disease. %A Mold, Matthew %A Linhart, Caroline %A Gómez-Ramírez, Johana %A Villegas-Lanau, Andrés %A Exley, Christopher %X

Genetic predispositions associated with metabolism of the amyloid-β protein precursor underlie familial Alzheimer's disease; a form of dementia characterized by early disease onset and elevated levels of cortical amyloid-β. Human exposure to aluminum is linked to the etiology of Alzheimer's disease and recent research measured a high content of aluminum in brain tissue in familial Alzheimer's disease. To elaborate upon this finding, we have obtained brain tissues from a Colombian cohort of donors with familial Alzheimer's disease. We have used established methods to measure the aluminum content of these tissues and we have compared the data with a recently measured dataset for control brain tissues. We report significantly higher levels of aluminum in brain tissues in donors with familial Alzheimer's disease than in control tissues from donors without neurological impairment or neurodegeneration. We have used aluminum-specific fluorescence microscopy along with complementary imaging for amyloid-β to demonstrate a very high degree of co-localization of these two risk factors in brain tissue in familial Alzheimer's disease. Aluminum and amyloid-β were co-located in senile plaques as well as vasculature, the latter resembling cerebral amyloid angiopathy. Aluminum was also found separately from amyloid-β in intracellular compartments including glia and neuronal axons. The research has identified an arguably unique association between high brain aluminum content and amyloid-β and allows postulation that genetic predispositions defining familial Alzheimer's disease underlie this relationship.

%B J Alzheimers Dis %V 73 %P 1627-1635 %8 2020 Feb 18 %G eng %N 4 %R 10.3233/JAD-191140 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Aluminum and Neurofibrillary Tangle Co-Localization in Familial Alzheimer's Disease and Related Neurological Disorders. %A Mold, Matthew John %A O'Farrell, Adam %A Morris, Benjamin %A Exley, Christopher %X

BACKGROUND: Protein misfolding disorders are frequently implicated in neurodegenerative conditions. Familial Alzheimer's disease (fAD) is an early-onset and aggressive form of Alzheimer's disease (AD), driven through autosomal dominant mutations in genes encoding the amyloid precursor protein and presenilins 1 and 2. The incidence of epilepsy is higher in AD patients with shared neuropathological hallmarks in both disease states, including the formation of neurofibrillary tangles. Similarly, in Parkinson's disease, dementia onset is known to follow neurofibrillary tangle deposition.

OBJECTIVE: Human exposure to aluminum has been linked to the etiology of neurodegenerative conditions and recent studies have demonstrated a high level of co-localization between amyloid-β and aluminum in fAD. In contrast, in a donor exposed to high levels of aluminum later developing late-onset epilepsy, aluminum and neurofibrillary tangles were found to deposit independently. Herein, we sought to identify aluminum and neurofibrillary tangles in fAD, Parkinson's disease, and epilepsy donors.

METHODS: Aluminum-specific fluorescence microscopy was used to identify aluminum in neurofibrillary tangles in human brain tissue.

RESULTS: We observed aluminum and neurofibrillary-like tangles in identical cells in all respective disease states. Co-deposition varied across brain regions, with aluminum and neurofibrillary tangles depositing in different cellular locations of the same cell.

CONCLUSION: Neurofibrillary tangle deposition closely follows cognitive-decline, and in epilepsy, tau phosphorylation associates with increased mossy fiber sprouting and seizure onset. Therefore, the presence of aluminum in these cells may exacerbate the accumulation and misfolding of amyloidogenic proteins including hyperphosphorylated tau in fAD, epilepsy, and Parkinson's disease.

%B J Alzheimers Dis %V 78 %P 139-149 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32925074?dopt=Abstract %R 10.3233/JAD-200838 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Is Alzheimer's Disease a Liver Disease of the Brain? %A Bassendine, Margaret F %A Taylor-Robinson, Simon D %A Fertleman, Michael %A Khan, Michael %A Neely, Dermot %X

Clinical specialization is not only a force for progress, but it has also led to the fragmentation of medical knowledge. The focus of research in the field of Alzheimer's disease (AD) is neurobiology, while hepatologists focus on liver diseases and lipid specialists on atherosclerosis. This article on AD focuses on the role of the liver and lipid homeostasis in the development of AD. Amyloid-β (Aβ) deposits accumulate as plaques in the brain of an AD patient long before cognitive decline is evident. Aβ generation is a normal physiological process; the steady-state level of Aβ in the brain is determined by balance between Aβ production and its clearance. We present evidence suggesting that the liver is the origin of brain Aβ deposits and that it is involved in peripheral clearance of circulating Aβ in the blood. Hence the liver could be targeted to decrease Aβ production or increase peripheral clearance.

%B J Alzheimers Dis %V 75 %P 1-14 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32250293?dopt=Abstract %R 10.3233/JAD-190848 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Alzheimer's Disease-Like Neurodegeneration in Porphyromonas gingivalis Infected Neurons with Persistent Expression of Active Gingipains. %A Haditsch, Ursula %A Roth, Theresa %A Rodriguez, Leo %A Hancock, Sandy %A Cecere, Thomas %A Nguyen, Mai %A Arastu-Kapur, Shirin %A Broce, Sean %A Raha, Debasish %A Lynch, Casey C %A Holsinger, Leslie J %A Dominy, Stephen S %A Ermini, Florian %X

BACKGROUND: Porphyromonas gingivalis (P. gingivalis) and its gingipain virulence factors have been identified as pathogenic effectors in Alzheimer's disease (AD). In a recent study we demonstrated the presence of gingipains in over 90% of postmortem AD brains, with gingipains localizing to the cytoplasm of neurons. However, infection of neurons by P. gingivalis has not been previously reported.

OBJECTIVE: To demonstrate intraneuronal P. gingivalis and gingipain expression in vitro after infecting neurons derived from human inducible pluripotent stem cells (iPSC) with P. gingivalis for 24, 48, and 72 h.

METHODS: Infection was characterized by transmission electron microscopy, confocal microscopy, and bacterial colony forming unit assays. Gingipain expression was monitored by immunofluorescence and RT-qPCR, and protease activity monitored with activity-based probes. Neurodegenerative endpoints were assessed by immunofluorescence, western blot, and ELISA.

RESULTS: Neurons survived the initial infection and showed time dependent, infection induced cell death. P. gingivalis was found free in the cytoplasm or in lysosomes. Infected neurons displayed an accumulation of autophagic vacuoles and multivesicular bodies. Tau protein was strongly degraded, and phosphorylation increased at T231. Over time, the density of presynaptic boutons was decreased.

CONCLUSION: P. gingivalis can invade and persist in mature neurons. Infected neurons display signs of AD-like neuropathology including the accumulation of autophagic vacuoles and multivesicular bodies, cytoskeleton disruption, an increase in phospho-tau/tau ratio, and synapse loss. Infection of iPSC-derived mature neurons by P. gingivalis provides a novel model system to study the cellular mechanisms leading to AD and to investigate the potential of new therapeutic approaches.

%B J Alzheimers Dis %V 75 %P 1361-1376 %8 2020 Jun 16 %G eng %N 4 %R 10.3233/JAD-200393 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Alzheimer's/Vascular Spectrum Dementia: Classification in Addition to Diagnosis. %A Emrani, Sheina %A Lamar, Melissa %A Price, Catherine C %A Wasserman, Victor %A Matusz, Emily %A Au, Rhoda %A Swenson, Rodney %A Nagele, Robert %A Heilman, Kenneth M %A Libon, David J %X

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common types of dementia. Although the combination of these disorders, called 'mixed' dementia, is recognized, the prevailing clinical and research perspective continues to consider AD and VaD as independent disorders. A review of recent neuropathological and neuropsychological literature reveals that these two disorders frequently co-occur and so-called 'pure' AD or VaD is comparatively rare. In addition, recent research shows that vascular dysfunction not only potentiates AD pathology, but that pathological changes in AD may subsequently induce vascular disorders. On the basis of these data, we propose that the neurobiological underpinnings underlying AD/VaD dementia and their neuropsychological phenotypes are best understood as existing along a clinical/pathological continuum or spectrum. We further propose that in conjunction with current diagnostic criteria, statistical modeling techniques using neuropsychological test performance should be leveraged to construct a system to classify AD/VaD spectrum dementia in order to test hypotheses regarding how mechanisms related to AD and VaD pathology interact and influence each other.

%B J Alzheimers Dis %V 73 %P 63-71 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31815693?dopt=Abstract %R 10.3233/JAD-190654 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Amyloid Hypothesis: The Emperor's New Clothes? %A Høilund-Carlsen, Poul F %A Barrio, Jorge R %A Werner, Tom J %A Newberg, Andrew %A Alavi, Abass %X

The lengthy debate on the validity of the amyloid hypothesis and the usefulness of amyloid imaging and anti-amyloid therapeutic interventions in dementia continues unabated, even though none of them have been able to convince the medical world of their correctness and clinical value. There are huge financial interests associated with promoting both, but in spite of the large sums of money in their support, no effective anti-amyloid treatments or diagnostic use of amyloid imaging have emerged. There are solid scientific reasons that explain these negative results, and it is time to move forward to other promising options for the benefit of the patients.

%B J Alzheimers Dis %V 78 %P 1363-1366 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33164938?dopt=Abstract %R 10.3233/JAD-200990 %0 Journal Article %J J Alzheimers Dis %D 2020 %T The Amyloid, Tau, and Neurodegeneration (A/T/N) Classification Applied to a Clinical Research Cohort with Long-Term Follow-Up. %A Grøntvedt, Gøril Rolfseng %A Lauridsen, Camilla %A Berge, Guro %A White, Linda R %A Salvesen, Øyvind %A Bråthen, Geir %A Sando, Sigrid Botne %X

BACKGROUND: The unbiased amyloid, tau, and neurodegeneration (A/T/N) classification is designed to characterize individuals in the Alzheimer continuum and is currently little explored in clinical cohorts.

OBJECTIVE: A retrospective comparison of the A/T/N classification system with the results of a two-year clinical study, with extended follow-up up to 10 years after inclusion.

METHODS: Patients (n = 102) clinically diagnosed as Alzheimer's disease (AD) with dementia or amnestic mild cognitive impairment (MCI), and 61 cognitively healthy control individuals were included. Baseline cerebrospinal fluid core biomarkers for AD (Aβ42, phosphorylated tau, and total tau) were applied to the A/T/N classification using the final clinical diagnosis at extended follow-up as the gold standard.

RESULTS: A + T + N+ was a strong predictor for AD dementia, even among cognitively healthy individuals. Amnestic MCI was heterogenous, considering both clinical outcome and distribution within A/T/N. Some individuals with amnestic MCI progressed to clinical AD dementia within all four major A/T/N groups. The highest proportion of progression was among triple positive cases, but progression was also common in individuals with suspected non-Alzheimer pathophysiology (A-T + N+), and those with triple negative status. A-T-N- individuals who were cognitively healthy overwhelmingly remained cognitively intact over time, but in amnestic MCI the clinical outcome was heterogenous, including AD dementia, other dementias, and recovery.

CONCLUSION: The A/T/N framework accentuates biomarkers over clinical status. However, when selecting individuals for research, a combination of the two may be necessary since the prognostic value of the A/T/N framework depends on clinical status.

%B J Alzheimers Dis %V 74 %P 829-837 %8 2020 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/32116257?dopt=Abstract %R 10.3233/JAD-191227 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Amyloid-β Causes Mitochondrial Dysfunction via a Ca2+-Driven Upregulation of Oxidative Phosphorylation and Superoxide Production in Cerebrovascular Endothelial Cells. %A Quintana, Dominic D %A Garcia, Jorge A %A Anantula, Yamini %A Rellick, Stephanie L %A Engler-Chiurazzi, Elizabeth B %A Sarkar, Saumyendra N %A Brown, Candice M %A Simpkins, James W %X

Cerebrovascular pathology is pervasive in Alzheimer's disease (AD), yet it is unknown whether cerebrovascular dysfunction contributes to the progression or etiology of AD. In human subjects and in animal models of AD, cerebral hypoperfusion and hypometabolism are reported to manifest during the early stages of the disease and persist for its duration. Amyloid-β is known to cause cellular injury in both neurons and endothelial cells by inducing the production of reactive oxygen species and disrupting intracellular Ca2+ homeostasis. We present a mechanism for mitochondrial degeneration caused by the production of mitochondrial superoxide, which is driven by increased mitochondrial Ca2+ uptake. We found that persistent superoxide production injures mitochondria and disrupts electron transport in cerebrovascular endothelial cells. These observations provide a mechanism for the mitochondrial deficits that contribute to cerebrovascular dysfunction in patients with AD.

%B J Alzheimers Dis %V 75 %P 119-138 %8 2020 May 05 %G eng %N 1 %R 10.3233/JAD-190964 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Amyloid-β in Alzheimer's Disease: A Study of Citation Practices of the Amyloid Cascade Hypothesis Between 1992 and 2019. %A Daly, Timothy %A Houot, Marion %A Barberousse, Anouk %A Agid, Yves %A Epelbaum, Stéphane %X

The amyloid cascade hypothesis (ACH) has dominated contemporary biomedical research into Alzheimer's disease (AD) since the 1990 s but still lacks definitive confirmation by successful clinical trials of anti-amyloid medicines in human AD. In this uncertain period regarding the centrality of amyloid-β (Aβ) in AD pathophysiology, and with the community apparently divided about the ACH's validity, we used citation practices as a proxy for measuring how researchers have invested their belief in the hypothesis between 1992 and 2019. We sampled 445 articles citing Hardy & Higgins (1992, "HH92") and classified the polarity of their HH92 citation according to Greenberg (2009)'s citation taxonomy of positive, neutral, and negative citations, and then tested four hypotheses. We identified two major attitudes towards HH92: a majority (62%) of neutral attitudes with consistent properties across the time period, and a positive attitude (35%), tending to cite HH92 earlier on within the bibliography as time went by, tending to take HH92 as an established authority. Despite the majority of neutral HH92 citations, there was a positive majority of attitudes toward different versions of the ACH and anti-amyloid therapeutic strategies (65%), suggesting that the ACH has been dominant and has undergone significant refinement since 1992. Finally, of those 110 original articles within the sample also testing the ACH empirically, an overwhelming majority (89%) returned a pro-ACH test result, suggesting that the ACH's central claim is reproducible. Further studies will quantify the extent to which results from different methods within such original studies convergence to provide a robust conclusion vis-à-vis Aβ's pathogenicity in AD.

%B J Alzheimers Dis %V 74 %P 1309-1317 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32250306?dopt=Abstract %R 10.3233/JAD-191321 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Analysis of Taste Sensitivities in App Knock-In Mouse Model of Alzheimer's Disease. %A Narukawa, Masataka %A Takahashi, Suzuka %A Saito, Takashi %A Saido, Takaomi C %A Misaka, Takumi %X

BACKGROUND: Some studies have reported a decline in taste sensitivities in patients with Alzheimer's disease. However, the detail remains unknown.

OBJECTIVE: We investigated the effect of cognitive impairment on taste sensitivity using an App knock-in mouse model of Alzheimer's disease.

METHODS: Behavioral assays, a brief access test, and a 48 h two-bottle preference test, to assess taste sensitivities were started from 12 months of age in mice that were confirmed to have impaired cognition.

RESULTS: In the assays, there was no significant difference in taste sensitivities between wild type and App knock-in mice. Additionally, no apparent difference was observed in the expression of taste markers in their taste bud cells.

CONCLUSION: We concluded that cognitive impairment might not greatly affect taste sensitivity.

%B J Alzheimers Dis %V 76 %P 997-1004 %8 2020 Aug 04 %G eng %N 3 %R 10.3233/JAD-200284 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Angiotensin II Blood Levels Are Associated with Smaller Hippocampal and Cortical Volumes in Cognitively Normal Older Adults. %A Yasar, Sevil %A Moored, Kyle D %A Adam, Atif %A Zabel, Fiona %A Chuang, Yi-Fang %A Varma, Vijay R %A Carlson, Michelle C %X

BACKGROUND: There is emerging evidence about possible involvement of the renin-angiotensin system (RAS) in the pathogenesis of Alzheimer's disease (AD) and decline of cognitive function. However, little is known about associations with brain biomarkers.

OBJECTIVE: Our study aimed to examine associations between blood ACE-1 and ANG II levels and brain MRI based volumes in non-demented participants, and whether these associations were mediated by blood pressure.

METHODS: This cross-sectional study was conducted in 34 older participants from the Baltimore Experience Corps Trial (BECT) Brain Health Sub-study (BHS). Blood ANGII and ACE-1 levels were measured by ELISA and brain MRI volumes were generated using FreeSurfer 6.0. Multiple linear regression analysis, adjusting for intracranial volume and confounders, was used to determine associations between log transformed ANGII and ACE-1 levels and MRI volumes (mm3).

RESULTS: Participants were predominantly female (76%), African-American (94%), with mean age of 66.9 and education of 14.4 years. In the fully adjusted model we observed significant inverse associations between log ANGII levels and total grey matter (β=Angiotensin II associated with smaller hippocampus14,935.50, ±7,444.83, p = 0.05), total hippocampus (β=-129.97, ±105.27, p = 0.03), rostral middle frontal (β= -1580.40, ±584.74, p = 0.02), and supramarginal parietal (β= -978.90, ±365.54, p = 0.02) volumes. There were no associations between ANGII levels and total white matter or entorhinal cortex volumes, or ACE-1 levels and any brain volumes.

CONCLUSION: We observed that increased blood ANGII levels were associated with lower total grey matter, hippocampal, rostral middle frontal, and supramarginal parietal volumes, which are associated with cognitive domains that decline in preclinical AD.

%B J Alzheimers Dis %V 75 %P 521-529 %8 2020 May 19 %G eng %N 2 %R 10.3233/JAD-200118 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Animal Models of Alzheimer's Disease Should Be Controlled for Roseolovirus. %A Denner, Joachim %A Tanzi, Rudolph %A Jacobson, Steve %X

Animal models to study Alzheimer's disease (AD) pathogenesis are under development. Since herpesviruses have been postulated to be capable of triggering the pathogenic process, AD animal models (mouse, pig, and non-human primates) should be controlled for the presence of these viruses. Only virus-free models allow studying the genetic factors and the effect of adding viruses. Roseoloviruses such as human herpesvirus 6 and the related viruses in the animals are the main topic of this commentary.

%B J Alzheimers Dis %V 77 %P 543-545 %8 2020 Sep 15 %G eng %N 2 %R 10.3233/JAD-200591 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Anterior Cingulate Structure and Perfusion Is Associated with Cerebrospinal Fluid Tau Among Cognitively Normal Older Adult APOEɛ4 Carriers. %A Hays, Chelsea C %A Zlatar, Zvinka Z %A Meloy, M J %A Osuna, Jessica %A Liu, Thomas T %A Galasko, Douglas R %A Wierenga, Christina E %X

Evidence suggests the ɛ4 allele of the apolipoprotein E gene (APOE) may accelerate an age-related process of cortical thickening and cerebral blood flow (CBF) reduction in the anterior cingulate cortex (ACC). Although the neural basis of this association remains unclear, evidence suggests it might reflect early neurodegenerative processes. However, to date, associations between cerebrospinal fluid (CSF) biomarkers of neurodegeneration, such as CSF tau, and APOE-related alterations in ACC cortical thickness (CTH) and CBF have yet to be explored. The current study explored the interaction of CSF tau and APOE genotype (ɛ4+, ɛ4-) on FreeSurfer-derived CTH and arterial spin labeling MRI-measured resting CBF in the ACC (caudal ACC [cACC] and rostral ACC [rACC]) among a sample of 45 cognitively normal older adults. Secondary analyses also examined associations between APOE, CTH/CBF, and cognitive performance. In the cACC, higher CSF tau was associated with higher CTH and lower CBF in ɛ4+, whereas these relationships were not evident in ɛ4-. In the rACC, higher CSF tau was associated with higher CTH for both ɛ4+ and ɛ4-, and with lower CBF only in ɛ4+. Significant interactions of CSF tau and APOE on CTH/CBF were not observed in two posterior reference regions implicated in Alzheimer's disease. Secondary analyses revealed a negative relationship between cACC CTH and executive functioning in ɛ4+ and a positive relationship in ɛ4-. Findings suggest the presence of an ɛ4-related pattern of increased CTH and CBF reduction in the ACC that is associated with biomarkers of neurodegeneration and subtle decrements in cognition.

%B J Alzheimers Dis %V 73 %P 87-101 %8 2020 Jan 07 %G eng %N 1 %R 10.3233/JAD-190504 %0 Journal Article %J J Alzheimers Dis %D 2020 %T APOE4 Status is Related to Differences in Memory-Related Brain Function in Asymptomatic Older Adults with Family History of Alzheimer's Disease: Baseline Analysis of the PREVENT-AD Task Functional MRI Dataset. %A Rabipour, Sheida %A Rajagopal, Sricharana %A Yu, Elsa %A Pasvanis, Stamatoula %A Lafaille-Magnan, Marie-Elyse %A Breitner, John %A Rajah, M Natasha %X

BACKGROUND: Episodic memory decline is one of the earliest symptoms of late-onset Alzheimer's disease (AD). Older adults with the apolipoprotein E ɛ4 (+APOE4) genetic risk factor for AD may exhibit altered patterns of memory-related brain activity years prior to initial symptom onset.

OBJECTIVE: Here we report the baseline episodic memory task functional MRI results from the PRe-symptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease cohort in Montreal, Canada, in which 327 healthy older adults were scanned within 15 years of their parent's conversion to AD.

METHODS: Volunteers were scanned as they encoded and retrieved object-location spatial source associations. The task was designed to discriminate between brain activity related to spatial source recollection and object-only (recognition) memory. We used multivariate partial least squares (PLS) to test the hypothesis that +APOE4 adults with family history of AD would exhibit altered patterns of brain activity in the recollection-related memory network, comprised of medial frontal, parietal, and medial temporal cortices, compared to APOE4 non-carriers (-APOE4). We also examined group differences in the correlation between event-related brain activity and memory performance.

RESULTS: We found group similarities in memory performance and in task-related brain activity in the recollection network, but differences in brain activity-behavior correlations in ventral occipito-temporal, medial temporal, and medial prefrontal cortices during episodic encoding.

CONCLUSION: These findings are consistent with previous literature on the influence of APOE4 on brain activity and provide new perspective on potential gene-based differences in brain-behavior relationships in people with first-degree family history of AD.

%B J Alzheimers Dis %V 76 %P 97-119 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32474466?dopt=Abstract %R 10.3233/JAD-191292 %0 Journal Article %J J Alzheimers Dis %D 2020 %T APOEɛ4-TOMM40L Haplotype Increases the Risk of Mild Cognitive Impairment Conversion to Alzheimer's Disease. %A Cardoso, Remy %A Lemos, Carolina %A Oliveiros, Bárbara %A Rosário Almeida, Maria %A Baldeiras, Ines %A Fragão Pereira, Cláudia %A Santos, Ana %A Duro, Diana %A Vieira, Daniela %A Santana, Isabel %A Resende Oliveira, Catarina %X

BACKGROUND: Mild cognitive impairment (MCI) has been considered as a pre-dementia stage, although the factors leading to Alzheimer's disease (AD) conversion remain controversial.

OBJECTIVE: Evaluate whether TOMM40 poly-T (TOMM40' 523) polymorphism is associated with the risk and conversion time from MCI to AD and secondly with AD cerebrospinal fluid (CSF) biomarkers, disentangling the APOE genotype.

METHODS: 147 AD patients, 102 MCI patients, and 105 cognitively normal controls were genotyped for poly-T polymorphism. MCI patients were subdivided into two groups, the group of patients that converted to AD (MCI-AD) and the group of those that remained stable (MCI-S).

RESULTS: TOMM40' 523 L allele was significantly more frequent in the MCI-AD group and having at least one L allele significantly increased the risk of conversion from MCI to AD (OR = 8.346, p <  0.001, 95% CI: 2.830 to 24.617). However, when adjusted for the presence of APOEɛ4 allele, both the L allele and ɛ4 allele lost significance in the model (p >  0.05). We then analyzed the APOEɛ4-TOMM40' 523 haplotype and observed that patients carrying this haplotype had significantly higher risk (OR = 5.83; 95% CI = 2.30-14.83) and mean lower times of conversion to AD (p = 0.003). This haplotype was also significantly associated with a biomarker profile compatible with AD (p = 0.007).

CONCLUSION: This study shows that the APOEɛ4-TOMM40' 523 haplotype is associated with a higher risk and shorter times of conversion from MCI to AD, possibly driven by CSF biomarkers and mitochondrial dysfunction.

%B J Alzheimers Dis %V 78 %P 587-601 %8 2020 Nov 10 %G eng %N 2 %R 10.3233/JAD-200556 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Association of Low Systolic Blood Pressure with Postmortem Amyloid-β and Tau. %A Oveisgharan, Shahram %A Capuano, Ana W %A Kapasi, Alifiya %A Buchman, Aron S %A Schneider, Julie A %A Bennett, David A %A Arvanitakis, Zoe %X

BACKGROUND: Vascular mechanisms may contribute to the accumulation of AD pathology.

OBJECTIVE: We examined whether the burden of vascular risk factors proximate to death is associated with amyloid-β and tau levels or modified their known association.

METHODS: We examined the brains of 1, 585 participants from two longitudinal community-based studies of older adults. Amyloid-β and tau were quantified by postmortem examination. The burden of vascular risk factors was summarized by calculating the Framingham general cardiovascular risk score (FRS) proximate to death. Using linear regressions, we examined the association of the FRS with the amyloid-β and tau levels and examined if the FRS modified the association of the amyloid-β with tau.

RESULTS: On average, participants were nearly 90 years old and two-thirds were women. The FRS was not associated with amyloid-β (Spearman r  = -0.00, p  = 0.918) or tau (r = 0.01, p = 0.701). However, the FRS as a whole (estimate = -0.022, SE = 0.008, p = 0.009), and specifically the systolic blood pressure (SBP) component (estimate = -0.033, SE = 0.012, p = 0.009), modified the association of the amyloid-β with tau. Further analysis showed that the association between amyloid-β and tau was stronger at lower levels of SBP.

CONCLUSION: Late-life vascular risk scores were not related to postmortem levels of amyloid-β or tau. However, lower levels of vascular risk scores and SBP were associated with a stronger association between amyloid-β and tau. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another.

%B J Alzheimers Dis %V 78 %P 1755-1764 %8 2020 Dec 08 %G eng %N 4 %R 10.3233/JAD-200412 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Association of Peripheral Insulin Resistance and Other Markers of Type 2 Diabetes Mellitus with Brain Amyloid Deposition in Healthy Individuals at Risk of Dementia. %A Pekkala, Timo %A Hall, Anette %A Mangialasche, Francesca %A Kemppainen, Nina %A Mecocci, Patrizia %A Ngandu, Tiia %A Rinne, Juha O %A Soininen, Hilkka %A Tuomilehto, Jaakko %A Kivipelto, Miia %A Solomon, Alina %X

We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOEɛ4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.

%B J Alzheimers Dis %V 76 %P 1243-1248 %8 2020 Aug 18 %G eng %N 4 %R 10.3233/JAD-200145 %0 Journal Article %J J Alzheimers Dis %D 2020 %T The Association of Post-Stroke Cognitive Impairment and Gut Microbiota and its Corresponding Metabolites. %A Liu, Yongqiang %A Kong, Cheng %A Gong, Li %A Zhang, Xiaohui %A Zhu, Yuefei %A Wang, Haichao %A Qu, Xiao %A Gao, Renyuan %A Yin, Fang %A Liu, Xueyuan %A Qin, Huanlong %X

BACKGROUND: Post-stroke cognitive impairment (PSCI) is an important factor causing disabilities after acute ischemic stroke (AIS). Emerging evidence suggested that gut microbiota play an important role in cognitive impairment.

OBJECTIVE: This study aimed to explore the association between PSCI and gut microbiota.

METHOD: 65 patients with newly diagnostic AIS finished the fecal collection on admission and cognitive assessment 3 months later in the clinic. Fecal samples were subjected to 16SrRNA gene sequencing and gas chromatography-mass spectrometry analysis. Additionally, we enrolled new 18 AIS patients, whose treatment was supplemented by probiotics, to assess the potential of microbial treatment in PSCI.

RESULTS: PSCI patients were characterized by the significantly decreased alpha-diversity, disturbed microbial composition, and corresponding metabolites compared with non-PSCI patients. Increased Fusobacterium and deficiency of microbial metabolized short-chain fatty acids (SCFAs) were significantly associated with PSCI. A model based on gut microbiota and SCFAs could predict 3 months or longer PSCI early and accurately after stroke onset. While traditional probiotic administration had little effect on PSCI, it could ameliorate patients' mood, including depression and anxiety in the 3 months after stroke.

CONCLUSION: Our study revealed the association between PSCI and gut microbiota and its corresponding metabolites for the first time, suggesting the potential for applying microbiota and its corresponding metabolites to early clinical diagnosis and treatment of PSCI.

%B J Alzheimers Dis %V 73 %P 1455-1466 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/31929168?dopt=Abstract %R 10.3233/JAD-191066 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Awareness of the COVID-19 Outbreak and Resultant Depressive Tendencies in Patients with Severe Alzheimer's Disease. %A Tsugawa, Akito %A Sakurai, Shu %A Inagawa, Yuta %A Hirose, Daisuke %A Kaneko, Yoshitsugu %A Ogawa, Yusuke %A Serisawa, Shuntaro %A Takenoshita, Naoto %A Sakurai, Hirofumi %A Kanetaka, Hidekazu %A Hirao, Kentaro %A Shimizu, Soichiro %K Aged %K Alzheimer Disease %K Awareness %K Betacoronavirus %K Caregivers %K Communicable Disease Control %K Coronavirus Infections %K COVID-19 %K Female %K Humans %K Japan %K Male %K Mental Competency %K Pandemics %K Patient Care %K Pneumonia, Viral %K Psychosocial Support Systems %K SARS-CoV-2 %K Severity of Illness Index %X

The ongoing coronavirus disease 2019 (COVID-19) pandemic has substantially affected patients with dementia and their caregivers. However, we found not all Alzheimer's disease (AD) patients were afraid of COVID-19 infection. Therefore, we investigated the association between rate of awareness of COVID-19 and depressive tendency in AD. 126 consecutive outpatients with AD were enrolled in this study from May 25, on the day when the declaration of emergency was lifted in Japan, through June 30, 2020. In addition to routine psychological tests, the participants were asked the following two questions: "Do you know COVID-19?" and "Why are you wearing a face mask?". Moderate to severe AD patients were found to have a low COVID-19 recognition rate and did not fully understand why they were wearing face masks. In addition, because they did not understand the seriousness of the COVID-19 outbreak, their Geriatric Depression Scale scores were also substantially lower. These results may appear to simply indicate that people with severe dementia are unaware of current events. However, these results provide insights into how to care for patients with dementia and how to allocate the time and support of our limited staff during the COVID-19 outbreak.

%B J Alzheimers Dis %V 77 %P 539-541 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32925073?dopt=Abstract %R 10.3233/JAD-200832 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Braak Stage, Cerebral Amyloid Angiopathy, and Cognitive Decline in Early Alzheimer's Disease. %A Malek-Ahmadi, Michael %A Perez, Sylvia E %A Chen, Kewei %A Mufson, Elliott J %X

The aim of this study was to determine the interaction between cerebral amyloid angiopathy (CAA) and Braak staging on cognition in the elderly. 141 [72 non-cognitively impaired (NCI), 33 mild cognitive impairment (MCI), 36 Alzheimer's disease (AD)] cases consisting of Braak stages 0-II and III from the Rush Religious Order Study cohort were used. The association between Braak stage and CAA status and cognition was evaluated using a series of regression models that adjusted for age at death, sex, education, APOEɛ4 status, and Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropathological diagnosis. Individuals with CAA were more likely to be classified as Braak stage III relative to those without CAA [OR = 2.33, 95% CI (1.06, 5.14), p = 0.04]. A significant interaction was found between Braak stage and CAA status on a global cognitive score (β= -0.58, SE = 0.25, p = 0.02). Episodic memory also showed a significant association between Braak stage and CAA (β= -0.75, SE = 0.35, p = 0.03). These data suggest that there is a significant interaction between tau pathology and cerebrovascular lesions on cognition within the AD clinical spectrum. These findings show that CAA plays a key role in the early stages of tau pathology and cognitive decline in AD.

%B J Alzheimers Dis %V 74 %P 189-197 %8 2020 Mar 10 %G eng %N 1 %R 10.3233/JAD-191151 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Brain Volume Predicts Behavioral and Psychological Symptoms in Alzheimer's Disease. %A Boublay, Nawele %A Bouet, Romain %A Dorey, Jean-Michel %A Padovan, Catherine %A Makaroff, Zaza %A Federico, Denis %A Gallice, Isabelle %A Barrellon, Marie-Odile %A Robert, Philippe %A Moreaud, Olivier %A Rouch, Isabelle %A Krolak-Salmon, Pierre %X

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are frequent and troublesome for patients and caregivers. Considering possible preventive approaches, a better understanding of underlying neural correlates of BPSD is crucial.

OBJECTIVE: The aim is to assess whether brain regional volume predicts behavioral changes in mild AD.

METHODS: This work took part from the PACO study, a multicenter and prospective study that included 252 patients with mild AD from 2009 to 2014. Fifty-three patients were retained. Forty healthy matched control subjects from the ADNI cohort were included as controls. Voxel-based morphometry analysis was conducted to assess regional brain volume using baseline MRI scans as a predictor of future behavioral changes over a period of 18 months. Behavior was assessed at baseline and longitudinally at 6-month intervals using the shortened form of the Neuropsychiatric Inventory (NPI).

RESULTS: The volume of 23 brain structures in frontal, temporal, parietal, occipital, subcortical regions and cerebellum predicted the evolution of NPI scores. Frontal volume was the most powerful predictor with frontal gyri, anterior cingulate cortex, and orbital gyri being particularly involved.

CONCLUSION: To our knowledge, this is the first study assessing regional brain volumes as predictors of behavioral changes considered at earlier stages of AD. Up to 23 brain structures were associated with an increased risk of developing BPSD. Frontal lobe volume was the strongest predictor of future evolution of NPI. The involvement of multiple structures in the prediction of behavior suggests a role of the main large-scale networks involved in cognition.

%B J Alzheimers Dis %V 73 %P 1343-1353 %8 2020 Feb 18 %G eng %N 4 %R 10.3233/JAD-190612 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Cerebrospinal Fluid Metals and the Association with Cerebral Small Vessel Disease. %A Shams, Mana %A Martola, Juha %A Charidimou, Andreas %A Granberg, Tobias %A Ferreira, Daniel %A Westman, Eric %A Wintermark, Max %A Iv, Michael %A Larvie, Mykol %A Kristoffersen Wiberg, Maria %A Kaijser, Magnus %A Forsgard, Niklas %A Zetterberg, Henrik %A Wahlund, Lars-Olof %A Shams, Sara %X

BACKGROUND: Brain metal homeostasis is essential for brain health, and deregulation can result in oxidative stress on the brain parenchyma.

OBJECTIVE: Our objective in this study was to focus on two hemorrhagic MRI manifestations of small vessel disease [cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS)] and associations with cerebrospinal fluid (CSF) iron levels. In addition, we aimed to analyze CSF biomarkers for dementia and associations with CSF metal levels.

METHODS: This is a cross-sectional study of 196 patients who underwent memory clinic investigation, including brain MRI. CSF was collected and analyzed for metals, amyloid-β (Aβ) 42, total tau (T-tau), and phosphorylated tau (P-tau), and CSF/serum albumin ratios. Statistical analyses were performed using generalized linear models.

RESULTS: No significant difference was found between CSF metal levels across diagnostic groups. Higher iron and copper levels were associated with higher CSF levels of Aβ42, T-tau, P-tau, and CSF/serum albumin ratios (p < 0.05). Zinc was associated with higher CSF/serum albumin ratios. There was no significant association between CMBs or cSS and CSF iron levels. An increase in CSF iron with the number of CMBs was seen in APOEɛ4 carriers.

CONCLUSION: CSF iron levels are elevated with cerebral microbleeds in APOEɛ4 carriers, with no other association seen with hemorrhagic markers of small vessel disease. The association of elevated CSF iron and copper with tau could represent findings of increased neurodegeneration in these patients.

%B J Alzheimers Dis %V 78 %P 1229-1236 %8 2020 Nov 24 %G eng %N 3 %R 10.3233/JAD-200656 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Characterizing Clinical and Neuropathological Traits of APOE Haplotypes in African Americans and Europeans. %A Mezlini, Aziz M %A Magdamo, Colin %A Merrill, Emily %A Chibnik, Lori B %A Blacker, Deborah L %A Hyman, Bradley T %A Das, Sudeshna %X

BACKGROUND: The APOEɛ4 allele is the largest genetic risk factor for late-onset Alzheimer's disease (AD). Recent literature suggested that the contribution of APOEɛ4 to AD risk could be population-specific, with ɛ4 conferring a lower risk to Blacks or African Americans.

OBJECTIVE: To investigate the effect of APOE haplotypes on AD risk in individuals with European ancestry (EU) and Blacks or African Americans (AA).

METHODS: We selected data from 1) the National Alzheimer's Coordinating Center: a total of 3,486 AD cases and 4,511 controls (N = 7,997, 60% female) with genotypes from the Alzheimer's Disease Genetics Consortium (ADGC), and 2) the Rush University Religious Orders Study and Memory and Aging Project (ROSMAP) cohort with 578 AD and 670 controls (N = 1,248, 60% female). Using ɛ3 homozygotes as the reference, we compared the association of various APOE haplotypes with the clinical and neuropathological correlates of dementia in AA and EU.

RESULTS: In both cohorts, we find no difference in the odds or age of onset of AD among the ɛ4-linked haplotypes defined by rs769449 within either AA or EU. Additionally, while APOEɛ4 was associated with a faster rate of decline, no differences were found in rate of decline, clinical or neuropathological features among the ɛ4-linked haplotypes. Further analysis with other variants near the APOE locus failed to identify any effect modification.

CONCLUSION: Our study finds similar effects of the ɛ4-linked haplotypes defined by rs769449 on AD as compared to ɛ3 in both AA and EU. Future studies are required to understand the heterogeneity of APOE conferred risk of AD among various genotypes and populations.

%B J Alzheimers Dis %V 78 %P 467-477 %8 2020 Oct 27 %G eng %N 1 %R 10.3233/JAD-200228 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Circulating Vitamin D Levels and Alzheimer's Disease: A Mendelian Randomization Study in the IGAP and UK Biobank. %A Wang, Longcai %A Qiao, Yanchun %A Zhang, Haihua %A Zhang, Yan %A Hua, Jiao %A Jin, Shuilin %A Liu, Guiyou %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biological Specimen Banks %K Cognition Disorders %K Databases, Factual %K Female %K Genome-Wide Association Study %K Humans %K Hydroxycholecalciferols %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Nutritional Status %K United Kingdom %K Vitamin D %K Vitamin D Deficiency %X

Observational studies strongly supported the association of low levels of circulating 25-hydroxyvitamin D (25OHD) and cognitive impairment or dementia in aging populations. However, randomized controlled trials have not shown clear evidence that vitamin D supplementation could improve cognitive outcomes. In fact, some studies reported the association between vitamin D and cognitive impairment based on individuals aged 60 years and over. However, it is still unclear that whether vitamin D levels are causally associated with Alzheimer's disease (AD) risk in individuals aged 60 years and over. Here, we performed a Mendelian randomization (MR) study to investigate the causal association between vitamin D levels and AD using a large-scale vitamin D genome-wide association study (GWAS) dataset and two large-scale AD GWAS datasets from the IGAP and UK Biobank with individuals aged 60 years and over. Our results showed that genetically increased 25OHD levels were significantly associated with reduced AD risk in individuals aged 60 years and over. Hence, our findings in combination with previous literature indicate that maintaining adequate vitamin D status in older people especially aged 60 years and over, may contribute to slow down cognitive decline and forestall AD. Long-term randomized controlled trials are required to test whether vitamin D supplementation may prevent AD in older people especially those aged 60 years and may be recommended as preventive agents.

%B J Alzheimers Dis %V 73 %P 609-618 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/31815694?dopt=Abstract %R 10.3233/JAD-190713 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer's Disease Dementia in a Large National Survey. %A Beydoun, May A %A Beydoun, Hind A %A Hossain, Sharmin %A El-Hajj, Ziad W %A Weiss, Jordan %A Zonderman, Alan B %X

Microbial agents including periodontal pathogens have recently appeared as important actors in Alzheimer's disease (AD) pathology. We examined associations of clinical periodontal and bacterial parameters with incident all-cause and AD dementia as well as AD mortality among US middle-aged and older adults. Clinical [Attachment Loss (AL); probing pocket depth (PPD)] and bacterial [pathogen immunoglobulin G (IgG)] periodontal markers were investigated in relation to AD and all-cause dementia incidence and to AD mortality, using data from the third National Health and Nutrition Examination Surveys (NHANES III, 1988-1994) linked longitudinally with National Death Index and Medicare data through January 1, 2014, with up to 26 years of follow-up. Sex- and age-specific multivariable-adjusted Cox proportional hazards models were conducted. Among those ≥65 years, AD incidence and mortality were consistently associated with PPD, two factors and one cluster comprised of IgG titers against Porphyromonas gingivalis (P. gingivalis), Prevotella melaninogenica (P. melaninogenica) and Campylobacter rectus (C. rectus) among others. Specifically, AD incidence was linked to a composite of C. rectus and P. gingivalis titers (per SD, aHR = 1.22; 95% CI, 1.04-1.43, p = 0.012), while AD mortality risk was increased with another composite (per SD, aHR = 1.46; 95% CI, 1.09-1.96, p = 0.017) loading highly on IgG for P. gingivalis, Prevotella intermedia, Prevotella nigrescens, Fusobacterium nucleatum, C. rectus, Streptococcus intermedius, Capnocylophaga Ochracea, and P. melaninogenica. This study provides evidence for an association between periodontal pathogens and AD, which was stronger for older adults. Effectiveness of periodontal pathogen treatment on reducing sequelae of neurodegeneration should be tested in randomized controlled trials.

%B J Alzheimers Dis %V 75 %P 157-172 %8 2020 May 05 %G eng %N 1 %R 10.3233/JAD-200064 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Cognitive Impairment Is a Common Comorbidity in Deceased COVID-19 Patients: A Hospital-Based Retrospective Cohort Study. %A Martín-Jiménez, Paloma %A Muñoz-García, Mariana I %A Seoane, David %A Roca-Rodríguez, Lucas %A García-Reyne, Ana %A Lalueza, Antonio %A Maestro, Guillermo %A Folgueira, Dolores %A Blanco-Palmero, Víctor A %A Herrero-San Martín, Alejandro %A Llamas-Velasco, Sara %A Pérez-Martínez, David A %A González-Sánchez, Marta %A Villarejo-Galende, Alberto %K Adolescent %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Comorbidity %K COVID-19 %K Female %K Hospital Mortality %K Hospitals %K Humans %K Male %K Middle Aged %K Palliative Care %K Patient Admission %K Retrospective Studies %K Spain %K Young Adult %X

We analyzed the frequency of cognitive impairment (CI) in deceased COVID-19 patients at a tertiary hospital in Spain. Among the 477 adult cases who died after admission from March 1 to March 31, 2020, 281 had confirmed COVID-19. CI (21.1% dementia and 8.9% mild cognitive impairment) was a common comorbidity. Subjects with CI were older, tended to live in nursing homes, had shorter time from symptom onset to death, and were rarely admitted to the ICU, receiving palliative care more often. CI is a frequent comorbidity in deceased COVID-19 subjects and is associated with differences in care.

%B J Alzheimers Dis %V 78 %P 1367-1372 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33074239?dopt=Abstract %R 10.3233/JAD-200937 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Combining Select Blood-Based Biomarkers with Neuropsychological Assessment to Detect Mild Cognitive Impairment among Mexican Americans. %A Petersen, Melissa %A Hall, James %A Parsons, Thomas %A Johnson, Leigh %A O'Bryant, Sid %X

BACKGROUND: Recent work has supported use of blood-based biomarkers in detection of amnestic mild cognitive impairment (MCI). Inclusion of neuropsychological measures has shown promise in enhancing utility of biomarkers to detect disease.

OBJECTIVE: The present study sought to develop cognitive-biomarker profiles for detection of MCI.

METHODS: Data were analyzed on 463 participants (normal control n = 378; MCI n = 85) from HABLE. Random forest analyses determined proteomic profile of MCI. Separate linear regression analyses determined variance accounted for by select biomarkers per neuropsychological measure. When neuropsychological measure with the least shared variance was identified, it was then combined with select biomarkers to create a biomarker-cognitive profile.

RESULTS: The biomarker-cognitive profile was 90% accurate in detecting MCI. Among amnestic MCI cases, the detection accuracy of the biomarker-cognitive profile was 92% and increased to 94% with demographic variables.

CONCLUSION: The biomarker-cognitive profile for MCI was highly accurate in its detection with use of only five biomarkers.

%B J Alzheimers Dis %V 75 %P 739-750 %8 2020 Jun 02 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/32310167?dopt=Abstract %R 10.3233/JAD-191264 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Common Bacterial Infections and Risk of Dementia or Cognitive Decline: A Systematic Review. %A Muzambi, Rutendo %A Bhaskaran, Krishnan %A Brayne, Carol %A Davidson, Jennifer A %A Smeeth, Liam %A Warren-Gash, Charlotte %X

BACKGROUND: Bacterial infections may be associated with dementia, but the temporality of any relationship remains unclear.

OBJECTIVES: To summarize existing literature on the association between common bacterial infections and the risk of dementia and cognitive decline in longitudinal studies.

METHODS: We performed a comprehensive search of 10 databases of published and grey literature from inception to 18 March 2019 using search terms for common bacterial infections, dementia, cognitive decline, and longitudinal study designs. Two reviewers independently performed the study selection, data extraction, risk of bias and overall quality assessment. Data were summarized through a narrative synthesis as high heterogeneity precluded a meta-analysis.

RESULTS: We identified 3,488 studies. 9 met the eligibility criteria; 6 were conducted in the United States and 3 in Taiwan. 7 studies reported on dementia and 2 investigated cognitive decline. Multiple infections were assessed in two studies. All studies found sepsis (n = 6), pneumonia (n = 3), urinary tract infection (n = 1), and cellulitis (n = 1) increased dementia risk (HR 1.10; 95% CI 1.02-1.19) to (OR 2.60; 95% CI 1.84-3.66). The range of effect estimates was similar when limited to three studies with no domains at high risk of bias. However, the overall quality of evidence was rated very low. Studies on cognitive decline found no association with infection but had low power.

CONCLUSION: Our review suggests common bacterial infections may be associated with an increased risk of subsequent dementia, after adjustment for multiple confounders, but further high-quality, large-scale longitudinal studies, across different healthcare settings, are recommended to further explore this association.

%B J Alzheimers Dis %V 76 %P 1609-1626 %8 2020 Aug 18 %G eng %N 4 %R 10.3233/JAD-200303 %0 Journal Article %J J Alzheimers Dis %D 2020 %T A Community-Based Study Identifying Metabolic Biomarkers of Mild Cognitive Impairment and Alzheimer's Disease Using Artificial Intelligence and Machine Learning. %A Yilmaz, Ali %A Ustun, Ilyas %A Ugur, Zafer %A Akyol, Sumeyya %A Hu, William T %A Fiandaca, Massimo S %A Mapstone, Mark %A Federoff, Howard %A Maddens, Michael %A Graham, Stewart F %X

BACKGROUND: Currently, there is no objective, clinically available tool for the accurate diagnosis of Alzheimer's disease (AD). There is a pressing need for a novel, minimally invasive, cost friendly, and easily accessible tool to diagnose AD, assess disease severity, and prognosticate course. Metabolomics is a promising tool for discovery of new, biologically, and clinically relevant biomarkers for AD detection and classification.

OBJECTIVE: Utilizing artificial intelligence and machine learning, we aim to assess whether a panel of metabolites as detected in serum can be used as an objective and clinically feasible tool for the diagnosis of mild cognitive impairment (MCI) and AD.

METHODS: Using a community-based sample cohort acquired from different sites across the US, we adopted an approach combining Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR), Liquid Chromatography coupled with Mass Spectrometry (LC-MS). and various machine learning statistical approaches to identify a biomarker panel capable of identifying those patients with AD and MCI from healthy controls.

RESULTS: Of the 212 measured metabolites, 5 were identified as optimal to discriminate between controls, and individuals with MCI or AD. Our models performed with AUC values in the range of 0.72-0.76, with the sensitivity and specificity values ranging from 0.75-0.85 and 0.69-0.81, respectively. Univariate and pathway analysis identified lipid metabolism as the most perturbed biochemical pathway in MCI and AD.

CONCLUSION: A comprehensive method of acquiring metabolomics data, coupled with machine learning techniques, has identified a strong panel of diagnostic biomarkers capable of identifying individuals with MCI and AD. Further, our data confirm what other groups have reported in that lipid metabolism is significantly perturbed in those individuals suffering with dementia. This work may provide additional insight into AD pathogenesis and encourage more in-depth analysis of the AD lipidome.

%B J Alzheimers Dis %V 78 %P 1381-1392 %8 2020 Dec 08 %G eng %N 4 %R 10.3233/JAD-200305 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Comorbidity of Cerebrovascular and Alzheimer's Disease in Aging. %A Xia, Ying %A Yassi, Nawaf %A Raniga, Parnesh %A Bourgeat, Pierrick %A Desmond, Patricia %A Doecke, James %A Ames, David %A Laws, Simon M %A Fowler, Christopher %A Rainey-Smith, Stephanie R %A Martins, Ralph %A Maruff, Paul %A Villemagne, Victor L %A Masters, Colin L %A Rowe, Christopher C %A Fripp, Jurgen %A Salvado, Olivier %X

BACKGROUND: Cerebrovascular disease often coexists with Alzheimer's disease (AD). While both diseases share common risk factors, their interrelationship remains unclear. Increasing the understanding of how cerebrovascular changes interact with AD is essential to develop therapeutic strategies and refine biomarkers for early diagnosis.

OBJECTIVE: We investigate the prevalence and risk factors for the comorbidity of amyloid-β (Aβ) and cerebrovascular disease in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing, and further examine their cross-sectional association.

METHODS: A total of 598 participants (422 cognitively normal, 89 with mild cognitive impairment, 87 with AD) underwent positron emission tomography and structural magnetic resonance imaging for assessment of Aβ deposition and cerebrovascular disease. Individuals were categorized based on the comorbidity status of Aβ and cerebrovascular disease (V) as Aβ-V-, Aβ-V+, Aβ+V-, or Aβ+V+.

RESULTS: Advancing age was associated with greater likelihood of cerebrovascular disease, high Aβ load and their comorbidity. Apolipoprotein E ɛ4 carriage was only associated with Aβ positivity. Greater total and regional WMH burden were observed in participants with AD. However, no association were observed between Aβ and WMH measures after stratification by clinical classification, suggesting that the observed association between AD and cerebrovascular disease was driven by the common risk factor of age.

CONCLUSION: Our observations demonstrate common comorbid condition of Aβ and cerebrovascular disease in later life. While our study did not demonstrate a convincing cross-sectional association between Aβ and WMH burden, future longitudinal studies are required to further confirm this.

%B J Alzheimers Dis %V 78 %P 321-334 %8 2020 Oct 27 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32986666?dopt=Abstract %R 10.3233/JAD-200419 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Comparative Cognitive Effects of Choreographed Exercise and Multimodal Physical Therapy in Older Adults with Amnestic Mild Cognitive Impairment: Randomized Clinical Trial. %A Bisbe, Marta %A Fuente-Vidal, Andrea %A López, Elisabet %A Moreno, Marta %A Naya, Marian %A de Benetti, Claudio %A Milà, Raimon %A Bruna, Olga %A Boada, Merce %A Alegret, Montserrat %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Combined Modality Therapy %K Dance Therapy %K Exercise Therapy %K Female %K Humans %K Linear Models %K Male %K Neuropsychological Tests %K Physical Therapy Modalities %K Single-Blind Method %X

BACKGROUND: Recent research on mild cognitive impairment (MCI) has primarily focused on searching for measures to prevent or delay the progression of MCI to dementia. Physical exercise has shown to be effective in the prevention of age-related cognitive decline in elderly adults with MCI. However, the most effective type and dose of exercise for the improvement of cognition are yet to be determined.

OBJECTIVE: To compare the cognitive effects of choreographed exercise (Choreography group) with a multimodal physical therapy program (Physical Therapy group) in elderly adults with amnestic MCI, a population with an increased risk of developing dementia.

METHODS: We conducted a randomized clinical trial with two parallel groups under allocation concealment and assessor blinding. Participants were allocated into Choreography or Physical Therapy group and performed exercises twice per week in 60-minute sessions during 12 weeks.

RESULTS: Thirty-six participants with amnestic MCI, ages 65 to 85, were assessed at baseline and after 12 weeks of intervention, by comprehensive validated neuropsychological and physical assessments. A Repeated measures General Lineal Model showed statistically significant differences in cognitive and physical outcomes. Both groups significantly improved in visual delayed recall. The Choreography group exhibited significantly more benefits on verbal recognition memory than the Physical Therapy group.

CONCLUSION: Greater cognitive benefits were achieved in the choreographic intervention than in the multimodal physical therapy, mainly in those functions more related to the risk of conversion to dementia. Additional studies are needed to confirm whether the observed effects are related to delayed onset of Alzheimer's disease in elderly adults with amnestic MCI.

%B J Alzheimers Dis %V 73 %P 769-783 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/31868666?dopt=Abstract %R 10.3233/JAD-190552 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Computational Modeling of Catecholamines Dysfunction in Alzheimer's Disease at Pre-Plaque Stage. %A Caligiore, Daniele %A Silvetti, Massimo %A D'Amelio, Marcello %A Puglisi-Allegra, Stefano %A Baldassarre, Gianluca %X

BACKGROUND: Alzheimer's disease (AD) etiopathogenesis remains partially unexplained. The main conceptual framework used to study AD is the Amyloid Cascade Hypothesis, although the failure of recent clinical experimentation seems to reduce its potential in AD research.

OBJECTIVE: A possible explanation for the failure of clinical trials is that they are set too late in AD progression. Recent studies suggest that the ventral tegmental area (VTA) degeneration could be one of the first events occurring in AD progression (pre-plaque stage).

METHODS: Here we investigate this hypothesis through a computational model and computer simulations validated with behavioral and neural data from patients.

RESULTS: We show that VTA degeneration might lead to system-level adjustments of catecholamine release, triggering a sequence of events leading to relevant clinical and pathological signs of AD. These changes consist first in a midfrontal-driven compensatory hyperactivation of both VTA and locus coeruleus (norepinephrine) followed, with the progression of the VTA impairment, by a downregulation of catecholamine release. These processes could then trigger the neural degeneration at the cortical and hippocampal levels, due to the chronic loss of the neuroprotective role of norepinephrine.

CONCLUSION: Our novel hypothesis might contribute to the formulation of a wider system-level view of AD which might help to devise early diagnostic and therapeutic interventions.

%B J Alzheimers Dis %V 77 %P 275-290 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32741822?dopt=Abstract %R 10.3233/JAD-200276 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia. %A Shiells, Helen %A Schelter, Bjoern O %A Bentham, Peter %A Baddeley, Thomas C %A Rubino, Christopher M %A Ganesan, Harish %A Hammel, Jeffrey %A Vuksanovic, Vesna %A Staff, Roger T %A Murray, Alison D %A Bracoud, Luc %A Wischik, Damon J %A Riedel, Gernot %A Gauthier, Serge %A Jia, Jianping %A Moebius, Hans J %A Hardlund, Jiri %A Kipps, Christopher M %A Kook, Karin %A Storey, John M D %A Harrington, Charles R %A Wischik, Claude M %X

BACKGROUND: Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins.

OBJECTIVE: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD.

METHODS: We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination - Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug.

RESULTS: There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3-0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8 mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day.

CONCLUSIONS: Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20-60 mg/day. A confirmatory placebo-controlled trial is now planned.

%B J Alzheimers Dis %V 75 %P 501-519 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32280089?dopt=Abstract %R 10.3233/JAD-191173 %0 Journal Article %J J Alzheimers Dis %D 2020 %T The Contribution of Vascular Pathology Toward Cognitive Impairment in Older Individuals with Intermediate Braak Stage Tau Pathology. %A Robinson, Andrew C %A Roncaroli, Federico %A Chew-Graham, Stephen %A Davidson, Yvonne S %A Minshull, James %A Horan, Michael A %A Payton, Antony %A Pendleton, Neil %A Mann, David M A %X

BACKGROUND: The pathological features of Alzheimer's disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment.

OBJECTIVE: The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages.

METHODS: We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment.

RESULTS: We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia.

CONCLUSION: Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer's type pathology.

%B J Alzheimers Dis %V 77 %P 1005-1015 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200339 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Costs and Resource Use Associated with Community-Dwelling Patients with Alzheimer's Disease in Japan: Baseline Results from the Prospective Observational GERAS-J Study. %A Nakanishi, Miharu %A Igarashi, Ataru %A Ueda, Kaname %A Brnabic, Alan J M %A Treuer, Tamas %A Sato, Masayo %A Kahle-Wrobleski, Kristin %A Meguro, Kenichi %A Yamada, Masahito %A Mimura, Masaru %A Arai, Heii %X

BACKGROUND: As the Japanese population ages, caring for people with Alzheimer's disease (AD) dementia is becoming a major socioeconomic issue.

OBJECTIVE: To determine the contribution of patient and caregiver costs to total societal costs associated with AD dementia.

METHODS: Baseline data was used from the longitudinal, observational GERAS-J study. Using the Mini-Mental State Examination (MMSE) score, patients routinely visiting memory clinics were stratified into three groups based on AD severity. Health care resource utilizationwas recorded using the Resource Utilization in Dementia questionnaire. Total monthly societal costs were estimated using Japan-specific unit costs of services and products (patient direct health care use, patient social care use, and informal caregiving time). Uncertainty around mean costs was estimated using bootstrapping methods.

RESULTS: Overall, 553 community-dwelling patients withADdementia (28.3% mild[MMSE21-26], 37.8% moderate[MMSE 15-20], and 34.0% moderately severe/severe [MMSE < 14]) and their caregivers were enrolled. Patient characteristics were: mean age 80.3 years, 72.7% female, and 13.6% living alone. Caregiver characteristics were: mean age 62.1 years, 70.7% female, 78.8% living with patient, 49.0% child of patient, and 39.2% sole caregiver. Total monthly societal costs of AD dementia (Japanese yen) were: 158,454 (mild), 211,301 (moderate), and 294,224 (moderately severe/severe). Informal caregiving costs comprised over 50% of total costs.

CONCLUSION: Baseline results of GERAS-J showed that total monthly societal costs associated with AD dementia increased with AD severity. Caregiver-related costs were the largest cost component. Interventions are needed to decrease informal costs and decrease caregiver burden.

%B J Alzheimers Dis %V 74 %P 127-138 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31985460?dopt=Abstract %R 10.3233/JAD-190811 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Costs of Early Stage Alzheimer's Disease in the United States: Cross-Sectional Analysis of a Prospective Cohort Study (GERAS-US)1. %A Robinson, Rebecca L %A Rentz, Dorene M %A Andrews, Jeffrey Scott %A Zagar, Anthony %A Kim, Yongin %A Bruemmer, Valerie %A Schwartz, Ronald L %A Ye, Wenyu %A Fillit, Howard M %X

BACKGROUND: Costs associated with early stages of Alzheimer's disease (AD; mild cognitive impairment [MCI] and mild dementia [MILD]) are understudied.

OBJECTIVE: To compare costs associated with MCI and MILD due to AD in the United States.

METHODS: Data included baseline patient/study partner medical history, healthcare resource utilization, and outcome assessments as part of a prospective cohort study. Direct, indirect, and total societal costs were derived by applying standardized unit costs to resources for the 1-month pre-baseline period (USD2017). Costs/month for MCI and MILD cohorts were compared using analysis of variance models. To strengthen the confidence of diagnosis, amyloid-β (Aβ) tests were included and analyses were replicated stratifying within each cohort by amyloid status [+ /-].

RESULTS: Patients (N = 1327) with MILD versus MCI had higher total societal costs/month ($4243 versus $2816; p < 0.001). These costs were not significantly different within each severity cohort by amyloid status. The largest fraction of overall costs were informal caregiver costs (45.1%) for the MILD cohort, whereas direct medical patient costs were the largest for the MCI cohort (39.0%). Correspondingly, caregiver time spent on basic activities of daily living (ADLs), instrumental ADLs, and supervision time was twice as high for MILD versus MCI (all p < 0.001).

CONCLUSION: Early AD poses a financial burden, and despite higher functioning among those with MCI, caregivers were significantly impacted. The major cost driver was the patient's clinical cognitive-functional status and not amyloid status. Differences were primarily due to rising need for caregiver support.

%B J Alzheimers Dis %V 75 %P 437-450 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32250304?dopt=Abstract %R 10.3233/JAD-191212 %0 Journal Article %J J Alzheimers Dis %D 2020 %T COVID-19: Review of a 21st Century Pandemic from Etiology to Neuro-psychiatric Implications. %A Yamamoto, Vicky %A Bolanos, Joe F %A Fiallos, John %A Strand, Susanne E %A Morris, Kevin %A Shahrokhinia, Sanam %A Cushing, Tim R %A Hopp, Lawrence %A Tiwari, Ambooj %A Hariri, Robert %A Sokolov, Rick %A Wheeler, Christopher %A Kaushik, Ajeet %A Elsayegh, Ashraf %A Eliashiv, Dawn %A Hedrick, Rebecca %A Jafari, Behrouz %A Johnson, J Patrick %A Khorsandi, Mehran %A Gonzalez, Nestor %A Balakhani, Guita %A Lahiri, Shouri %A Ghavidel, Kazem %A Amaya, Marco %A Kloor, Harry %A Hussain, Namath %A Huang, Edmund %A Cormier, Jason %A Wesson Ashford, J %A Wang, Jeffrey C %A Yaghobian, Shadi %A Khorrami, Payman %A Shamloo, Bahman %A Moon, Charles %A Shadi, Payam %A Kateb, Babak %K Coronavirus Infections %K COVID-19 %K Humans %K Immunotherapy %K Mental Health %K Nutritional Support %K Pandemics %K Pneumonia, Viral %X

COVID-19 is a severe infectious disease that has claimed >150,000 lives and infected millions in the United States thus far, especially the elderly population. Emerging evidence has shown the virus to cause hemorrhagic and immunologic responses, which impact all organs, including lungs, kidneys, and the brain, as well as extremities. SARS-CoV-2 also affects patients', families', and society's mental health at large. There is growing evidence of re-infection in some patients. The goal of this paper is to provide a comprehensive review of SARS-CoV-2-induced disease, its mechanism of infection, diagnostics, therapeutics, and treatment strategies, while also focusing on less attended aspects by previous studies, including nutritional support, psychological, and rehabilitation of the pandemic and its management. We performed a systematic review of >1,000 articles and included 425 references from online databases, including, PubMed, Google Scholar, and California Baptist University's library. COVID-19 patients go through acute respiratory distress syndrome, cytokine storm, acute hypercoagulable state, and autonomic dysfunction, which must be managed by a multidisciplinary team including nursing, nutrition, and rehabilitation. The elderly population and those who are suffering from Alzheimer's disease and dementia related illnesses seem to be at the higher risk. There are 28 vaccines under development, and new treatment strategies/protocols are being investigated. The future management for COVID-19 should include B-cell and T-cell immunotherapy in combination with emerging prophylaxis. The mental health and illness aspect of COVID-19 are among the most important side effects of this pandemic which requires a national plan for prevention, diagnosis and treatment.

%B J Alzheimers Dis %V 77 %P 459-504 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32925078?dopt=Abstract %R 10.3233/JAD-200831 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Day-to-Day Home Blood Pressure Variability is Associated with Cerebral Small Vessel Disease Burden in a Memory Clinic Population. %A de Heus, Rianne A A %A Reumers, Stacha F I %A van der Have, Alba %A Tumelaire, Maxime %A Tully, Phillip J %A Claassen, Jurgen A H R %X

BACKGROUND: High visit-to-visit blood pressure variability (BPV) has been associated with cognitive decline and cerebral small vessel disease (cSVD), in particular cerebrovascular lesions. Whether day-to-day BPV also relates to cSVD has not been investigated.

OBJECTIVE: To investigate the cross-sectional association between day-to-day BPV and total cSVD MRI burden in older memory clinic patients.

METHODS: We included outpatients referred to our memory clinic, who underwent cerebral MRI as part of their diagnostic assessment. We determined the validated total cSVD score (ranging from 0-4) by combining four markers of cSVD that were visually rated. Home blood pressure (BP) measurements were performed for one week, twice a day, according to international guidelines. BPV was defined as the within-subject coefficient of variation (CV; standard deviation/mean BP*100). We used multivariable ordinal logistic regression analyses adjusted for age, sex, smoking, diabetes, antihypertensive medication, history of cardiovascular disease, and mean BP.

RESULTS: For 82 patients (aged 71.2±7.9 years), mean home BP was 140/79±15/9 mmHg. Dementia and mild cognitive impairment were diagnosed in 46% and 34%, respectively. 78% had one or more markers of cSVD. Systolic CV was associated with cSVD burden (adjusted odds ratio per point increase in CV = 1.29, 95% confidence interval = 1.04-1.60, p = 0.022). There were no differences in diastolic CV and mean BP between the cSVD groups. When we differentiated between morning and evening BP, only evening BPV remained significantly associated with total cSVD burden.

CONCLUSION: Day-to-day systolic BPV is associated with cSVD burden in memory clinic patients. Future research should indicate whether lowering BPV should be included in BP management in older people with memory complaints.

%B J Alzheimers Dis %V 74 %P 463-472 %8 2020 Mar 24 %G eng %N 2 %R 10.3233/JAD-191134 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Death Rate Due to COVID-19 in Alzheimer's Disease and Frontotemporal Dementia. %A Matías-Guiu, Jordi A %A Pytel, Vanesa %A Matías-Guiu, Jorge %K Age Factors %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Coronavirus Infections %K COVID-19 %K Female %K Frontotemporal Dementia %K Humans %K Hypertension %K Independent Living %K Male %K Nursing Homes %K Pandemics %K Pneumonia, Viral %K Prevalence %K Risk Factors %X

We aimed to evaluate the frequency and mortality of COVID-19 in patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD). We conducted an observational case series. We enrolled 204 patients, 15.2% of whom were diagnosed with COVID-19, and 41.9% of patients with the infection died. Patients with AD were older than patients with FTD (80.36±8.77 versus 72.00±8.35 years old) and had a higher prevalence of arterial hypertension (55.8% versus 26.3%). COVID-19 occurred in 7.3% of patients living at home, but 72.0% of those living at care homes. Living in care facilities and diagnosis of AD were independently associated with a higher probability of death. We found that living in care homes is the most relevant factor for an increased risk of COVID-19 infection and death, with AD patients exhibiting a higher risk than those with FTD.

%B J Alzheimers Dis %V 78 %P 537-541 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33074240?dopt=Abstract %R 10.3233/JAD-200940 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Dementia Care in the Time of COVID-19 Pandemic. %A Tousi, Babak %K Betacoronavirus %K Coronavirus Infections %K Dementia %K Health Services Accessibility %K Humans %K Pandemics %K Pneumonia, Viral %K Telemedicine %X

Patients with dementia are particularly vulnerable during the COVID-19 pandemic. The initial response to COVID-19 promoted behavioral changes in both society and healthcare, while a long-term solution is sought by prioritizing societal values. In addition, there has been disruption to clinical care and clinical research. This pandemic might have significantly changed the care for our patients with dementia toward increased acceptance of telemedicine by the patients and providers, and its utilization in both clinical care and research.

%B J Alzheimers Dis %V 76 %P 475-479 %8 2020 Jul 21 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32651326?dopt=Abstract %R 10.3233/JAD-200461 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Dementia Care in Times of COVID-19: Experience at Fundació ACE in Barcelona, Spain. %A Benaque, Alba %A Gurruchaga, Miren Jone %A Abdelnour, Carla %A Hernandez, Isabel %A Cañabate, Pilar %A Alegret, Montserrat %A Rodríguez, Isabel %A Rosende-Roca, Maitee %A Tartari, Juan Pablo %A Esteban, Ester %A López, Rogelio %A Gil, Silvia %A Vargas, Liliana %A Mauleón, Ana %A Espinosa, Ana %A Ortega, Gemma %A Sanabria, Ángela %A Pérez, Alba %A Alarcón, Emilio %A González-Pérez, Antonio %A Marquié, Marta %A Valero, Sergi %A Tárraga, Lluís %A Ruiz, Agustin %A Boada, Merce %K Aged %K Aged, 80 and over %K Betacoronavirus %K Coronavirus Infections %K COVID-19 %K Dementia %K Female %K Follow-Up Studies %K Holistic Health %K Humans %K Male %K Pandemics %K Patient-Centered Care %K Pneumonia, Viral %K SARS-CoV-2 %K Spain %K Telemedicine %X

BACKGROUND: Fundació ACE is a non-profit organization providing care based on a holistic model to persons with cognitive disorders and their families for 25 years in Barcelona, Spain. Delivering care to this vulnerable population amidst the COVID-19 pandemic has represented a major challenge to our institution.

OBJECTIVE: To share our experience in adapting our model of care to the new situation to ensure continuity of care.

METHODS: We detail the sequence of events and the actions taken within Fundació ACE to swiftly adapt our face-to-face model of care to one based on telemedicine consultations. We characterize individuals under follow-up by the Memory Unit from 2017 to 2019 and compare the number of weekly visits in 2020 performed before and after the lockdown was imposed.

RESULTS: The total number of individuals being actively followed by Fundació ACE Memory Unit grew from 6,928 in 2017 to 8,147 in 2019. Among those newly diagnosed in 2019, most patients had mild cognitive impairment or mild dementia (42% and 25%, respectively). Weekly visits dropped by 60% following the suspension of face-to-face activity. However, by April 24 we were able to perform 78% of the visits we averaged in the weeks before confinement began.

DISCUSSION: We have shown that Fundació ACE model of care has been able to successfully adapt to a health and social critical situation as COVID-19 pandemic. Overall, we were able to guarantee the continuity of care while preserving the safety of patients, families, and professionals. We also seized the opportunity to improve our model of care.

%B J Alzheimers Dis %V 76 %P 33-40 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32538856?dopt=Abstract %R 10.3233/JAD-200547 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Dementia in the COVID-19 Period. %A Korczyn, Amos D %K Betacoronavirus %K Coronavirus %K Coronavirus Infections %K COVID-19 %K Dementia %K Humans %K Nervous System Diseases %K Pandemics %K Pneumonia, Viral %K SARS-CoV-2 %K Telemedicine %B J Alzheimers Dis %V 75 %P 1071-1072 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32538858?dopt=Abstract %R 10.3233/JAD-200609 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Detection of Mild Cognitive Impairment in an At-Risk Group of Older Adults: Can a Novel Self-Administered Serious Game-Based Screening Test Improve Diagnostic Accuracy? %A Zygouris, Stelios %A Iliadou, Paraskevi %A Lazarou, Eftychia %A Giakoumis, Dimitrios %A Votis, Konstantinos %A Alexiadis, Anastasios %A Triantafyllidis, Andreas %A Segkouli, Sofia %A Tzovaras, Dimitrios %A Tsiatsos, Thrasyvoulos %A Papagianopoulos, Sotirios %A Tsolaki, Magda %X

BACKGROUND: Literature supports the use of serious games and virtual environments to assess cognitive functions and detect cognitive decline. This promising assessment method, however, has not yet been translated into self-administered screening instruments for pre-clinical dementia.

OBJECTIVE: The aim of this study is to assess the performance of a novel self-administered serious game-based test, namely the Virtual Supermarket Test (VST), in detecting mild cognitive impairment (MCI) in a sample of older adults with subjective memory complaints (SMC), in comparison with two well-established screening instruments, the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE).

METHODS: Two groups, one of healthy older adults with SMC (N = 48) and one of MCI patients (N = 47) were recruited from day centers for cognitive disorders and administered the VST, the MoCA, the MMSE, and an extended pencil and paper neuropsychological test battery.

RESULTS: The VST displayed a correct classification rate (CCR) of 81.91% when differentiating between MCI patients and older adults with SMC, while the MoCA displayed of CCR of 72.04% and the MMSE displayed a CCR of 64.89%.

CONCLUSION: The three instruments assessed in this study displayed significantly different performances in differentiating between healthy older adults with SMC and MCI patients. The VST displayed a good CCR, while the MoCA displayed an average CCR and the MMSE displayed a poor CCR. The VST appears to be a robust tool for detecting MCI in a population of older adults with SMC.

%B J Alzheimers Dis %V 78 %P 405-412 %8 2020 Oct 27 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32986676?dopt=Abstract %R 10.3233/JAD-200880 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Development and Validation of a High Sensitivity Assay for Measuring p217 + tau in Cerebrospinal Fluid. %A Triana-Baltzer, Gallen %A Van Kolen, Kristof %A Theunis, Clara %A Moughadam, Setareh %A Slemmon, Randy %A Mercken, Marc %A Galpern, Wendy %A Sun, Hong %A Kolb, Hartmuth %X

BACKGROUND: Early and accurate detection and staging is critical to managing Alzheimer's disease (AD) and supporting clinical trials. Cerebrospinal fluid (CSF) biomarkers for amyloid-β peptides, tau species, and various neurodegenerative and inflammatory analytes are leading the way in this regard, yet there is room for improved sensitivity and specificity. In particular tau is known to be present in many different fragments, conformations, and post-translationally modified forms. While the exact tau species that might best reflect AD pathology is unknown, a growing body of evidence suggests that forms with high levels of phosphorylation in the mid-region may be especially enriched in AD.

OBJECTIVE: Develop an assay for measuring p217tau in CSF.

METHODS: Here we describe the development and validation of a novel sELISA for measuring CSF tau species containing phosphorylation at threonines 212 & 217, aka p217 + tau, using the PT3 antibody.

RESULTS: While the analyte is present at extremely low levels the assay is sufficiently sensitive and specific to quantitate p217 + tau with excellent precision, accuracy, and dilution linearity, allowing good differentiation between diagnostic subgroups. The p217 + tau measurements appear to track AD pathology better than the commonly used p181tau epitope, suggesting superior diagnostic and staging performance. Finally, the assay can also be configured to differentiate antibody-bound versus antibody-free tau, and therefore can be used to measure target engagement by p217 + tau-targeting immunotherapeutics.

CONCLUSION: The assay for measuring p217 + tau described here is highly sensitive, accurate, precise, dilution linear, and shows good potential for identifying and staging AD.

%B J Alzheimers Dis %V 77 %P 1417-1430 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32831201?dopt=Abstract %R 10.3233/JAD-200463 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Development of Classification Models for the Prediction of Alzheimer's Disease Utilizing Circulating Sex Hormone Ratios. %A Hayashi, Kentaro %A Gonzales, Tina K %A Kapoor, Amita %A Ziegler, Toni E %A Meethal, Sivan Vadakkadath %A Atwood, Craig S %X

BACKGROUND: While sex hormones are essential for normal cognitive health, those individuals with greater endocrine dyscrasia around menopause and with andropause are more likely to develop cognitive loss and Alzheimer's disease (AD).

OBJECTIVE: To assess whether circulating sex hormones may provide an etiologically significant, surrogate biomarker, for cognitive decline.

METHODS: Plasma (n = 152) and serum (n = 107) samples from age- and gender-matched AD and control subjects from the Wisconsin Alzheimer's Disease Research Center (ADRC) were analyzed for11 steroids and follicle-stimulating hormone. Logistic regression (LR), correlation analyses, and recursive partitioning (RP) were used to examine the interactions of hormones and hormone ratios and their association with AD. Models generated were then tested on an additional 43 ADRC samples.

RESULTS: The wide variation and substantial overlap in the concentrations of all circulating sex steroids across control and AD groups precluded their use for predicting AD. Classification tree analyses (RP) revealed interactions among single hormones and hormone ratios that associated with AD status, the most predictive including only the hormone ratios identified by LR. The strongest associations were observed between cortisol, cortisone, and androstenedione with AD, with contributions from progesterone and 17β-estradiol. Utilizing this model, we correctly predicted 81% of AD test cases and 64% of control test cases.

CONCLUSION: We have developed a diagnostic model for AD, the Wisconsin Hormone Algorithm Test for Cognition (WHAT-Cog), that utilizes classification tree analyses of hormone ratios. Further refinement of this technology could provide a quick and cheap diagnostic method for screening those with AD.

%B J Alzheimers Dis %V 76 %P 1029-1046 %8 2020 Aug 04 %G eng %N 3 %R 10.3233/JAD-200418 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology. %A Shi, Liu %A Winchester, Laura M %A Liu, Benjamine Y %A Killick, Richard %A Ribe, Elena M %A Westwood, Sarah %A Baird, Alison L %A Buckley, Noel J %A Hong, Shengjun %A Dobricic, Valerija %A Kilpert, Fabian %A Franke, Andre %A Kiddle, Steven %A Sattlecker, Martina %A Dobson, Richard %A Cuadrado, Antonio %A Hye, Abdul %A Ashton, Nicholas J %A Morgan, Angharad R %A Bos, Isabelle %A Vos, Stephanie J B %A Ten Kate, Mara %A Scheltens, Philip %A Vandenberghe, Rik %A Gabel, Silvy %A Meersmans, Karen %A Engelborghs, Sebastiaan %A De Roeck, Ellen E %A Sleegers, Kristel %A Frisoni, Giovanni B %A Blin, Olivier %A Richardson, Jill C %A Bordet, Régis %A Molinuevo, José L %A Rami, Lorena %A Wallin, Anders %A Kettunen, Petronella %A Tsolaki, Magda %A Verhey, Frans %A Lleo, Alberto %A Alcolea, Daniel %A Popp, Julius %A Peyratout, Gwendoline %A Martínez-Lage, Pablo %A Tainta, Mikel %A Johannsen, Peter %A Teunissen, Charlotte E %A Freund-Levi, Yvonne %A Frölich, Lutz %A Legido-Quigley, Cristina %A Barkhof, Frederik %A Blennow, Kaj %A Rasmussen, Katrine Laura %A Nordestgaard, Børge Grønne %A Frikke-Schmidt, Ruth %A Nielsen, Sune Fallgaard %A Soininen, Hilkka %A Vellas, Bruno %A Kloszewska, Iwona %A Mecocci, Patrizia %A Zetterberg, Henrik %A Morgan, B Paul %A Streffer, Johannes %A Visser, Pieter Jelle %A Bertram, Lars %A Nevado-Holgado, Alejo J %A Lovestone, Simon %X

BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.

OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.

METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).

RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.

CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.

%B J Alzheimers Dis %V 77 %P 1353-1368 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200208 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Drug Repositioning for Alzheimer's Disease: Finding Hidden Clues in Old Drugs. %A Ihara, Masafumi %A Saito, Satoshi %X

Although more than 100 years have passed since Alois Alzheimer reported a case of Alzheimer's disease (AD), a definitive answer to the causes of cognitive impairment in the disease remains elusive. Despite significant enthusiasm and investment from the pharmaceutical industry, clinical trials of many disease-modifying drugs for AD have been largely unsuccessful. Drug repositioning (DR) or repurposing approaches are relatively inexpensive and more reliable compared to de novo drug development in AD. About 30% of clinical trials for AD in progress around the world use the DR method and hold potential in halting the current deadlock in treatment options. By using drugs approved for other indications, these clinical trials target dysregulated pathways in AD with different or a combination of modes of action, including anti-amyloid, cardiovascular, anti-tau, anti-inflammatory, immunomodulatory, metabolic, neuroprotective, and neurotransmission-based approaches. For instance, anti-diabetic drugs, such as insulin, metformin, liraglutide, and dapagliflozin, and cardiovascular drugs, such as cilostazol, candesartan, telmisartan, prazosin, and dabigatran, could serendipitously provide previously unearthed benefits in AD. This is in line with recent thinking, which views AD as a complex multifactorial disorder, not dominated by one dominant biological factor, such as amyloid-β, and likely a confluence of many pathobiological mechanisms, including vascular dysregulation. Such increasingly available knowledge of phenotyping may be used to design 'tailor-made' DR and relatively homogeneous AD subpopulations specifically targeted with existing drugs based on known modes of action. It is thus expected that DR approaches will create a major paradigm shift in AD research and development.

%B J Alzheimers Dis %V 74 %P 1013-1028 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32144994?dopt=Abstract %R 10.3233/JAD-200049 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Dyadic Group Exercises for Persons with Memory Deficits and Care Partners: Mixed-Method Findings from the Paired Preventing Loss of Independence through Exercise (PLIÉ) Randomized Trial. %A Mehling, E Wolf %A Scott, M Travis %A Duffy, James %A Whitmer, A Rachel %A Chesney, A Margaret %A Boscardin, W John %A Barnes, E Deborah %X

BACKGROUND: Non-pharmacological therapies for persons with dementia (PWD) are needed.

OBJECTIVE: To develop and test the Paired Preventing Loss of Independence through Exercise (PLIÉ) program, an integrative group movement program for PWD and care partners (CPs).

METHODS: Participants were randomized to immediate or delayed start to Paired PLIÉ in community-based classes (1 hour, 2 days/week, 12 weeks, 3 home visits). Co-primary outcomes included standard measures of cognition, physical function,and quality of life (PWD) and caregiver burden (CPs) assessed by blinded assessors, analyzed using linear mixed models to calculate effect sizes for outcome changes during Paired PLIÉ, controlling for randomization group. Anonymous satisfaction surveys included satisfaction ratings and thematic analysis of open-ended responses.

RESULTS: Thirty dyads enrolled, 24 (80%) completed. PWD (mean age 80; 55% female) experienced significant improvement in self-rated quality of life (Effect Size+0.23; p = 0.016) when participating in Paired PLIÉ, while CPs experienced a non-significant increase in burden (-0.23, p = 0.079). Changes in physical and cognitive function in PWD were not significant. All CPs returning the satisfaction survey (n = 20) reported being moderately-to-highly satisfied with the program. Thematic analyses identified physical (e.g., sit-to-stand, more energy), emotional (enjoyment), and social benefits (peer-to-peer interaction) for PWD and CPs; challenges were primarily related to getting to the in-person classes.

CONCLUSION: Paired PLIÉ is a promising integrative group movement program that warrants further study. It is feasible and may improve self-rated quality of life in PWD. Although CPs may experience increased burden due to logistical challenges, most reported high satisfaction and physical, emotional, and social benefits.

%B J Alzheimers Dis %V 78 %P 1689-1706 %8 2020 Dec 08 %G eng %N 4 %R 10.3233/JAD-200713 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Effect of Mentally Challenging Occupations on Incident Dementia Differs Between African Americans and Non-Hispanic Whites. %A Hyun, Jinshil %A Hall, Charles B %A Sliwinski, Martin J %A Katz, Mindy J %A Wang, Cuiling %A Ezzati, Ali %A Lipton, Richard B %X

BACKGROUND: Engaging in mentally challenging activities may protect against dementia in late life. However, little is known whether the association between mentally challenging activities and dementia risk varies with race/ethnicity.

OBJECTIVE: The current study investigates whether having jobs with higher mental stimulation is differentially associated with a decreased risk of dementia between African Americans (AAs) and non-Hispanic Whites (nHWs).

METHODS: The sample consisted of 1,079 individuals (66% nHWs, 28% AAs; age = 78.6±5.3) from the longitudinal Einstein Aging Study. Occupation information of each participant was collected retrospectively at baseline and was linked to the substantive complexity of work score from the Dictionary of Occupational Titles. Cox proportional hazards models were used to evaluate the associations of occupational complexity with risk of dementia.

RESULTS: Individuals whose jobs had moderate-to-high levels of complexity, compared to those with the lowest complexity, were at modestly decreased risk for incident dementia. When stratified by race, moderate-to-high levels of occupational complexity were significantly associated with lower risk of developing dementia for AAs (HR = 0.35). When risk of dementia was evaluated based on the combinations of race×occupational complexity, AAs with lowest occupational complexity showed the highest risk of developing dementia, while other combinations exhibited lower risk of developing dementia (HRs = 0.36 0.43).

CONCLUSION: Our results suggest that moderate-to-high levels of complexity at work are associated with a decreased risk of incident dementia in AAs. Understanding the differential effects of mentally challenging occupations across race/ethnicity may suggest important intervention strategies that could mitigate racial disparities in dementia rates.

%B J Alzheimers Dis %V 75 %P 1405-1416 %8 2020 Jun 16 %G eng %N 4 %R 10.3233/JAD-191222 %0 Journal Article %J J Alzheimers Dis %D 2020 %T The Effects of Confinement on Neuropsychiatric Symptoms in Alzheimer's Disease During the COVID-19 Crisis. %A Boutoleau-Bretonnière, Claire %A Pouclet-Courtemanche, Hélene %A Gillet, Aurelie %A Bernard, Amelie %A Deruet, Anne Laure %A Gouraud, Ines %A Mazoue, Aurelien %A Lamy, Estelle %A Rocher, Laetitia %A Kapogiannis, Dimitrios %A El Haj, Mohamad %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Betacoronavirus %K Cohort Studies %K Coronavirus Infections %K COVID-19 %K Female %K Humans %K Male %K Mental Disorders %K Mental Status and Dementia Tests %K Middle Aged %K Pandemics %K Pneumonia, Viral %K Quarantine %K SARS-CoV-2 %X

BACKGROUND: Neuropsychiatric symptoms, such as depression, anxiety, apathy, agitation, and hallucinations, are frequent in Alzheimer's disease (AD) and their prevalence tends to increase with external stressors.

OBJECTIVE: We offer the first investigation of the effects of confinement during the COVID-19 crisis on neuropsychiatric symptoms in patients with AD.

METHODS: We contacted caregivers of 38 patients with AD who were confined to their homes for nearly two months and asked them to report whether patients experienced any change in neuropsychiatric symptoms during, compared to before, the confinement and rate its severity and impact on themselves using the Neuropsychiatric Inventory-Questionnaire.

RESULTS: Among the 38 patients, only 10 demonstrated neuropsychiatric changes during the confinement. Cognitive function of these 10 patients, assessed with the Mini-Mental State Examination, was worse than that of patients who did not demonstrate neuropsychiatric changes. Interestingly, among the 10 patients with neuropsychiatric changes, the duration of confinement significantly correlated with the severity of symptoms as well as with their caregivers' distress.

DISCUSSION: The confinement seems to impact neuropsychiatric symptomatology in AD patients with low baseline cognitive function.

%B J Alzheimers Dis %V 76 %P 41-47 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32568211?dopt=Abstract %R 10.3233/JAD-200604 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Effects of LDL Cholesterol and Statin Use on Verbal Learning and Memory in Older Adults at Genetic Risk for Alzheimer's Disease. %A Wroolie, Tonita %A Roat-Shumway, Siena %A Watson, Katie %A Reiman, Eric %A Rasgon, Natalie %X

BACKGROUND: The apolipoprotein epsilon 4 (APOE4) allele is a well-established genetic risk factor for Alzheimer's disease (AD). However, there are mixed findings as to how the APOE4 allele modifies the effects of both higher low-density lipoprotein cholesterol (LDL) and statin use on cognitive functioning.

OBJECTIVE: This study sought to examine the effects of LDL levels and statin use on verbal learning and memory, as modified by the presence of the APOE4 allele, in a sample of cognitively unimpaired, older adults at risk for AD.

METHODS: Neuropsychological, LDL, statin use, and APOE4 data were extracted from an ongoing longitudinal study at the Banner Alzheimer's Institute in Arizona. Participants were cognitively unimpaired based on Mini-Mental State Examination scores within a normal range, aged 47-75, with a family history of probable AD in at least one first-degree relative.

RESULTS: In the whole sample, higher LDL was associated with worse immediate verbal memory in APOE4 non-carriers, but did not have an effect on immediate verbal memory in APOE4 carriers. In APOE4 non-carriers, statin use was associated with better verbal learning, but did not have an effect on verbal learning in APOE4 carriers. Among women, higher LDL in APOE4 carriers was associated with worse verbal learning than in APOE4 non-carriers, and statin use in APOE4 non-carriers was associated with better verbal learning and immediate and delayed verbal memory but worse performances on these tasks in APOE4 carriers.

CONCLUSION: LDL and statin use may have differential effects on verbal learning and/or memory depending on genetic risk for AD. Women appear to be particularly vulnerable to statin use depending on their APOE4 status.

%B J Alzheimers Dis %V 75 %P 903-910 %8 2020 Jun 02 %G eng %N 3 %R 10.3233/JAD-191090 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Effects of Probiotic Supplementation on Short Chain Fatty Acids in the AppNL-G-F Mouse Model of Alzheimer's Disease. %A Kaur, Harpreet %A Golovko, Svetlana %A Golovko, Mikhail Y %A Singh, Surjeet %A Darland, Diane C %A Combs, Colin K %X

BACKGROUND: The intestinal microbiota and its metabolites, particularly short-chain fatty acids (SCFAs), have been implicated in immune function, host metabolism, and even behavior.

OBJECTIVE: This study was performed to investigate whether probiotic administration influences levels of intestinal microbiota and their metabolites in a fashion that may attenuate brain changes in a mouse model of Alzheimer's disease (AD).

METHODS: C57BL/6 wild-type (WT) mice were compared to AppNL-G-Fmice. The animals were treated with either vehicle or probiotic (VSL#3) for 8 weeks. Fecal microbiome analysis along with Aβ, GFAP, Iba-1, c-Fos, and Ki-67 immunohistochemistry was done. SCFAs were analyzed in serum and brains using UPLC-MS/MS.

RESULTS: Probiotic (VSL#3) supplementation for 2 months resulted in altered microbiota in both WT and AppNL-G-Fmice. An increase in serum SCFAs acetate, butyrate, and lactate were found in both genotypes following VSL#3 treatment. Propionate and isobutyrate were only increased in AppNL-G-Fmice. Surprisingly, VSL#3 only increased lactate and acetate in brains of AppNL-G-Fmice. No significant differences were observed between vehicle and VSL#3 fed AppNL-G-Fhippocampal immunore activities of Aβ, GFAP, Iba-1, and Ki-67. However, hippocampal c-Fos staining increased in VSL#3 fed AppNL-G-Fmice.

CONCLUSION: These data demonstrate intestinal dysbiosis in the AppNL-G-Fmouse model of AD. Probiotic VSL#3 feeding altered both serum and brain levels of lactate and acetate in AppNL-G-Fmice correlating with increased expression of the neuronal activity marker, c-Fos.

%B J Alzheimers Dis %V 76 %P 1083-1102 %8 2020 Aug 04 %G eng %N 3 %R 10.3233/JAD-200436 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Environmental Nanoparticles, SARS-CoV-2 Brain Involvement, and Potential Acceleration of Alzheimer's and Parkinson's Diseases in Young Urbanites Exposed to Air Pollution. %A Calderón-Garcidueñas, Lilian %A Torres-Jardón, Ricardo %A Franco-Lira, Maricela %A Kulesza, Randy %A González-Maciel, Angelica %A Reynoso-Robles, Rafael %A Brito-Aguilar, Rafael %A García-Arreola, Berenice %A Revueltas-Ficachi, Paula %A Barrera-Velázquez, Juana Adriana %A García-Alonso, Griselda %A García-Rojas, Edgar %A Mukherjee, Partha S %A Delgado-Chávez, Ricardo %K Adult %K Air Pollution %K Alzheimer Disease %K Brain Diseases %K Coronavirus Infections %K COVID-19 %K Disease Progression %K Environmental Pollutants %K Humans %K Middle Aged %K Nanoparticles %K Pandemics %K Parkinson Disease %K Pneumonia, Viral %K Suicide %K Urban Population %X

Alzheimer's and Parkinson's diseases (AD, PD) have a pediatric and young adult onset in Metropolitan Mexico City (MMC). The SARS-CoV-2 neurotropic RNA virus is triggering neurological complications and deep concern regarding acceleration of neuroinflammatory and neurodegenerative processes already in progress. This review, based on our MMC experience, will discuss two major issues: 1) why residents chronically exposed to air pollution are likely to be more susceptible to SARS-CoV-2 systemic and brain effects and 2) why young people with AD and PD already in progress will accelerate neurodegenerative processes. Secondary mental consequences of social distancing and isolation, fear, financial insecurity, violence, poor health support, and lack of understanding of the complex crisis are expected in MMC residents infected or free of SARS-CoV-2. MMC residents with pre-SARS-CoV-2 accumulation of misfolded proteins diagnostic of AD and PD and metal-rich, magnetic nanoparticles damaging key neural organelles are an ideal host for neurotropic SARS-CoV-2 RNA virus invading the body through the same portals damaged by nanoparticles: nasal olfactory epithelium, the gastrointestinal tract, and the alveolar-capillary portal. We urgently need MMC multicenter retrospective-prospective neurological and psychiatric population follow-up and intervention strategies in place in case of acceleration of neurodegenerative processes, increased risk of suicide, and mental disease worsening. Identification of vulnerable populations and continuous effort to lower air pollution ought to be critical steps.

%B J Alzheimers Dis %V 78 %P 479-503 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32955466?dopt=Abstract %R 10.3233/JAD-200891 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Epilepsy in Neurodegenerative Dementias: A Clinical, Epidemiological, and EEG Study. %A Arnaldi, Dario %A Donniaquio, Andrea %A Mattioli, Pietro %A Massa, Federico %A Grazzini, Matteo %A Meli, Riccardo %A Filippi, Laura %A Grisanti, Stefano %A Famá, Francesco %A Terzaghi, Michele %A Girtler, Nicola %A Brugnolo, Andrea %A Doglione, Elisa %A Pardini, Matteo %A Villani, Flavio %A Nobili, Flavio %X

BACKGROUND: Seizures are common in patients with dementia but precise epidemiologic data of epilepsy in neurodegenerative dementia is lacking.

OBJECTIVE: The first aim of the study was to investigate prevalence and clinical characteristics of epilepsy in a large cohort of patients with neurodegenerative dementias. Subsequently, we explored clinical, neuropsychological, and quantitative electroencephalogram (qEEG) data of Alzheimer's disease (AD) patients with epilepsy (AD-EPI) as compared to AD patients without epilepsy (AD-CTR).

METHODS: We retrospectively evaluated consecutive patients with a diagnosis of a neurodegenerative dementia and a clinically diagnosed epilepsy that required antiepileptic drugs (AED). All patients underwent baseline comprehensive neuropsychological assessment. A follow-up of at least one year was requested to confirm the dementia diagnosis. In AD patients, qEEG power band analysis was performed. AD-CTR and AD-EPI patients were matched for age, Mini-Mental State Examination score, and gender.

RESULTS: Thirty-eight out of 2,054 neurodegenerative dementia patients had epilepsy requiring AED. The prevalence of epilepsy was 1.82% for AD, 1.28% for the behavioral variant of frontotemporal dementia (bvFTD), 2.47% for dementia with Lewy bodies (DLB), and 12% for primary progressive aphasia. Epilepsy were more drug-responsive in AD than in non-AD dementias. Finally, no significant differences were found in neuropsychological and qEEG data between AD-EPI and AD-CTR patients.

CONCLUSION: In our cohort, AD, FTD, and DLB dementias have similar prevalence of epilepsy, even if AD patients were more responsive to AED. Moreover, AD-EPI patients did not have significant clinical, neuropsychological qEEG differences compared with AD-CTR patients.

%B J Alzheimers Dis %V 74 %P 865-874 %8 2020 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/32116260?dopt=Abstract %R 10.3233/JAD-191315 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Estrogens Inhibit Amyloid-β-Mediated Paired Helical Filament-Like Conformation of Tau Through Antioxidant Activity and miRNA 218 Regulation in hTau Mice. %A Guglielmotto, Michela %A Manassero, Giusi %A Vasciaveo, Valeria %A Venezia, Marika %A Tabaton, Massimo %A Tamagno, Elena %X

BACKGROUND: The risk of developing Alzheimer's disease as well as its progression and severity are known to be different in men and women, and cognitive decline is greater in women than in men at the same stage of disease and could be correlated at least in part on estradiol levels.

OBJECTIVE: In our work we found that biological sex influences the effect of amyloid-β42 (Aβ42) monomers on pathological tau conformational change.

METHODS: In this study we used transgenic mice expressing the wild-type human tau (hTau) which were subjected to intraventricular (ICV) injections of Aβ peptides in nanomolar concentration.

RESULTS: We found that Aβ42 produces pathological conformational changes and hyperphosphorylation of tau protein in male or ovariectomized female mice but not in control females. The treatment of ovariectomized females with estradiol replacement protects against the pathological conformation of tau and seems to be mediated by antioxidant activity as well as the ability to modulate the expression of miRNA 218 linked to tau phosphorylation.

CONCLUSION: Our study indicates that factors as age, reproductive stage, hormone levels, and the interplay with other risk factors should be considered in women, in order to identify the best appropriate therapeutic approach in prevention of cognitive impairment.

%B J Alzheimers Dis %V 77 %P 1339-1351 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200707 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Examining Cognitive Decline Across Black and White Participants in the Harvard Aging Brain Study. %A Amariglio, Rebecca E %A Buckley, Rachel F %A Rabin, Jennifer S %A Papp, Kathryn V %A Quiroz, Yakeel T %A Mormino, Elizabeth C %A Sparks, Kathryn P %A Johnson, Keith A %A Rentz, Dorene M %A Sperling, Reisa A %X

BACKGROUND: Black Americans are approximately twice as likely to develop dementia as compared to White Americans and the magnitude of this disparity is often attributed to a variety of factors that include psychosocial and vascular risk factors. However, less is known about the potential contribution of Alzheimer's disease pathological differences.

OBJECTIVE: To examine potential differences incross-sectional and longitudinal cognitive performance in black and white participants who were clinically normal at baseline.

METHODS: 296 participants (48 African-American/black participants) underwent MRI and amyloid PET at baseline. Linear mixed models were used to examine the main effects of race, years of education, reading ability, Framingham Heart Study cardiovascular risk score (FHS-CVD), white matter hyperintensities (WMH), and amyloid (Aβ) burden on the Preclinical Alzheimer Cognitive Composite-5 (PACC5).

RESULTS: Lower levels of educationalattainment and reading ability were found for blacks compared to whites. By contrast, no differences in FHS-CVD, WMH, or Aβ were found by racial group. Baseline differences in PACC5 score were attenuated after adjusting for educationalfactors, vascular factors, and Aβ, but remained lower for blacks compared to whites (β= -0.24, p = 0.014). Further, blacks demonstrated a faster rate of PACC5 decline longitudinally compared to whites (β  = -0.055, p = 0.025) after adjusting for covariates.

CONCLUSION: Accounting for educationalfactors, vascular factors, and Aβ burden diminished, but did not eliminate, racial differences in PACC5 performance longitudinally. Understanding potential differences in longitudinal cognitive outcomes by race may be important for upcoming secondary prevention trials.

%B J Alzheimers Dis %V 75 %P 1437-1446 %8 2020 Jun 16 %G eng %N 4 %R 10.3233/JAD-191291 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Exploration of Plasma Lipids in Mild Cognitive Impairment due to Alzheimer's Disease. %A Bergland, Anne Katrine %A Proitsi, Petroula %A Kirsebom, Bjørn-Eivind %A Soennesyn, Hogne %A Hye, Abdul %A Larsen, Alf Inge %A Xu, Jin %A Legido-Quigley, Cristina %A Rajendran, Lawrence %A Fladby, Tormod %A Aarsland, Dag %X

BACKGROUND: Lipids have important structural roles in cell membranes and changes to these membrane lipids may influence β- and γ-secretase activities and thus contribute to Alzheimer's disease (AD) pathology.

OBJECTIVE: To explore baseline plasma lipid profiling in participants with mild cognitive impairment (MCI) with and without AD pathology.

METHODS: We analyzed 261 plasma lipid profiles using reversed phase chromatography mass spectrometry in cerebrospinal fluid amyloid positive (Aβ+) or negative (Aβ-) participants with MCI as compared to controls. Additionally, we analyzed the potential associations of plasma lipid profiles with performance on neuropsychological tests at baseline and after two years.

RESULTS: Sphingomyelin (SM) concentrations, particularly, SM(d43:2), were lower in MCI Aβ+ individuals compared to controls. Further, SM(d43:2) was also nominally reduced in MCI Aβ+ individuals compared to MCI Aβ-. No plasma lipids were associated with performance on neuropsychological tests at baseline or between the two time points after correction for multiple testing.

CONCLUSION: Reduced plasma concentrations of SM were associated with AD.

%B J Alzheimers Dis %V 77 %P 1117-1127 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200441 %0 Journal Article %J J Alzheimers Dis %D 2020 %T An Exploratory Phase IIa Study of the PPAR delta/gamma Agonist T3D-959 Assessing Metabolic and Cognitive Function in Subjects with Mild to Moderate Alzheimer's Disease. %A Chamberlain, Stanley %A Gabriel, Hoda %A Strittmatter, Warren %A Didsbury, John %X

BACKGROUND: T3D-959 is a chemically unique, brain penetrant, dual PPAR delta/gamma agonist with 15-fold higher PPAR delta selectivity. Ubiquitous brain expression of PPAR delta, its critical role in regulating glucose and lipid metabolism, and the Alzheimer's disease (AD)-like phenotype of PPAR delta null mice motivated this study.

OBJECTIVE: To determine safety and tolerability of multiple doses of T3D-959 in subjects with mild to moderate AD, examine systemic and central drug pharmacology and in an exploratory manner, perform cognitive assessments.

METHODS: Thirty-four subjects with mild-to-moderate AD were orally administered 3, 10, 30, or 90 mg of T3D-959 daily for 14 days. There was no inclusion of a placebo arm. Safety and tolerability were monitored. Systemic drug pharmacology was examined via plasma metabolomics LC-MS-MS analysis, cerebral drug pharmacology via FDG-PET measures of changes in Relative CMRgl (R CMRgl, AD-effected regions relative to brain reference regions), and cognitive function assessed before and after drug treatment and again one week after completion of drug treatment, by ADAS-cog11 and the Digit Symbol Substitution Test (DSST).

RESULTS: T3D-959 was in general safe and well tolerated. Single point pharmacokinetics at the Tmax showed dose dependent exposure. Plasma metabolome profile changes showed dose-dependent systemic effects on lipid metabolism and metabolism related to insulin sensitization. Relative FDG-PET imaging demonstrated dose-dependent, regional, effects of T3D-959 on R CMRgl based on the use of multiple reference regions. ADAS-cog11 and DSST cognitive assessments showed improvements with possible ApoE genotype association and pharmacodynamics related to the mechanism of drug action.

CONCLUSIONS: Exploratory data from this Phase IIa clinical trial supports further clinical investigation of T3D-959 in a larger placebo-controlled clinical study.

%B J Alzheimers Dis %V 73 %P 1085-1103 %8 2020 %G eng %N 3 %R 10.3233/JAD-190864 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Falls Associate with Neurodegenerative Changes in ATN Framework of Alzheimer's Disease. %A Keleman, Audrey %A Wisch, Julie K %A Bollinger, Rebecca M %A Grant, Elizabeth A %A Benzinger, Tammie L %A Morris, John C %A Ances, Beau M %A Stark, Susan L %X

BACKGROUND: Behavioral markers for Alzheimer's disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework.

OBJECTIVE: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD.

METHODS: This cross-sectional study recorded falls among CN participants (n = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, and hippocampal volume were compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall.

RESULTS: Participants who fell had smaller hippocampal volumes (p = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = -0.75, p = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p = 0.081) for preclinical AD participants who did not fall.

CONCLUSION: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD.

%B J Alzheimers Dis %V 77 %P 843-853 %8 2020 Sep 15 %G eng %N 2 %R 10.3233/JAD-200192 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Fascicle- and Glucose-Specific Deterioration in White Matter Energy Supply in Alzheimer's Disease. %A Roy, Maggie %A Rheault, François %A Croteau, Etienne %A Castellano, Christian-Alexandre %A Fortier, Mélanie %A St-Pierre, Valérie %A Houde, Jean-Christophe %A Turcotte, Éric E %A Bocti, Christian %A Fülöp, Tamás %A Cunnane, Stephen C %A Descoteaux, Maxime %X

BACKGROUND: White matter energy supply to oligodendrocytes and the axonal compartment is crucial for normal axonal function. Although gray matter glucose hypometabolism is extensively reported in Alzheimer's disease (AD), glucose and ketones, the brain's two main fuels, are rarely quantified in white matter in AD.

OBJECTIVE: Using adual-tracer PET method combined with a fascicle-specific diffusion MRI approach, robust to white matter hyper intensities and crossing fibers, we aimed to quantify both glucose and ketone metabolismin specific white matter fascicles associated with mild cognitive impairment (MCI; n = 51) and AD (n = 13) compared to cognitively healthy age-matched controls (Controls; n = 14).

METHODS: Eight white matter fascicles of the limbic lobe and corpus callosum were extracted and analyzed into fascicle profiles of five sections. Glucose (18F-fluorodeoxyglucose) and ketone (11C-acetoacetate) uptake rates, corrected for partial volume effect, were calculated along each fascicle.

RESULTS: The only fascicle with significantly lower glucose uptake in AD compared to Controls was the left posterior cingulate segment of the cingulum (-22%; p = 0.016). Non-significantly lower glucose uptake in this fascicle was also observed in MCI. In contrast to glucose, ketone uptake was either unchanged or higher in sections of the fornix and parahippocampal segment of the cingulum in AD.

CONCLUSION: To our knowledge, this is the first report of brain fuel uptake calculated along white matter fascicles in humans. Energetic deterioration in white matter in AD appears to be specific to glucose and occurs first in the posterior cingulum.

%B J Alzheimers Dis %V 76 %P 863-881 %8 2020 Aug 04 %G eng %N 3 %R 10.3233/JAD-200213 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Feasibility and Efficacy of Intra-Arterial Administration of Embryonic Stem Cell Derived-Mesenchymal Stem Cells in Animal Model of Alzheimer's Disease. %A Kim, Dong Yeol %A Choi, Sung Hyun %A Lee, Jee Sun %A Kim, Hyoung Jun %A Kim, Ha Na %A Lee, Ji Eun %A Shin, Jin Young %A Lee, Phil Hyu %X

Mesenchymal stem cells (MSCs) promote functional recoveries in pathological experimental models of the central nervous system and are currently being tested in clinical trials for neurological disorders. However, no studies have examined the various roles of embryonic stem cell derived (ES)-MSCs in eliciting therapeutic effects for Alzheimer's disease (AD). In the present study, we investigated the neuroprotective effect of ES-MSCs in cellular and animal models of AD, as well as the safety of the intra-arterial administration of ES-MSCs in an AD animal model. ES-MSCs displayed higher cell viability than that of bone marrow (BM)-MSCs in amyloid-β (Aβ)-induced cellular models. Moreover, the efficacy of autophagy induction in ES-MSCs was comparable to that of BM-MSCs; however, intracellular Aβ levels were more significantly reduced in ES-MSCs than in BM-MSCs. In a rat model of AD, ES-MSCs significantly inhibited Aβ-induced cell death in the hippocampus and promoted autophagolysosomal clearance of Aβ, which was concomitantly followed by decreased levels of Aβ in the hippocampus. Furthermore, ES-MSC treatment in Aβ-treated rats featured a higher memory performance than that of rats injected solely with Aβ. Finally, intra-arterial administration of an appropriate cell density of ES-MSCs was safe and free from in situ occlusion or cerebral ischemia. These data support the therapeutic potential of ES-MSCs and clinical applications of the intra-arterial route of ES-MSC administration in AD.

%B J Alzheimers Dis %V 76 %P 1281-1296 %8 2020 Aug 18 %G eng %N 4 %R 10.3233/JAD-200026 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Flickering Red-Light Stimulus for Promoting Coherent 40 Hz Neural Oscillation: A Feasibility Study. %A Sahin, Levent %A Figueiro, Mariana G %X

BACKGROUND: Coherent 40 Hz (gamma) neural oscillation indicates healthy brain activity and is known to be disrupted in Alzheimer's disease (AD) patients. 40 Hz entrainment by flickering light is known to significantly attenuate AD pathology in mice.

OBJECTIVE: To demonstrate the feasibility of using a lighting intervention to promote coherent 40 Hz neural oscillation, improved working memory performance, and reduced subjective sleepiness among a population of healthy young adults. If successful, the intervention could be extended to address cognitive impairment associated with mild cognitive impairment and AD.

METHODS: Nine healthy participants (median age 22 years, 5 females) were exposed to one of two lighting conditions per session in a within-subjects counterbalanced manner. The study's two sessions were separated by 1 week. Custom-built light masks provided either a 40 Hz flickering red light (FRL) intervention or a dark control condition (i.e., total darkness, light mask not energized) at participants' eyes. Data were collected 4 times per session: pre-exposure, after 25-min exposure, after 50-min exposure, and post-exposure. Each data collection period included a Karolinska Sleepiness Scale report, an electroencephalogram, and working memory (n-back) auditory performance testing.

RESULTS: The FRL intervention induced a significant increase in 40 Hz power and a modest increase in low gamma power. The intervention had no significant impact on working memory performance and subjective sleepiness compared to the control. However, increases in 40 Hz power were significantly correlated with reduced subjective sleepiness.

CONCLUSION: The results clearly demonstrate the feasibility of using a flickering light to increase 40 Hz power.

%B J Alzheimers Dis %V 75 %P 911-921 %8 2020 Jun 02 %G eng %N 3 %R 10.3233/JAD-200179 %0 Journal Article %J J Alzheimers Dis %D 2020 %T From Polygenic Scores to Precision Medicine in Alzheimer's Disease: A Systematic Review. %A Harrison, Judith R %A Mistry, Sumit %A Muskett, Natalie %A Escott-Price, Valentina %X

BACKGROUND: Late-onset Alzheimer's disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs), confer risk. Variants are clustered in areas of biology, notably immunity and inflammation, cholesterol metabolism, endocytosis, and ubiquitination. Polygenic scores (PRS), which weight the sum of an individual's risk alleles, have been used to draw inferences about the pathological processes underpinning AD.

OBJECTIVE: This paper aims to systematically review how AD PRS are being used to study a range of outcomes and phenotypes related to neurodegeneration.

METHODS: We searched the literature from July 2008-July 2018 following PRISMA guidelines.

RESULTS: 57 studies met criteria. The AD PRS can distinguish AD cases from controls. The ability of AD PRS to predict conversion from mild cognitive impairment (MCI) to AD was less clear. There was strong evidence of association between AD PRS and cognitive impairment. AD PRS were correlated with a number of biological phenotypes associated with AD pathology, such as neuroimaging changes and amyloid and tau measures. Pathway-specific polygenic scores were also associated with AD-related biologically relevant phenotypes.

CONCLUSION: PRS can predict AD effectively and are associated with cognitive impairment. There is also evidence of association between AD PRS and other phenotypes relevant to neurodegeneration. The associations between pathway specific polygenic scores and phenotypic changes may allow us to define the biology of the disease in individuals and indicate who may benefit from specific treatments. Longitudinal cohort studies are required to test the ability of PGS to delineate pathway-specific disease activity.

%B J Alzheimers Dis %V 74 %P 1271-1283 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32250305?dopt=Abstract %R 10.3233/JAD-191233 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Functional Connectivity Alterations of the Temporal Lobe and Hippocampus in Semantic Dementia and Alzheimer's Disease. %A Schwab, Simon %A Afyouni, Soroosh %A Chen, Yan %A Han, Zaizhu %A Guo, Qihao %A Dierks, Thomas %A Wahlund, Lars-Olof %A Grieder, Matthias %X

BACKGROUND: Semantic memory impairments in semantic dementia are attributed to atrophy and functional disruption of the anterior temporal lobes. In contrast, the posterior medial temporal neurodegeneration found in Alzheimer's disease is associated with episodic memory disturbance. The two dementia subtypes share hippocampal deterioration, despite a relatively spared episodic memory in semantic dementia.

OBJECTIVE: To unravel mutual and divergent functional alterations in Alzheimer's disease and semantic dementia, we assessed functional connectivity between temporal lobe regions in Alzheimer's disease (n = 16), semantic dementia (n = 23), and healthy controls (n = 17).

METHODS: In an exploratory study, we used a functional parcellation of the temporal cortex to extract time series from 66 regions for correlation analysis.

RESULTS: Apart from differing connections between Alzheimer's disease and semantic dementia that yielded reduced functional connectivity, we identified a common pathway between the right anterior temporal lobe and the right orbitofrontal cortex in both dementia subtypes. This disconnectivity might be related to social knowledge deficits as part of semantic memory decline. However, such interpretations are preferably made in a holistic context of disease-specific semantic impairments and functional connectivity changes.

CONCLUSION: Despite a major limitation owed to unbalanced databases between study groups, this study provides a preliminary picture of the brain's functional disconnectivity in Alzheimer's disease and semantic dementia. Future studies are needed to replicate findings of a common pathway with consistent diagnostic criteria and neuropsychological evaluation, balanced designs, and matched data MRI acquisition procedures.

%B J Alzheimers Dis %V 76 %P 1461-1475 %8 2020 Aug 18 %G eng %N 4 %R 10.3233/JAD-191113 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Functional Integrity of Synapses in the Central Nervous System of Cognitively Intact Individuals with High Alzheimer's Disease Neuropathology is Associated with Absence of Synaptic Tau Oligomers. %A Singh, Ayush %A Allen, Dyron %A Fracassi, Anna %A Tumurbaatar, Batbayar %A Natarajan, Chandramouli %A Scaduto, Pietro %A Woltjer, Randy %A Kayed, Rakez %A Limon, Agenor %A Krishnan, Balaji %A Taglialatela, Giulio %X

BACKGROUND: Certain individuals, here referred to as Non-Demented with Alzheimer Neuropathology (NDAN), do not show overt neurodegeneration (N - ) and remain cognitively intact despite the presence of plaques (A+) and tangles (T+) that would normally be consistent with fully symptomatic Alzheimer's disease (AD).

OBJECTIVE: The existence of NDAN (A + T +N - ) subjects suggests that the human brain utilizes intrinsic mechanisms that can naturally evade cognitive decline normally associated with the symptomatic stages of AD (A + T +N +). Deciphering the underlying mechanisms would prove relevant to develop complementing therapeutics to prevent progression of AD-related cognitive decline.

METHODS: Previously, we have reported that NDAN present with preserved neurogenesis and synaptic integrity paralleled by absence of amyloid oligomers at synapses. Using postmortem brain samples from age-matched control subjects, demented AD patients and NDAN individuals, we performed immunofluorescence, western blots, micro transplantation of synaptic membranes in Xenopus oocytes followed by twin electrode voltage clamp electrophysiology and fluorescence assisted single synaptosome-long term potentiation studies.

RESULTS: We report decreased tau oligomers at synapses in the brains of NDAN subjects. Furthermore, using novel approaches we report, for the first time, that such absence of tau oligomers at synapses is associated with synaptic functional integrity in NDAN subjects as compared to demented AD patients.

CONCLUSION: Overall, these results give further credence to tau oligomers as primary actors of synaptic destruction underscoring cognitive demise in AD and support their targeting as a viable therapeutic strategy for AD and related tauopathies.

%B J Alzheimers Dis %V 78 %P 1661-1678 %8 2020 Dec 08 %G eng %N 4 %R 10.3233/JAD-200716 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Gait Disturbances are Associated with Increased Cognitive Impairment and Cerebrospinal Fluid Tau Levels in a Memory Clinic Cohort. %A Muurling, Marijn %A Rhodius-Meester, Hanneke F M %A Pärkkä, Juha %A van Gils, Mark %A Frederiksen, Kristian S %A Bruun, Marie %A Hasselbalch, Steen G %A Soininen, Hilkka %A Herukka, Sanna-Kaisa %A Hallikainen, Merja %A Teunissen, Charlotte E %A Visser, Pieter Jelle %A Scheltens, Philip %A van der Flier, Wiesje M %A Mattila, Jussi %A Lötjönen, Jyrki %A de Boer, Casper %X

BACKGROUND: Gait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer's disease and other dementias. It is not clear, however, which gait features are most informative and how these measures relate to Alzheimer's disease pathology.

OBJECTIVE: In this study, we tested if calculated features of gait 1) differ between cognitively normal subjects (CN), mild cognitive impairment (MCI) patients, and dementia patients, 2) are correlated with cerebrospinal fluid (CSF) biomarkers related to Alzheimer's disease, and 3) predict cognitive decline.

METHODS: Gait was measured using tri-axial accelerometers attached to the fifth lumbar vertebra (L5) in 58 CN, 58 MCI, and 26 dementia participants, while performing a walk and dual task. Ten gait features were calculated from the vertical L5 accelerations, following principal component analysis clustered in four domains, namely pace, rhythm, time variability, and length variability. Cognitive decline over time was measured using MMSE, and CSF biomarkers were available in a sub-group.

RESULTS: Linear mixed models showed that dementia patients had lower pace scores than MCI patients and CN subjects (p < 0.05). In addition, we found associations between the rhythm domain and CSF-tau, especially in the dual task. Gait was not associated with CSF Aβ42 levels and cognitive decline over time as measured with the MMSE.

CONCLUSION: These findings suggest that gait-particularly measures related to pace and rhythm-are altered in dementia and have a direct link with measures of neurodegeneration.

%B J Alzheimers Dis %V 76 %P 1061-1070 %8 2020 Aug 04 %G eng %N 3 %R 10.3233/JAD-200225 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Gamma Entrainment in a Large Retrospective Cohort: Implications for Photic Stimulation Therapy for Alzheimer's Disease. %A Zibrandtsen, Ivan C %A Agger, Mikkel %A Kjaer, Troels W %X

BACKGROUND: Studies on mice models of Alzheimer's disease (AD) have suggested potential therapeutic benefits of intermittent photic stimulation at 40 Hz.

OBJECTIVE: We examined the physiological response of 40 Hz intermittent photic stimulation (IPS) on routine EEG in a large retrospective cohort to investigate the effects of age on induced gamma oscillations by intermittent photic stimulation. Since most AD patients are elderly, it is important for future research to know if age affects photic stimulation.

METHODS: Retrospective data from 1,464 subjects aged 0- 91. We performed frequency analysis and automatic peak detection and used regression analysis to investigate the effects of age and sex on peak frequencies and amplitude changes. To investigate the spread of the induced gamma oscillations, we assessed averaged topographies of 40 Hz band power.

RESULTS: There was a statistically significant but very minor effect of age on amplitude change (- 0.002 normalized power per year, p < 0.0001) but not for sex (p = 0.728). Detection probability of induced peaks was significantly predicted by both age (OR = 0.988, CI 95 % [0.984, 0.993], p < 0.00001) and sex (OR = 0.625, CI 95 % [0.496, 0.787>], p < 0.0001). The induced 40 Hz gamma entrainment is spatially confined to the occipital area.

CONCLUSION: There is a significant effect of age on induced gamma activity, but advanced age does not fundamentally change the behavior of the response in either magnitude or spatial distribution. This fact is important regarding future research into the possible therapeutic effects of photic stimulation in patients with AD.

%B J Alzheimers Dis %V 75 %P 1181-1190 %8 2020 Jun 16 %G eng %N 4 %R 10.3233/JAD-200083 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Gene Ontology Curation of Neuroinflammation Biology Improves the Interpretation of Alzheimer's Disease Gene Expression Data. %A Kramarz, Barbara %A Huntley, Rachael P %A Rodríguez-López, Milagros %A Roncaglia, Paola %A Saverimuttu, Shirin C C %A Parkinson, Helen %A Bandopadhyay, Rina %A Martin, Maria-Jesus %A Orchard, Sandra %A Hooper, Nigel M %A Brough, David %A Lovering, Ruth C %X

BACKGROUND: Gene Ontology (GO) is a major bioinformatic resource used for analysis of large biomedical datasets, for example from genome-wide association studies, applied universally across biological fields, including Alzheimer's disease (AD) research.

OBJECTIVE: We aim to demonstrate the applicability of GO for interpretation of AD datasets to improve the understanding of the underlying molecular disease mechanisms, including the involvement of inflammatory pathways and dysregulated microRNAs (miRs).

METHODS: We have undertaken a systematic full article GO annotation approach focused on microglial proteins implicated in AD and the miRs regulating their expression. PANTHER was used for enrichment analysis of previously published AD data. Cytoscape was used for visualizing and analyzing miR-target interactions captured from published experimental evidence.

RESULTS: We contributed 3,084 new annotations for 494 entities, i.e., on average six new annotations per entity. This included a total of 1,352 annotations for 40 prioritized microglial proteins implicated in AD and 66 miRs regulating their expression, yielding an average of twelve annotations per prioritized entity. The updated GO resource was then used to re-analyze previously published data. The re-analysis showed novel processes associated with AD-related genes, not identified in the original study, such as 'gliogenesis', 'regulation of neuron projection development', or 'response to cytokine', demonstrating enhanced applicability of GO for neuroscience research.

CONCLUSIONS: This study highlights ongoing development of the neurobiological aspects of GO and demonstrates the value of biocuration activities in the area, thus helping to delineate the molecular bases of AD to aid the development of diagnostic tools and treatments.

%B J Alzheimers Dis %V 75 %P 1417-1435 %8 2020 %G eng %N 4 %R 10.3233/JAD-200207 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Generation of Transgenic Cynomolgus Monkeys Overexpressing the Gene for Amyloid-β Precursor Protein. %A Seita, Yasunari %A Morimura, Toshifumi %A Watanabe, Naoki %A Iwatani, Chizuru %A Tsuchiya, Hideaki %A Nakamura, Shinichiro %A Suzuki, Toshiharu %A Yanagisawa, Daijiro %A Tsukiyama, Tomoyuki %A Nakaya, Masataka %A Okamura, Eiichi %A Muto, Masanaga %A Ema, Masatsugu %A Nishimura, Masaki %A Tooyama, Ikuo %X

Alzheimer's disease (AD) is the most common cause of dementia and understanding its pathogenesis should lead to improved therapeutic and diagnostic methods. Although several groups have developed transgenic mouse models overexpressing the human amyloid-β precursor protein (APP) gene with AD mutations, with and without presenilin mutations, as well as APP gene knock-in mouse models, these animals display amyloid pathology but do not show neurofibrillary tangles or neuronal loss. This presumably is due to differences between the etiology of the aged-related human disease and the mouse models. Here we report the generation of two transgenic cynomolgus monkeys overexpressing the human gene for APP with Swedish, Artic, and Iberian mutations, and demonstrated expression of gene tagged green fluorescent protein marker in the placenta, amnion, hair follicles, and peripheral blood. We believe that these nonhuman primate models will be very useful to study the pathogenesis of dementia and AD. However, generated Tg monkeys still have some limitations. We employed the CAG promoter, which will promote gene expression in a non-tissue specific manner. Moreover, we used transgenic models but not knock-in models. Thus, the inserted transgene destroys endogenous gene(s) and may affect the phenotype(s). Nevertheless, it will be of great interest to determine whether these Tg monkeys will develop tauopathy and neurodegeneration similar to human AD.

%B J Alzheimers Dis %V 75 %P 45-60 %8 2020 May 05 %G eng %N 1 %R 10.3233/JAD-191081 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Glucose Fluctuations Are Linked to Disrupted Brain Functional Architecture and Cognitive Impairment. %A Xia, Wenqing %A Luo, Yong %A Chen, Yu-Chen %A Chen, Huiyou %A Ma, Jianhua %A Yin, Xindao %X

BACKGROUND: Type 2 diabetes mellitus (T2DM) accelerates cognitive decline, which is believed to be triggered by aberrant neural activity.

OBJECTIVE: To explore how glucose fluctuations impact brain functional architecture and cognition in T2DM patients.

METHODS: T2DM patients were divided according to glycemic variability, forming two categories: patients with fluctuating glucose levels and patients with stable glucose levels. Degree centrality (DC) was calculated within the cerebral gray matter of each participant and was compared among the two patient groups and a healthy control group. The relationships between glucose fluctuations and aberrant DC and cognitive performance, as well as the relationship between aberrant DC and cognitive performance, were further explored.

RESULTS: Compared with T2DM patients with stable glucose levels, T2DM patients with fluctuating glucose levels exhibited significantly worse performance on the Montreal Cognitive Assessment, Trail Making Test-B (TMT-B), and verbal fluency test (VFT), as well as significant decreases in DC in certain regions, most of which were within the default mode network. In the combined T2DM group, the mean amplitude of glycemic excursions (MAGE) was positively correlated with TMT-B scores and negatively correlated with VFT scores. Moreover, the MAGE was negatively correlated with DC in the left medial prefrontal cortex (mPFC). In addition, TMT-B scores were negatively correlated with reduced DC in the left mPFC.

CONCLUSION: These findings further contribute to the mounting evidence of the effects of glycemic variability on the diabetic brain. Tightened control of glucose fluctuations might prevent cognitive decline and changes in brain functional architecture in T2DM individuals.

%B J Alzheimers Dis %V 74 %8 2020 Mar 24 %G eng %N 2 %R 10.3233/JAD-191217 %0 Journal Article %J J Alzheimers Dis %D 2020 %T The GSM BPN-15606 as a Potential Candidate for Preventative Therapy in Alzheimer's Disease. %A Prikhodko, Olga %A Rynearson, Kevin D %A Sekhon, Travis %A Mante, Mike M %A Nguyen, Phuong D %A Rissman, Robert A %A Tanzi, Rudolph E %A Wagner, Steven L %X

BACKGROUND: In the amyloid hypothesis of Alzheimer's disease (AD), the dysregulation of amyloid-β protein (Aβ) production and clearance leads to amyloid deposits, tau tangles, neuronal loss, and cognitive dysfunction. Thus far, therapies targeting the enzymes responsible for Aβ production have been found ineffective or having significant side effects.

OBJECTIVE: To test whether a γ-secretase modulator, BPN-15606, is an effective disease-modifying or preventative treatment in the PSAPP mouse model of AD.

METHODS: We treated pre-plaque (3-month-old) and post-plaque (6-month-old) PSAPP AD transgenic mice for 3 months and examined behavioral, biochemical, and pathological end points.

RESULTS: BPN-15606 attenuated cognitive impairment and reduced amyloid plaque load, microgliosis, and astrogliosis associated with the AD phenotype of PSAPP mice when administered to pre-plaque (3-month-old) but was ineffective when administered to post-plaque (6-month-old) mice. No treatment-related toxicity was observed.

CONCLUSION: BPN-15606 appears efficacious when administered prior to significant pathology.

%B J Alzheimers Dis %V 73 %P 1541-1554 %8 2020 Feb 18 %G eng %N 4 %R 10.3233/JAD-190442 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Heavy Metals Exposure and Alzheimer's Disease and Related Dementias. %A Bakulski, Kelly M %A Seo, Young Ah %A Hickman, Ruby C %A Brandt, Daniel %A Vadari, Harita S %A Hu, Howard %A Park, Sung Kyun %X

Alzheimer's disease and related dementias lack effective treatment or cures and are major public health challenges. Risk for Alzheimer's disease and related dementias is partially attributable to environmental factors. The heavy metals lead, cadmium, and manganese are widespread and persistent in our environments. Once persons are exposed to these metals, they are adept at entering cells and reaching the brain. Lead and cadmium are associated with numerous health outcomes even at low levels of exposure. Although manganese is an essential metal, deficiency or environmental exposure or high levels of the metal can be toxic. In cell and animal model systems, lead, cadmium, and manganese are well documented neurotoxicants that contribute to canonical Alzheimer's disease pathologies. Adult human epidemiologic studies have consistently shown lead, cadmium, and manganese are associated with impaired cognitive function and cognitive decline. No longitudinal human epidemiology study has assessed lead or manganese exposure on Alzheimer's disease specifically though two studies have reported a link between cadmium and Alzheimer's disease mortality. More longitudinal epidemiologic studies with high-quality time course exposure data and incident cases of Alzheimer's disease and related dementias are warranted to confirm and estimate the proportion of risk attributable to these exposures. Given the widespread and global exposure to lead, cadmium, and manganese, even small increases in the risks of Alzheimer's disease and related dementias would have a major population impact on the burden on disease. This article reviews the experimental and epidemiologic literature of the associations between lead, cadmium, and manganese on Alzheimer's disease and related dementias and makes recommendations of critical areas of future investment.

%B J Alzheimers Dis %V 76 %P 1215-1242 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32651318?dopt=Abstract %R 10.3233/JAD-200282 %0 Journal Article %J J Alzheimers Dis %D 2020 %T An Immunomodulatory Therapeutic Vaccine Targeting Oligomeric Amyloid-β. %A Song, Ge %A Yang, Haiqiang %A Shen, Ning %A Pham, Phillip %A Brown, Breanna %A Lin, Xiaoyang %A Hong, Yuzhu %A Sinu, Paul %A Cai, Jianfeng %A Li, Xiaopeng %A Leon, Michael %A Gordon, Marcia %A Morgan, David %A Zhang, Sai %A Cao, Chuanhai %X

BACKGROUND: Aging is considered the most important risk factor for Alzheimer's disease (AD). Recent research supports the theory that immunotherapy targeting the "oligomeric" forms of amyloid-β (Aβ) may halt the progression of AD. However, previous clinical trial of the vaccine against Aβ, called AN1792, was suspended due to cases of meningoencephalitis in patients.

OBJECTIVE: To develop a peptide sensitized dendritic cells (DCs) vaccine that would target oligomer Aβ and prevent an autoimmune response.

METHODS: Double transgenic APPswe/PS1ΔE9 (Tg) and C57BL/6J control mice were used in this study. Cytokine expression profile detection, characterization of antisera, brain GSK-3β, LC3 expression, and spatial working memory testing before and post-vaccination were obtained.

RESULTS: Epitope prediction indicated that E22W42 could generate 13 new T cell epitopes which can strengthen immunity in aged subjects and silence several T cell epitopes of the wild type Aβ. The silenced T cell epitope could help avoid the autoimmune response that was seen in some patients of the AN-1792 vaccine. The E22W42 not only helped sensitize bone marrow-derived DCs for the development of an oligomeric Aβ-specific antibody, but also delayed memory impairment in the APP/PS1 mouse model. Most importantly, this E22W42 peptide will not alter the DC's natural immunomodulatory properties.

CONCLUSION: The E22W42 vaccine is possibly safer for patients with impaired immune systems. Since there is increasing evidence that oligomeric form of Aβ are the toxic species to neurons, the E22W42 antibody's specificity for these "oligomeric" Aβ species could provide the opportunity to produce some clinical benefits in AD subjects.

%B J Alzheimers Dis %V 77 %P 1639-1653 %8 2020 Oct 13 %G eng %N 4 %R 10.3233/JAD-200413 %0 Journal Article %J J Alzheimers Dis %D 2020 %T The Impact of Amyloid-β or Tau on Cognitive Change in the Presence of Severe Cerebrovascular Disease. %A Jang, Hyemin %A Kim, Hee Jin %A Sim Choe, Yeong %A Kim, Soo-Jong %A Park, Seongbeom %A Kim, Yeshin %A Woon Kim, Ko %A Hyoung Lyoo, Chul %A Cho, Hanna %A Hoon Ryu, Young %A Choi, Jae Yong %A DeCarli, Charles %A Na, Duk L %A Won Seo, Sang %X

BACKGROUND: As Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) commonly coexist, the interaction between two has been of the considerable interest.

OBJECTIVE: We determined whether the association of Aβ and tau with cognitive decline differs by the presence of significant CSVD.

METHODS: We included 60 subcortical vascular cognitive impairment (SVCI) from Samsung Medical Center and 82 Alzheimer's disease-related cognitive impairment (ADCI) from ADNI, who underwent Aβ (florbetaben or florbetapir) and tau (flortaucipir, FTP) PET imaging. They were retrospectively assessed for 5.0±3.9 and 5.6±1.9 years with Clinical Dementia Rating-sum of boxes (CDR-SB)/Mini-Mental State Examination (MMSE). Mixed effects models were used to investigate the interaction between Aβ/tau and group on CDR-SB/MMSE changes.

RESULTS: The frequency of Aβ positivity (45% versus 54.9%, p = 0.556) and mean global FTP SUVR (1.17±0.21 versus 1.16±0.17, p = 0.702) were not different between the two groups. We found a significant interaction effect of Aβ positivity and SVCI group on CDR-SB increase/MMSE decrease (p = 0.013/p <  0.001) change, and a significant interaction effect of global FTP uptake and SVCI group on CDR-SB increase/MMSE decrease (p <  0.001 and p = 0.030) change. Finally, the interaction effects of regional tau and group were prominent in the Braak III/IV (p = 0.001) and V/VI (p = 0.003) not in Braak I/II region (p = 0.398).

CONCLUSION: The association between Aβ/tau and cognitive decline is stronger in SVCI than in ADCI. Therefore, our findings suggested that Aβ positivity or tau burden (particularly in the Braak III/IV or V/VI regions) and CSVD might synergistically affect cognitive decline.

%B J Alzheimers Dis %V 78 %P 573-585 %8 2020 Nov 10 %G eng %N 2 %R 10.3233/JAD-200680 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Impact of APOE and BDNF Val66Met Gene Polymorphisms on Cognitive Functions in Patients with Amnestic Mild Cognitive Impairment. %A Cechova, Katerina %A Andel, Ross %A Angelucci, Francesco %A Chmatalova, Zuzana %A Marková, Hana %A Laczó, Jan %A Vyhnálek, Martin %A Matoska, Vaclav %A Kaplan, Vojtech %A Nedelska, Zuzana %A Ward, David D %A Hort, Jakub %X

Apolipoprotein (APOE) ɛ4 is a well-known risk factor for late-onset Alzheimer's disease (AD), but other AD-related gene polymorphisms might also be important, such as the polymorphism within the brain-derived neurotrophic factor (BDNF) gene. Carriage of BDNF Val66Met has been associated with faster cognitive decline and greater hippocampal atrophy in cognitively normal elderly. Thus, we examined the effects of the concurrent presence of APOE and BDNF polymorphisms on cognitive functions and brain morphometry in amnestic mild cognitive impairment (aMCI) patients. 107 aMCI patients (mean age = 72.2) were recruited from the Czech Brain Aging Study and, based on APOE and BDNF genes polymorphisms, were divided into four groups: ɛ4-BDNFVal/Val (n = 37), ɛ4-BDNFMet (n = 19), ɛ4+BDNFVal/Val (n = 35), and ɛ4+BDNFMet (n = 16). All patients underwent clinical examination, magnetic resonance imaging, and complex neuropsychological battery. The combination of APOEɛ4+ and BDNF Met was associated with significantly worse memory performance in immediate and delayed recall compared to other polymorphism groups. We did not observe increased atrophy in areas related to memory function in the ɛ4+BDNFMet group. Our findings suggest that carriage of ɛ4+BDNFMet is associated with more pronounced memory dysfunction, a typical feature of early AD, but not with structural brain changes in aMCI patients. These findings suggest that in APOEɛ4/BDNF Met carriers, synaptic dysfunction affecting memory may precede pronounced structural changes.

%B J Alzheimers Dis %V 73 %P 247-257 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31771052?dopt=Abstract %R 10.3233/JAD-190464 %0 Journal Article %J J Alzheimers Dis %D 2020 %T In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice. %A Davidowitz, Eliot J %A Krishnamurthy, Pavan K %A Lopez, Patricia %A Jimenez, Heidy %A Adrien, Leslie %A Davies, Peter %A Moe, James G %X

Tau oligomers have been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimer's disease (AD) and related tauopathies. To develop a small molecule therapeutic for AD and related tauopathies, we have developed in vitro and cellular assays to select molecules inhibiting the first step in tau aggregation, the self-association of tau into oligomers. In vivo validation studies of an optimized lead compound were independently performed in the htau mouse model of tauopathy that expresses the human isoforms of tau without inherited tauopathy mutations that are irrelevant to AD. Treated mice did not show any adverse events related to the compound. The lead compound significantly reduced the level of self-associated tau and total and phosphorylated insoluble tau aggregates. The dose response was linear with respect to levels of compound in the brain. A confirmatory study was performed with male htau mice that gave consistent results. The results validated our screening approach by showing that targeting tau self-association can inhibit the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from in vitro and cellular assays to an in vivo model of tau aggregation.

%B J Alzheimers Dis %V 73 %P 147-161 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31771053?dopt=Abstract %R 10.3233/JAD-190465 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Individual Differences in the Effects of Physical Activity on Cognitive Function in People with Mild to Moderate Dementia. %A Uijen, Iris L %A Aaronson, Justine A %A Karssemeijer, Esther G A %A Olde Rikkert, Marcel G M %A Kessels, Roy P C %X

The aim of this study was to investigate whether the effect of physical activity on cognitive function in persons with dementia is moderated by patient characteristics as Apolipoprotein E and dementia type. We included 101 individuals with dementia and calculated the reliable change index to determine the change in global cognition, executive function, episodic memory, working memory, and processing speed before and after a 12-week exercise training. We found a higher treatment-related benefit in episodic memory in persons with non-Alzheimer's disease compared to persons with Alzheimer's disease, and in executive function in individuals with better baseline cognitive function.

%B J Alzheimers Dis %V 74 %P 435-439 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32039840?dopt=Abstract %R 10.3233/JAD-190606 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Inflammation in Traumatic Brain Injury. %A Postolache, Teodor T %A Wadhawan, Abhishek %A Can, Adem %A Lowry, Christopher A %A Woodbury, Margaret %A Makkar, Hina %A Hoisington, Andrew J %A Scott, Alison J %A Potocki, Eileen %A Benros, Michael E %A Stiller, John W %X

There is an increasing evidence that inflammation contributes to clinical and functional outcomes in traumatic brain injury (TBI). Many successful target-engaging, lesion-reducing, symptom-alleviating, and function-improving interventions in animal models of TBI have failed to show efficacy in clinical trials. Timing and immunological context are paramount for the direction, quality, and intensity of immune responses to TBI and the resulting neuroanatomical, clinical, and functional course. We present components of the immune system implicated in TBI, potential immune targets, and target-engaging interventions. The main objective of our article is to point toward modifiable molecular and cellular mechanisms that may modify the outcomes in TBI, and contribute to increasing the translational value of interventions that have been identified in animal models of TBI.

%B J Alzheimers Dis %V 74 %P 1-28 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32176646?dopt=Abstract %R 10.3233/JAD-191150 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Influence of Comorbidity of Cerebrovascular Disease and Amyloid-β on Alzheimer's Disease. %A Yassi, Nawaf %A Hilal, Saima %A Xia, Ying %A Lim, Yen Ying %A Watson, Rosie %A Kuijf, Hugo %A Fowler, Christopher %A Yates, Paul %A Maruff, Paul %A Martins, Ralph %A Ames, David %A Chen, Christopher %A Rowe, Christopher %A Villemagne, Victor %A Salvado, Olivier %A Desmond, Patricia M %A Masters, Colin L %X

BACKGROUND: Quantifying the contribution of cerebrovascular disease to the clinical and pathological profile of Alzheimer's disease is challenging.

OBJECTIVE: We aimed to determine the influence of cerebrovascular disease, amyloid-β (Aβ), and their comorbidity on cognitive decline, hippocampal atrophy, and Aβ deposition, by evaluating data from the Australian Imaging, Biomarker and Lifestyle Study of Ageing.

METHODS: Two-hundred and eighteen participants underwent Aβ PET, MRI, and cognitive assessment at 18-month intervals for up to 90 months. Aβ status was determined on baseline PET. Participants were also classified as V + on baseline MRI if they had≥1 large cortical infarcts, subcortical infarcts, or cortical cerebral microinfarcts; or white matter hyperintensity volume greater than the 90th percentile of healthy controls. Linear mixed models were conducted comparing slopes of change in cognition, hippocampal volume, and Aβ load between the four resultant groups.

RESULTS: Mean age at baseline was 74 years (range 59-96). One-hundred and fifteen participants were cognitively normal, 54 had mild cognitive impairment, and 49 had Alzheimer's disease. Compared to the Aβ-/V- group, the Aβ+/V- and Aβ+/V+groups showed significantly faster cognitive decline and hippocampal atrophy over 90 months. V + status was associated with greater cognitive decline (Cohen's d = 0.85, p < 0.001) and hippocampal atrophy (d = 2.05, p < 0.001) in the Aβ+group but not in the Aβ- group. V + status was not associated with Aβ accumulation in any group.

CONCLUSION: Comorbidity of cerebrovascular disease and Aβ was associated with cognitive decline and neurodegeneration. Cerebrovascular disease was not associated with the rate of Aβ accumulation.

%B J Alzheimers Dis %V 73 %P 897-907 %8 2020 Feb 04 %G eng %N 3 %R 10.3233/JAD-191028 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Levels of Retinal Amyloid-β Correlate with Levels of Retinal IAPP and Hippocampal Amyloid-β in Neuropathologically Evaluated Individuals. %A Schultz, Nina %A Byman, Elin %A Wennström, Malin %X

BACKGROUND: Previous studies have used immunohistology to demonstrate Alzheimer's disease (AD) characteristic accumulation of amyloid-β (Aβ) in the retina of AD patients, a finding indicating retina examination as a potential diagnostic tool for AD pathology.

OBJECTIVE: To further explore this idea by investigating whether levels of Aβ42 and Aβ40 in retina are associated with corresponding levels in hippocampus, neuropathological assessments, apolipoprotein E (APOE) genotype, and levels of islet amyloid polypeptide (IAPP).

METHODS: Levels of high molecular weight (HMW) Aβ42, Aβ40, and IAPP in ultra-centrifuged homogenates of retina and hippocampus from patients with AD, multiple sclerosis, AD with Lewy bodies, and non-demented controls were analyzed using Mesoscale Discovery electrochemiluminescence technology employing immunoassay and enzyme-linked immunosorbent assay.

RESULTS: Higher levels of retinal and hippocampal Aβ42-HMW, Aβ40-HMW, and IAPP-HMW were found in individuals with high neuropathological scores of Aβ plaques and in individuals carrying the APOEɛ4 allele. The retinal levels of Aβ42-HMW and Aβ40-HMW correlated with corresponding levels in hippocampus as well as with neurofibrillary tangles (NFT) and Aβ scores. Retinal IAPP-HMW correlated with retinal levels of Aβ42-HMW and with NFT and Aβ scores.

CONCLUSION: These results show that different isoforms of Aβ can be detected in the human retina and moreover support the growing number of studies indicating that AD-related pathological changes occurring in the brain could be reflected in the retina.

%B J Alzheimers Dis %V 73 %P 1201-1209 %8 2020 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/31884473?dopt=Abstract %R 10.3233/JAD-190868 %0 Journal Article %J J Alzheimers Dis %D 2020 %T lncRNA SNHG1 Knockdown Alleviates Amyloid-β-Induced Neuronal Injury by Regulating ZNF217 via Sponging miR-361-3p in Alzheimer's Disease. %A Gao, Yiwen %A Zhang, Nan %A Lv, Chunmei %A Li, Na %A Li, Xueqin %A Li, Weiwei %X

BACKGROUND: Long noncoding RNAs have been proven to play an important role in the progression of Alzheimer's disease (AD). However, the function of small nucleolar RNA host gene 1 (SNHG1) in AD progression remains to be studied.

OBJECTIVE: To explore the role of SNHG1 in AD progression and clarify its potential mechanism.

METHODS: Amyloid β-protein (Aβ) was used to construct an AD cell model in vitro. The expression levels of SNHG1 and miR-361-3p were determined by quantitative real-time polymerase chain reaction. Cell viability and apoptosis were measured by cell counting kit 8 assay and flow cytometry. The levels of apoptosis-related proteins and zinc finger gene 217 (ZNF217) protein were evaluated by western blot analysis. Additionally, the contents of inflammatory cytokines and oxidative stress markers were tested by enzyme-linked immunosorbent assay. Furthermore, dual-luciferase reporter and RNA immunoprecipitation assays were used to verify the interaction between miR-361-3p and SNHG1 or ZNF217.

RESULTS: Aβ could induce cell injury, while resveratrol could reverse this effect. SNHG1 expression was positively regulated by Aβ and negatively regulated by resveratrol. SNHG1 knockdown could reverse the promotion effect of Aβ on cell injury. Moreover, SNHG1 sponged miR-361-3p, and miR-361-3p targeted ZNF217. Additionally, miR-361-3p overexpression reversed the promotion effect of SNHG1 overexpression on cell injury, and ZNF217 silencing also reversed the promotion effect of miR-361-3p inhibitor on cell injury.

CONCLUSION: SNHG1 promoted cell injury by regulating the miR-361-3p/ZNF217 axis, which might provide a theoretical basis for molecular therapy of AD.

%B J Alzheimers Dis %V 77 %P 85-98 %8 2020 Sep 01 %G eng %N 1 %R 10.3233/JAD-191303 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Loss of Functional Dentition is Associated with Cognitive Impairment. %A Han, Ji Hyun %A Lee, Hyo-Jung %A Han, Ji Won %A Suh, Seung Wan %A Lee, Ju Ri %A Byun, Seonjeong %A Kim, Keun Suh %A Kim, Sung Yeol %A Lee, Jung-Tae %A Yoo, Eunha %A Chang, Na-Hee %A Kim, Tae Hui %A Kim, Ki Woong %X

BACKGROUND: Although tooth loss is known to increase the risk of cognitive impairment and dementia, few studies have investigated the association between functional teeth including rehabilitated lost teeth and cognitive functionObjective:We investigated the associations of the numbers of functional teeth and functional occlusal units with cognitive impairment and cognitive function in late life.

METHODS: The current study was conducted as a part of the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD), a community-based elderly cohort study. We analyzed 411 participants who have agreed with the additional dental exam. Geriatric psychiatrists and neuropsychologists administered the Consortium to Establish a Registry for Alzheimer's disease Assessment Packet Clinical and Neuropsychological Assessment Battery to all participants, and dentists examined their dental status.

RESULTS: Higher number of functional teeth (OR = 0.955, 95% CI = 0.914-0.997, p = 0.037) and higher number of functional occlusal units (OR = 0.900, 95% CI = 0.813-0.996, p = 0.042) were associated with lower odds of cognitive impairment. When we analyzed these relationships separated by the location of teeth, only the numbers of functional teeth (OR = 0.566, 95% CI = 0.373-0.857, p = 0.007) and functional occlusal units (OR = 0.399, 95% CI = 0.213-0.748, p = 0.004) in the premolar area were associated with lower odds of cognitive impairment.

CONCLUSION: Loss of functional teeth and functional occlusal units (especially in the premolar region) were associated with increased cognitive impairment.

%B J Alzheimers Dis %V 73 %P 1313-1320 %8 2020 Feb 18 %G eng %N 4 %R 10.3233/JAD-190971 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Metabolic Changes Detected by 18F-FDG PET in the Preclinical Stage of Familial Creutzfeldt-Jakob Disease. %A Lu, Hui %A Jing, Donglai %A Chen, Yaojing %A Cui, Chunlei %A Gao, Ran %A Wang, Lin %A Liang, Zhigang %A Chen, Kewei %A Wu, Liyong %X

BACKGROUND: Pathologic processes in Creutzfeldt-Jakob disease (CJD) are not fully understood. Familial CJD (fCJD) gives opportunities to discover pathologic changes in the preclinical stage.

OBJECTIVE: To investigate cerebral glucose metabolism in the preclinical stage via 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in fCJD.

METHODS: Seven asymptomatic carriers of G114V mutation and six family members without PRNP mutation from the same fCJD kindred were included, and were followed for 2 years. Ten symptomatic CJD patients were also recruited. All subjects underwent standardized clinical examinations and 18F-FDG PET scans. Results were compared in three groups: baseline carriers against non-carriers (baseline analysis), changes after 2 years in carriers (follow-up analysis), and differences between symptomatic CJD patients and healthy controls (CJD patients analysis).

RESULTS: No carriers developed any neurological symptoms during 2-year follow-up. Baseline analysis: carriers demonstrates decreased metabolism (p < 0.001) in left and right postcentral, left fusiform, left superior temporal, left lingual, left superior parietal, and left Heschl gyrus. Follow-up analysis shows metabolic decline (p < 0.001) in right inferior temporal, left supra-marginal and left postcentral lobe, and increased metabolism (p < 0.001) in left fusiform, left angular, left thalamus, left Heschl's, right Rolandic operculum, and left superior parietal gyrus. CJD patients demonstrates decreased metabolism in right inferior triangularis frontal gyrus, right middle occipital gyrus, right putamen, right thalamus, and right middle temporal gyrus.

CONCLUSION: Hypo-metabolism of parietal and temporal lobe can be detected by 18F-FDG PET in the preclinical stage of CJD. Subcortical area might compensate in the preclinical stage and decompensate in the symptomatic stage.

%B J Alzheimers Dis %V 77 %P 1513-1521 %8 2020 Oct 13 %G eng %N 4 %R 10.3233/JAD-200576 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Metabolic Profiles Help Discriminate Mild Cognitive Impairment from Dementia Stage in Alzheimer's Disease. %A Jääskeläinen, Olli %A Hall, Anette %A Tiainen, Mika %A van Gils, Mark %A Lötjönen, Jyrki %A Kangas, Antti J %A Helisalmi, Seppo %A Pikkarainen, Maria %A Hallikainen, Merja %A Koivisto, Anne %A Hartikainen, Päivi %A Hiltunen, Mikko %A Ala-Korpela, Mika %A Soininen, Pasi %A Soininen, Hilkka %A Herukka, Sanna-Kaisa %X

Accurate differentiation between neurodegenerative diseases is developing quickly and has reached an effective level in disease recognition. However, there has been less focus on effectively distinguishing the prodromal state from later dementia stages due to a lack of suitable biomarkers. We utilized the Disease State Index (DSI) machine learning classifier to see how well quantified metabolomics data compares to clinically used cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD). The metabolic profiles were quantified for 498 serum and CSF samples using proton nuclear magnetic resonance spectroscopy. The patient cohorts in this study were dementia (with a clinical AD diagnosis) (N = 359), mild cognitive impairment (MCI) (N = 96), and control patients with subjective memory complaints (N = 43). DSI classification was conducted for MCI (N = 51) and dementia (N = 214) patients with low CSF amyloid-β levels indicating AD pathology and controls without such amyloid pathology (N = 36). We saw that the conventional CSF markers of AD were better at classifying controls from both dementia and MCI patients. However, quantified metabolic subclasses were more effective in classifying MCI from dementia. Our results show the consistent effectiveness of traditional CSF biomarkers in AD diagnostics. However, these markers are relatively ineffective in differentiating between MCI and the dementia stage, where the quantified metabolomics data provided significant benefit.

%B J Alzheimers Dis %V 74 %P 277-286 %8 2020 Mar 10 %G eng %N 1 %R 10.3233/JAD-191226 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Mitochondrial DNA Manipulations Affect Tau Oligomerization. %A Weidling, Ian W %A Wilkins, Heather M %A Koppel, Scott J %A Hutfles, Lewis %A Wang, Xiaowan %A Kalani, Anuradha %A Menta, Blaise W %A Ryan, Benjamin %A Perez-Ortiz, Judit %A Gamblin, T Chris %A Swerdlow, Russell H %X

BACKGROUND: Mitochondrial dysfunction and tau aggregation occur in Alzheimer's disease (AD), and exposing cells or rodents to mitochondrial toxins alters their tau.

OBJECTIVE: To further explore how mitochondria influence tau, we measured tau oligomer levels in human neuronal SH-SY5Y cells with different mitochondrial DNA (mtDNA) manipulations.

METHODS: Specifically, we analyzed cells undergoing ethidium bromide-induced acute mtDNA depletion, ρ0 cells with chronic mtDNA depletion, and cytoplasmic hybrid (cybrid) cell lines containing mtDNA from AD subjects.

RESULTS: We found cytochrome oxidase activity was particularly sensitive to acute mtDNA depletion, evidence of metabolic re-programming in the ρ0 cells, and a relatively reduced mtDNA content in cybrids generated through AD subject mitochondrial transfer. In each case tau oligomer levels increased, and acutely depleted and AD cybrid cells also showed a monomer to oligomer shift.

CONCLUSION: We conclude a cell's mtDNA affects tau oligomerization. Overlapping tau changes across three mtDNA-manipulated models establishes the reproducibility of the phenomenon, and its presence in AD cybrids supports its AD-relevance.

%B J Alzheimers Dis %V 77 %P 149-163 %8 2020 Sep 01 %G eng %N 1 %R 10.3233/JAD-200286 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Mixed Brain Pathology Is the Most Common Cause of Cognitive Impairment in the Elderly. %A Alafuzoff, Irina %A Libard, Sylwia %X

BACKGROUND: Systemic diseases, diabetes mellitus (DM), and cardiovascular disease (CaVD) have been suggested being risk factors for cognitive impairment (CI) and/or influence Alzheimer's disease neuropathologic change (ADNC).

OBJECTIVE: The purpose was to assess the type and the extent of neuropathological alterations in the brain and to assess whether brain pathology was associated with CaVD or DM related alterations in peripheral organs, i.e., vessels, heart, and kidney.

METHODS: 119 subjects, 15% with DM and 24% with CI, age range 80 to 89 years, were chosen and neuropathological alterations were assessed applying immunohistochemistry.

RESULTS: Hyperphosphorylated τ (HPτ) was seen in 99%, amyloid-β (Aβ) in 71%, transactive DNA binding protein 43 (TDP43) in 62%, and α-synuclein (αS) in 21% of the subjects. Primary age related tauopathy was diagnosed in 29% (more common in females), limbic predominant age-related TDP encephalopathy in 4% (14% of subjects with CI), and dementia with Lewy bodies in 3% (14% of subjects with CI) of the subjects. High/intermediate level of ADNC was seen in 47% and the extent of HPτ increased with age. The extent of ADNC was not associated with the extent of pathology observed in peripheral organs, i.e., DM or CaVD. Contrary, brain alterations such as pTDP43 and cerebrovascular lesions (CeVL) were influenced by DM, and CeVL correlated significantly with the extent of vessel pathology.

CONCLUSION: In most (66%) subjects with CI, the cause of impairment was "mixed pathology", i.e., ADNC combined with TDP43, αS, or vascular brain lesions. Furthermore, our results suggest that systemic diseases, DM and CaVD, are risk factors for CI but not related to ADNC.

%B J Alzheimers Dis %V 78 %P 453-465 %8 2020 Oct 27 %G eng %N 1 %R 10.3233/JAD-200925 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Morphometric Analysis of Hippocampal and Neocortical Pyramidal Neurons in a Mouse Model of Late Onset Alzheimer's Disease. %A Mehder, Rasha H %A Bennett, Brian M %A Andrew, R David %X

The study of late-onset (sporadic) Alzheimer's disease (LOAD) has lacked animal models where impairments develop with aging. Oxidative stress promotes LOAD, so we have developed an oxidative stress-based model of age-related cognitive impairment based on gene deletion of aldehyde dehydrogenase 2 (ALDH2). This enzyme is important for the detoxification of endogenous aldehydes arising from lipid peroxidation. Compared to wildtype (WT) mice, the knockout (KO) mice exhibit a progressive decline in recognition and spatial memory and AD-like pathologies. Here we performed morphometric analyses in the dorsal and ventral hippocampal CA1 regions (dCA1 and vCA1) as well as in overlying primary sensory cortex to determine if altered neuronal structure can help account for the cognitive impairment in 12-month old KO mice. Dendritic morphology was quantitatively analyzed following Golgi-Cox staining using 9 WT mice (108 neurons) and 15 KO mice (180 neurons). Four pyramidal neurons were traced per mouse in each region, followed by branched structured analysis and Sholl analysis. Compared to WT controls, the morphology and complexity of dCA1 pyramidal neurons from KOs showed significant reductions in apical and basal dendritic length, dendrite intersections, ends, and nodes. As well, spine density along dorsal CA1 apical dendrites was significantly lower in KO versus WT. In contrast, pyramidal arborization in the vCA1 and primary sensory cortex were only minimally reduced in KO versus WT mice. These data suggest a region-specific vulnerability to oxidative stress-induced damage and/or a major and specific reduction in synaptic input to the pyramidal neurons of the dorsal hippocampus. This is in keeping with studies showing that lesions to the dorsal hippocampus impair primarily cognitive memory whereas ventral hippocampal lesions cause deficits in stress, emotion, and affect.

%B J Alzheimers Dis %V 74 %P 1069-1083 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32144984?dopt=Abstract %R 10.3233/JAD-191067 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Multi-Target Effects of the Cannabinoid CP55940 on Familial Alzheimer's Disease PSEN1 E280A Cholinergic-Like Neurons: Role of CB1 Receptor. %A Soto-Mercado, Viviana %A Mendivil-Perez, Miguel %A Jimenez-Del-Rio, Marlene %A Velez-Pardo, Carlos %X

BACKGROUND: Alzheimer's disease (AD) is characterized by structural damage, death, and functional disruption of cholinergic neurons (ChNs) as a result of intracellular amyloid-β (Aβ) aggregation, extracellular neuritic plaques, and hyperphosphorylation of protein tau (p-Tau) overtime.

OBJECTIVE: To evaluate the effect of the synthetic cannabinoid CP55940 (CP) on PSEN1 E280A cholinergic-like nerve cells (PSEN1 ChLNs)-a natural model of familial AD.

METHODS: Wild type (WT) and PSEN1 ChLNs were exposed to CP (1μM) only or in the presence of the CB1 and CB2 receptors (CB1Rs, CB2Rs) inverse agonist SR141716 (1μM) and SR144528 (1μM) respectively, for 24 h. Untreated or treated neurons were assessed for biochemical and functional analysis.

RESULTS: CP in the presence of both inverse agonists (hereafter SR) almost completely inhibits the aggregation of intracellular sAβPPβf and p-Tau, increases ΔΨm, decreases oxidation of DJ-1Cys106-SH residue, and blocks the activation of c-Jun, p53, PUMA, and caspase-3 independently of CB1Rs signaling in mutant ChLNs. CP also inhibits the generation of reactive oxygen species partially dependent on CB1Rs. Although CP reduced extracellular Aβ 42, it was unable to reverse the Ca2 + influx dysregulation as a response to acetylcholine stimuli in mutant ChLNs. Exposure to anti-Aβ antibody 6E10 (1:300) in the absence or presence of SR plus CP completely recovered transient [Ca2 +]i signal as a response to acetylcholine in mutant ChLNs.

CONCLUSION: Taken together our findings suggest that the combination of cannabinoids, CB1Rs inverse agonists, and anti-Aβ antibodies might be a promising therapeutic approach for the treatment of familial AD.

%B J Alzheimers Dis %8 2020 Nov 23 %G eng %R 10.3233/JAD-201045 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Music Playlists for People with Dementia: Trialing A Guide for Caregivers. %A Garrido, Sandra %A Dunne, Laura %A Stevens, Catherine J %A Chang, Esther %X

BACKGROUND: Music programs have the potential to provide an effective non-pharmacological tool for caregivers to reduce depression and agitation and increase quality of life in people with dementia. However, where such programs are not facilitated by a trained music therapist, caregivers need greater access to information about how to use music most effectively in response to key challenges to care, and how to pre-empt and manage adverse responses.

OBJECTIVE: This study reports on the trial of a Guide for use of music with 45 people with dementia and their caregivers in residential care facilities and home-based care.

METHODS: The study used a pre-post experimental design in which participants were randomly allocated to a treatment group or a waitlist control group.

RESULTS: Improvements to quality of life were found in the experimental group over the 6-week period. Significant increases in Interest, Responsiveness, Initiation, Involvement, and Enjoyment were reported for individual listening sessions.

CONCLUSION: The Guide can provide an effective protocol for caregivers to follow in selecting music to manage particular challenges to care, confirming the need for caregivers to be prepared to monitor and manage potential negative responses.

%B J Alzheimers Dis %V 77 %P 219-226 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32741829?dopt=Abstract %R 10.3233/JAD-200457 %0 Journal Article %J J Alzheimers Dis %D 2020 %T A Narrative Review of Alzheimer's Disease Stigma. %A Rosin, Eric R %A Blasco, Drew %A Pilozzi, Alexander R %A Yang, Lawrence H %A Huang, Xudong %X

As the most common form of senile dementia, Alzheimer's disease (AD) is accompanied by a great deal of uncertainty which can lead to fear and stigma for those identified with this devastating disease. As the AD definition evolves from a syndromal to a biological construct, and early diagnoses becomes more commonplace, more confusion and stigma may result. We conducted a narrative review of the literature on AD stigma to consolidate information on this body of research. From the perspective of several stigma theories, we identified relevant studies to inform our understanding of the way in which implementation of the new framework for a biological based AD diagnosis may have resulted in new and emerging stigma. Herein, we discuss the emergence of new AD stigma as our understanding of the definition of the disease changes. We further propose recommendations for future research to reduce the stigma associated with AD.

%B J Alzheimers Dis %V 78 %P 515-528 %8 2020 Nov 10 %G eng %N 2 %R 10.3233/JAD-200932 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Neurobiology of COVID-19. %A Fotuhi, Majid %A Mian, Ali %A Meysami, Somayeh %A Raji, Cyrus A %K Betacoronavirus %K Brain %K Coronavirus Infections %K COVID-19 %K Humans %K Inflammation Mediators %K Nervous System Diseases %K Pandemics %K Pneumonia, Viral %K SARS-CoV-2 %X

Anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, and seizures are some of the neurological complications in patients with coronavirus disease-19 (COVID-19) which is caused by acute respiratory syndrome coronavirus 2 (SARS-Cov2). There remains a challenge to determine the extent to which neurological abnormalities in COVID-19 are caused by SARS-Cov2 itself, the exaggerated cytokine response it triggers, and/or the resulting hypercoagulapathy and formation of blood clots in blood vessels throughout the body and the brain. In this article, we review the reports that address neurological manifestations in patients with COVID-19 who may present with acute neurological symptoms (e.g., stroke), even without typical respiratory symptoms such as fever, cough, or shortness of breath. Next, we discuss the different neurobiological processes and mechanisms that may underlie the link between SARS-Cov2 and COVID-19 in the brain, cranial nerves, peripheral nerves, and muscles. Finally, we propose a basic "NeuroCovid" classification scheme that integrates these concepts and highlights some of the short-term challenges for the practice of neurology today and the long-term sequalae of COVID-19 such as depression, OCD, insomnia, cognitive decline, accelerated aging, Parkinson's disease, or Alzheimer's disease in the future. In doing so, we intend to provide a basis from which to build on future hypotheses and investigations regarding SARS-Cov2 and the nervous system.

%B J Alzheimers Dis %V 76 %P 3-19 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32538857?dopt=Abstract %R 10.3233/JAD-200581 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Neuroimaging in Vascular Cognitive Impairment and Dementia: A Systematic Review. %A Frantellizzi, Viviana %A Pani, Arianna %A Ricci, Maria %A Locuratolo, Nicoletta %A Fattapposta, Francesco %A De Vincentis, Giuseppe %X

Cerebrovascular diseases are well established causes of cognitive impairment. Different etiologic entities, such as vascular dementia (VaD), vascular cognitive impairment, subcortical (ischemic) VaD, and vascular cognitive disorder, are included in the umbrella definition of vascular cognitive impairment and dementia (VCID). Because of the variability of VCID clinical presentation, there is no agreement on criteria defining the neuropathological threshold of this disorder. In fact, VCID is characterized by cerebral hemodynamic alteration which ranges from decreased cerebral blood flow to small vessels disease and involves a multifactorial process that leads to demyelination and gliosis, including blood-brain barrier disruption, hypoxia, and hypoperfusion, oxidative stress, neuroinflammation and alteration on neurovascular unit coupling, cerebral microbleeds, or superficial siderosis. Numerous criteria for the definition of VaD have been described: the National Institute of Neurological Disorders and Stroke Association Internationale pour Recherche'-et-l'Enseignement en Neurosciences criteria, the State of California Alzheimer's Disease Diagnostic and Treatment Centers criteria, DSM-V criteria, the Diagnostic Criteria for Vascular Cognitive Disorders (a VASCOG Statement), and Vascular Impairment of Cognition Classification Consensus Study. Neuroimaging is fundamental for definition and diagnosis of VCID and should be used to assess the extent, location, and type of vascular lesions. MRI is the most sensible technique, especially if used according to standardized protocols, even if CT plays an important role in several conditions. Functional neuroimaging, in particular functional MRI and PET, may facilitate differential diagnosis among different forms of dementia. This systematic review aims to explore the state of the art and future perspective of non-invasive diagnostics of VCID.

%B J Alzheimers Dis %V 73 %P 1279-1294 %8 2020 %G eng %N 4 %R 10.3233/JAD-191046 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Neuropathologic Correlates of White Matter Hyperintensities in a Community-Based Cohort of Older Adults. %A Arfanakis, Konstantinos %A Evia, Arnold M %A Leurgans, Sue E %A Cardoso, Luis F C %A Kulkarni, Arman %A Alqam, Nabil %A Lopes, Lucas F %A Vieira, Diego %A Bennett, David A %A Schneider, Julie A %X

BACKGROUND: The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood.

OBJECTIVE: The objective of this work was to elucidate the neuropathologic correlates of WMH in a large community-based cohort of older adults.

METHODS: Cerebral hemispheres from 603 community-based older adults were imaged with MRI ex vivo. All participants underwent annual clinical evaluation, cognitive assessment, and neuropathologic examination. WMH burden was assessed using a modified Fazekas rating scale. Multiple ordinal logistic regression was used to test the association of WMH burden with an array of age-related neuropathologies, adjusting for demographics. Mixed effects models of cognition controlling for neuropathologies and demographics were used to determine whether WMH burden contributes to cognitive decline beyond measured pathologies.

RESULTS: WMH burden in the whole group was associated with both vascular and Alzheimer's disease (AD) pathologies: arteriolosclerosis (p < 10-4), gross (p < 10-4), and microscopic infarcts (p = 0.04), and amyloid-β plaques (p = 0.028). In non-demented participants (mild or no cognitive impairment) (N = 332), WMH burden was related to gross infarcts (p = 10-4) and arteriolosclerosis (p < 10-4), but not to AD pathology. Similarly, in those with no cognitive impairment (N = 178), WMH burden was related to gross infarcts (p = 8×10-4) and arteriolosclerosis (p = 0.014). WMH burden was associated with faster decline in perceptual speed in both the whole (p = 0.038) and non-demented (p = 0.006) groups.

CONCLUSION: WMH burden has independent associations with vascular pathologies in older adults regardless of clinical status, and with AD pathology later in the progression of AD. Moreover, WMH burden may reflect additional tissue injury not captured with traditional neuropathologic indices.

%B J Alzheimers Dis %V 73 %P 333-345 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31771057?dopt=Abstract %R 10.3233/JAD-190687 %0 Journal Article %J J Alzheimers Dis %D 2020 %T New BACE1 Chimeric Peptide Inhibitors Selectively Prevent AβPPβ Cleavage Decreasing Amyloid-β Production and Accumulation in Alzheimer's Disease Models. %A Resende, Rosa %A Ferreira-Marques, Marisa %A Moreira, Patrícia %A Coimbra, Judite R M %A Baptista, Salete J %A Isidoro, Ciro %A Salvador, Jorge A R %A Dinis, Teresa C P %A Pereira, Cláudia F %A Santos, Armanda E %X

BACKGROUND: A disease-modifying therapy for Alzheimer's disease (AD) is still an unmet clinical need. The formation of amyloid-β (Aβ) requires the initial cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (beta-site AβPP cleaving enzyme 1), which is a prime therapeutic target for AD.

OBJECTIVE: We aimed to design and develop a selective BACE1 inhibitor suitable to AD treatment.

METHODS: The new BACE1 inhibitors consist on a chimeric peptide including a sequence related to the human Swedish mutant form of AβPP (AβPPswe) conjugated with the TAT carrier that facilitates cell membrane permeation and the crossing of the blood-brain barrier. Additionally to the chimeric peptide in the L-form, we developed a D-retro in verso chimeric peptide. The latter strategy, never used with BACE1 inhibitors, is considered to favor a significantly higher half-life and lower immunogenicity.

RESULTS: We found that both chimeric peptides inhibit recombinant BACE1 activity and decrease Aβ40/42 production in Neuro-2a (N2A) cells expressing AβPPswe without inducing cytotoxicity. The intraperitoneal administration of these peptides to 3xTg-AD mice decreased plasma and brain Aβ40/42 levels, as well as brain soluble AβPPβ production. Also, a reduction of insoluble Aβ was observed in the brain after chronic treatment. Noteworthy, the chimeric peptides selectively inhibited the AβPPβ cleavage relatively to the proteolysis of other BACE1 substrates such as close homologue of L1 (CHL1) and seizure-related gene 6 (SEZ6).

CONCLUSIONS: Overall these new BACE1 chimeric peptideshold promising potential as a selective disease-modifying therapy for AD.

%B J Alzheimers Dis %V 76 %P 1317-1337 %8 2020 Aug 18 %G eng %N 4 %R 10.3233/JAD-200381 %0 Journal Article %J J Alzheimers Dis %D 2020 %T A New Serum Biomarker Set to Detect Mild Cognitive Impairment and Alzheimer's Disease by Peptidome Technology. %A Abe, Koji %A Shang, Jingwei %A Shi, Xiaowen %A Yamashita, Toru %A Hishikawa, Nozomi %A Takemoto, Mami %A Morihara, Ryuta %A Nakano, Yumiko %A Ohta, Yasuyuki %A Deguchi, Kentaro %A Ikeda, Masaki %A Ikeda, Yoshio %A Okamoto, Koichi %A Shoji, Mikio %A Takatama, Masamitsu %A Kojo, Motohisa %A Kuroda, Takeshi %A Ono, Kenjiro %A Kimura, Noriyuki %A Matsubara, Etsuro %A Osakada, Yosuke %A Wakutani, Yosuke %A Takao, Yoshiki %A Higashi, Yasuto %A Asada, Kyoichi %A Senga, Takehito %A Lee, Lyang-Ja %A Tanaka, Kenji %X

BACKGROUND: Because dementia is an emerging problem in the world, biochemical markers of cerebrospinal fluid (CSF) and radio-isotopic analyses are helpful for diagnosing Alzheimer's disease (AD). Although blood sample is more feasible and plausible than CSF or radiological biomarkers for screening potential AD, measurements of serum amyloid- β (Aβ), plasma tau, and serum antibodies for Aβ1 - 42 are not yet well established.

OBJECTIVE: We aimed to identify a new serum biomarker to detect mild cognitive impairment (MCI) and AD in comparison to cognitively healthy control by a new peptidome technology.

METHODS: With only 1.5μl of serum, we examined a new target plate "BLOTCHIP®" plus a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) to discriminate control (n = 100), MCI (n = 60), and AD (n = 99). In some subjects, cognitive Mini-Mental State Examination (MMSE) were compared to positron emission tomography (PET) with Pittsburgh compound B (PiB) and the serum probability of dementia (SPD). The mother proteins of candidate serum peptides were examined in autopsied AD brains.

RESULTS: Apart from Aβ or tau, the present study discovered a new diagnostic 4-peptides-set biomarker for discriminating control, MCI, and AD with 87% of sensitivity and 65% of specificity between control and AD (***p < 0.001). MMSE score was well correlated to brain Aβ deposition and to SPD of AD. The mother proteins of the four peptides were upregulated for coagulation, complement, and plasticity (three proteins), and was downregulated for anti-inflammation (one protein) in AD brains.

CONCLUSION: The present serum biomarker set provides a new, rapid, non-invasive, highly quantitative and low-cost clinical application for dementia screening, and also suggests an alternative pathomechanism of AD for neuroinflammation and neurovascular unit damage.

%B J Alzheimers Dis %V 73 %P 217-227 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31771070?dopt=Abstract %R 10.3233/JAD-191016 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Non-Coding RNAs Based Molecular Links in Type 2 Diabetes, Ischemic Stroke, and Vascular Dementia. %A Vijayan, Murali %A Reddy, P Hemachandra %X

This article reviews recent advances in the study of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and their functions in type 2 diabetes mellitus (T2DM), ischemic stroke (IS), and vascular dementia (VaD). miRNAs and lncRNAs are gene regulation markers that both regulate translational aspects of a wide range of proteins and biological processes in healthy and disease states. Recent studies from our laboratory and others have revealed that miRNAs and lncRNAs expressed differently are potential therapeutic targets for neurological diseases, especially T2DM, IS, VaD, and Alzheimer's disease (AD). Currently, the effect of aging in T2DM, IS, and VaD and the cellular and molecular pathways are largely unknown. In this article, we highlight results from the works on the molecular connections between T2DM and IS, and IS and VaD. In each disease, we also summarize the pathophysiology and the differential expressions of miRNAs and lncRNAs. Based on current research findings, we hypothesize that 1) T2DM bi-directionally and age-dependently induces IS and VaD, and 2) these changes are precursors to the onset of dementia in elderly people. Research into these hypotheses is required to examine further whether research efforts on reducing T2DM, IS, and VaD may affect dementia and/or delay the AD disease process in the aged population.

%B J Alzheimers Dis %V 75 %P 353-383 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32310177?dopt=Abstract %R 10.3233/JAD-200070 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Normal Pressure Hydrocephalus in Down Syndrome: The Report of Two Cases. %A Marano, Massimo %A Pompucci, Angelo %A Motolese, Francesco %A Rossi, Mariagrazia %A Coletta, Ernesto %A Di Lazzaro, Vincenzo %A Fasano, Alfonso %A Petrella, Gianpaolo %X

Down syndrome (DS) is the most common cause of intellectual disability in infants and has a well-known relationship with the Alzheimer's disease. The association between DS and the other pathologies of senescence, such as normal pressure hydrocephalus (NPH), has been poorly investigated. This series included two DS patients with NPH. In both cases, NPH symptoms were initially misdiagnosed as DS associated senescence. Patients were treated with ventricular-peritoneal shunt, showing a sustained improvement (1 and 4 years of follow-up). To our knowledge, this is the first description of the occurrence of NPH in adult patients with DS and surgical outcomes.

%B J Alzheimers Dis %V 77 %P 979-984 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200409 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Novel Markers of Angiogenesis in the Setting of Cognitive Impairment and Dementia. %A Callahan, Christopher M %A Apostolova, Liana G %A Gao, Sujuan %A Risacher, Shannon L %A Case, Jamie %A Saykin, Andrew J %A Lane, Kathleen A %A Swinford, Cecily G %A Yoder, Mervin C %X

BACKGROUND: Aberrant angiogenesis may play a role in the development of Alzheimer's disease and related dementia.

OBJECTIVE: To explore the relationship between angiogenesis activity and evidence of neurodegeneration among older adults.

METHODS: Cross-sectional study of 49 older adults clinically characterized as cognitively normal, mild cognitive impairment, or early Alzheimer's disease. In addition to neuroimaging, we completed assays on peripheral blood, including: vascular endothelial growth factor, tumor necrosis factor, fibroblast growth factor, and amyloid-β peptide 40. We used advanced polychromatic flow cytometry to phenotype circulating mononuclear cells to assess angiogenesis activity.

RESULTS: Although we documented differences in cognitive performance, structural changes on neuroimaging, and burden of amyloid and tau on positron emission tomography, angiogenesis activity did not vary by group. Interestingly, VEGF levels were shown to be increased among subjects with mild cognitive impairment. In ANCOVA models controlling for age, sex, intracranial volume, and monocyte subpopulations, angiogenesis activity was correlated with increased white matter hyperintensities.

CONCLUSION: We demonstrate a significant association between angiogenesis activity and cerebrovascular disease. To better understand the potential of angiogenesis as an intervention target, longitudinal studies are needed.

%B J Alzheimers Dis %V 75 %P 959-969 %8 2020 Jun 02 %G eng %N 3 %R 10.3233/JAD-191293 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Odor Identification Impairment and Change with Cholinesterase Inhibitor Treatment in Mild Cognitive Impairment. %A Devanand, D P %A Liu, Xinhua %A Chunga, Richard E %A Cohen, Hannah %A Andrews, Howard %A Schofield, Peter W %A Stern, Yaakov %A Huey, Edward D %A Choi, Jongwoo %A Pelton, Gregory H %X

BACKGROUND: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease (AD) pathology, and short-term change in odor identification impairment with cholinesterase inhibitor (CheI) treatment may predict longer term cognitive outcomes.

OBJECTIVE: In patients with mild cognitive impairment (MCI) treated prospectively with donepezil, a CheI, for 52 weeks, to determine if 1) acute decline in odor identification ability with anticholinergic challenge can predict cognitive improvement, and 2) change in odor identification over 8 weeks can predict cognitive improvement.

METHODS: MCI was diagnosed clinically without AD biomarkers. At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and this dose was maintained for 52 weeks. Main outcomes were ADAS-Cog total score and Selective Reminding Test (SRT) total immediate recall score measured at baseline, 26 and 52 weeks.

RESULTS: In 100 study participants, mean age 70.14 (SD 9.35) years, atropine-induced decrease in UPSIT score at baseline was not associated with change in ADAS-Cog or SRT scores over 52 weeks. Change in UPSIT score from 0 to 8 weeks did not show a significant association with change in the ADAS-Cog or SRT measures over 52 weeks.

CONCLUSION: These negative findings in a relatively large sample of patients with MCI did not replicate results in much smaller samples. Change in odor identification with anticholinergic challenge, and over 8 weeks, may not be useful predictors of cognitive improvement with CheI in patients with MCI.

%B J Alzheimers Dis %V 75 %P 845-854 %8 2020 Jun 02 %G eng %N 3 %R 10.3233/JAD-200021 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Older Patients with Alzheimer's Disease-Related Cortical Atrophy Who Develop Post-Operative Delirium May Be at Increased Risk of Long-Term Cognitive Decline After Surgery. %A Racine, Annie M %A Touroutoglou, Alexandra %A Abrantes, Tatiana %A Wong, Bonnie %A Fong, Tamara G %A Cavallari, Michele %A Travison, Thomas G %A Gou, Yun %A Marcantonio, Edward R %A Alsop, David C %A Jones, Richard N %A Inouye, Sharon K %A Dickerson, Bradford C %X

BACKGROUND: Older surgical patients with Alzheimer's disease (AD) dementia and delirium are at increased risk for accelerated long-term cognitive decline.

OBJECTIVE: Investigate associations between a probabilistic marker of preclinical AD, delirium, and long-term cognitive decline.

METHODS: The Successful Aging after Elective Surgery cohort includes older adults (≥70 years) without dementia who underwent elective surgery. 140 patients underwent preoperative magnetic resonance imaging and had≥6 months cognitive follow-up. Cortical thickness was measured in 'AD-Signature' regions. Delirium was evaluated each postoperative day by the Confusion Assessment Method. Cognitive performance was assessed using a detailed neuropsychological battery at baseline; months 1, 2, and 6; and every 6 months thereafter until 36 months. Using either a General Cognitive Performance composite (GCP) or individual test scores as outcomes, we performed linear mixed effects models to examine main effects of AD-signature atrophy and the interaction of AD-signature atrophy and delirium on slopes of cognitive change from post-operative months 2-36.

RESULTS: Reduced baseline AD-signature cortical thickness was associated with greater 36-month cognitive decline in GCP (standardized beta coefficient, β = -0.030, 95% confidence interval [-0.060, -0.001]). Patients who developed delirium who also had thinner AD signature cortex showed greater decline on a verbal learning test (β = -0.100 [-0.192, -0.007]).

CONCLUSION: Patients with the greatest baseline AD-related cortical atrophy who develop delirium after elective surgery appear to experience the greatest long-term cognitive decline. Thus, atrophy suggestive of preclinical AD and the development of delirium may be high-risk indicators for long-term cognitive decline following surgery.

%B J Alzheimers Dis %V 75 %P 187-199 %8 2020 May 05 %G eng %N 1 %R 10.3233/JAD-190380 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Optimizing Use of Neuroimaging Tools in Evaluation of Prodromal Alzheimer's Disease and Related Disorders. %A Raji, Cyrus A %A Torosyan, Nare %A Silverman, Daniel H S %X

Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by preclinical, pre-dementia, and dementia phases. Progression of the disease leads to cognitive decline and is associated with loss of functional independence, personality changes, and behavioral disturbances. Current guidelines for AD diagnosis include the use of neuroimaging tools as biomarkers for identifying and monitoring pathological changes. Various imaging modalities, namely magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET) and PET with amyloid-beta tracers are available to facilitate early accurate diagnoses. Enhancing diagnosis in the early stages of the disease can allow for timely interventions that can delay progression of the disease. This paper will discuss the characteristic findings associated with each of the imaging tools for patients with AD, with a focus on FDG-PET due to its established accuracy in assisting with the differential diagnosis of dementia and discussion of other methods including MRI. Diagnostically-relevant features to aid clinicians in making a differential diagnosis will also be pointed out and multimodal imaging will be reviewed. We also discuss the role of quantification software in interpretation of brain imaging. Lastly, to guide evaluation of patients presenting with cognitive deficits, an algorithm for optimal integration of these imaging tools will be shared. Molecular imaging modalities used in dementia evaluations hold promise toward identifying AD-related pathology before symptoms are fully in evidence. The work describes state of the art functional and molecular imaging methods for AD. It will also overview a clinically applicable quantitative method for reproducible assessments of such scans in the early identification of AD.

%B J Alzheimers Dis %V 77 %P 935-947 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200487 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Oxidized Products of Omega-6 and Omega-3 Long Chain Fatty Acids Are Associated with Increased White Matter Hyperintensity and Poorer Executive Function Performance in a Cohort of Cognitively Normal Hypertensive Older Adults. %A Shinto, Lynne %A Lahna, David %A Murchison, Charles F %A Dodge, Hiroko %A Hagen, Kirsten %A David, Jason %A Kaye, Jeffrey %A Quinn, Joseph F %A Wall, Rachel %A Silbert, Lisa C %X

BACKGROUND: Cerebrovascular disease is a common cause of dementia in older adults, and potentially preventable with early intervention. Oxylipins are produced from the oxidation of long-chain polyunsaturated fatty acids (PUFA) possessing potent vascular effects. Oxylipins generated from the cytochrome P450 pathway are enzymatically converted to diols by soluble epoxide hydrolase (sEH); sEH products have been associated with small vessel ischemic disease. Little is known about oxylipins' impact on markers of dementia risk.

OBJECTIVE: An exploratory examination of the association between omega-6 and omega-3 derived oxylipins, brain MRI, and cognition.

METHODS: Thirty-seven non-demented participants with controlled hypertension (mean age 65.6 years) were enrolled in a dementia prevention study investigating fish oil and lipoic acid on preserving cognitive function. Baseline associations between plasma oxylipins, white matter hyperintensity (WMH), and Trails-B were examined using linear regression. P450-derived diol/epoxide ratio was an indirect measure of sEH activity.

RESULTS: Omega-6 derived 9-HODE was associated with increased WMH (p = 0.017) and reduced grey matter volume (p = 0.02). Omega-6 P450-derived diol/epoxide ratio 9,10-DiHOME/9,10-EpOME was associated with increased WMH (p = 0.035) and poorer performance on Trails-B (p = 0.05); ratio14,15-DHET/14,15-EET was associated with increased WMH (p = 0.045). Omega-3 P450-derived diol/epoxide ratio 19,20-DiHDPE/19,20-EpDPE was associated with increased WMH (p = 0.04) and poorer performance on Trails-B (p = 0.04). Arachidonic acid was associated with better performance on Trails-B (p = 0.012); Omega-3 derived 16,17-EpDPE was associated with decreased WMH (p = 0.005).

CONCLUSIONS: With the exception of arachidonic acid, it was specific oxylipin products, not their parent PUFAs, that were associated with unfavorable and favorable MRI and cognitive markers of dementia risk.

%B J Alzheimers Dis %V 74 %P 65-77 %8 2020 Mar 10 %G eng %N 1 %R 10.3233/JAD-191197 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Is the p3 Peptide (Aβ17-40, Aβ17-42) Relevant to the Pathology of Alzheimer's Disease?1. %A Kuhn, Ariel J %A Raskatov, Jevgenij %X

Despite the vast heterogeneity of amyloid plaques isolated from the brains of those with Alzheimer's Disease (AD), the basis of the Amyloid Cascade Hypothesis targets a single peptide, the amyloid-β (Aβ) peptide. The countless therapeutic efforts targeting the production and aggregation of this specific peptide have been met with disappointment, leaving many to question the role of Aβ in AD. An alternative cleavage product of the Amyloid-β protein precursor, called the p3 peptide, which has also been isolated from the brains of AD patients, has been largely absent from most Aβ-related studies. Typically referred to as non-amyloidogenic and even suggested as neuroprotective, the p3 peptide has garnered little attention aside from some conflicting findings on cytotoxicity and potential self-assembly to form higher order aggregates. Herein, we report an extensive analysis of the findings surrounding p3 and offer some evidence as to why it may not be as innocuous as previously suggested.

%B J Alzheimers Dis %V 74 %P 43-53 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32176648?dopt=Abstract %R 10.3233/JAD-191201 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice. %A Stojakovic, Andrea %A Chang, Su-Youne %A Nesbitt, Jarred %A Pichurin, Nicholas P %A Ostroot, Mark A %A Aikawa, Tomonori %A Kanekiyo, Takahisa %A Trushina, Eugenia %X

BACKGROUND: Accumulation of hyperphosphorylated tau (pTau) protein is associated with synaptic dysfunction in Alzheimer's disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown.

OBJECTIVE: To investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on levels of human pTau, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms.

METHODS: CP2 was administered to male and female 3xTg-AD mice from 3.5-18 months of age. Cognitive function was assessed using the Morris water maze. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting.

RESULTS: Chronic CP2 treatment restored synaptic activity in female 3xTg-AD mice; cognitive function, levels of synaptic proteins, glucose metabolism, and energy homeostasis were improved in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), and reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β).

CONCLUSION: CP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for treating AD.

%B J Alzheimers Dis %V 79 %P 335-353 %8 2021 Jan 5 %G eng %N 1 %R 10.3233/JAD-201015 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Patterns of Regional Cerebral Blood Flow as a Function of Obesity in Adults. %A Amen, Daniel G %A Wu, Joseph %A George, Noble %A Newberg, Andrew %X

BACKGROUND: While obesity has been shown to be a risk factor for Alzheimer's disease, the potential mechanisms underlying this risk may be clarified with better understanding of underlying physiology in obese persons.

OBJECTIVE: To identify patterns of cerebral perfusion abnormality in adults as a function of body mass index (BMI) defined weight categories, including overweight or obese status.

METHODS: A large psychiatric cohort of 35,442 brain scans across 17,721 adults (mean age 40.8±16.2 years, range 18-94 years) were imaged with SPECT during baseline and concentration scans, the latter done after each participant completed the Connors Continuous Performance Test II. ANOVA was done to identify patterns of perfusion abnormality in this cohort across BMI designations of underweight (BMI < 18.5), normal weight (BMI = 18.5 to 24.9), overweight (BMI 24.9 to 29.9), obesity (BMI≥30), and morbid obesity (BMI≥40). This analysis was done for 128 brain regions quantifying SPECT perfusion using the automated anatomical labeling (AAL) atlas.

RESULTS: Across adulthood, higher BMI correlated with decreased perfusion on both resting and concentration brain SPECT scans. These are seen in virtually all brain regions, including those influenced by AD pathology such as the hippocampus.

CONCLUSION: Greater BMI is associated with cerebral perfusion decreases in both resting and concentration SPECT scans across adulthood.

%B J Alzheimers Dis %V 77 %P 1331-1337 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200655 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Perceived Stress is Associated with Alzheimer's Disease Cerebrospinal Fluid Biomarkers in African Americans with Mild Cognitive Impairment. %A Trammell, Antoine R %A McDaniel, Darius J %A Obideen, Malik %A Okafor, Maureen %A Thomas, Tiffany L %A Goldstein, Felicia C %A Shaw, Leslie M %A Hajjar, Ihab M %X

BACKGROUND: African Americans (AA) have a higher Alzheimer's disease (AD) prevalence and report more perceived stress than White Americans. The biological basis of the stress-AD link is unclear. This study investigates the connection between stress and AD biomarkers in a biracial cohort.

OBJECTIVE: Establish biomarker evidence for the observed association between stress and AD, especially in AA.

METHODS: A cross-sectional study (n = 364, 41.8% AA) administering cognitive tests and the perceived stress scale (PSS) questionnaire. A subset (n = 309) provided cerebrospinal fluid for measurement of Aβ42, Tau, Ptau, Tau/Aβ42 (TAR), and Ptau/Aβ42 (PTAR). Multivariate linear regression, including factors that confound racial differences in AD, was performed.

RESULTS: Higher PSS scores were associated with higher Ptau (β= 0.43, p = 0.01) and PTAR (β= 0.005, p = 0.03) in AA with impaired cognition (mild cognitive impairment).

CONCLUSION: Higher PSS scores were associated with Tau-related AD biomarker indices in AA/MCI, suggesting a potential biological connection for stress with AD and its racial disparity.

%B J Alzheimers Dis %V 77 %P 843-853 %8 2020 Sep 15 %G eng %N 2 %R 10.3233/JAD-200089 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Performance of Validated MicroRNA Biomarkers for Alzheimer's Disease in Mild Cognitive Impairment. %A Sandau, Ursula S %A Wiedrick, Jack T %A Smith, Sierra J %A McFarland, Trevor J %A Lusardi, Theresa A %A Lind, Babett %A Harrington, Christina A %A Lapidus, Jodi A %A Galasko, Douglas R %A Quinn, Joseph F %A Saugstad, Julie A %X

BACKGROUND: Cerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer's disease (AD) have been identified, but have not been evaluated in prodromal AD, including mild cognitive impairment (MCI).

OBJECTIVE: To assess whether a set of validated AD miRNA biomarkers in CSF are also sensitive to early-stage pathology as exemplified by MCI diagnosis.

METHODS: We measured the expression of 17 miRNA biomarkers for AD in CSF samples from AD, MCI, and cognitively normal controls (NC). We then examined classification performance of the miRNAs individually and in combination. For each miRNA, we assessed median expression in each diagnostic group and classified markers as trending linearly, nonlinearly, or lacking any trend across the three groups. For trending miRNAs, we assessed multimarker classification performance alone and in combination with apolipoprotein E ɛ4 allele (APOEɛ4) genotype and amyloid-β42 to total tau ratio (Aβ42:T-Tau). We identified predicted targets of trending miRNAs using pathway analysis.

RESULTS: Five miRNAs showed a linear trend of decreasing median expression across the ordered diagnoses (control to MCI to AD). The trending miRNAs jointly predicted AD with area under the curve (AUC) of 0.770, and MCI with AUC of 0.705. Aβ42:T-Tau alone predicted MCI with AUC of 0.758 and the AUC improved to 0.813 (p = 0.051) after adding the trending miRNAs. Multivariate correlation of the five trending miRNAs with Aβ42:T-Tau was weak.

CONCLUSION: Selected miRNAs combined with Aβ42:T-Tau improved classification performance (relative to protein biomarkers alone) for MCI, despite a weak correlation with Aβ42:T-Tau. Together these data suggest that that these miRNAs carry novel information relevant to AD, even at the MCI stage. Preliminary target prediction analysis suggests novel roles for these biomarkers.

%B J Alzheimers Dis %V 78 %P 245-263 %8 2020 Oct 27 %G eng %N 1 %R 10.3233/JAD-200396 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Plasma High Density Lipoprotein Small Subclass is Reduced in Alzheimer's Disease Patients and Correlates with Cognitive Performance. %A Pedrini, Steve %A Hone, Eugene %A Gupta, Veer B %A James, Ian %A Teimouri, Elham %A Bush, Ashley I %A Rowe, Christopher C %A Villemagne, Victor L %A Ames, David %A Masters, Colin L %A Rainey-Smith, Stephanie %A Verdile, Giuseppe %A Sohrabi, Hamid R %A Raida, Manfred R %A Wenk, Markus R %A Taddei, Kevin %A Chatterjee, Pratishtha %A Martins, Ian %A Laws, Simon M %A Martins, Ralph N %X

BACKGROUND: The link between cholesterol and Alzheimer's disease (AD) has received much attention, as evidence suggests high levels of cholesterol might be an AD risk factor. The carriage of cholesterol and lipids through the body is mediated via lipoproteins, some of which, particularly apolipoprotein E (ApoE), are intimately linked with AD. In humans, high density lipoprotein (HDL) is regarded as a "good" lipid complex due to its ability to enable clearance of excess cholesterol via 'cholesterol reverse transport', although its activities in the pathogenesis of AD are poorly understood. There are several subclasses of HDL; these range from the newly formed small HDL, to much larger HDL.

OBJECTIVE: We examined the major subclasses of HDL in healthy controls, mild cognitively impaired, and AD patients who were not taking statins to determine whether there were HDL profile differences between the groups, and whether HDL subclass levels correlated with plasma amyloid-β (Aβ) levels or brain Aβ deposition.

METHODS: Samples from AIBL cohort were used in this study. HDL subclass levels were assessed by Lipoprint while Aβ1-42 levels were assessed by ELISA. Brain Aβ deposition was assessed by PET scan. Statistical analysis was performed using parametric and non-parametric tests.

RESULTS: We found that small HDL subclass is reduced in AD patients and it correlates with cognitive performance while plasma Aβ concentrations do not correlate with lipid profile or HDL subfraction levels.

CONCLUSION: Our data indicate that AD patients exhibit altered plasma HDL profile and that HDL subclasses correlate with cognitive performances.

%B J Alzheimers Dis %V 77 %P 733-744 %8 2020 Sep 15 %G eng %N 2 %R 10.3233/JAD-200291 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Plasma Tau Variants Detected by a Novel Anti-Tau Monoclonal Antibody: A Potential Biomarker for Alzheimer's Disease. %A Gonzlez, Andrea %A Guzmn-Martínez, Leonardo %A Maccioni, Ricardo B %X

BACKGROUND: A major drawback in Alzheimer's disease (AD) is the lack of validated biomarkers for routine clinical diagnostic. We have reported earlier a novel blood biomarker, named Alz-tau®, based on variants of platelet tau. This marker evaluates the ratio of high molecular weight tau (HMWtau) and the low molecular weight (LMWtau) tau.

OBJECTIVE: To analyze a potential novel source of antigen for Alz-tau®, plasma tau, detected by immunoreactivity with the novel monoclonal antibody, tau51.

METHODS: We evaluated tau variants in plasma precipitated with ammonium sulfate from 36 AD patients and 15 control subjects by western blot with this novel monoclonal antibody.

RESULTS: The HMW/LMWtau ratio was statistically different between AD patients and controls.

CONCLUSIONS: Plasma tau variants are suitable to be considered as a novel antigen source for the Alz-tau® biomarker for AD.

%B J Alzheimers Dis %V 77 %P 877-883 %8 2020 Sep 15 %G eng %N 2 %R 10.3233/JAD-200386 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Potential for Digital Monitoring to Enhance Wellbeing at Home for People with Mild Dementia and Their Family Carers. %A Fowler-Davis, Sally %A Barnett, Deborah %A Kelley, John %A Curtis, David %X

Digital technologies have the potential to assist people with dementia to monitor day to day activities and mitigate the risks of living independently. This purposive pilot study surveyed participants for frailty, wellbeing, and perceived carer burden using the 3Rings™ digital plug. 30 paired participants used the digital device for four months. People with dementia reported a decline in wellbeing and increased frailty. Family carers reported a decline in wellbeing but 18 reported a reduction in burden. The use of digital monitoring by family carers demonstrated a reduction in their perceived burden and the device was acceptable to people with mild dementia living alone.

%B J Alzheimers Dis %V 73 %P 867-872 %8 2020 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/31884471?dopt=Abstract %R 10.3233/JAD-190844 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Potential Novel Role of COVID-19 in Alzheimer's Disease and Preventative Mitigation Strategies. %A Naughton, Sean X %A Raval, Urdhva %A Pasinetti, Giulio M %K Aged %K Alzheimer Disease %K Betacoronavirus %K Coronavirus Infections %K COVID-19 %K Diabetes Mellitus, Type 2 %K Humans %K Interferon Type I %K Pandemics %K Pneumonia, Viral %K SARS-CoV-2 %K Synapses %X

There are a number of potential implications for the field of Alzheimer's disease (AD) stemming from the global spread of SARS-CoV-2. Neuroinflammation is known to be a prominent feature of neurodegeneration and plays a major role in AD pathology. Immune response and excessive inflammation in COVID-19 may also accelerate the progression of brain inflammatory neurodegeneration, and elderly individuals are more susceptible to severe outcomes after SARS-CoV-2 infection. Individuals with type 2 diabetes (T2D) are at an increased risk for AD as well as severe outcomes after SARS-CoV-2 infection. Genetic and socioeconomic factors influencing the rates of T2D, AD, and COVID-19 severity may create an exceptionally high-risk profile for certain demographics such as African Americans and Hispanic Americans. Type I interferon response plays an important role in both host response to viral infection, as well as AD pathology and may be a sensible therapeutic target in both AD and COVID-19.

%B J Alzheimers Dis %V 76 %P 21-25 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32538855?dopt=Abstract %R 10.3233/JAD-200537 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Potential of FTIR Spectroscopy Applied to Exosomes for Alzheimer's Disease Discrimination: A Pilot Study. %A Martins, Tânia Soares %A Magalhães, Sandra %A Rosa, Ilka Martins %A Vogelgsang, Jonathan %A Wiltfang, Jens %A Delgadillo, Ivonne %A Catita, José %A da Cruz E Silva, Odete A B %A Nunes, Alexandra %A Henriques, Ana Gabriela %X

Alzheimer's disease (AD) diagnosis is based on psychological and imaging tests but can also include monitoring cerebrospinal fluid (CSF) biomarkers. However, CSF based-neurochemical approaches are expensive and invasive, limiting their use to well-equipped settings. In contrast, blood-based biomarkers are minimally invasive, cost-effective, and a widely accessible alternative. Blood-derived exosomes have recently emerged as a reliable AD biomarker source, carrying disease-specific cargo. Fourier-transformed infrared (FTIR) spectroscopy meets the criteria for an ideal diagnostic methodology since it is rapid, easy to implement, and has high reproducibility. This metabolome-based technique is useful for diagnosing a broad range of diseases, although to our knowledge, no reports for FTIR spectroscopy applied to exosomes in AD exist. In this ground-breaking pilot study, FTIR spectra of serum and serum-derived exosomes from two independent cohorts were acquired and analyzed using multivariate analysis. The regional UA-cohort includes 9 individuals, clinically diagnosed with AD, mean age of 78.7 years old; and the UMG-cohort comprises 12 individuals, clinically diagnosed with AD (based on molecular and/or imaging data), mean age of 73.2 years old. Unsupervised principal component analysis of FTIR spectra of serum-derived exosomes revealed higher discriminatory value for AD cases when compared to serum as a whole. Consistently, the partial least-squares analysis revealed that serum-derived exosomes present higher correlations than serum. In addition, the second derivative peak area calculation also revealed significant differences among Controls and AD cases. The results obtained suggest that this methodology can discriminate cases from Controls and thus be potential useful to assist in AD clinical diagnosis.

%B J Alzheimers Dis %V 74 %P 391-405 %8 2020 Mar 10 %G eng %N 1 %R 10.3233/JAD-191034 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Potentially Pathogenic Calcium Oxalate Dihydrate and Titanium Dioxide Crystals in the Alzheimer's Disease Entorhinal Cortex. %A Heller, Adam %A Coffman, Sheryl S %A Jarvis, Karalee %X

Knowing that Alzheimer's disease (AD) nucleates in the entorhinal cortex (EC), samples of 12 EC specimens were probed for crystals by a protocol detecting fewer than 1/5000th of those present. Of the 61 crystals found, 31 were expected and 30 were novel. Twenty-one crystals of iron oxides and 10 atherosclerosis-associated calcium pyrophosphate dihydrate crystals were expected and found. The 30 unexpected crystals were NLRP3-inflammasome activating calcium oxalate dihydrate (12) and titanium dioxide (18). Their unusual distribution raises the possibility that some were of AD origination sites.

%B J Alzheimers Dis %V 77 %P 547-550 %8 2020 Sep 15 %G eng %N 2 %R 10.3233/JAD-200535 %0 Journal Article %J J Alzheimers Dis %D 2020 %T The Prevalence of Dementia: A Systematic Review and Meta-Analysis. %A Cao, Qing %A Tan, Chen-Chen %A Xu, Wei %A Hu, Hao %A Cao, Xi-Peng %A Dong, Qiang %A Tan, Lan %A Yu, Jin-Tai %X

Dementia is a severe neurodegenerative disorder and it can be categorized into several subtypes by different pathogenic causes. We sought to comprehensively analyzed the prevalence of dementia from perspectives of geographic region (Asia, Africa, South America, and Europe/North America), age, and gender. We searched PubMed and EMBASE for relevant articles on dementia published from January 1985 to August 2019. In these studies, analyses were stratified by geographic region, age, and gender. Meta-regression was conducted to identify if there were significant differences between groups. We included forty-seven studies. Among the individuals aged 50 and over in the community, the pooled prevalence for all-cause dementia, Alzheimer's disease, and vascular dementia were 697 (CI95%: 546-864) per 10,000 persons, 324 (CI95%: 228-460) per 10,000 persons, and 116 (CI95%: 86-157) per 10,000 persons, respectively. In our study, the prevalence of all-type dementia in individuals aged 100 years and older (6,592 per 10,000 cases) is 244 times higher than in those aged 50-59 (27 per 10,000 cases). The number of people living with dementia approximately doubles every five years. The prevalence was greater in women than in men (788 cases versus 561 cases per 10,000 persons) in overall analysis. In individuals aged 60 to 69 years, AD prevalence in females was 1.9 times greater than that in males (108 cases versus 56 cases per 10,000 persons), while the prevalence of VaD was 1.8 times greater in males than in females (56 cases versus 32 cases per 10,000 persons). Prevalence rate was higher in Europe and North America than in Asia, Africa, and South America.

%B J Alzheimers Dis %V 73 %P 1157-1166 %8 2020 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/31884487?dopt=Abstract %R 10.3233/JAD-191092 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Quantitative Mass Spectrometric Assay of Whole and CNBr-Cleaved Amyloid-β Peptides in Human Brain. %A Furman, Ran %A Ng, Sharon C W %A Komatsu, Hiroaki %A Axelsen, Paul H %X

Various amyloid-β (Aβ) peptides accumulate in brain in Alzheimer's disease, and the amounts of specific peptide variants may have pathological significance. The quantitative determination of these variants is challenging because losses inevitably occur during tissue processing and analysis. This report describes the use of stable-isotope-labeled Aβ peptides as internal standards for quantitative mass spectrometric assays, and the use of cyanogen bromide (CNBr) to remove C-terminal residues beyond Met35. The removal of residues beyond Met35 reduces losses due to aggregation, and facilitates the detection of post-translationally modified Aβ peptides. Results from 8 human brain samples suggest that the tissue concentrations of the 42-residue Aβ peptide tend to be similar in different patients. Concentrations of the 40-residue Aβ peptide are more variable, and may be greater or lesser than the 42-residue peptide. The concentration of the CNBr cleavage product closely matches the sum of the 40-residue and 42-residue peptide concentrations, indicating that these two Aβ peptides account for most of the C-terminal variants in these patients. CNBr treatment facilitated the detection of post-translational modifications such as pyroglutamyl and hexose-modified Aβ peptides.

%B J Alzheimers Dis %V 73 %P 1637-1645 %8 2020 Feb 18 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/31958092?dopt=Abstract %R 10.3233/JAD-190647 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Reduced Hippocampal Glutamate and Posterior Cingulate N-Acetyl Aspartate in Mild Cognitive Impairment and Alzheimer's Disease Is Associated with Episodic Memory Performance and White Matter Integrity in the Cingulum: A Pilot Study. %A Wong, Dickson %A Atiya, Samir %A Fogarty, Jennifer %A Montero-Odasso, Manuel %A Pasternak, Stephen H %A Brymer, Chris %A Borrie, Michael J %A Bartha, Robert %X

Identification of biological changes underlying the early symptoms of Alzheimer's disease (AD) will help to identify and stage individuals prior to symptom onset. The limbic system, which supports episodic memory and is impaired early in AD, is a primary target. In this study, brain metabolism and microstructure evaluated by high field (7 Tesla) proton magnetic resonance spectroscopy (1H-MRS) and diffusion tensor imaging (DTI) were evaluated in the limbic system of eight individuals with mild cognitive impairment (MCI), nine with AD, and sixteen normal elderly controls (NEC). Left hippocampal glutamate and posterior cingulate N-acetyl aspartate concentrations were reduced in MCI and AD compared to NEC. Differences in DTI metrics indicated volume and white matter loss along the cingulum in AD compared to NEC. Metabolic and microstructural changes were associated with episodic memory performance assessed using Craft Story 21 Recall and Benson Complex Figure Copy. The current study suggests that metabolite concentrations measured using 1H-MRS may provide insight into the underlying metabolic and microstructural processes of episodic memory impairment.

%B J Alzheimers Dis %V 73 %P 1385-1405 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/31958093?dopt=Abstract %R 10.3233/JAD-190773 %0 Journal Article %J J Alzheimers Dis %D 2020 %T The Relationship Between Anxiety and Incident Agitation in Alzheimer's Disease. %A Liu, Kathy Y %A Costello, Harry %A Reeves, Suzanne %A Howard, Robert %X

BACKGROUND: Agitation in Alzheimer's disease (AD) has been hypothesized to be an expression of anxiety, but whether anxiety early in the course of dementia could be a risk factor for developing later agitation is unknown.

OBJECTIVE: We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to examine the longitudinal relationship between anxiety and incident agitation in individuals with a diagnosis of AD at baseline or during follow-up.

METHODS: Longitudinal neuropsychiatric symptom data from AD individuals who were agitation-free at study baseline (N = 272) were analyzed using mixed effects regression models to test the longitudinal relationship between baseline and incident anxiety with incident agitation.

RESULTS: Anxiety at baseline was not associated with subsequent agitation, but there was a positive linear relationship between incident anxiety and agitation over the study duration. Baseline apathy and delusions were consistently associated with subsequent agitation and greater disease severity and illness duration also appeared to be risk factors for agitation.

CONCLUSION: Our findings support the concept that anxiety and agitation are likely to be distinct rather than equivalent constructs in mild-moderate AD. Future longitudinal cohort studies are needed to replicate these findings and further characterize potential risk factors for agitation, such as apathy and delusions.

%B J Alzheimers Dis %V 78 %P 1119-1127 %8 2020 Nov 24 %G eng %N 3 %R 10.3233/JAD-200516 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Resilience of Alzheimer's Disease to COVID-19. %A Li, Jingwen %A Long, Xi %A Huang, Heqing %A Tang, Jine %A Zhu, Chunli %A Hu, Shaoping %A Wu, Jing %A Li, Jinghong %A Lin, Zhicheng %A Xiong, Nian %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cluster Analysis %K Cohort Studies %K Coronavirus Infections %K COVID-19 %K Disease Progression %K Fatigue %K Female %K Humans %K Length of Stay %K Male %K Middle Aged %K Pandemics %K Patient Discharge %K Pleural Effusion %K Pneumonia %K Pneumonia, Viral %K Prognosis %K Resilience, Psychological %X

BACKGROUND: Facing the novel coronavirus disease 2019 (COVID-19), most vulnerable individuals are seniors, especially those with comorbidities. More attention needs to been paid to the COVID-19 patients with Alzheimer's disease (AD), which is the top age-related neurodegenerative disease.

OBJECTIVE: Since it is unclear whether AD patients are prone to COVID-19 infection and progression to severe stages, we report for the first time a retrospective analysis of the clinical characteristics of AD patients with COVID-19 pneumonia.

METHODS: We conducted a retrospective cohort study of the clinical data of 19 AD patients with COVID-19 pneumonia, compared with 23 non-AD COVID-19 patients admitted at the same time to our hospital. Demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed.

RESULTS: Between AD patients and non-AD patients with COVID-19 pneumonia, the pneumonia severity was not significantly different. AD patients had a higher clustering onset than non-AD patients. The median duration from symptom onset to hospitalization were shorter in AD patients than non-AD patients, indicating the former were sent to the hospital by their family or from nursing home earlier than the later. The median duration from hospitalization to discharge seemed shorter in AD patients than non-AD patients. Dementia patients seemed less likely to report fatigue. It is noticed that more AD patients might have pericardial effusion than the non-AD patients.

CONCLUSION: AD patients with COVID-19 were in milder conditions with a better prognosis than non-AD patients. AD patients who had adequate access to healthcare showed resilience to COVID-19 with shorter hospital stays.

%B J Alzheimers Dis %V 77 %P 67-73 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32804094?dopt=Abstract %R 10.3233/JAD-200649 %0 Journal Article %J J Alzheimers Dis %D 2020 %T A Review of the Brain-Gut-Microbiome Axis and the Potential Role of Microbiota in Alzheimer's Disease. %A Sun, Miao %A Ma, Kai %A Wen, Jie %A Wang, Guangxian %A Zhang, Changliang %A Li, Qi %A Bao, Xiaofeng %A Wang, Hui %X

Alzheimer's disease (AD) is a neurodegenerative process characterized by loss of neurons in the hippocampus and cerebral cortex, leading to progressive cognitive decline. Pathologically, the hallmark of AD is accumulation of "senile" plaques composed of amyloid-β (Aβ) protein surrounding neurons in affected regions. Despite extensive research into AD pathogenesis and therapeutic targets, there remains no breakthroughs in its management. In recent years, there has been a spark of interest in the connection between the brain and gastrointestinal tract, referred to as the brain-gut axis, and its potential implications for both metabolic and neurologic disease. Moreover, the gastrointestinal flora, referred to as the microbiome, appears to exert significant influence over the brain-gut axis. With the need for expanded horizons in understanding and treating AD, many have turned to the brain-gut-microbiome axis for answers. Here we provide a review of the brain-gut-microbiome axis and discuss the evidence supporting alterations of the axis in the pathogenesis of AD. Specifically, we highlight the role for the microbiome in disruption of Aβ metabolism/clearance, increased permeability of the blood-brain barrier and modulation of the neuroinflammatory response, and inhibition of hippocampal neurogenesis. The majority of the above described findings are the result of excellent, albeit basic and pre-clinical studies. Therefore, we conclude with a brief description of documented clinical support for brain-gut-microbiome axis alteration in AD, including potential microbiome-based therapeutics for AD. Collectively, these findings suggest that the brain-gut-microbiome axis may be a "lost link" in understanding and treating AD and call for future work.

%B J Alzheimers Dis %V 73 %P 849-865 %8 2020 %G eng %N 3 %R 10.3233/JAD-190872 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Revised Framingham Stroke Risk Profile: Association with Cognitive Status and MRI-Derived Volumetric Measures. %A Pelcher, Isabelle %A Puzo, Christian %A Tripodis, Yorghos %A Aparicio, Hugo J %A Steinberg, Eric G %A Phelps, Alyssa %A Martin, Brett %A Palmisano, Joseph N %A Vassey, Elizabeth %A Lindbergh, Cutter %A McKee, Ann C %A Stein, Thor D %A Killiany, Ronald J %A Au, Rhoda %A Kowall, Neil W %A Stern, Robert A %A Mez, Jesse %A Alosco, Michael L %X

BACKGROUND: The Framingham Stroke Risk Profile (FSRP) was created in 1991 to estimate 10-year risk of stroke. It was revised in 2017 (rFSRP) to reflect the modern data on vascular risk factors and stroke risk.

OBJECTIVE: This study examined the association between the rFSRP and cognitive and brain aging outcomes among participants from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS).

METHODS: Cross-sectional rFSRP was computed at baseline for 19,309 participants (mean age = 72.84, SD = 8.48) from the NACC-UDS [9,697 (50.2%) normal cognition, 4,705 (24.4%) MCI, 4,907 (25.4%) dementia]. Multivariable linear, logistic, or ordinal regressions examined the association between the rFSRP and diagnostic status, neuropsychological test performance, CDR® Sum of Boxes, as well as total brain volume (TBV), hippocampal volume (HCV), and log-transformed white matter hyperintensities (WMH) for an MRI subset (n = 1,196). Models controlled for age, sex, education, racial identity, APOEɛ4 status, and estimated intracranial volume for MRI models.

RESULTS: The mean rFSRP probability was 10.42% (min = 0.50%, max = 95.71%). Higher rFSRP scores corresponded to greater CDR Sum of Boxes (β= 0.02, p = 0.028) and worse performance on: Trail Making Test A (β= 0.05, p <  0.001) and B (β= 0.057, p <  0.001), and Digit Symbol (β= -0.058, p <  0.001). Higher rFSRP scores were associated with increased odds for a greater volume of log-transformed WMH (OR = 1.02 per quartile, p = 0.015). No associations were observed for diagnosis, episodic memory or language test scores, HCV, or TBV.

CONCLUSION: These results support the rFSRP as a useful metric to facilitate clinical research on the associations between cerebrovascular disease and cognitive and brain aging.

%B J Alzheimers Dis %V 78 %P 1393-1408 %8 2020 Dec 08 %G eng %N 4 %R 10.3233/JAD-200803 %0 Journal Article %J J Alzheimers Dis %D 2020 %T The Rhythmicity of Clock Genes is Disrupted in the Choroid Plexus of the APP/PS1 Mouse Model of Alzheimer's Disease. %A Furtado, André %A Astaburuaga, Rosario %A Costa, Ana %A Duarte, Ana C %A Gonçalves, Isabel %A Cipolla-Neto, José %A Lemos, Manuel C %A Carro, Eva %A Relógio, Angela %A Santos, Cecília R A %A Quintela, Telma %X

BACKGROUND: The choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, was recently identified as an important component of the circadian clock system.

OBJECTIVE: The fact that circadian rhythm disruption is closely associated to Alzheimer's disease (AD) led us to investigate whether AD pathology can contribute to disturbances of the circadian clock in the CP.

METHODS: For this purpose, we evaluated the expression of core-clock genes at different time points, in 6- and 12-month-old female and male APP/PS1 mouse models of AD. In addition, we also assessed the effect of melatonin pre-treatment in vitro before amyloid-β stimulus in the daily pattern of brain and muscle Arnt-like protein 1 (Bmal1) expression.

RESULTS: Our results showed a dysregulation of circadian rhythmicity of Bmal1 expression in female and male APP/PS1 transgenic 12-month-old mice and of Period 2 (Per2) expression in male mice. Besides, a significant circadian pattern of Bmal1 occurs in the intermittent melatonin pre-treatment group, showing that melatonin can reset the CP circadian clock.

CONCLUSION: These results demonstrated a connection between AD and the disruption of circadian rhythm in the CP, representing an attractive target for disease prevention and/or treatment.

%B J Alzheimers Dis %V 77 %P 795-806 %8 2020 Sep 15 %G eng %N 2 %R 10.3233/JAD-200331 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Role of Executive Functions in the Conversion from Mild Cognitive Impairment to Dementia. %A Junquera Fernández, Almudena %A García-Zamora, Estefanía %A Olazarán Rodríguez, Javier %A Parra Rodríguez, Mario A %A Fernández-Guinea, Sara %X

BACKGROUND: Recent research pointed to executive dysfunction as a potential early predictor of the progression of mild cognitive impairment (MCI)-dementia in Alzheimer's clinical syndrome (ACS). Such cognitive impairments account for functional impairments in instrumental activities of daily living (IADL).

OBJECTIVE: The present study analyzes the contributions of executive functions to predict MCI-dementia progression in ACS.

METHODS: We assessed 145 participants, 51 cognitively unimpaired and 94 MCI. The latter were divided using the traditional, memory-based MCI classification (single domain amnestic, multidomain amnestic, and non-amnestic). Eight tests assessing executive functions were administered at baseline and at 1-year follow-up, together with cognitive screening tools and IADL measures. MCI patients were reclassified based on the outcomes from a K-mean cluster analysis which identified three groups. A simple lineal regression model was used to examine whether the classification based on executive functioning could more accurately predict progression to dementia a year later.

RESULTS: Clusters based on executive function deficits explained a significant proportion of the variance linked to MCI-dementia conversion, even after controlling for the severity of MCI at baseline (F(1, 68) = 116.25, p = 0.000, R2 = 0.63). Classical memory-based MCI classification failed to predict such a conversion (F(1, 68) = 5.09, p = 0.955, R2 = 0.07). Switching, categories generation, and planning were the executive functions that best distinguished between MCI converters and stable.

CONCLUSION: MCI with a dysexecutive phenotype significantly predicts conversion to dementia in ACS a year later. Switching abilities and verbal fluency (categories) must be evaluated in MCI patients to assess risk of future dementia.

%B J Alzheimers Dis %V 77 %P 641-653 %8 2020 Sep 15 %G eng %N 2 %R 10.3233/JAD-200586 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Selective Peripheral Taste Dysfunction in APP/PS1 Mutant Transgenic Mice. %A Wood, Ryan M %A Garcia, Zacnite %A Daniels, Nathan %A Landon, Shannon M %A Humayun, Saima %A Lee, Hyoung-gon %A Macpherson, Lindsey J %X

BACKGROUND: Previous studies indicate that taste dysfunction occurs early in the development of Alzheimer's disease. It is debatable whether the deficit in taste is due primarily to peripheral sensory mechanisms or to central processing, or a combination of the two.

OBJECTIVE: The aim of our current study is to combine behavior and histological data in APP/PS1 transgenic mice to determine whether APP/PS1 transgenic mice show deficits in unconditioned taste preference and avoidance behaviors and whether taste impairments are due to defects in the peripheral taste system and/or problems with central processing of taste information.

METHODS: The APP/PS1 transgenic mutant mice were used as a model of Alzheimer's disease. We employed a brief-access gustometer test to assess immediate orosensory taste responses of APP/PS1 mice. We used immunohistochemistry to examine tongue, gustatory ganglion, and brain tissues to determine a cytological basis for behavioral deficits.

RESULTS: There is a significant, selective reduction of bitter taste sensitivity in APP/PS1 mice. These mice also have a loss of TRPM5-expressing taste receptor cells in the circumvallate papillae of the tongue. While we observed no overt loss of neuron cell bodies within the primary gustatory sensory neurons, degeneration of the neurons' peripheral axons innervating the taste bud may play a role in the observed loss of TRPM5-expressing taste receptor cells.

CONCLUSION: This data supports a potential role for peripheral taste dysfunction in AD through the selective loss of taste receptor cells. Further study is necessary to delineate the mechanisms and pathological significance of this deficit in AD.

%B J Alzheimers Dis %8 2020 Jun 06 %G eng %R 10.3233/JAD-200376 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Serum Hepcidin Levels in Cognitively Normal Older Adults with High Neocortical Amyloid-β Load. %A Chatterjee, Pratishtha %A Mohammadi, Maryam %A Goozee, Kathryn %A Shah, Tejal M %A Sohrabi, Hamid R %A Dias, Cintia B %A Shen, Kaikai %A Asih, Prita R %A Dave, Preeti %A Pedrini, Steve %A Ashton, Nicholas J %A Hye, Abdul %A Taddei, Kevin %A Lovejoy, David B %A Zetterberg, Henrik %A Blennow, Kaj %A Martins, Ralph N %X

BACKGROUND/OBJECTIVE: Hepcidin, an iron-regulating hormone, suppresses the release of iron by binding to the iron exporter protein, ferroportin, resulting in intracellular iron accumulation. Given that iron dyshomeostasis has been observed in Alzheimer's disease (AD) together with elevated serum hepcidin levels, the current study examined whether elevated serum hepcidin levels are an early event in AD pathogenesis by measuring the hormone in cognitively normal older adults at risk of AD, based on high neocortical amyloid-β load (NAL).

METHODS: Serum hepcidin levels in cognitively normal participants (n = 100) aged between 65-90 years were measured using ELISA. To evaluate NAL, all participants underwent 18F-florbetaben positron emission tomography. A standard uptake value ratio (SUVR)

RESULTS: Serum hepcidin was significantly higher in participants with high NAL compared to those with low NAL before and after adjusting for covariates: age, gender, and APOEɛ4 carriage (p < 0.05). A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve, AUC = 0.766), but was outperformed when serum hepcidin was added to the base model (AUC = 0.794) and further improved with plasma Aβ42/40 ratio (AUC = 0.829).

CONCLUSION: The present findings indicate that serum hepcidin is increased in individuals at risk for AD and contribute to the body of evidence supporting iron dyshomeostasis as an early event of AD. Further, hepcidin may add value to a panel of markers that contribute toward identifying individuals at risk of AD; however, further validation studies are required.

%B J Alzheimers Dis %V 76 %P 291-301 %8 2020 Jun 30 %G eng %N 1 %R 10.3233/JAD-200162 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Severity Distribution of Alzheimer's Disease Dementia and Mild Cognitive Impairment in the Framingham Heart Study. %A Yuan, Jing %A Maserejian, Nancy %A Liu, Yulin %A Devine, Sherral %A Gillis, Cai %A Massaro, Joseph %A Au, Rhoda %X

BACKGROUND: Studies providing Alzheimer's disease (AD) prevalence data have largely neglected to characterize the proportion of AD that is mild, moderate, or severe. Estimates of the severity distribution along the AD continuum, including the mild cognitive impairment (MCI) stage, are important to plan research and allocate future resources, particularly resources targeted at particular stages of disease.

OBJECTIVE: To characterize the distribution of severity of AD dementia and MCI among prevalent cases in the population-based Framingham Heart Study.

METHODS: Participants (aged 50-94) with prevalent MCI or AD dementia clinical syndrome were cross-sectionally selected from three time-windows of the population-based Framingham Heart Study in 2004-2005 (n = 381), 2006-2007 (n = 422), and 2008-2009 (n = 389). Summary estimates of the severity distribution were achieved by pooling results across time-windows. Diagnosis and severity were assessed by consensus dementia review. MCI-progressive was determined if the participant had documented progression to AD dementia clinical syndrome using longitudinal data.

RESULTS: Among AD dementia participants, the pooled percentages were 50.4%for mild, 30.3%for moderate, and 19.3%for severe. Among all MCI and AD participants, the pooled percentages were 29.5%, 19.6%, 25.7%, and 45.2%for MCI-not-progressive, MCI-progressive, mild AD dementia, and the combined group of MCI-progressive and mild AD dementia, respectively. Distributions by age and sex were presented.

CONCLUSION: The finding that half of the people living with AD have mild disease underscores the need for research and interventions to slow decline or prevent progression of this burdensome disease.

%B J Alzheimers Dis %V 79 %P 807-817 %8 2021 Jan 19 %G eng %N 2 %R 10.3233/JAD-200786 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Short-Chain Fatty Acids and Lipopolysaccharide as Mediators Between Gut Dysbiosis and Amyloid Pathology in Alzheimer's Disease. %A Marizzoni, Moira %A Cattaneo, Annamaria %A Mirabelli, Peppino %A Festari, Cristina %A Lopizzo, Nicola %A Nicolosi, Valentina %A Mombelli, Elisa %A Mazzelli, Monica %A Luongo, Delia %A Naviglio, Daniele %A Coppola, Luigi %A Salvatore, Marco %A Frisoni, Giovanni B %X

BACKGROUND: Metagenomic data support an association between certain bacterial strains and Alzheimer's disease (AD), but their functional dynamics remain elusive.

OBJECTIVE: To investigate the association between amyloid pathology, bacterial products such as lipopolysaccharide (LPS) and short chain fatty acids (SCFAs: acetate, valerate, butyrate), inflammatory mediators, and markers of endothelial dysfunction in AD.

METHODS: Eighty-nine older persons with cognitive performance from normal to dementia underwent florbetapir amyloid PET and blood collection. Brain amyloidosis was measured with standardized uptake value ratio versus cerebellum. Blood levels of LPS were measured by ELISA, SCFAs by mass spectrometry, cytokines by using real-time PCR, and biomarkers of endothelial dysfunction by flow cytometry. We investigated the association between the variables listed above with Spearman's rank test.

RESULTS: Amyloid SUVR uptake was positively associated with blood LPS (rho≥0.32, p≤0.006), acetate and valerate (rho≥0.45, p < 0.001), pro-inflammatory cytokines (rho≥0.25, p≤0.012), and biomarkers of endothelial dysfunction (rho≥0.25, p≤0.042). In contrast, it was negatively correlated with butyrate (rho≤-0.42, p≤0.020) and the anti-inflammatory cytokine IL10 (rho≤-0.26, p≤0.009). Endothelial dysfunction was positively associated with pro-inflammatory cytokines, acetate and valerate (rho≥0.25, p≤0.045) and negatively with butyrate and IL10 levels (rho≤-0.25, p≤0.038).

CONCLUSION: We report a novel association between gut microbiota-related products and systemic inflammation with brain amyloidosis via endothelial dysfunction, suggesting that SCFAs and LPS represent candidate pathophysiologic links between the gut microbiota and AD pathology.

%B J Alzheimers Dis %V 78 %P 683-697 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33074224?dopt=Abstract %R 10.3233/JAD-200306 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Sleep-Wake Cycle in Alzheimer's Disease Is Associated with Tau Pathology and Orexin Dysregulation. %A Liguori, Claudio %A Spanetta, Matteo %A Izzi, Francesca %A Franchini, Flaminia %A Nuccetelli, Marzia %A Sancesario, Giulia Maria %A Di Santo, Simona %A Bernardini, Sergio %A Mercuri, Nicola Biagio %A Placidi, Fabio %X

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. It is mainly characterized by a progressive deterioration of cognition, but sleep-wake cycle disturbances frequently occur. Irregular sleep-wake cycle, insomnia, and daytime napping usually occur in patients with AD in the course of the disease.

OBJECTIVE: The aim of the present study was to verify the sleep-wake cycle in mild to moderate AD patients compared to controls, and to evaluate the relationship between the sleep-wake cycle impairment and the neuropsychological testing, CSF AD biomarkers, and CSF orexin concentrations.

METHODS: Mild to moderate AD patients were enrolled and underwent 14-day actigraphic recording, sleep diary, neuropsychological testing, and CSF biomarkers analysis. All patients were compared to controls.

RESULTS: Eighteen AD patients were compared to ten controls. AD patients showed the alteration of the sleep-wake cycle, featured by sleep dysregulation and daytime wake fragmentation, with respect to controls. Considering the correlation analysis, we documented the correlation between tau proteins and orexin CSF levels and sleep-wake cycle dysregulation.

CONCLUSION: This study confirmed the dysregulation of sleep-wake cycle in AD patients, as reflected by the daytime wake fragmentation, irregular sleep-wake rhythm, and nocturnal sleep impairment. This sleep-wake cycle disorder correlates with AD neuropathological in vivo features and brain orexin activity. Hence, we suppose that a more marked AD pathology coupled with orexinergic system dysregulation may promote sleep-wake cycle impairment in AD patients.

%B J Alzheimers Dis %V 74 %P 501-508 %8 2020 Mar 24 %G eng %N 2 %R 10.3233/JAD-191124 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Soluble TREM2 and Inflammatory Proteins in Alzheimer's Disease Cerebrospinal Fluid. %A Rauchmann, Boris-Stephan %A Sadlon, Angélique %A Perneczky, Robert %X

The present study explores the associations of soluble TREM2, an important regulator of microglial activity linked to Alzheimer's disease (AD), with other known inflammatory proteins in cerebrospinal fluid (CSF). We studied 303 participants, including 89 controls, 135 mild cognitive impairment, and 79 AD dementia patients. Using established CSF biomarkers, subjects were classified according to the National Institute on Aging-Alzheimer's Association research framework, which groups markers into those of amyloid-β deposition (A), tau pathology (T), and neurodegeneration (N). TNFR1, TNFR2, TGF-β1, TGFβ2, IL-9, TNF-α, ICAM1, and VCAM1 showed significant concentration differences between the ATN groups, with higher concentrations in more advanced disease categories. sTREM2 was positively associated with the pro-inflammatory proteins TNF-α, TNFR1, TNFR2, ICAM1, VCAM1, and IP-10 and negatively with IL-21; also, positive associations with the anti-inflammatory proteins TGFβ1, IL-10, and IL-9 were found. Pathway enrichment analysis highlighted the involvement of sTREM2 in key functional clusters including immunoglobulin and cytokine production and cellular response to lipopolysaccharides, cytokines, and steroid hormones. Our work provides further evidence in support of TREM2 as amarker of neuroinflammatory response in AD.

%B J Alzheimers Dis %V 73 %P 1615-1626 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/31958095?dopt=Abstract %R 10.3233/JAD-191120 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Specific Neuropsychiatric Symptoms Are Associated with Faster Progression in Alzheimer's Disease: Results of the Prospective Dementia Registry (PRODEM-Austria). %A Defrancesco, Michaela %A Marksteiner, Josef %A Kemmler, Georg %A Dal-Bianco, Peter %A Ransmayr, Gerhard %A Benke, Thomas %A Mosbacher, Jochen %A Höller, Yvonne %A Schmidt, Reinhold %X

BACKGROUND: Neuropsychiatric symptoms (NPS) occur frequently in the course of Alzheimer's disease (AD) and are suspected to be associated with a faster dementia progression. Numerous reports have defined specific subsyndromes, summarized in clusters of items of the Neuropsychiatric Inventory (NPI).

OBJECTIVE: This study investigated the influence of specific NPI subsyndromes and clinical patient characteristics on dementia progression.

METHODS: Data of the prospective registry on dementia in Austria (PRODEM) were retrospectively analyzed. Cognitive functioning was determined at baseline and 2 yearly follow-up visits using the Mini-Mental State Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer's dementia neuropsychological test battery (CERAD). To assess NPS, the NPI was used: NPI items were classified in three subsyndromes (psychotic cluster, behavioral cluster, emotional cluster).

RESULTS: Out of the 662 included patients (mean age 76.4±8.4 years), 43% completed follow-up visits for two years. Significant correlation between higher scores in all three subsyndromes and worse cognitive performance were found for MMSE score, naming, and verbal fluency. Results of linear mixed model analysis revealed lower age and higher scores in the psychotic cluster as significant predictors of changes in MMSE with time.

CONCLUSION: In this study, we report the influence of psychotic subsyndromes and lower age on faster MMSE decline in early AD. These results emphasize the importance of not only assessing but also differentiating neuropsychiatric symptoms in subsyndromes in the early stages of AD as a possible predictor of disease progression.

%B J Alzheimers Dis %V 73 %P 125-133 %8 2020 Jan 07 %G eng %N 1 %R 10.3233/JAD-190662 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Structural Brain Changes in Pre-Clinical FTD MAPT Mutation Carriers. %A Domínguez-Vivero, Clara %A Wu, Liwen %A Lee, Seonjoo %A Manoochehri, Masood %A Cines, Sarah %A Brickman, Adam M %A Rizvi, Batool %A Chesebro, Anthony %A Gazes, Yunglin %A Fallon, Emer %A Lynch, Timothy %A Heidebrink, Judith L %A Paulson, Henry %A Goldman, Jill S %A Huey, Edward %A Cosentino, Stephanie %X

BACKGROUND: Frontotemporal dementia (FTD) is the second most common cause of early-onset neurodegenerative dementia. Several studies have focused on early imaging changes in FTD patients, but once subjects meet full criteria for the FTD diagnosis, structural changes are generally widespread.

OBJECTIVE: This study aims to determine the earliest structural brain changes in asymptomatic MAPT MUTATION carriers.

METHODS: This is a cross-sectional multicenter study comparing global and regional brain volume and white matter integrity in a group of MAPT mutation preclinical carriers and controls. Participants belong to multiple generations of six families with five MAPT mutations. All participants underwent a medical examination, neuropsychological tests, genetic analysis, and a magnetic resonance scan (3T, scout, T1-weighted image followed by EPI (BOLD), MPRAGE, DTI, FLAIR, and ASL sequences).

RESULTS: Volumes of five cortical and subcortical areas were strongly correlated with mutation status: temporal lobe (left amygdala, left temporal pole), cingulate cortex (left rostral anterior cingulate gyrus, right posterior cingulate), and the lingual gyrus in the occipital lobe. We did not find significant differences in whole brain volume, white matter hyperintensities volume, and white matter integrity using DTI analysis.

CONCLUSION: Temporal lobe, cingulate cortex and the lingual gyrus seem to be early targets of the disease and may serve as biomarkers for FTD prior to overt symptom onset.

%B J Alzheimers Dis %V 75 %P 595-606 %8 2020 May 19 %G eng %N 2 %R 10.3233/JAD-190820 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Structural Brain Magnetic Resonance Imaging to Rule Out Comorbid Pathology in the Assessment of Alzheimer's Disease Dementia: Findings from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) Study and Clinical Trials Over the Past 10 Years. %A Kapoor, Arunima %A Bartha, Robert %A Black, Sandra E %A Borrie, Michael %A Freedman, Morris %A Gao, Fuqiang %A Herrmann, Nathan %A Mandzia, Jennifer %A Ozzoude, Miracle %A Ramirez, Joel %A Scott, Christopher J M %A Symons, Sean %A Fischer, Corinne E %A Frank, Andrew %A Seitz, Dallas %A Wolf, Michael Uri %A Verhoeff, Nicolaas Paul L G %A Naglie, Gary %A Reichman, William %A Masellis, Mario %A Mitchell, Sara B %A Tang-Wai, David F %A Tartaglia, Maria Carmela %A Kumar, Sanjeev %A Pollock, Bruce G %A Rajji, Tarek K %A Finger, Elizabeth %A Pasternak, Stephen H %A Swartz, Richard H %X

BACKGROUND/OBJECTIVE: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer's disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies.

METHODS: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies.

RESULTS: Of 210 AD clinical trials, 105 (50%) included structural brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study.

DISCUSSION: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity.

%B J Alzheimers Dis %V 74 %P 747-757 %8 2020 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/32116253?dopt=Abstract %R 10.3233/JAD-191097 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Supplementation with Matured Hop Bitter Acids Improves Cognitive Performance and Mood State in Healthy Older Adults with Subjective Cognitive Decline. %A Fukuda, Takafumi %A Ohnuma, Tohru %A Obara, Kuniaki %A Kondo, Sumio %A Arai, Heii %A Ano, Yasuhisa %X

BACKGROUND: Prevention of age-related cognitive decline and depression is becoming urgent because of rapid growing aging populations. Effects of vagal nerve activation on brain function by food ingredients are inadequately investigated; matured hop bitter acid (MHBA) administration reportedly improves cognitive function and depression via vagal nerve activation in model mice.

OBJECTIVE: We investigated the effects of MHBA supplementation on cognitive function and mood state in healthy older adults with perceived subjective cognitive decline.

METHODS: Using a randomized double-blind placebo-controlled trial design, 100 subjects (aged 45-69 years) were randomly assigned into placebo (n = 50) and MHBA (n = 50) groups, and received placebo or MHBA capsules daily for 12 weeks.

RESULTS: Symbol Digit Modalities Test (SDMT) score assessing divided attention at week 12 was significantly higher (p = 0.045) and β-endorphin at week 12 was significantly lower (p = 0.043) in the subjects receiving MHBA. Transthyretin in serum, a putative mild cognitive impairment marker, was significantly higher at week 12 in the MHBA group than in the placebo group (p = 0.048). Subgroup analysis classified by the subjective cognitive decline questionnaire revealed that in addition to improved SDMT scores, memory retrieval assessed using the standard verbal paired-associate learning tests and the Ray Verbal Learning Test at week 12 had significantly improved in the subgroup with perceived subjective cognitive decline and without requirement for medical assistance in the MHBA group compared with that in the placebo group.

CONCLUSION: This study suggested that MHBA intake improves cognitive function, attention, and mood state in older adults.

%B J Alzheimers Dis %V 76 %P 387-398 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32474473?dopt=Abstract %R 10.3233/JAD-200229 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Synaptic Vesicle Protein 2B Negatively Regulates the Amyloidogenic Processing of AβPP as a Novel Interaction Partner of BACE1. %A Miyamoto, Masakazu %A Kuzuya, Akira %A Noda, Yasuha %A Ueda, Sakiho %A Asada-Utsugi, Megumi %A Ito, Shinji %A Fukusumi, Yoshiyasu %A Kawachi, Hiroshi %A Takahashi, Ryosuke %A Kinoshita, Ayae %X

BACKGROUND: Given that amyloid-β (Aβ) peptide is produced and released at synapses, synaptic Aβ is one of the promising therapeutic targets to prevent synaptic dysfunction in Alzheimer's disease (AD). Although Aβ production begins with the cleavage of the amyloid-β protein precursor (AβPP) by β-site AβPP cleaving enzyme 1 (BACE1), the mechanism on how BACE1 is involved in AβPP processing at synapses remains unclear.

OBJECTIVE: This study aimed to identify novel BACE1 interacting proteins regulating Aβ production at the synapse.

METHODS: BACE1 interacting proteins were pulled down using a mass spectrometry-based proteomics of wild-type (WT) rat brain synaptoneurosome lysates utilizing anti-BACE1 antibody. Then, a novel BACE1 interactor was identified and characterized using experimental systems that utilized transfected cells and knockout (KO) mice.

RESULTS: Synaptic vesicle protein 2B (SV2B) was identified as a novel presynaptic interaction partner of BACE1. In HEK293 cells, co-overexpression of SV2B with BACE1 significantly reduced the sAβPPβ and Aβ levels released in the media; thus, SV2B overexpression negatively affected the AβPP cleavage by BACE1. Compared with those of WT mice, the hippocampal lysates of SV2B knockout mice had significantly elevated Aβ levels, whereas the β-secretase activity and the AβPP and BACE1 protein levels remained unchanged. Finally, a fractionation assay revealed that BACE1 was mislocalized in SV2B KO mice; hence, SV2B may be involved in BACE1 trafficking downregulating the amyloidogenic pathway of AβPP.

CONCLUSION: SV2B has a novel role of negatively regulating the amyloidogenic processing of AβPP at the presynapses.

%B J Alzheimers Dis %V 75 %P 173-185 %8 2020 May 05 %G eng %N 1 %R 10.3233/JAD-200071 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Tau Acetylation in Entorhinal Cortex Induces its Chronic Hippocampal Propagation and Cognitive Deficits in Mice. %A Wang, Xin %A Liu, En-Jie %A Liu, Qian %A Li, Shi-Hong %A Li, Ting %A Zhou, Qiu-Zhi %A Liu, Yan-Chao %A Zhang, Huaqiu %A Wang, Jian-Zhi %X

BACKGROUND: Increased tau acetylation at K174, K274, K280, and K281 has been observed in the brains of Alzheimer's disease (AD) patients or in transgenic mice, but the role of acetylation in tau propagation is elusive.

OBJECTIVE: To study the effect of tau acetylation in entorhinal cortex on tau transmission and learning and memory.

METHODS: Stereotactic brain injection, behavioral test, electrophysiological recording, immunohistochemistry, and immunofluorescence were used.

RESULTS: We constructed the hyperacetylation mimics of tau (AAV-Tau-4Q), the non-acetylation tau mutant (AAV-Tau-4R), and the wild-type tau (AAV-Tau-WT). By overexpressing these different tau proteins in the entorhinal cortex (EC) of 2-month-old mice, we found that overexpressing Tau-4Q in EC for 3 or 6 months (to 5 or 8 months of age) neither induces tau propagation to dentate gyrus (DG) nor glial activation in DG, nor spatial memory deficit. However, overexpressing Tau-WT and Tau-4Q in EC for 13.5 months (15.5 months of age) at 2 months promoted tau propagation respectively to granulosa and hilus of DG with glial activation, synaptic dysfunction, and memory deficit, while overexpressing Tau-4R abolished tau propagation with improved cellular pathologies and cognitive functions. Furthermore, overexpressing Tau-4Q in unilateral DG of 2-month-old mice for 8 weeks also promoted its contralateral transmission with glial activation, and mice with tau (Tau-WT, Tau-4Q, and Tau-4R) overexpression in DG showed cognitive deficits compared with the empty vector controls.

CONCLUSION: Tau acetylation induces a time-dependent propagation from EC to DG, and only hippocampus but not EC tau accumulation induces cognitive deficits.

%B J Alzheimers Dis %V 77 %P 241-255 %8 2020 Sep 1 %G eng %N 1 %R 10.3233/JAD-200529 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Telemedicine for Delivery of Care in Frontotemporal Lobar Degeneration During COVID-19 Pandemic: Results from Southern Italy. %A Capozzo, Rosa %A Zoccolella, Stefano %A Frisullo, Maria Elisa %A Barone, Roberta %A Dell'Abate, Maria Teresa %A Barulli, Maria Rosaria %A Musio, Marco %A Accogli, Miriam %A Logroscino, Giancarlo %K Aged %K Aged, 80 and over %K Behavior %K Coronavirus Infections %K COVID-19 %K Delivery of Health Care %K Disease Progression %K Female %K Frontotemporal Lobar Degeneration %K Humans %K Italy %K Language %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Pandemics %K Pneumonia, Viral %K Quality of Life %K Quarantine %K Surveys and Questionnaires %K Telemedicine %K Triage %X

BACKGROUND: The COVID-19 pandemic is changing clinical practice in neurology, after the governments decided the introduction of social distancing and interruption of medical non-emergency services in many countries. Teleneurology is an effective tool for the remote evaluation of patients but its adoption for frontotemporal lobar dementia (FTD) is in a preliminary stage.

OBJECTIVE: We evaluated multidisciplinary assessment of patients with FTD using telehealth during the COVID-19 pandemic.

METHODS: All patients received a diagnosis of FTD during 2018-2019 according to international criteria. A structured questionnaire and Clinical Dementia Rating Scale (CDR)-FTD were used by the neurologist with patients and/or caregivers. Index symptoms of COVID-19 infection were searched.

RESULTS: Twenty-eight clinical interviews were completed with caregivers and four with both patients/caregivers. Most patients and caregivers were satisfied with the neurological interview and expressed their willingness to continue to be included in remote evaluation programs (90%). Fifty percent of patients experienced significant worsening of clinical picture and quality of life since the start of social distancing. The CDR-FTD scale revealed a significant worsening of behavior (p = 0.01) and language functions (p = 0.009), compared to the last in-person evaluation at the center. One patient presented index symptoms of COVID-19 infection and was confirmed to be positive for COVID-19 with pharyngeal swab.

CONCLUSION: The study was conducted in Italy, one of the countries hit particularly hard by the COVID-19 pandemic, with interruption of all non-emergency medical services. Our study indicates that telemedicine is a valid tool to triage patients with FTD to increase practice outreach and efficiency.

%B J Alzheimers Dis %V 76 %P 481-489 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32651328?dopt=Abstract %R 10.3233/JAD-200589 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Ultra-High Field MRI in Alzheimer's Disease: Effective Transverse Relaxation Rate and Quantitative Susceptibility Mapping of Human Brain In Vivo and Ex Vivo Compared to Histology. %A Tuzzi, Elisa %A Balla, David Z %A Loureiro, Joana R A %A Neumann, Manuela %A Laske, Christoph %A Pohmann, Rolf %A Preische, Oliver %A Scheffler, Klaus %A Hagberg, Gisela E %X

Alzheimer's disease (AD) is the most common cause of dementia worldwide. So far, diagnosis of AD is only unequivocally defined through postmortem histology. Amyloid plaques are a classical hallmark of AD and amyloid load is currently quantified by Positron Emission tomography (PET) in vivo. Ultra-high field magnetic resonance imaging (UHF-MRI) can potentially provide a non-invasive biomarker for AD by allowing imaging of pathological processes at a very-high spatial resolution. The first aim of this work was to reproduce the characteristic cortical pattern previously observed in vivo in AD patients using weighted-imaging at 7T. We extended these findings using quantitative susceptibility mapping (QSM) and quantification of the effective transverse relaxation rate (R2*) at 9.4T. The second aim was to investigate the origin of the contrast patterns observed in vivo in the cortex of AD patients at 9.4T by comparing quantitative UHF-MRI (9.4T and 14.1T) of postmortem samples with histology. We observed a distinctive cortical pattern in vivo in patients compared to healthy controls (HC), and these findings were confirmed ex vivo. Specifically, we found a close link between the signal changes detected by QSM in the AD sample at 14.1T and the distribution pattern of amyloid plaques in the histological sections of the same specimen. Our findings showed that QSM and R2* maps can distinguish AD from HC at UHF by detecting cortical alterations directly related to amyloid plaques in AD patients. Furthermore, we provided a method to quantify amyloid plaque load in AD patients at UHF non-invasively.

%B J Alzheimers Dis %V 73 %P 1481-1499 %8 2020 Feb 18 %G eng %N 4 %R 10.3233/JAD-190424 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Use of Immersive Virtual Reality in the Assessment and Treatment of Alzheimer's Disease: A Systematic Review. %A Clay, Felix %A Howett, David %A Fitzgerald, James %A Fletcher, Paul %A Chan, Dennis %A Price, Annabel %X

BACKGROUND: Immersive virtual reality (iVR) allows seamless interaction with simulated environments and is becoming an established tool in clinical research. It is unclear whether iVR is acceptable to people with Alzheimer's disease (AD) dementia or useful in their care. We explore whether iVR is a viable research tool that may aid the detection and treatment of AD.

OBJECTIVES: This review examines the use of iVR in people with AD or mild cognitive impairment (MCI).

METHODS: Medline, PsycINFO, Embase, CINAHL, and Web of Science databases were searched from inception. PRISMA guidelines were used with studies selected by at least two researchers.

RESULTS: Nine studies were eligible for inclusion. None reported any issues with iVR tolerability in participants with MCI and AD on assessment or treatment tasks. One study demonstrated capability for detecting prodromal AD and correlated with neuroanatomical substrates. Two studies showed iVR to have high accuracy in differentiating participants with AD from controls but were not hypothesis driven or with adequate controls measures. In a small validation study and two longitudinal case studies, iVR cognitive training was positively rated but did not demonstrate reliable benefit.

CONCLUSION: iVR is emerging as a viable method of assessing older adults and people with AD. Strongest benefits were seen when closely integrated with theoretical models of neurodegeneration and existing screening methods. Further randomized controlled trials integrated with clinical populations are required. This will consolidate the power of iVR for assessment of MCI and clarify treatment efficacy beyond current applications in physical rehabilitation.

%B J Alzheimers Dis %V 75 %P 23-43 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32280091?dopt=Abstract %R 10.3233/JAD-191218 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Using Machine Learning to Predict Dementia from Neuropsychiatric Symptom and Neuroimaging Data. %A Gill, Sascha %A Mouches, Pauline %A Hu, Sophie %A Rajashekar, Deepthi %A MacMaster, Frank P %A Smith, Eric E %A Forkert, Nils D %A Ismail, Zahinoor %X

BACKGROUND: Machine learning (ML) is a promising technique for patient-specific prediction of mild cognitive impairment (MCI) and dementia development. Neuropsychiatric symptoms (NPS) might improve the accuracy of ML models but have barely been used for this purpose.

OBJECTIVES: To investigate if baseline mild behavioral impairment (MBI) status used for NPS quantification along with brain morphology features are predictive of follow-up diagnosis, median 40 months later in patients with normal cognition (NC) or MCI.

METHOD: Baseline neuroimaging, neuropsychiatric, and clinical data from 102 individuals with NC and 239 with MCI were extracted from the Alzheimer's Disease Neuroimaging Initiative database. Neuropsychiatric inventory questionnaire items were transformed to MBI domains using a published algorithm. Diagnosis at latest follow-up was used as the outcome variable and ground truth classification. A logistic model tree classifier combined with information gain feature selection was trained to predict follow-up diagnosis.

RESULTS: In the binary classification (NC versus MCI/AD), the optimal ML model required only two features from over 200, MBI total score and left hippocampal volume. These features correctly classified participants as remaining normal or developing cognitive impairment with 84.4% accuracy (area under the receiver operating characteristics curve [ROC-AUC] = 0.86). Seven features were selected for the three-class model (NC versus MCI versus dementia) achieving an accuracy of 58.8% (ROC-AUC=0.73).

CONCLUSION: Baseline NPS, categorized for MBI domain and duration, have prognostic utility in addition to brain morphology measures for predicting diagnosis change using ML. MBI total score, followed by impulse dyscontrol and affective dysregulation were most predictive of future diagnosis.

%B J Alzheimers Dis %V 75 %P 277-288 %8 2020 %G eng %N 1 %R 10.3233/JAD-191169 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Utility of MemTrax and Machine Learning Modeling in Classification of Mild Cognitive Impairment. %A Bergeron, Michael F %A Landset, Sara %A Zhou, Xianbo %A Ding, Tao %A Khoshgoftaar, Taghi M %A Zhao, Feng %A Du, Bo %A Chen, Xinjie %A Wang, Xuan %A Zhong, Lianmei %A Liu, Xiaolei %A Ashford, J Wesson %X

BACKGROUND: The widespread incidence and prevalence of Alzheimer's disease and mild cognitive impairment (MCI) has prompted an urgent call for research to validate early detection cognitive screening and assessment.

OBJECTIVE: Our primary research aim was to determine if selected MemTrax performance metrics and relevant demographics and health profile characteristics can be effectively utilized in predictive models developed with machine learning to classify cognitive health (normal versus MCI), as would be indicated by the Montreal Cognitive Assessment (MoCA).

METHODS: We conducted a cross-sectional study on 259 neurology, memory clinic, and internal medicine adult patients recruited from two hospitals in China. Each patient was given the Chinese-language MoCA and self-administered the continuous recognition MemTrax online episodic memory test on the same day. Predictive classification models were built using machine learning with 10-fold cross validation, and model performance was measured using Area Under the Receiver Operating Characteristic Curve (AUC). Models were built using two MemTrax performance metrics (percent correct, response time), along with the eight common demographic and personal history features.

RESULTS: Comparing the learners across selected combinations of MoCA scores and thresholds, Naïve Bayes was generally the top-performing learner with an overall classification performance of 0.9093. Further, among the top three learners, MemTrax-based classification performance overall was superior using just the top-ranked four features (0.9119) compared to using all 10 common features (0.8999).

CONCLUSION: MemTrax performance can be effectively utilized in a machine learning classification predictive model screening application for detecting early stage cognitive impairment.

%B J Alzheimers Dis %V 77 %P 1545-1558 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32894241?dopt=Abstract %R 10.3233/JAD-191340 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort. %A Westwood, Sarah %A Baird, Alison L %A Anand, Sneha N %A Nevado-Holgado, Alejo J %A Kormilitzin, Andrey %A Shi, Liu %A Hye, Abdul %A Ashton, Nicholas J %A Morgan, Angharad R %A Bos, Isabelle %A Vos, Stephanie J B %A Baker, Susan %A Buckley, Noel J %A Ten Kate, Mara %A Scheltens, Philip %A Teunissen, Charlotte E %A Vandenberghe, Rik %A Gabel, Silvy %A Meersmans, Karen %A Engelborghs, Sebastiaan %A De Roeck, Ellen E %A Sleegers, Kristel %A Frisoni, Giovanni B %A Blin, Olivier %A Richardson, Jill C %A Bordet, Régis %A Molinuevo, José L %A Rami, Lorena %A Wallin, Anders %A Kettunen, Petronella %A Tsolaki, Magda %A Verhey, Frans %A Lleo, Alberto %A Sala, Isabel %A Popp, Julius %A Peyratout, Gwendoline %A Martínez-Lage, Pablo %A Tainta, Mikel %A Johannsen, Peter %A Freund-Levi, Yvonne %A Frölich, Lutz %A Dobricic, Valerija %A Legido-Quigley, Cristina %A Bertram, Lars %A Barkhof, Frederik %A Zetterberg, Henrik %A Morgan, B Paul %A Streffer, Johannes %A Visser, Pieter Jelle %A Lovestone, Simon %X

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.

%B J Alzheimers Dis %V 74 %P 213-225 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31985466?dopt=Abstract %R 10.3233/JAD-190434 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Vascular Risk Factors and Alzheimer's Disease: Blood-Brain Barrier Disruption, Metabolic Syndromes, and Molecular Links. %A He, Jin-Ting %A Zhao, Xin %A Xu, Lei %A Mao, Cui-Ying %X

Alzheimer's disease (AD) is a neurodegenerative disorder, marked by cortical and hippocampal deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles and cognitive impairment. Studies indicate a prominent link between cerebrovascular abnormalities and the onset and progression of AD, where blood-brain barrier (BBB) dysfunction and metabolic disorders play key risk factors. Pericyte degeneration, endothelial cell damage, astrocyte depolarization, diminished tight junction integrity, and basement membrane disarray trigger BBB damage. Subsequently, the altered expression of low-density lipoprotein receptor-related protein 1 and receptor for advanced glycation end products at the microvascular endothelial cells dysregulate Aβ transport across the BBB. White matter lesions and microhemorrhages, dyslipidemia, altered brain insulin signaling, and insulin resistance contribute to tau and Aβ pathogenesis, and oxidative stress, mitochondrial damage, inflammation, and hypoperfusion serve as mechanistic links between pathophysiological features of AD and ischemia. Deregulated calcium homeostasis, voltage gated calcium channel functioning, and protein kinase C signaling are also common mechanisms for both AD pathogenesis and cerebrovascular abnormalities. Additionally, APOE polymorphic alleles that characterize impaired cerebrovascular integrity function as primary genetic determinants of AD. Overall, the current review enlightens key vascular risk factors for AD and underscores pathophysiologic relationship between AD and vascular dysfunction.

%B J Alzheimers Dis %V 73 %P 39-58 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31815697?dopt=Abstract %R 10.3233/JAD-190764 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Waist Circumference and Domain-Specific Cognitive Function Among Non-Demented Japanese Older Adults Stratified by Sex: Results from the Takashima Cognition Study. %A Waki, Takashi %A Tanaka-Mizuno, Sachiko %A Takashima, Naoyuki %A Takechi, Hajime %A Hayakawa, Takehito %A Miura, Katsuyuki %A Ueshima, Hirotsugu %A Kita, Yoshikuni %A Dodge, Hiroko H %X

BACKGROUND: While being obese in mid-life is associated with an increased risk of dementia and cognitive decline in late-life, being obese in late-life is shown to be associated with a lower risk of these outcomes in some studies. This phenomenon is known as the "obesity paradox", but the underlying reasons and potential sex difference have not been well understood.

OBJECTIVE: To investigate the association between cognition and waist circumference (WC), an alternative measure of body fat which can be measured easier than body mass index (BMI), among older adults in each generation of late-life for men and women separately.

METHODS: Three hundred thirty-five participants were used in the current study who were identified by random sampling of residents aged 65-74, 75-84, and 85 + years in Takashima County, Shiga Prefecture, Japan during 2005-2006. Associations between WC and domain-specific cognitive functions measured by 12 neuropsychological tests were examined using multivariable linear regression models with covariates: age, education, and hypertension.

RESULTS: Larger WC was associated with better attention/working memory among 65-74-year old women and with better learning/acquisition among 65-74-year-old men, while larger WC was associated with worse learning/acquisition, memory, attention/working memory, and language/fluency among 75-84-year old men.

CONCLUSION: We found age and sex differences in the association between WC and domain-specific cognitive functions. Among older old men (age 75-84) larger WC had negative effects on various domains including memory, attention, language, and executive functions, while we did not find any negative effects of larger WC on cognition among women in any age groups.

%B J Alzheimers Dis %V 73 %P 887-896 %8 2020 Feb 04 %G eng %N 3 %R 10.3233/JAD-190395 %0 Journal Article %J J Alzheimers Dis %D 2019 %T 18F-FDG Is a Superior Indicator of Cognitive Performance Compared to 18F-Florbetapir in Alzheimer's Disease and Mild Cognitive Impairment Evaluation: A Global Quantitative Analysis. %A Khosravi, Mohsen %A Peter, Jonah %A Wintering, Nancy A %A Serruya, Mijail %A Shamchi, Sara Pourhassan %A Werner, Thomas J %A Alavi, Abass %A Newberg, Andrew B %X

BACKGROUND: 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and 18F-florbetapir PET are approved neuroimaging biomarkers for the Alzheimer's disease (AD) and mild cognitive impairment (MCI).

OBJECTIVES: This study aims to compare the efficacy of 18F-FDG and 18F-florbetapir PET at evaluating the cognitive performance of patients with AD, MCI, and normal controls (NCs).

METHODS: 63 subjects (36 male/27 female, mean age = 68.3) including 19 AD, 23 MCI, and 21 NCs underwent 18F-FDG and 18F-florbetapir PET imaging. A global quantification approach was applied on supra-tentorial, frontal, parieto-occipital, temporal, and cerebellar brain regions by calculating the global SUVmean ratios (GSUVr) as the weighted average of all regional SUVmean. 18F-FDG and 18F-florbetapir GSUVr of each region were subsequently correlated with the Mini-Mental Status Examination (MMSE).

RESULTS: Subjects were studied in five categories as NC, MCI patients, AD patients, MCI and AD patients grouped together (MCI/AD), and a group including all the subjects (NC/MCI/AD). Both 18F-FDG and 18F-florbetapir could successfully detect subjects with dementia (p <  0.001). Studied in all regions and groups, the correlation analysis of 18F-FDG GSUVr with MMSE scores was significant in more regions and groups compared to that of 18F-florbetapir. We also demonstrated that the correlation of 18F-FDG GSUVr with MMSE is stronger than that of 18F-florbetapir in the supra-tentorial and temporal regions.

CONCLUSIONS: This study reveals how 18F-FDG-PET global quantification is a superior indicator of cognitive performance in AD and MCI patients compared to 18F-florbetapir PET. Accordingly, we still recommend 18F-FDG-PET over amyloid imaging in the evaluation for AD and MCI.

%B J Alzheimers Dis %V 70 %P 1197-1207 %8 2019 Aug 20 %G eng %N 4 %R 10.3233/JAD-190220 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Adverse Vascular Risk Relates to Cerebrospinal Fluid Biomarker Evidence of Axonal Injury in the Presence of Alzheimer's Disease Pathology. %A Osborn, Katie E %A Alverio, Jonathan M %A Dumitrescu, Logan %A Pechman, Kimberly R %A Gifford, Katherine A %A Hohman, Timothy J %A Blennow, Kaj %A Zetterberg, Henrik %A Jefferson, Angela L %X

BACKGROUND: Vascular risk factors promote cerebral small vessel disease and neuropathological changes, particularly in white matter where large-caliber axons are located. How Alzheimer's disease pathology influences the brain's vulnerability in this regard is not well understood.

OBJECTIVE: Systemic vascular risk was assessed in relation to cerebrospinal fluid concentrations of neurofilament light, a biomarker of large-caliber axonal injury, evaluating for interactions by clinical and protein markers of Alzheimer's disease.

METHODS: Among Alzheimer's Disease Neuroimaging Initiative participants with normal cognition (n = 117), mild cognitive impairment (n = 190), and Alzheimer's disease (n = 95), linear regression related vascular risk (as measured by the modified Framingham Stroke Risk Profile) to neurofilament light, adjusting for age, sex, education, and cognitive diagnosis. Interactions were assessed by cognitive diagnosis, and by cerebrospinal fluid markers of Aβ42, hyperphosphorylated tau, and total tau.

RESULTS: Vascular risk and neurofilament light were not related in the main effect model (p = 0.08). However, interactions emerged for total tau (p = 0.01) and hyperphosphorylated tau (p = 0.002) reflecting vascular risk becoming more associated with cerebrospinal fluid neurofilament light in the context of greater concentrations of tau biomarkers. An interaction also emerged for the Alzheimer's disease biomarker profiles (p = 0.046) where in comparison to the referent 'normal' biomarker group, individuals with abnormal levels of both Aβ42 and total tau showed stronger associations between vascular risk and neurofilament light.

CONCLUSION: Older adults may be more vulnerable to axonal injury in response to higher vascular risk burdens in the context of concomitant Alzheimer's disease pathology.

%B J Alzheimers Dis %V 71 %P 281-290 %8 2019 Sep 3 %G eng %N 1 %R 10.3233/JAD-190077 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Air Pollution and Dementia: A Systematic Review. %A Peters, Ruth %A Ee, Nicole %A Peters, Jean %A Booth, Andrew %A Mudway, Ian %A Anstey, Kaarin J %X

BACKGROUND: Both air pollution and dementia are current and growing global issues. There are plausible links between exposure to specific air pollutants and dementia.

OBJECTIVE: To systematically review the evidence base with respect to the relationship between air pollution and later cognitive decline and dementia.

METHODS: Medline, Embase, and PsychINFO® were searched from their inception to September 2018, for publications reporting on longitudinal studies of exposure to air pollution and incident dementia or cognitive decline in adults. Studies reporting on exposure to tobacco smoke including passive smoking or on occupational exposure to pollutants were excluded. Using standard Cochrane methodology, two readers identified relevant abstracts, read full text publications, and extracted data into structured tables from relevant papers, as defined by inclusion and exclusion criteria. Papers were also assessed for validity. CRD42018094299Results:From 3,720 records, 13 papers were found to be relevant, with studies from the USA, Canada, Taiwan, Sweden, and the UK. Study follow-up ranged from one to 15 years. Pollutants examined included particulate matter ≤2.5 μ (PM2.5), nitrogen dioxide (NO2), nitrous oxides (NOx), carbon monoxide (CO), and ozone. Studies varied in their methodology, population selection, assessment of exposure to pollution, and method of cognitive testing. Greater exposure to PM2.5, NO2/NOx, and CO were all associated with increased risk of dementia. The evidence for air pollutant exposure and cognitive decline was more equivocal.

CONCLUSION: Evidence is emerging that greater exposure to airborne pollutants is associated with increased risk of dementia.

%B J Alzheimers Dis %V 70 %P S145-S163 %8 2019 %G eng %N s1 %R 10.3233/JAD-180631 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Alzheimer's and Parkinson's Diseases and the Risk of Cancer: A Cohort Study. %A Ording, Anne G %A Veres, Katalin %A Horváth-Puhó, Erzsébet %A Glymour, M Maria %A Rørth, Mikael %A Henderson, Victor W %A Sørensen, Henrik T %X

 Observational studies have shown inverse associations between neurological diseases, particularly dementia, and subsequent cancer risk, but is unknown whether this association is valid or arises from bias. We conducted a Danish nationwide cohort study using population-based health registries (1980-2012). The study included patients with dementia (n = 173,434) and with Parkinson's disease (n = 28,835). We followed patients for 10 years to assess subsequent cancer diagnoses. We computed absolute reduction in cancer risk attributable to dementia or Parkinson's disease (expected minus the observed number of cancer cases divided by the person time) and standardized incidence rate ratios (SIRs) as the observed to expected number of cancers, based on sex-, age-, and calendar year-standardized national incidence rates. During 10 years, the reduction in cancer cases were 79.9 per 10,000 person-years for Alzheimer's disease [SIR = 0.68 (95% CI: 0.66, 0.70)], 74.4 per 10,000 person-years for vascular dementia [SIR = 0.71 (95% CI: 0.67, 0.74)], 55.8 per 10,000 person-years [SIR = 0.77 (95% CI: 0.75, 0.78)] for all-cause dementia, and 4.0 per 10,000 person-years [SIR = 0.98 (95% CI: 0.95, 1.02) for Parkinson's disease. Associations were nearly similar for solid tumors diagnosed at localized, regional, or distant stages. We found an inverse association between dementia and cancer risk, with similar associations when considering only cancers diagnosed at distant stage. The cancer risk varied by type of dementia, with a gradient toward a stronger protective effect associated with Alzheimer's disease and vascular dementia, which may favor a biological explanation. Overall results do not show an inverse association between Parkinson's disease and cancer.

%B J Alzheimers Dis %V 72 %P 1269-1277 %8 2019 Dec 12 %G eng %N 4 %R 10.3233/JAD-190867 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Amyloidogenic Nanoplaques in Blood Serum of Patients with Alzheimer's Disease Revealed by Time-Resolved Thioflavin T Fluorescence Intensity Fluctuation Analysis. %A Tiiman, Ann %A Jelic, Vesna %A Jarvet, Jüri %A Järemo, Petter %A Bogdanovic, Nenad %A Rigler, Rudolf %A Terenius, Lars %A Gräslund, Astrid %A Vukojević, Vladana %X

BACKGROUND: Biomarkers are central to current research on molecular mechanisms underlying Alzheimer's disease (AD). Their further development is of paramount importance for understanding pathophysiological processes that eventually lead to disease onset. Biomarkers are also crucial for early disease detection, before clinical manifestation, and for development of new disease modifying therapies.

OBJECTIVE: The overall aim of this work is to develop a minimally invasive method for fast, ultra-sensitive and cost-effective detection of structurally modified peptide/protein self-assemblies in the peripheral blood and in other biological fluids. Specifically, we focus here on using this method to detect structured amyloidogenic oligomeric aggregates in the blood serum of apparently healthy individuals and patients in early AD stage, and measure their concentration and size.

METHODS: Time-resolved detection of Thioflavin T (ThT) fluorescence intensity fluctuations in a sub-femtoliter observation volume element was used to identify in blood serum ThT-active structured amyloidogenic oligomeric aggregates, hereafter called nanoplaques, and measure with single-particle sensitivity their concentration and size.

RESULTS: The concentration and size of structured amyloidogenic nanoplaques are significantly higher in the blood serum of individuals diagnosed with AD than in control subjects.

CONCLUSION: A new method with the ultimate, single-particle sensitivity was successfully developed. The proposed approach neither relies on the use of immune-based probes, nor on the use of radiotracers, signal-amplification or protein separation techniques, and provides a minimally invasive test for fast and cost-effective early determination of structurally modified peptides/proteins in the peripheral blood, as shown here, but also in other biological fluids.

%B J Alzheimers Dis %V 68 %P 571-582 %8 2019 Mar 29 %G eng %N 2 %R 10.3233/JAD-181144 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Anemia in Association with Cognitive Impairment: A Systematic Review and Meta-Analysis. %A Kim, Hong-Bae %A Park, Byoungjin %A Shim, Jae-Yong %X

BACKGROUND: Prevalence of both anemia and cognitive impairment tends to increase with age. Individual studies have recently shown that anemia could be associated with cognitive impairment.

OBJECTIVE: To investigate the association between anemia and cognitive impairment including dementia.

METHODS: Two of the authors systematically searched PubMed, EMBASE, and the Cochrane library to retrieve observational studies reporting a relationship between anemia and cognitive impairment from 1964 to July 10, 2019. Case-control and cohort studies were included, and odds ratios (ORs) or relative risks (RRs) with 95% confidence intervals (CIs) for the risk of cognitive impairment were calculated using a random-effects model.

RESULTS: In total, 16 observational studies including eight case-control studies and eight cohort studies were included in the final analysis. Anemia was significantly linked to cognitive impairment (OR or RR 1.51; 95% CI: 1.32-1.73) in a random-effects meta-analysis, albeit with medium heterogeneity (I2 = 47.8%). Meta-estimates of dementia from prospective population-based cohort studies were similar (RR 1.46; 95% CI: 1.22-1.76) without substantial heterogeneity (I2 = 23.2%).

CONCLUSION: Our meta-analysis indicates that anemia is associated with cognitive impairment. Further prospective research is warranted to determine the cause-effect relationship of anemia with cognitive impairment and whether treatment of anemia might reduce the risk of dementia.

%B J Alzheimers Dis %V 72 %P 803-814 %8 2019 Nov 26 %G eng %N 3 %R 10.3233/JAD-190521 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Antiepileptic Drug Use Is Associated with an Increased Risk of Pneumonia Among Community-Dwelling Persons with Alzheimer's Disease-Matched Cohort Study. %A Taipale, Heidi %A Lampela, Pasi %A Koponen, Marjaana %A Tanskanen, Antti %A Tiihonen, Jari %A Hartikainen, Sirpa %A Tolppanen, Anna-Maija %X

BACKGROUND: Antiepileptic drugs (AEDs) have sedative properties which may lead to an increased risk of pneumonia.

OBJECTIVES: To investigate whether incident AED use is associated with an increased risk of pneumonia among community-dwelling persons with Alzheimer's disease (AD). In addition, we determined the risk according to duration of AED use and specific AEDs.

METHODS: Persons with AD were identified from the MEDALZ dataset which includes all community-dwelling persons who received a clinically verified diagnosis of AD during 2005-2011 in Finland (N=70,718). New AED users were identified with one-year washout period. A matched cohort (1 : 1, N=5,769, matching criteria age, gender, and time since AD diagnoses) of nonusers was formed. Data from nationwide registers included dispensed medications which were modelled with PRE2DUP method, hospitalizations, and causes of death. The association between AED use and hospital admission or death due to pneumonia was analyzed with Cox proportional hazard models.

RESULTS: AED use was associated with an increased risk of pneumonia (adjusted HR 1.92, 95% CI 1.63-2.26; incidence rate per 100 person-years 12.58, 95% CI 12.49-12.66 during AED use and 6.41, 95% CI 6.37-6.45 during nonuse). The highest risk was observed during the first month of use (aHR 3.59, 95% CI 2.29-5.61) and the risk remained elevated until two years of use. Of specific drug substances, phenytoin, carbamazepine, valproic acid, and pregabalin were associated with an increased risk.

CONCLUSION: Antiepileptic drug use may increase the risk of pneumonia which is concerning as persons with AD have elevated risk of pneumonia.

%B J Alzheimers Dis %V 68 %P 127-136 %8 2019 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/30775987?dopt=Abstract %R 10.3233/JAD-180912 %0 Journal Article %J J Alzheimers Dis %D 2019 %T APOE Effect on Amyloid-β PET Spatial Distribution, Deposition Rate, and Cut-Points. %A Toledo, Jon B %A Habes, Mohamad %A Sotiras, Aristeidis %A Bjerke, Maria %A Fan, Yong %A Weiner, Michael W %A Shaw, Leslie M %A Davatzikos, Christos %A Trojanowski, John Q %X

There are conflicting results regarding how APOE genotype, the strongest genetic risk factor for Alzheimer's disease (AD), influences spatial and longitudinal amyloid-β (Aβ) deposition and its impact on the selection of biomarker cut-points. In our study, we sought to determine the impact of APOE genotype on cross-sectional and longitudinal florbetapir positron emission tomography (PET) amyloid measures and its impact in classification of patients and interpretation of clinical cohort results. We included 1,019 and 1,072 Alzheimer's Disease Neuroimaging Initiative participants with cerebrospinal fluid Aβ1 - 42 and florbetapir PET values, respectively. 623 of these subjects had a second florbetapir PET scans two years after the baseline visit. We evaluated the effect of APOE genotype on Aβ distribution pattern, pathological biomarker cut-points, cross-sectional clinical associations with Aβ load, and longitudinal Aβ deposition rate measured using florbetapir PET scans. 1) APOEɛ4 genotype influences brain amyloid deposition pattern; 2) APOEɛ4 genotype does not modify Aβ biomarker cut-points estimated using unsupervised mixture modeling methods if white matter and brainstem references are used (but not when cerebellum is used as a reference); 3) findings of large differences in Aβ biomarker value differences based on APOE genotype are due to increased probability of having AD neuropathology and are most significant in mild cognitive impairment subjects; and 4) APOE genotype and age (but not gender) were associated with increased Aβ deposition rate. APOEɛ4 carrier status affects rate and location of brain Aβ deposition but does not affect choice of biomarker cut-points if adequate references are selected for florbetapir PET processing.

%B J Alzheimers Dis %V 69 %P 783-793 %8 2019 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/31127775?dopt=Abstract %R 10.3233/JAD-181282 %0 Journal Article %J J Alzheimers Dis %D 2019 %T APOE ɛ4 Carriers Show Delayed Recovery of Verbal Memory and Smaller Entorhinal Volume in the First Year After Ischemic Stroke. %A Werden, Emilio %A Khlif, Mohamed Salah %A Bird, Laura J %A Cumming, Toby %A Bradshaw, Jennifer %A Khan, Wasim %A Pase, Matthew %A Restrepo, Carolina %A Veldsman, Michele %A Egorova, Natalia %A Patel, Sheila K %A Gottlieb, Elie %A Brodtmann, Amy %X

BACKGROUND: The apolipoprotein E (APOE) gene ɛ4 allele is a risk factor for Alzheimer's disease and cardiovascular disease. However, its relationship with cognition and brain volume after stroke is not clear.

OBJECTIVE: We compared cognition and medial temporal lobe volumes in APOEɛ4 carriers and non-carriers in the first year after ischemic stroke.

METHODS: We sampled 20 APOEɛ4 carriers and 20 non-carriers from a larger cohort of 135 ischemic stroke participants in the longitudinal CANVAS study. Participants were matched on a range of demographic and stroke characteristics. We used linear mixed-effect models to compare cognitive domain z-scores (attention, processing speed, executive function, verbal and visual memory, language, visuospatial function) and regional medial temporal lobe volumes (hippocampal, entorhinal cortex) between groups at each time-point (three, 12-months post-stroke), and within groups across time-points. APOE gene single nucleotide polymorphisms (SNPs; rs7412, rs429358) were genotyped on venous blood.

RESULTS: APOEɛ4 carriers and non-carriers did not differ on any demographic, clinical, or stroke variable. Carriers performed worse than non-carriers in verbal memory at three months post-stroke (p = 0.046), but were better in executive function at 12 months (p = 0.035). Carriers demonstrated a significant improvement in verbal memory (p = 0.012) and executive function (p = 0.015) between time-points. Non-carriers demonstrated a significant improvement in visual memory (p = 0.0005). Carriers had smaller bilateral entorhinal cortex volumes (p <  0.05), and larger-right-sided and contralesional hippocampal volumes, at both time-points (p <  0.05).

CONCLUSION: APOE ɛ4 is associated with delayed recovery of verbal memory function and reduced entorhinal cortex volumes in the first year after ischemic stroke.

%B J Alzheimers Dis %V 71 %P 245-259 %8 2019 Sep 3 %G eng %N 1 %R 10.3233/JAD-190566 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Association between Adipokines and Biomarkers of Alzheimer's Disease: A Cross-Sectional Study. %A Letra, Liliana %A Matafome, Paulo %A Rodrigues, Tiago %A Duro, Diana %A Lemos, Raquel %A Baldeiras, Ines %A Patrício, Miguel %A Castelo-Branco, Miguel %A Caetano, Gina %A Seiça, Raquel %A Santana, Isabel %X

BACKGROUND: Adipose tissue dysfunction has been implicated in the pathophysiology of Alzheimer's disease. However, the involvement of adipokines, particularly adiponectin, remains unclear.

OBJECTIVE: To compare serum and cerebrospinal fluid (CSF) levels of adiponectin, leptin and leptin-to-adiponectin ratio in patients within the spectrum of Alzheimer's disease and evaluate their relationship with classical biomarkers and their value as markers of progression.

METHODS: Amnestic mild cognitive impairment (MCI, n = 71) and Alzheimer's dementia (AD, n = 53) subjects were consecutively recruited for serum and CSF adiponectin and leptin determination using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). Correlations were explored using adjusted Spearman's correlation coefficients. A logistic regression model and ROC analysis were performed to evaluate the staging predictive value of adipokines.

RESULTS: Serum adiponectin was 33% higher in AD when compared to MCI patients. Adiponectin CSF levels, similar in both groups, were positively correlated with Aβ42 and cognitive function, though only in women. The area under the ROC curve was 0.673 (95% CI:0.57-0.78) for serum adiponectin as predictor of dementia stage and the cut-off 10.85μg/ml maximized the sum of specificity (87%) and sensitivity (44%).

CONCLUSION: Although longitudinal studies are required, we hypothesize that higher serum adiponectin in AD patients constitutes a strategy to compensate possible central signaling defects. In addition, adiponectin might be specifically assigned to neuroprotective functions in women and eventually involved in the female-biased incidence of Alzheimer's disease.

%B J Alzheimers Dis %V 67 %P 725-735 %8 2019 %G eng %N 2 %R 10.3233/JAD-180669 %0 Journal Article %J J Alzheimers Dis %D 2019 %T The Association between Mushroom Consumption and Mild Cognitive Impairment: A Community-Based Cross-Sectional Study in Singapore. %A Feng, Lei %A Cheah, Irwin Kee-Mun %A Ng, Maisie Mei-Xi %A Li, Jialiang %A Chan, Sue Mei %A Lim, Su Lin %A Mahendran, Rathi %A Kua, Ee-Heok %A Halliwell, Barry %X

We examined the cross-sectional association between mushroom intake and mild cognitive impairment (MCI) using data from 663 participants aged 60 and above from the Diet and Healthy Aging (DaHA) study in Singapore. Compared with participants who consumed mushrooms less than once per week, participants who consumed mushrooms >2 portions per week had reduced odds of having MCI (odds ratio = 0.43, 95% CI 0.23-0.78, p = 0.006) and this association was independent of age, gender, education, cigarette smoking, alcohol consumption, hypertension, diabetes, heart disease, stroke, physical activities, and social activities. Our cross-sectional data support the potential role of mushrooms and their bioactive compounds in delaying neurodegeneration.

%B J Alzheimers Dis %V 68 %P 197-203 %8 2019 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/30775990?dopt=Abstract %R 10.3233/JAD-180959 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Association of Cognitive Function with Amyloid-β and Tau Proteins in the Vitreous Humor. %A Wright, Lauren M %A Stein, Thor D %A Jun, Gyungah %A Chung, Jaeyoon %A McConnell, Kate %A Fiorello, Marissa %A Siegel, Nicole %A Ness, Steven %A Xia, Weiming %A Turner, Kelley L %A Subramanian, Manju L %X

BACKGROUND: The eye may serve as source for diagnostic testing for early detection of Alzheimer's disease (AD). Examination of amyloid-β (Aβ) and tau protein content in human vitreous and its correlation to neuro-cognition may improve ocular-based AD detection methods.

OBJECTIVE: To evaluate levels of Aβ and tau protein in human vitreous humor and investigate the clinical predictive role of these proteins as early diagnostic markers of AD.

METHODS: A prospective, single-center, multi-surgeon cohort study. Vitreous humor samples from 80 eyes were measured quantitatively for Aβ40-42, pTau, and tTau. Linear regression was used to test associations between AD biomarker levels, Mini-Mental State Exam (MMSE), and serum apolipoprotein E (APOE) allele status, with adjustment for age, sex, and education level of patients.

RESULTS: Lower MMSE scores were significantly associated with lower levels of vitreous Aβ40 (p = 0.015), Aβ42 (p = 0.0066), and tTau (p = 0.0085), and these biomarkers were not associated with any pre-existing eye conditions. Presence of the ɛ4 allele and the ɛ2 allele approached significance with reduced Aβ40 level (p = 0.053) and increased p-Tau level (p = 0.056), respectively.

CONCLUSION: Patients with poor cognitive function have significantly lower vitreous humor levels of AD-related biomarkers Aβ40, Aβ42, and tTau. These biomarkers do not correlate with underlying eye conditions, suggesting their specificity in association with cognitive change. This is the first study to our knowledge to correlate cognition with AD-related proteins in the vitreous humor. Results suggest ocular proteins may have a role for early dementia detection in individuals at risk for AD.

%B J Alzheimers Dis %V 68 %P 1429-1438 %8 2019 Apr 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30856114?dopt=Abstract %R 10.3233/JAD-181104 %0 Journal Article %J J Alzheimers Dis %D 2019 %T A Brief Ischemic Postconditioning Protects Against Amyloid-β Peptide Neurotoxicity by Downregulating MLK3-MKK3/6-P38MAPK Signal in Rat Hippocampus. %A Li, Hui %A Luo, Xiao-Bing %A Xu, Yan %A Hou, Xiao-Yu %X

BACKGROUND: Oligomeric amyloid-β peptide (Aβ) is associated with dysfunctional neuronal networks and neuronal loss in the development of Alzheimer's disease (AD). Ischemic postconditioning protects against post-ischemic excitotoxicity, oxidative stress, and inflammatory process that have also been implicated in the pathogenesis of AD. Evaluating the roles of ischemic postconditioning in oligomeric Aβ-induced neurotoxicity and underlying signal events may provide potential strategy for medical therapy in AD.

OBJECTIVES: The aim of the present study was to explore whether and how a brief ischemic postconditioning protects against Aβ neurotoxicity in rat hippocampus.

METHODS: Oligomeric Aβ25-35 (20 nmol/rat) or Aβ1-42 (5 nmol/rat) was infused by intracerebroventricular injection in adult male Sprague-Dawley rats. Ischemic postconditioning, a brief episode of global brain ischemia (3 min), was conducted at 1, 3, or 7 days after Aβ treatment, respectively.

RESULTS: A brief ischemic postconditioning reduced neuronal loss and inhibited the activation of MLK3, MKK3/6, and P38MAPKs in rat hippocampal CA1 and CA3 subfields after Aβ oligomer infusion. An N-methyl-D-aspartate (NMDA) receptor antagonist amantadine, but not non-NMDA receptor antagonist CNQX, reversed the MLK3-MKK3/6-P38MAPK signal events and beneficial effect of ischemic postconditioning on neuronal survival. Such reversion was also realized by NVP-AAM077, a GluN2A-subunit-selective NMDA receptor antagonist. Moreover, posttreatment with low doses of NMDA (5 nmol-40 nmol/rat) suppressed the Aβ-induced P38MAPK signaling and imitated the neuroprotection of ischemic postconditioning against Aβ neurotoxicity.

CONCLUSIONS: Ischemic postconditioning provides neuroprotection against Aβ neurotoxicity by moderate upregulation of NMDA receptor signaling, especially GluN2A-containing NMDA receptor pathway, and thereafter downregulation of MLK3-MKK3/6-P38MAPK signal events.

%B J Alzheimers Dis %V 71 %P 671-684 %8 2019 Sep 17 %G eng %N 2 %R 10.3233/JAD-190207 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Can Subjective Memory Complaints Identify Aβ Positive and Aβ Negative Amnestic Mild Cognitive Impairment Patients? %A Mendes, Tiago %A Cardoso, Sandra %A Guerreiro, Manuela %A Maroco, João %A Silva, Dina %A Alves, Luísa %A Schmand, Ben %A Gerardo, Bianca %A Lima, Marisa %A Santana, Isabel %A de Mendonça, Alexandre %X

BACKGROUND: The use of biomarkers, in particular amyloid-β (Aβ) changes, has allowed the possibility to identify patients with subjective memory complaints (SMCs) and amnestic mild cognitive impairment (aMCI) who suffer from Alzheimer's disease (AD). Since it is unfeasible that all patients with aMCI could presently undergo biomarkers assessment, it would be important that SMCs might contribute to identify the aMCI patients who have AD amyloid pathology.

OBJECTIVES: To know whether aMCI patients with amyloid biomarkers (Aβ+) present greater SMCs as compared to those without amyloid biomarkers (Aβ-).

METHODS: Participants were selected from a cohort of nondemented patients with cognitive complaints and a comprehensive neuropsychological evaluation, on the basis of 1) diagnosis of aMCI; 2) detailed assessment of memory difficulties with the SMC Scale; and 3) known amyloid status. The amyloid status was determined on the basis of either CSF Aβ1-42 concentration or amyloid PET imaging.

RESULTS: Of the 176 patients with aMCI studied, 90 were Aβ+ and 86 were Aβ-. The two groups did not differ in terms of age, gender, and education. The SMC total score was not significantly different in the Aβ+ aMCI patients (9.48±4.18) when compared to the Aβ- aMCI patients (10.52±4.57). The Aβ+ aMCI patients had lower scores on the MMSE and memory/learning tests, but not on the Geriatric Depression Scale, when comparing to the Aβ- aMCI patients.

CONCLUSIONS: Evaluating SMCs does not seem helpful to identify, among patients with aMCI, those who have AD.

%B J Alzheimers Dis %V 70 %P 1103-1111 %8 2019 Aug 20 %G eng %N 4 %R 10.3233/JAD-190414 %0 Journal Article %J J Alzheimers Dis %D 2019 %T CD14 and Toll-Like Receptor 4 Promote Fibrillar Aβ42 Uptake by Microglia Through A Clathrin-Mediated Pathway. %A Fujikura, Mai %A Iwahara, Naotoshi %A Hisahara, Shin %A Kawamata, Jun %A Matsumura, Akihiro %A Yokokawa, Kazuki %A Saito, Taro %A Manabe, Tatsuo %A Matsushita, Takashi %A Suzuki, Syuuichirou %A Shimohama, Shun %X

We previously demonstrated that microglia play an essential role in clearance of amyloid-β (Aβ) in Alzheimer's disease (AD)-like pathology. Our prior work also showed that several receptors expressed on microglia participated in Aβ phagocytosis. However, clathrin-mediated endocytosis (CME), which is associated with production and release of Aβ in neurons, has received much less attention in the context of microglial Aβ uptake. To elucidate the detailed mechanisms of microglial Aβ uptake pathways, we focused on CD14 and Toll-like receptor 4 (TLR4), which have been shown to mediate fibrillar Aβ1 - 42 (fAβ42) phagocytosis in microglia. CD14 has also been known to control lipopolysaccharide-induced internalization of TLR4 in a clathrin-dependent manner. However, it remains unclear whether CD14 and TLR4 engage in CME in microglial fAβ42 uptake, including whether CD14 interacts with TLR4 in the process. In the present study, we found that CD14-positive microglia increased in an age-dependent manner in the cortex of AD model mice. Immunostaining showed that CD14 interacted with TLR4 to internalize fAβ42 in the mouse microglial cell line MG6. Knock-down of CD14 and TLR4 in MG6 cells significantly reduced intracellular fAβ42, showing their involvement in fAβ42 uptake. We also found that clathrin participated in fAβ42 uptake by MG6 cells. Furthermore, CD14 and TLR4 mediated fAβ42 uptake via clathrin-dependent mechanisms. These results indicate that CD14 and TLR4 participate not only in phagocytosis but also in clathrin-dependent fAβ42 internalization in microglia. These findings provide novel molecular understanding of microglial fAβ42 uptake, which could be of therapeutic relevance for AD.

%B J Alzheimers Dis %V 68 %P 323-337 %8 2019 Mar 12 %G eng %N 1 %R 10.3233/JAD-180904 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Cerebral Amyloid Angiopathy and Neuritic Plaque Pathology Correlate with Cognitive Decline in Elderly Non-Demented Individuals. %A Malek-Ahmadi, Michael %A Chen, Kewei %A Perez, Sylvia E %A Mufson, Elliott J %X

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a vascular neuropathology commonly reported in non-cognitively impaired (NCI), mild cognitive impairment, and Alzheimer's disease (AD) brains. However, it is unknown whether similar findings are present in non-demented elderly subjects.

OBJECTIVE: This study determined the association between CAA and cognition among elderly NCI subjects with varying levels of AD pathology.

METHODS: Data from 182 cases that received a diagnosis of NCI at their first clinical assessment were obtained from the Rush Religious Orders study (RROS). A cognitive composite score was used to measure cognitive decline. CAA was dichotomized as present or absent. Cases were also dichotomized according to CERAD neuropathological diagnosis and Braak staging. A mixed model-repeated measures analysis assessed decline on the cognitive composite score.

RESULTS: CAA, alone, was not associated with cognitive decline [-0.87 (95% CI: -3.33, 1.58), p = 0.49]. However, among those with CAA, the High CERAD group had significantly greater decline relative to the Low CERAD group [-4.08 (95% CI: -7.10, -1.06), p = 0.008]. The High and Low CERAD groups were not significantly different [-1.77 (95% CI: -6.14, 2.60), p = 0.43] in those without CAA. Composite score decline in the High and Low Braak groups with [-1.32 (95% CI: -4.40, 1.75), p = 0.40] or without [0.27 (95% CI: -4.01, 4.56), p = 0.90] CAA was not significantly different.

CONCLUSION: The current data shows that an interaction between CAA and plaque load is associated with greater decline on a cognitive composite score used to test non-cognitively impaired elderly participants in AD prevention trials.

%B J Alzheimers Dis %V 67 %P 411-422 %8 2019 %G eng %N 1 %R 10.3233/JAD-180765 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Cerebral Microbleeds Are Associated with Cerebral Hypoperfusion in Patients with Alzheimer's Disease. %A Hatada, Yutaka %A Hashimoto, Mamoru %A Shiraishi, Shinya %A Ishikawa, Tomohisa %A Fukuhara, Ryuji %A Yuki, Seiji %A Tanaka, Hibiki %A Miyagawa, Yusuke %A Kitajima, Mika %A Uetani, Hiroyuki %A Tsunoda, Naoko %A Koyama, Asuka %A Ikeda, Manabu %X

BACKGROUND: Although cerebral microbleeds (CMBs) are commonly observed in patients with Alzheimer's disease (AD), their clinical relevance for AD remains unclear.

OBJECTIVE: We investigated the significance of CMBs in AD by examining the relationship between CMBs and cerebral blood flow (CBF) in patients with AD.

METHODS: Thirty-four patients (aged 77.9±7.6 years; 17 men) with probable AD and multiple (≥8) CMBs were selected from 394 consecutive patients. For each lobe of the brain, the correlation between the number of CMBs observed on susceptibility-weighted images and the decrease in CBF observed on single-photon emission computed tomography was assessed.

RESULTS: The number of microbleeds was significantly correlated with the severity of decrease in the occipital lobe (Spearman's r = 0.531, p <  0.001) and temporal lobe (r = 0.437, p <  0.001) but not in the frontal lobe (r = 0.201, p = 0.101) and parietal lobe (r = 0.178, p = 0.146). These results were unchanged in the partial correlational analysis after controlling the effect of other small vessel disease such as lacunars and white matter hyperintensities.

CONCLUSION: Multiple CMBs are associated with cerebral hypoperfusion in AD. The effects of CMBs on CBF differed according to brain location, possibly reflecting different distributions of the underlying cerebral amyloid angiopathy and AD-related histopathology, such as neurofibrillary tangles.

%B J Alzheimers Dis %V 71 %P 273-280 %8 2019 Sep 3 %G eng %N 1 %R 10.3233/JAD-190272 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Cerebrospinal Fluid Level of Aquaporin4: A New Window on Glymphatic System Involvement in Neurodegenerative Disease? %A Arighi, Andrea %A Di Cristofori, Andrea %A Fenoglio, Chiara %A Borsa, Stefano %A D'Anca, Marianna %A Fumagalli, Giorgio Giulio %A Locatelli, Marco %A Carrabba, Giorgio %A Pietroboni, Anna Margherita %A Ghezzi, Laura %A Carandini, Tiziana %A Colombi, Annalisa %A Scarioni, Marta %A De Riz, Milena Alessandra %A Serpente, Maria %A Rampini, Paolo Maria %A Scarpini, Elio %A Galimberti, Daniela %X

 Aquaporin4 (AQP4) is a water channel protein located at astrocyte foot processes that plays a role in glymphatic system, a highly organized fluid transport pathway which seems to be involved in Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) pathophysiology. Cerebrospinal fluid (CSF) AQP4 levels were determined in 11 patients with AD, 10 patients with NPH, and 9 controls. We found significantly reduced AQP4 in AD patients, a trend in reduction in NPH patients, and a correlation between AQP4 and amyloid-β CSF levels. This study indicates the potential role of AQP4 and glymphatic system in neurodegenerative diseases pathophysiology.

%B J Alzheimers Dis %V 69 %P 663-669 %8 2019 Jun 4 %G eng %N 3 %R 10.3233/JAD-190119 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Choroid Plexus Acts as Gatekeeper for TREM2, Abnormal Accumulation of ApoE, and Fibrillary Tau in Alzheimer's Disease and in Down Syndrome Dementia. %A Raha-Chowdhury, Ruma %A Henderson, James W %A Raha, Animesh Alexander %A Vuono, Romina %A Bickerton, Anastasia %A Jones, Elizabeth %A Fincham, Robert %A Allinson, Kieren %A Holland, Anthony %A Zaman, Shahid H %X

BACKGROUND: Genetic factors that influence Alzheimer's disease (AD) risk include mutations in TREM2 and allelic variants of Apolipoprotein E, influencing AD pathology in the general population and in Down syndrome (DS). Evidence shows that dysfunction of the choroid plexus may compromise the blood-cerebrospinal fluid (CSF) barrier, altering secretary, transport and immune function that can affect AD pathology.

OBJECTIVE: To investigate the genotype and phenotype of DS individuals in relation to choroid plexus damage and blood-CSF barrier leakage to identify markers that could facilitate early diagnosis of AD in DS.

METHODS: To assess allele frequency and haplotype associations ApoE, Tau, TREM2, and HLA-DR were analyzed by SNP analysis in DS participants (n = 47) and controls (n = 50). The corresponding plasma protein levels were measured by ELISA. Postmortem brains from DS, AD, and age-matched controls were analyzed by immunohistochemistry.

RESULTS: Haplotype analysis showed that individuals with Tau H1/H1 and ApoEɛ4 genotypes were more prevalent among DS participants with an earlier diagnosis of dementia (17%) compared to H1/H2 haplotypes (6%). Plasma TREM2 levels decreased whereas phospho-tau levels increased with age in DS. In AD and DS brain, insoluble tau and ApoE were found to accumulate in the choroid plexus.

CONCLUSION: Accumulation of tau and ApoE in the choroid plexus may increase the oligomerization rate of Aβ42 and impair tau trafficking, leading to AD pathology. We have identified a high-risk haplotype: ApoEɛ4, Tau/H1, and TREM2/T, that manifests age-related changes potentially opening a window for treatment many years prior to the manifestation of the AD dementia.

%B J Alzheimers Dis %V 69 %P 91-109 %8 2019 May 7 %G eng %N 1 %R 10.3233/JAD-181179 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Circulating and Extracellular Vesicles Levels of N-(1-Carboxymethyl)-L-Lysine (CML) Differentiate Early to Moderate Alzheimer's Disease. %A Haddad, Mohamed %A Perrotte, Morgane %A Landri, Sarra %A Lepage, Aurelie %A Fülöp, Tamás %A Ramassamy, Charles %X

BACKGROUND: Both advanced glycation end products (AGEs) N-(1-carboxymethyl)-L-lysine (CML) and pentosidine were found in the brain from Alzheimer's disease (AD) patients and were associated with the neuropathological hallmarks of AD. In AD patients, the circulating level of both AGEs remains unknown. Moreover, their levels in peripheral extracellular vesicles (EVs) and their association with AD remain to be determined. Finally, it is not known if neuronal cells can release AGEs via EVs and propagate AGEs.

OBJECTIVE: To determine the levels of circulating CML and pentosidine during the progression of AD. Moreover, their levels in circulating EVs were determined and their association with the clinical cognitive scores were analyzed. Finally, we have studied the possibility that neuronal cells eliminate and transfer these AGEs through EVs.

METHODS: CML and pentosidine levels were measured in serum and in circulating EVs. Released-EVs from SK-N-SH neuronal cells were isolated and CML levels were also determined.

RESULTS: The levels of CML in albumin-free serum proteins were higher in the early stage of AD while the levels of pentosidine remained unchanged. In contrast, the levels of CML in the EVs were lower in the moderate stage of AD. Interestingly, the levels of CML in serum were negatively correlated with the clinical cognitive scores MMSE and MoCA. For the first time, we were able to demonstrate that CML was present in EVs released from neuronal cells in culture.

CONCLUSION: Peripheral and circulating EVs levels of CML can differentiate early to moderate AD. In the brain, neuronal CML can propagate from cells-to-cells via EVs.

%B J Alzheimers Dis %V 69 %P 751-762 %8 2019 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/31127773?dopt=Abstract %R 10.3233/JAD-181272 %0 Journal Article %J J Alzheimers Dis %D 2019 %T The Clinical Phenotype of Vascular Cognitive Impairment in Patients with Type 2 Diabetes Mellitus. %A Groeneveld, Onno N %A Moneti, Costanza %A Heinen, Rutger %A de Bresser, Jeroen %A Kuijf, Hugo J %A Exalto, Lieza G %A Boomsma, Jooske M F %A Kappelle, L Jaap %A Barkhof, Frederik %A Prins, Niels D %A Scheltens, Philip %A van der Flier, Wiesje M %A Biessels, Geert Jan %X

BACKGROUND: Type 2 diabetes mellitus (T2DM) increases the risk of vascular cognitive impairment (VCI). It is unknown which type of vascular lesions and co-morbid etiologies, in particular Alzheimer's disease pathology, are associated with T2DM in patients with VCI, and how this relates to cognition and prognosis.

OBJECTIVE: To compare brain MRI and cerebrospinal fluid (CSF) markers, cognition, and prognosis in patients with possible VCI with and without T2DM.

METHODS: We included 851 memory clinic patients with vascular brain injury on MRI (i.e., possible VCI) from a prospective cohort study (T2DM: n = 147, 68.4±7.9 years, 63% men; no T2DM: n = 704, 67.6±8.5 years, 52% men). At baseline, we assessed between-group differences in brain MRI abnormalities, CSF markers of Alzheimer's disease, and cognitive profile. After two years follow-up, we compared occurrence of cognitive decline, stroke, and death.

RESULTS: The distribution of clinical diagnoses did not differ between patients with and without T2DM. T2DM patients had more pronounced brain atrophy (total and white matter volume), and more lacunar infarcts, whereas microbleeds were less common (all p <  0.05). CSF amyloid-β levels were similar between the groups. T2DM patients performed worse on working memory (effect size: - 0.17, p = 0.03) than those without, whereas performance on other domains was similar. During follow-up, risk of further cognitive decline was not increased in T2DM.∥Conclusion: In patients with possible VCI, presence of T2DM is related to more pronounced brain atrophy and a higher burden of lacunar infarcts, but T2DM does not have a major impact on cognitive profile or prognosis.∥.

%B J Alzheimers Dis %V 68 %P 311-322 %8 2019 Mar 12 %G eng %N 1 %R 10.3233/JAD-180914 %0 Journal Article %J J Alzheimers Dis %D 2019 %T A Clinical Trial of Transcranial Electromagnetic Treatment in Alzheimer's Disease: Cognitive Enhancement and Associated Changes in Cerebrospinal Fluid, Blood, and Brain Imaging. %A Arendash, Gary %A Cao, Chuanhai %A Abulaban, Haitham %A Baranowski, Rob %A Wisniewski, Gary %A Becerra, Lino %A Andel, Ross %A Lin, Xiaoyang %A Zhang, Xiaolin %A Wittwer, David %A Moulton, Jay %A Arrington, John %A Smith, Amanda %X

BACKGROUND: Small aggregates (oligomers) of the toxic proteins amyloid-β (Aβ) and phospho-tau (p-tau) are essential contributors to Alzheimer's disease (AD). In mouse models for AD or human AD brain extracts, Transcranial Electromagnetic Treatment (TEMT) disaggregates both Aβ and p-tau oligomers, and induces brain mitochondrial enhancement. These apparent "disease-modifying" actions of TEMT both prevent and reverse memory impairment in AD transgenic mice.

OBJECTIVE: To evaluate the safety and initial clinical efficacy of TEMT against AD, a comprehensive open-label clinical trial was performed.

METHODS: Eight mild/moderate AD patients were treated with TEMT in-home by their caregivers for 2 months utilizing a unique head device. TEMT was given for two 1-hour periods each day, with subjects primarily evaluated at baseline, end-of-treatment, and 2 weeks following treatment completion.

RESULTS: No deleterious behavioral effects, discomfort, or physiologic changes resulted from 2 months of TEMT, as well as no evidence of tumor or microhemorrhage induction. TEMT induced clinically important and statistically significant improvements in ADAS-cog, as well as in the Rey AVLT. TEMT also produced increases in cerebrospinal fluid (CSF) levels of soluble Aβ1-40 and Aβ1-42, cognition-related changes in CSF oligomeric Aβ, a decreased CSF p-tau/Aβ1-42 ratio, and reduced levels of oligomeric Aβ in plasma. Pre- versus post-treatment FDG-PET brain scans revealed stable cerebral glucose utilization, with several subjects exhibiting enhanced glucose utilization. Evaluation of diffusion tensor imaging (fractional anisotropy) scans in individual subjects provided support for TEMT-induced increases in functional connectivity within the cognitively-important cingulate cortex/cingulum.

CONCLUSION: TEMT administration to AD subjects appears to be safe, while providing cognitive enhancement, changes to CSF/blood AD markers, and evidence of stable/enhanced brain connectivity.

%B J Alzheimers Dis %V 71 %P 57-82 %8 2019 %G eng %N 1 %R 10.3233/JAD-190367 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Clinico-Neuropathological Findings in the Oldest Old from the Georgia Centenarian Study. %A Tanprasertsuk, Jirayu %A Johnson, Elizabeth J %A Johnson, Mary Ann %A Poon, Leonard W %A Nelson, Peter T %A Davey, Adam %A Martin, Peter %A Barbey, Aron K %A Barger, Kathryn %A Wang, Xiang-Dong %A Scott, Tammy M %X

BACKGROUND: Centenarian studies are important sources for understanding of factors that contribute to longevity and healthy aging. Clinico-neuropathological finding is a key in identifying pathology and factors contributing to age-related cognitive decline and dementia in the oldest old.

OBJECTIVE: To characterize the cross-sectional relationship between neuropathologies and measures of premortem cognitive performance in centenarians.

METHODS: Data were acquired from 49 centenarians (≥98 years) from the Georgia Centenarian Study. Cognitive assessment from the time point closest to mortality was used (

RESULTS: Wide ranges of AD-type neuropathological changes were observed in both non-demented and demented subjects. Neocortical NFT and Braak staging were related to clinical dementia rating. Neocortical NFT and NP, Braak and NIARI staging, cerebral and ventricular atrophy, HS, CAA, and TDP-43 proteinopathy were differentially associated with poor performance in multiple cognitive domains and activities of daily living.

CONCLUSION: AD-type pathology was associated with severe dementia and poor cognition but was not the only variable that explained cognitive impairment, indicating the complexity and heterogeneity of pathophysiology of dementia in the oldest old.

%B J Alzheimers Dis %V 70 %P 35-49 %8 2019 Jul 2 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/31177211?dopt=Abstract %R 10.3233/JAD-181110 %0 Journal Article %J J Alzheimers Dis %D 2019 %T A Comparison of Partial Volume Correction Techniques for Measuring Change in Serial Amyloid PET SUVR. %A Schwarz, Christopher G %A Gunter, Jeffrey L %A Lowe, Val J %A Weigand, Stephen %A Vemuri, Prashanthi %A Senjem, Matthew L %A Petersen, Ronald C %A Knopman, David S %A Jack, Clifford R %X

Longitudinal PET studies in aging and Alzheimer's disease populations rely on accurate and precise measurements of change over time from serial PET scans. Various methods for partial volume correction (PVC) are commonly applied to such studies, but existing comparisons and validations of these PVC methods have focused on cross-sectional measurements. Rate of change measurements inherently have smaller magnitudes than cross-sectional measurements, so levels of noise amplification due to PVC must be smaller, and it is necessary to re-evaluate methods in this context. Here we compare the relative precision in longitudinal measurements from serial amyloid PET scans when using geometric transfer matrix (GTM) PVC versus the traditional two-compartment (Meltzer-style), three-compartment (Müller-Gärtner-style), and no-PVC approaches. We used two independent implementations of standardized uptake value ratio (SUVR) measurement and PVC (one in-house pipeline based on SPM12 and ANTs, and one using FreeSurfer 6.0). For each approach, we also tested longitudinal-specific variants. Overall, we found that measurements using GTM PVC had significantly worse relative precision (unexplained within-subject variability ≈4-8%) than those using two-compartment, three-compartment, or no PVC (≈2-4%). Longitudinally-stabilized approaches did not improve these properties. This data suggests that GTM PVC methods may be less suitable than traditional approaches when measuring within-person change over time in longitudinal amyloid PET.

%B J Alzheimers Dis %V 67 %P 181-195 %8 2019 %G eng %N 1 %R 10.3233/JAD-180749 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Developing Effective Alzheimer's Disease Therapies: Clinical Experience and Future Directions. %A Elmaleh, David R %A Farlow, Martin R %A Conti, Peter S %A Tompkins, Ronald G %A Kundakovic, Ljiljana %A Tanzi, Rudolph E %X

Alzheimer's disease (AD) clinical trials, focused on disease modifying drugs and conducted in patients with mild to moderate AD, as well as prodromal (early) AD, have failed to reach efficacy endpoints in improving cognitive function in most cases to date or have been terminated due to adverse events. Drugs that have reached clinical stage were reviewed using web resources (such as clinicaltrials.gov, alzforum.org, company press releases, and peer reviewed literature) to identify late stage (Phase II and Phase III) efficacy clinical trials and summarize reasons for their failure. For each drug, only the latest clinical trials and ongoing trials that aimed at improving cognitive function were included in the analysis. Here we highlight the potential reasons that have hindered clinical success, including clinical trial design and choice of outcome measures, heterogeneity of patient populations, difficulties in diagnosing and staging the disease, drug design, mechanism of action, and toxicity related to the long-term use. We review and suggest approaches for AD clinical trial design aimed at improving our ability to identify novel therapies for this devastating disease.

%B J Alzheimers Dis %V 71 %P 715-732 %8 2019 Oct 1 %G eng %N 3 %R 10.3233/JAD-190507 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Dietary Patterns and Cognitive Health in Older Adults: A Systematic Review. %A Chen, Xi %A Maguire, Brook %A Brodaty, Henry %A O'Leary, Fiona %X

While the role of diet and nutrition in cognitive health and prevention of dementia in older adults has attracted much attention, the efficacy of different dietary patterns remains uncertain. Previous reviews have mainly focused on the Mediterranean diet, but either omitted other dietary patterns, lacked more recent studies, were based on cross-sectional studies, or combined older and younger populations. We followed PRISMA guidelines, and examined the efficacy of current research from randomized controlled trials and cohort studies on the effects of different dietary patterns. We reviewed the Mediterranean diet, Dietary Approach to Stop Hypertension (DASH) diet, the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diet, Anti-inflammatory diet, Healthy diet recommended by guidelines via dietary index, or Prudent healthy diets generated via statistical approaches, and their impact on cognitive health among older adults. Of 38 studies, the Mediterranean diet was the most investigated with evidence supporting protection against cognitive decline among older adults. Evidence from other dietary patterns such as the MIND, DASH, Anti-inflammatory, and Prudent healthy diets was more limited but showed promising results, especially for those at risk of cardiovascular disease. Overall, this review found positive effects of dietary patterns including the Mediterranean, DASH, MIND, and Anti-inflammatory diets on cognitive health outcomes in older adults. These dietary patterns are plant-based, rich in poly- and mono-unsaturated fatty acids with lower consumption of processed foods. Better understanding of the underlying mechanisms and effectiveness is needed to develop comprehensive and practical dietary recommendations against age-related cognitive decline among older adult.

%B J Alzheimers Dis %V 67 %P 583-619 %8 2019 %G eng %N 2 %R 10.3233/JAD-180468 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Distinctive Neurochemistry in Alzheimer's Disease via 7 T In Vivo Magnetic Resonance Spectroscopy. %A Marjańska, Małgorzata %A McCarten, J Riley %A Hodges, James S %A Hemmy, Laura S %A Terpstra, Melissa %X

This study's objective was to increase understanding of biological mechanisms underlying clinical Alzheimer's disease (AD) by noninvasively measuring an expanded neurochemical profile and exploring how well this advanced technology distinguishes AD from cognitively normal controls. We measured concentrations of 14 neurochemicals using ultra-high field (7 T) ultra-short echo time (8 ms) magnetic resonance spectroscopy (MRS) in 16 participants with mild to moderate clinical AD and 33 age- and gender-matched control participants. MRS was localized to the posterior cingulate cortex (PCC), a region known to be impacted by AD, and the occipital cortex (OCC), a control region. Participants with AD were recruited from dementia specialty clinics. Concentration of the antioxidant ascorbate was higher (p < 0.0007) in both brain regions. Concentrations of the glial marker myo-inositol and the choline-containing compounds involved in membrane turnover were higher (p≤0.0004) in PCC of participants with AD. Ascorbate and myo-inositol concentrations were strongly associated, especially in the PCC. Random forests, using the 14 neurochemicals in the two regions, distinguished participants with AD from controls: same-sample sensitivity and specificity were 88% and 97%, respectively, though out-of-sample-values would be lower. Ultra-high field ultra-short echo time MRS identified the co-occurrence of elevated ascorbate and myo-inositol in the PCC as markers that distinguish participants with mild to moderate AD from controls. While elevated myo-inositol may be a surrogate marker of neuroinflammation, the unexpected elevation of the antioxidant ascorbate may reflect infiltration of ascorbate-rich leukocytes.

%B J Alzheimers Dis %V 68 %P 559-569 %8 2019 Mar 29 %G eng %N 2 %R 10.3233/JAD-180861 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Early-Stage Alzheimer's Disease Is Associated with Simultaneous Systemic and Central Nervous System Dysregulation of Insulin-Linked Metabolic Pathways. %A de la Monte, Suzanne M %A Tong, Ming %A Daiello, Lori A %A Ott, Brian R %X

BACKGROUND: Brain insulin resistance is a well-recognized abnormality in Alzheimer's disease (AD) and the likely mediator of impaired glucose utilization that emerges early and progresses with disease severity. Moreover, the rates of mild cognitive impairment (MCI) or AD are significantly greater in people with diabetes mellitus or obesity.

OBJECTIVE: This study was designed to determine whether systemic and central nervous system (CNS) insulin resistant disease states emerge together and thus may be integrally related.

METHODS: Insulin-related molecules were measured in paired human serum and cerebrospinal fluid (CSF) samples from 19 with MCI or early AD, and 21 controls using a multiplex ELISA platform.

RESULTS: In MCI/AD, both the CSF and serum samples had significantly altered mean levels of C-peptide (both elevated), Visfatin, incretins, PAI-1, ghrelin, and leptin, whereas only CSF showed a significant reduction in insulin and only serum had increased glucagon levels. Although the overall CSF and serum responses reflected insulin resistance together with insulin deficiency, the specific alterations measured in CSF and serum were different.

CONCLUSION: In MCI and early-stage AD, CNS and systemic insulin-related metabolic dysfunctions, including insulin resistance, occur simultaneously, suggesting that they are integrally related and possibly mediated similar pathogenic factors.

%B J Alzheimers Dis %V 68 %P 657-668 %8 2019 Mar 29 %G eng %N 2 %R 10.3233/JAD-180906 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Education Moderates the Relation Between APOE ɛ4 and Memory in Nondemented Non-Hispanic Black Older Adults. %A Vonk, Jet M J %A Rentería, Miguel Arce %A Medina, Valerie M %A Pericak-Vance, Margaret A %A Byrd, Goldie S %A Haines, Jonathan %A Brickman, Adam M %A Manly, Jennifer J %X

BACKGROUND: The APOEɛ4 allele is a well-known risk factor for Alzheimer's disease (AD). Previous research argues that higher education helps to preserve cognition in older adults with AD pathology because of its key role in cognitive reserve and resilience.

OBJECTIVE: To test if higher educational level buffers the effect of APOEɛ4 on cognition among older non-Hispanic Blacks.

METHODS: Participants were 849 non-demented older non-Hispanic Blacks (38.3% APOEɛ4+), who underwent a comprehensive neuropsychological evaluation. Multiple linear regression models tested the relationship between APOEɛ4 status and twelve cognitive measures with education (up to high school and beyond high school) as a moderator.

RESULTS: Education buffered the effects of the APOEɛ4 allele, such that there was no impact of APOEɛ4 status on word-list memory retention and working memory among participants with more than a high school degree. This pattern was not observed for ten other cognitive measures of verbal and visual episodic memory, semantic memory, executive function, and processing speed-although a similar trend was observed for switching ability in executive functioning. The buffering effect of education was stronger among women than men.

CONCLUSION: Our findings suggest that genetic effects on late-life cognition may be modified by environmental factors such as educational attainment. These results are consistent with the framework of cognitive reserve such that engaging in cognitively enriching activities and acquiring skills and knowledge with more years of education may increase the capacity to maintain cognitive function despite high genetic risk for impairment.

%B J Alzheimers Dis %V 72 %P 495-506 %8 2019 Nov 12 %G eng %N 2 %R 10.3233/JAD-190415 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Effect of Advanced Glycation End Products on the Progression of Alzheimer's Disease. %A Chou, Ping-Song %A Wu, Meng-Ni %A Yang, Chen-Cheng %A Shen, Cheng-Ting %A Yang, Yuan-Han %X

BACKGROUND: Shared links between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) have been well-known. A high concentration of advanced glycation end products (AGEs) has been reported to contribute to impaired mobility in patients with AD, but there is limited understanding regarding the longitudinal impact of AGEs on cognitive performance.

OBJECTIVE: This study aims to explore whether the concentrations of AGEs mediate the clinical progression of cognitive performance in patients with AD and T2DM.

METHODS: Twenty-five patients aged 79.0±5.8 years who were diagnosed with probable AD with a Clinical Dementia Rating (CDR) of 0.5 or 1 and T2DM were enrolled in this study. When patients participated in the study, the concentration of plasma AGEs was tested. A series of neuropsychological tests, namely the Mini-Mental Status Examination (MMSE), Cognitive Assessment Screening Instrument (CASI), and CDR, were performed annually during follow-up. The association between the concentration of AGEs and changes in overall cognition and cognition related daily living performance was analyzed.

RESULTS: After the mean 48.6±2.1 months of follow-up, AGEs were found to be significantly associated with a change in CDR. A total of 12 (48% ) patients experienced a decline in CDR; they had a significantly higher concentration of AGEs than did those whose CDR did not deteriorate (100.5 ± 14.2 versus 81.5 ± 17.7; p = 0.007). This difference in CDR remained significant after adjustment for age, sex, education level, and apolipoprotein E4 status (adjusted p = 0.020).

CONCLUSION: In conclusion, this study indicates that a high concentration of AGEs may be a predictor of a long-term decline in cognition related daily living performance in patients with AD and T2DM.

%B J Alzheimers Dis %V 72 %P 191-197 %8 2019 Oct 29 %G eng %N 1 %R 10.3233/JAD-190639 %0 Journal Article %J J Alzheimers Dis %D 2019 %T The Effects of APOE4 on Mitochondrial Dynamics and Proteins in vivo. %A Simonovitch, Shira %A Schmukler, Eran %A Masliah, Eliezer %A Pinkas-Kramarski, Ronit %A Michaelson, Daniel M %X

This study examined the effects of apolipoprotein E4 (APOE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), on proteins involved in mitochondrial dynamics and autophagy, in the hippocampus of targeted replacement mice. Immunohistochemical measurements revealed that the levels of the mitochondrial fusion-mediating protein, MFN1, were higher, whereas those of corresponding fission-regulating protein, DRP-1, were lower in the hippocampus of ApoE4 mice than in the corresponding ApoE3 mice, indicating that APOE4 is associated with increased mitochondrial fusion and decreased fission. A similar ApoE4-driven decrease in DRP-1 was also observed in AD brains. The levels of the mitochondrial proteins COX1 and Tom40, were higher in the ApoE4 mice, which is consistent with the increased fusion. Measurements of the levels of cleaved PINK1 and parkin, which mark and target mitochondria for mitophagic degradation, revealed lower levels of cleaved PINK1, suggesting reduced mitochondrial membrane potential, and higher levels of parkin in the hippocampus of ApoE4 compared with the ApoE3 mice, indicating altered mitophagy. The levels of the ubiquitin-binding scaffold protein, p62/SQSTM1, which directs selected cargo to the autophagosomes, were also higher in the ApoE4 mice. These findings suggest that APOE4 is associated with enhanced mitochondrial fusion and decreased fission. Additionally, the results indicate that the mitophagy/autophagy is reduced in ApoE4 mice, resulting in higher levels of proteins such as parkin and p62, which are normally degraded during this process. Taken together, these results suggest a novel mechanism that may underlie the pathological effects of APOE4 and indicate that use of APOE4 genotyping could pave the way for identification of novel APOE4-related therapeutic targets.

%B J Alzheimers Dis %V 70 %P 861-875 %8 2019 Aug 3 %G eng %N 3 %R 10.3233/JAD-190074 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Ethical Issues in the Treatment of Late-Stage Alzheimer's Disease. %A Watt, Andrew D %A Jenkins, Nicole L %A McColl, Gawain %A Collins, Steven %A Desmond, Patricia M %X

There is hope that the continuing efforts of researchers will yield a disease-modifying drug for Alzheimer's disease. Such a drug is likely to be capable of halting, or significantly slowing, the underlying pathological processes driving cognitive decline; however, it is unlikely to be capable of restoring brain function already lost through the pathological process. A therapy capable of halting Alzheimer's disease, while not providing restoration of function, may prompt serious ethical questions. For example, is there a stage in the disease process when it becomes too late for therapeutic intervention to commence? And who bears the responsibility of making such a decision? Conversations regarding the ethics of treating neurodegenerative conditions with non-restorative drugs have been largely absent within both clinical and research communities. Such discussions are urgently required to ensure that patients' rights and well-being are protected when such therapeutic options become available.

%B J Alzheimers Dis %V 68 %P 1311-1316 %8 2019 %G eng %N 4 %R 10.3233/JAD-180865 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Evaluation of Associations of Alzheimer's Disease Risk Variants that Are Highly Expressed in Microglia with Neuropathological Outcome Measures. %A Sakae, Nobutaka %A Heckman, Michael G %A Vargas, Emily R %A Carrasquillo, Minerva M %A Murray, Melissa E %A Kasanuki, Koji %A Ertekin-Taner, Nilufer %A Younkin, Steven G %A Dickson, Dennis W %X

 A number of Alzheimer's disease (AD) susceptibility loci are expressed abundantly in microglia. We examined associations between AD risk variants in genes that are highly expressed in microglia and neuropathological outcomes, including cerebral amyloid angiopathy (CAA) and microglial activation, in 93 AD patients. We observed significant associations of CAA pathology with APOEɛ4 and PTK2B rs28834970. Nominally significant associations with measures of microglial activation in white matter were observed for variants in PTK2B, PICALM, and CR1. Our findings suggest that several AD risk variants may also function as disease modifiers through amyloid-β metabolism and white matter microglial activity.

%B J Alzheimers Dis %V 70 %P 659-666 %8 2019 Aug 3 %G eng %N 3 %R 10.3233/JAD-190451 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Evaluation of Medicare Claims Data as a Tool to Identify Dementia. %A Lee, Eunjung %A Gatz, Margaret %A Tseng, Chiuchen %A Schneider, Lon S %A Pawluczyk, Sonia %A Wu, Anna H %A Deapen, Dennis %X

BACKGROUND: Medicare claims record linkage has been used to identify diagnosed dementia cases in order to estimate dementia prevalence and cost of care. Claims records in the 1990 s and early 2000 s have been found to provide 85% - ∼90% sensitivity and specificity.

OBJECTIVE: Considering that dementia awareness has improved over time, we sought to examine sensitivity and specificity of more recent Medicare claims records against a standard criterion, clinical diagnosis of dementia.

METHODS: For a sample of patients evaluated at the University of Southern California Alzheimer Disease Research Center (ADRC), we performed database linkage with Medicare claims files for a six-year period, 2007-2012. We used clinical diagnosis at the ADRC as the criterion diagnosis in order to calculate sensitivity and specificity.

RESULTS: Medicare claims correctly identified 85% of dementia patients and 77% of individuals with normal cognition. About half of patients clinically diagnosed with mild cognitive impairment had dementia diagnoses in Medicare claims. Misclassified dementia patients (i.e., missed diagnosis by Medicare claims) had more favorable Mini-Mental State Examination and Clinical Dementia Rating scores and were less likely to present behavioral symptoms than correctly-classified dementia patients.

CONCLUSIONS: Database linkage to Medicare claims records is an efficient and reasonably accurate tool to identify dementia cases in a population-based cohort. However, possibilities of obtaining biased results due to misclassification of dementia status need to be carefully considered to use Medicare claims diagnosis for etiologic research studies. Additional confirmation of dementia diagnosis may also be considered. A larger study is warranted to confirm our findings.

%B J Alzheimers Dis %V 67 %P 769-778 %8 2019 %G eng %N 2 %R 10.3233/JAD-181005 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Exercise Training in Amnestic Mild Cognitive Impairment: A One-Year Randomized Controlled Trial. %A Tarumi, Takashi %A Rossetti, Heidi %A Thomas, Binu P %A Harris, Thomas %A Tseng, Benjamin Y %A Turner, Marcel %A Wang, Ciwen %A German, Zohre %A Martin-Cook, Kristin %A Stowe, Ann M %A Womack, Kyle B %A Mathews, Dana %A Kerwin, Diana R %A Hynan, Linda %A Diaz-Arrastia, Ramon %A Lu, Hanzhang %A Munro Cullum, C %A Zhang, Rong %X

BACKGROUND: The current evidence is inconclusive to support the benefits of aerobic exercise training (AET) for preventing neurocognitive decline in patients with amnestic mild cognitive impairment (aMCI).

OBJECTIVE: To examine the effect of a progressive, moderate-to-high intensity AET program on memory and executive function, brain volume, and cortical amyloid-β (Aβ) plaque deposition in aMCI patients.

METHODS: This is a proof-of-concept trial that randomized 70 aMCI patients to 12 months of AET or stretching and toning (SAT, active control) interventions. Primary neuropsychological outcomes were assessed by using the California Verbal Learning Test-second edition (CVLT-II) and the Delis-Kaplan Executive Function System (D-KEFS). Secondary outcomes were the global and hippocampal brain volumes and the mean cortical and precuneus Aβ deposition.

RESULTS: Baseline cognitive scores were similar between the groups. Memory and executive function performance improved over time but did not differ between the AET and SAT groups. Brain volume decreased and precuneus Aβ plaque deposition increased over time but did not differ between the groups. Cardiorespiratory fitness was significantly improved in the AET compared with SAT group. In amyloid positive patients, AET was associated with reduced hippocampal atrophy when compared with the SAT group.

CONCLUSION: The AET and SAT groups both showed evidence of slightly improved neuropsychological scores in previously sedentary aMCI patients. However, these interventions did not prevent brain atrophy or increases in cortical Aβ deposition over 12 months. In amyloid positive patients, AET reduced hippocampal atrophy when compared with the SAT group.

%B J Alzheimers Dis %V 71 %P 421-433 %8 2019 Sep 17 %G eng %N 2 %R 10.3233/JAD-181175 %0 Journal Article %J J Alzheimers Dis %D 2019 %T A Fragment of S38AA is a Novel Plasma Biomarker of Alzheimer's Disease. %A Hashimoto, Masakazu %A Yamazaki, Akira %A Ohno, Atsushi %A Kimura, Toru %A Winblad, Bengt %A Tjernberg, Lars O %X

Alzheimer's disease (AD) is a progressive neurodegenerative disease without a cure. The pathological process starts decades before clinical onset, and thus clinical trials of drugs aimed at treating AD should start at a presymptomatic stage. Therefore, it is critical to diagnose AD at an early stage. Tau, phosphorylated tau, and amyloid-β peptide (Aβ) in cerebrospinal fluid (CSF), and positron emission tomography (PET) imaging of Aβ or tau accumulation are supportive biomarkers for AD diagnosis, but there is no reliable presymptomatic diagnostic marker. Since CSF sampling is invasive, and PET imaging is expensive and available only at specialized centers, a reliable blood biomarker has long been sought for. Here we describe a novel extramembrane fragment from solute carrier family 38 member 10 (SLC38A10, S38AA) that we found to be decreased in pyramidal neurons in AD cases by proteomics and immunohistochemical analysis. We detected a S38AA fragment in CSF and found the levels to correlate with severity of AD and APOE genotype. Importantly, the plasma levels of the fragment also showed a significant correlation with Mini-Mental State Examination scores in AD. Moreover, plasma from other neurodegenerative disease was analyzed and the fragment was found to be increased specifically in AD. Interestingly, the fragment is detected in mouse, rat, and monkey, and increases in amyloid precursor protein transgenic mice as the AD-like pathology progresses. We propose that the S38AA fragment in plasma could be a novel quantitative diagnostic marker for AD and potentially a marker of disease progression in AD.

%B J Alzheimers Dis %V 71 %P 1163-1174 %8 2019 Oct 15 %G eng %N 4 %R 10.3233/JAD-190700 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Gender and Educational Differences in the Association between Lifestyle and Cognitive Decline over 10 Years: The Doetinchem Cohort Study. %A Deckers, Kay %A Nooyens, Astrid %A van Boxtel, Martin %A Verhey, Frans %A Verschuren, Monique %A Köhler, Sebastian %X

BACKGROUND: Several modifiable risk factors for cognitive decline have been identified, but whether differences by gender and educational level exist is unclear.

OBJECTIVE: The present study aims to clarify this by prospectively investigating the relationship between health and lifestyle factors and cognitive functioning in different subgroups defined by gender and educational level.

METHODS: 2,347 cognitive healthy individuals (mean age = 54.8, SD = 6.8, range: 41-71; 51.8% female; 26.2% low education) from the Doetinchem Cohort Study were examined for cognitive function at baseline, and at 5- and 10-year follow-up. Health- and lifestyle factors were captured by a poly-environmental risk score labelled 'LIfestyle for BRAin Health' (LIBRA). This score consists of 12 modifiable risk and protective factors for cognitive decline and dementia, with higher scores indicating greater risk (range: -2.7 to +12.7). Heterogeneity in associations between LIBRA and decline in verbal memory, cognitive flexibility, and mental speed between males and females and individuals with different levels of education were assessed in linear mixed models.

RESULTS: Overall, higher LIBRA scores predicted faster decline in verbal memory, cognitive flexibility, and mental speed over 10 years. Higher LIBRA scores were further associated with increased risk for incident cognitive impairment (one-point increase in LIBRA: HR = 1.09, 1.04-1.14, p = 0.001). In general, these effects were similar across gender and educational level.

CONCLUSION: A composite risk score comprising unhealthy lifestyle and relatively poor health in midlife is significantly associated with a worse course of cognition 10 years later. These associations were for the most part unrelated to gender or educational differences.

%B J Alzheimers Dis %V 70 %P S31-S41 %8 2019 %G eng %N s1 %R 10.3233/JAD-180492 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Genome-Wide Methylation of Mild Cognitive Impairment in Mexican Americans Highlights Genes Involved in Synaptic Transport, Alzheimer's Disease-Precursor Phenotypes, and Metabolic Morbidities. %A Pathak, Gita A %A Silzer, Talisa K %A Sun, Jie %A Zhou, Zhengyang %A Daniel, Ann A %A Johnson, Leigh %A O'Bryant, Sid %A Phillips, Nicole R %A Barber, Robert C %X

The Mexican American population is among the fastest growing aging population and has a younger onset of cognitive decline. This group is also heavily burdened with metabolic conditions such as hypertension, diabetes, and obesity. Unfortunately, limited research has been conducted in this group. Understanding methylation alterations, which are influenced by both genetic and lifestyle factors, is key to identifying and addressing the root cause for mild cognitive impairment, a clinical precursor for dementia. We conducted an epigenome-wide association study on a community-based Mexican American population using the Illumina EPIC array. Following rigorous quality control measures, we identified 10 CpG sites to be differentially methylated between normal controls and individuals with mild cognitive impairment annotated to PKIB, KLHL29, SEPT9, OR2C3, CPLX3, BCL2L2-PABPN1, and CCNY. We found four regions to be differentially methylated in TMEM232, SLC17A8, ALOX12, and SEPT8. Functional gene-set analysis identified four gene-sets, RIN3, SPEG, CTSG, and UBE2L3, as significant. The gene ontology and pathway analyses point to neuronal cell death, metabolic dysfunction, and inflammatory processes. We found 1,450 processes to be enriched using empirical Bayes gene-set enrichment. In conclusion, the functional overlap of differentially methylated genes associated with cognitive impairment in Mexican Americans implies cross-talk between metabolically-instigated systemic inflammation and disruption of synaptic vesicular transport.

%B J Alzheimers Dis %V 72 %P 733-749 %8 2019 Nov 26 %G eng %N 3 %R 10.3233/JAD-190634 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Geographical Variation in the Diagnostic Rate and Quality of Dementia Diagnoses. %A Zakarias, Johanne Købstrup %A Jensen-Dahm, Christina %A Nørgaard, Ane %A Roos, Peter %A Gasse, Christiane %A Phung, Thien Kieu Thi %A Waldemar, Gunhild %X

BACKGROUND: Early and accurate diagnosis of dementia opens the door to appropriate treatment, support, and counseling. Despite availability of evidence-based guidelines for diagnostic evaluation of dementia, the diagnostic rate in people with dementia is low and the quality of dementia diagnoses is unknown.

OBJECTIVE: The overall aim of this register-based study was to analyze the quality of diagnostic evaluation of dementia by assessing nationwide geographical variations in a range of indicators.

METHODS: A register-based cross-sectional study of the entire Danish population aged 65 years or older in 2015 was conducted. The surrogate indicators for diagnostic quality included 1) prevalence rates of dementia diagnoses, 2) incidence rates of dementia diagnoses, 3) age at first diagnosis of dementia, 4) medical specialty responsible for diagnosis, 5) diagnostic rate of dementia subtypes, and 6) use of anti-dementia medication. The indicators were compared across the five Danish regions.

RESULTS: The national prevalence and incidence of registered dementia diagnoses was 3.0% and 0.5%, respectively. The proportion of patients diagnosed at a dementia specialist department ranged from 60.9% to 90.5% across the five regions, subtype specific diagnosis ranged from 45.3% to 75.5%, and use of anti-dementia medication ranged from 29.2% to 58.3%.

CONCLUSION: The observed geographical variations in dementia diagnoses and treatment indicate inequality in the access to appropriate diagnostic evaluation and care for patients with dementia. Our findings call for more awareness of the benefits of timely diagnosis and for improvement in the quality of diagnostic evaluation of dementia.

%B J Alzheimers Dis %V 69 %P 513-520 %8 2019 May 21 %G eng %N 2 %R 10.3233/JAD-190030 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Glial Fibrillary Acidic Protein in Serum is Increased in Alzheimer's Disease and Correlates with Cognitive Impairment. %A Oeckl, Patrick %A Halbgebauer, Steffen %A Anderl-Straub, Sarah %A Steinacker, Petra %A Huss, André M %A Neugebauer, Hermann %A von Arnim, Christine A F %A Diehl-Schmid, Janine %A Grimmer, Timo %A Kornhuber, Johannes %A Lewczuk, Piotr %A Danek, Adrian %A Ludolph, Albert C %A Otto, Markus %X

Reliable blood biomarkers for Alzheimer's disease (AD) are missing. We measured astroglial GFAP in patients with AD (n = 28), frontotemporal dementia (bvFTD, n = 35), Parkinson's disease (n = 11), Lewy body dementias (n = 19), and controls (n = 34). Serum GFAP was increased in AD (p < 0.001) and DLB/PDD (p < 0.01), and cerebrospinal fluid GFAP was increased in all neurodegenerative diseases (p < 0.001). Serum GFAP correlated with the Mini-Mental State Examination score (r= -0.42, p < 0.001) and might be a follow-up marker in clinical trials. Sensitivity and specificity of serum GFAP for AD versus bvFTD was 89% and 79% and might be the first blood biomarker in the differential diagnosis of AD and bvFTD.

%B J Alzheimers Dis %V 67 %P 481-488 %8 2019 %G eng %N 2 %R 10.3233/JAD-180325 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Global Metabolic Shifts in Age and Alzheimer's Disease Mouse Brains Pivot at NAD +/NADH Redox Sites. %A Dong, Yue %A Brewer, Gregory J %X

Age and Alzheimer's disease (AD) share some common features such as cognitive impairments, memory loss, metabolic disturbances, bioenergetic deficits, and inflammation. Yet little is known on how systematic shifts in metabolic networks depend on age and AD. In this work, we investigated the global metabolomic alterations in non-transgenic (NTg) and triple-transgenic (3xTg-AD) mouse brain hippocampus as a function of age by using untargeted Ultrahigh Performance Liquid Chromatography-tandem Mass Spectroscopy (UPLC-MS/MS). We observed common metabolic patterns with aging in both NTg and 3xTg-AD brains involved in energy-generating pathways, fatty acids oxidation, glutamate, and sphingolipid metabolism. We found age-related downregulation of metabolites from reactions in glycolysis that consumed ATP and in the TCA cycle, especially at NAD +/NADH-dependent redox sites, where age- and AD-associated limitations in the free NADH may alter reactions. Conversely, metabolites increased in glycolytic reactions in which ATP is produced. With age, inputs to the TCA cycle were increased including fatty acid β-oxidation and glutamine. Overall age- and AD-related changes were >  2-fold when comparing the declines of upstream metabolites of NAD +/NADH-dependent reactions to the increases of downstream metabolites (p = 10 - 5, n = 8 redox reactions). Inflammatory metabolites such as ceramides and sphingosine-1-phosphate also increased with age. Age-related decreases in glutamate, GABA, and sphingolipid were seen which worsened with AD genetic load in 3xTg-AD brains, possibly contributing to synaptic, learning- and memory-related deficits. The data support the novel hypothesis that age- and AD-associated metabolic shifts respond to NAD(P) +/NAD(P)H redox-dependent reactions, which may contribute to decreased energetic capacity.

%B J Alzheimers Dis %V 71 %P 119-140 %8 2019 Sep 3 %G eng %N 1 %R 10.3233/JAD-190408 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Greater Regional Cortical Thickness is Associated with Selective Vulnerability to Atrophy in Alzheimer's Disease, Independent of Amyloid Load and APOE Genotype. %A Li, Chunfei %A Duara, Ranjan %A Loewenstein, David A %A Izquierdo, Walter %A Cabrerizo, Mercedes %A Barker, Warren %A Adjouadi, Malek %X

BACKGROUND: Regional cortical thickness (rCTh) among cognitively normal (CN) adults (rCThCN) varies greatly between brain regions, as does the vulnerability to neurodegeneration.

OBJECTIVE: The goal of this study was to: 1) rank order rCThCN for various brain regions, and 2) explore their vulnerability to neurodegeneration in Alzheimer's disease (AD) within these brain regions.

METHODS: The relationship between rCTh among the CN group (rCThCN) and the percent difference in CTh (% CThDiff) in each region between the CN group and AD patients was examined. Pearson correlation analysis was performed accounting for amyloid-β (Aβ) protein and APOE genotype using 210 age, gender, and APOE matched CN (n = 105, age range: 56-90) and AD (n = 105, age range: 56-90) ADNI participants.

RESULTS: Strong positive correlations were observed between rCThCN and % CThDiff accounting for Aβ deposition and APOE status. Regions, such as the entorhinal cortex, which had the greatest CTh in the CN state, were also the regions which had the greatest % CThDiff.

CONCLUSIONS: Regions with the greatest CTh at the CN stage are found to aggregate in disease prone regions of AD, namely in the medial temporal lobe, including the temporal pole, ERC, parahippocampal gyrus, fusiform and the middle and inferior temporal gyrus. Although rCTh has been found to vary considerably across the different regions of the brain, our results indicate that regions with the greatest CTh at the CN stage are actually regions which have been found to be most vulnerable to neurodegeneration in AD.

%B J Alzheimers Dis %V 69 %P 145-156 %8 2019 May 7 %G eng %N 1 %R 10.3233/JAD-180231 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Gut Microbiota Alteration and Its Time Course in a Tauopathy Mouse Model. %A Sun, Bin-Lu %A Li, Wei-Wei %A Wang, Jun %A Xu, Ya-Li %A Sun, Hao-Lun %A Tian, Ding-Yuan %A Wang, Yan-Jiang %A Yao, Xiu-Qing %X

Emerging evidence suggests that gut microbiota dysbiosis plays a role in neurodegenerative disorders. However, whether the composition and diversity of the gut microbiota are altered in tauopathies remains largely unknown. This study was aimed to examine the diversity and composition of the gut microbiota in tauopathies, as well as the correlation with pathological changes in the brain. We collected fecal samples from 32 P301L tau transgenic mice and 32 age- and gender-matched littermate mice at different ages. The 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. Brain tau pathology levels were measured by immunohistochemistry. The diversity and composition of the gut microbiota significantly changed with aging. At the phylum level, the relative abundance of Bacteroidetes was increased, while Firmicutes were decreased in P301L mice compared with that in Wt mice after 3 months of age. In addition, Actinobacteria was decreased in P301L mice at 3 and 6 months of age, meanwhile Tenericutes was decreased in P301L mice at 10 months of age. Moreover, several specific macrobiota were highly associated with the levels of paired helical filament-tau or pT231-tau protein in the brain. Our findings suggest that gut microbiota changed with aging, as well as in the tauopathy mice model. Modulation of the gut microbiota may be a potential strategy for treatment of tauopathy.

%B J Alzheimers Dis %V 70 %P 399-412 %8 2019 Jul 23 %G eng %N 2 %R 10.3233/JAD-181220 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Head Position During Sleep: Potential Implications for Patients with Neurodegenerative Disease. %A Levendowski, Daniel J %A Gamaldo, Charlene %A St Louis, Erik K %A Ferini-Strambi, Luigi %A Hamilton, Joanne M %A Salat, David %A Westbrook, Philip R %A Berka, Chris %X

BACKGROUND: The characterization of sleep in those with neurodegenerative disease (NDD) is essential in understanding the potential neurobiological mechanisms that underlie the connection between sleep disruption and NDD manifestations and progression.

OBJECTIVE: Explore the inter-relationships between NDD and age, sex, diagnosis of obstructive sleep apnea, snoring, and duration of sleep time with the head in the supine and non-supine positions.

METHODS: A case-control design was used to evaluate differences in sleep position obtained from multi-night, in-home Sleep Profiler recordings in 45 patients with diagnosed NDD (24 with mild cognitive impairment, 15 with Alzheimer's disease, and 6 with Lewy Body, Parkinson's, or other dementias) and 120 age-sex matched controls with normal cognition (NC).

RESULTS: The frequency of supine sleep >2 h/night was significantly greater in the NDD than in the NC group (p < 0.001, odds ratio = 3.7), and remained significant after controlling for age, sex, snoring, and obstructive sleep apnea diagnosis (p = 0.01). There were no group differences in nocturnal mobility i.e., number of head position changes/h.

CONCLUSION: This study demonstrates the utility of in-home measurements of sleep in defining the association of supine sleep position with neurodegenerative disorders. Our findings warrant further investigation, particularly in light of the recent evidence suggesting that sleep may an active role in the brain's ability to clear CNS neurotoxins and metabolites.

%B J Alzheimers Dis %V 67 %P 631-638 %8 2019 %G eng %N 2 %R 10.3233/JAD-180697 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Herpes Simplex Virus, APOEɛ4, and Cognitive Decline in Old Age: Results from the Betula Cohort Study. %A Lövheim, Hugo %A Norman, Tove %A Weidung, Bodil %A Olsson, Jan %A Josefsson, Maria %A Adolfsson, Rolf %A Nyberg, Lars %A Elgh, Fredrik %X

BACKGROUND: Herpes simplex virus (HSV) has been suggested to play a role in Alzheimer's disease (AD) development.

OBJECTIVE: The aim of the present study was to investigate the early AD-related symptom episodic memory decline in relation to HSV and carriage of allele 4 of the apolipoprotein E gene (APOEɛ4) in a large population-based cohort with a long follow-up time.

METHODS: The study included 3,413 persons, with longitudinal data available for 1,293 persons with a mean follow-up time of 11.6 years. The associations between HSV carriage, APOEɛ4 carriage, and episodic memory was investigated at baseline, as well as in longitudinal analyses where individuals with and without HSV antibodies (HSV1/2 non-specific) were matched and episodic memory decline compared.

RESULTS: Cross-sectional analyses revealed an age-dependent association of HSV carriage with lower episodic memory function, particularly among APOEɛ4 carriers (p = 0.008). Longitudinal analyses showed an increased risk of episodic memory decline in HSV carriers (≥65 years: p < 0.001, all ages: non-significant), and a significant interaction between HSV and APOEɛ4 for episodic memory decline (p < 0.001).

CONCLUSION: In this large population-based cohort study, both cross-sectional and longitudinal results support an association between HSV carriage and declining episodic memory function, especially among APOEɛ4 carriers. The results strengthen the hypothesis that HSV is associated with AD development.

%B J Alzheimers Dis %V 67 %P 211-220 %8 2019 Jan 08 %G eng %N 1 %R 10.3233/JAD-171162 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Higher Body Mass Index Is Associated with Lower Cortical Amyloid-β Burden in Cognitively Normal Individuals in Late-Life. %A Thirunavu, Vineeth %A McCullough, Austin %A Su, Yi %A Flores, Shaney %A Dincer, Aylin %A Morris, John C %A Cruchaga, Carlos %A Benzinger, Tammie L S %A Gordon, Brian A %X

BACKGROUND: Both low and high body mass index (BMI) have been associated with an increased risk of dementia, including that caused by Alzheimer's disease (AD). Specifically, high middle-age BMI or a low late-age BMI has been considered a predictor for the development of AD dementia. Less studied is the relationship between BMI and AD pathology.

OBJECTIVE: We explored the association between BMI and cortical amyloid-β (Aβ) burden in cognitively normal participants that were either in mid-life (45-60 years) or late-life (>60).

METHODS: We analyzed cross-sectional baseline data from the Knight Alzheimer Disease Research Center (ADRC) at Washington University. Aβ pathology was measured in 373 individuals with Aβ PET imaging and was quantified using Centiloid units. We split the cohort into mid- and late-life groups for analyses (n = 96 and n = 277, respectively). We ran general linear regression models to predict Aβ levels from BMI while controlling for age, sex, years of education, and APOE4 status. Analyses were also conducted to test the interaction between BMI and APOE4 genotype and between BMI and sex.

RESULTS: Higher BMI was associated with lower cortical Aβ burden in late-life (β= -0.81, p = 0.0066), but no relationship was found in mid-life (β= 0.04, p > 0.5). The BMI×APOE4+ and BMI×male interaction terms were not significant in the mid-life (β= 0.28, p = 0.41; β= 0.64, p = 0.13) or the late-life (β= 0.17, p > 0.5; β= 0.50, p = 0.43) groups.

CONCLUSION: Higher late-life BMI is associated with lower cortical Aβ burden in cognitively normal individuals.

%B J Alzheimers Dis %V 69 %P 817-827 %8 2019 Jun 4 %G eng %N 3 %R 10.3233/JAD-190154 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Highly Elevated Cerebrospinal Fluid Total Tau Level Reflects Higher Likelihood of Non-Amnestic Subtype of Alzheimer's Disease. %A Pillai, Jagan A %A Bonner-Jackson, Aaron %A Bekris, Lynn M %A Safar, Jiri %A Bena, Jim %A Leverenz, James B %X

BACKGROUND: Cerebrospinal fluid (CSF) levels of total tau (t-tau) protein are thought to reflect the intensity of the neuronal damage in neurodegeneration, including Alzheimer's disease (AD). The recent link of CSF t-tau to rapidly progressive AD raises the question among other AD clinical variants regarding CSF t-tau. We investigated the clinical phenotypes of AD patients with varying CSF t-tau levels.

OBJECTIVE: We tested the hypothesis that highly elevated CSF t-tau level would have a higher likelihood of presenting with atypical non-amnestic variants of AD.

METHODS: Retrospective comparative case study of 97 patients evaluated in a memory clinic with clinical presentation and CSF biomarkers consistent with AD. We compared the age, sex, education, APOEɛ4 status, Montreal Cognitive Assessment (MoCA) score, clinical phenotype, and MRI volumetric measures by CSF t-tau quartile at baseline. Multivariable logistic regression models were used to evaluate if CSF t-tau levels predict non-amnestic presentations controlling for covariates.

RESULTS: Non-amnestic AD had a higher median CSF t-tau level compared to amnestic-AD (p = 0.014). Each 50 pg/ml increase in CSF t-tau was associated with an increase in the odds of having a non-amnestic presentation (7.4%) and aphasia (10.6 %) as the initial presenting symptom even after taking into account; age, sex, education, APOEɛ4, MoCA, and CSF Aβ42. Logopenic AD had higher t-tau and p-tau levels compared to other variants.

CONCLUSIONS: Highly elevated CSF t-tau levels could indicate more cortical involvement presenting with early non-amnestic symptoms in atypical AD subtypes, particularly in the logopenic variant.

%B J Alzheimers Dis %V 70 %P 1051-1058 %8 2019 Aug 20 %G eng %N 4 %R 10.3233/JAD-190519 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Identifying Unmet Needs of Family Dementia Caregivers: Results of the Baseline Assessment of a Cluster-Randomized Controlled Intervention Trial. %A Zwingmann, Ina %A Michalowsky, Bernhard %A Esser, Alexander %A Kaczynski, Anika %A Monsees, Jessica %A Keller, Armin %A Hertel, Johannes %A Wucherer, Diana %A Thyrian, Jochen René %A Eichler, Tilly %A Kilimann, Ingo %A Teipel, Stefan %A Dreier Wolfgramm, Adina %A Hoffmann, Wolfgang %X

BACKGROUND: Caregivers providing informal care for people with dementia (PwD) often report unmet needs, burden, and health impairments. Optimal support for family dementia caregivers will likely benefit from better understanding and assessment of the prevalence and types of caregivers' unmet needs and associated socio-demographic and clinical characteristics.

OBJECTIVE: The present study investigates 1) the number and types of caregivers' unmet needs, 2) socio-demographic and clinical characteristics of both PwD and caregivers, and 3) caregivers' burden and health-related outcomes that are related to caregivers' unmet needs.

METHODS: The present analyses are based on cross-sectional data of n = 226 dyads of caregivers and their community-dwelling PwD participating in a comprehensive standardized, computer-based caregivers' needs assessment within a general practitioner (GP)-based, cluster-randomized intervention trial.

RESULTS: A total of n = 505 unmet needs were identified for n = 171 caregivers from the intervention group at baseline. Only 24.3% caregivers reported no unmet need (n = 55), whereas 75.7% caregivers had at least one unmet need (n = 171). Caregivers had on average 2.19 unmet needs (mean = 2.19, SD = 2.15). Specifically, 53.1% of caregivers had one up to three unmet needs (n = 120), 18.6% (n = 42) had three up to six unmet needs, and 4.0% (n = 9) had more than six unmet needs.

DISCUSSION: Our results underline the importance of a comprehensive needs assessment for family dementia caregivers to develop and implement concepts that can provide family dementia caregivers with optimal support.

%B J Alzheimers Dis %V 67 %P 527-539 %8 2019 %G eng %N 2 %R 10.3233/JAD-180244 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Impacts of Overweight and Obesity in Older Age on the Risk of Dementia: A Systematic Literature Review and a Meta-Analysis. %A Danat, Isaac M %A Clifford, Angela %A Partridge, Martin %A Zhou, Weiju %A Bakre, Aishat T %A Chen, Anthony %A McFeeters, Danielle %A Smith, Tina %A Wan, Yuhui %A Copeland, John %A Anstey, Kaarin J %A Chen, Ruoling %X

BACKGROUND: It is unclear whether overweight and obesity in older age reduces or increases the risk of incident dementia.

OBJECTIVE: To assess the impacts of overweight and obesity in older age on incident dementia.

METHODS: We searched cohort studies reporting body weight measured in older age and dementia through PubMed, Embase, Medline, PyschInfo, and Cochrane library until July 2016. Sixteen articles were identified for the review. We pooled data from them and a new unpublished study from China, to calculate relative risk (RR) of incident dementia in relation to body mass index (BMI) and waist circumference (WC).

RESULTS: All 16 cohort studies were undertaken in high income countries, with follow-up periods ranging between 3 to 18 years. Thirteen studies showed an inverse association between BMI and dementia, and three studies demonstrated a positive association. Pooled RR of dementia in relation to continuous BMI from 14 studied populations, including the new Chinese data, was 0.97 (95% CI 0.95-1.00); in those followed up

CONCLUSION: The current evidence did not support a paradox on beneficial impacts of overweight and obesity in older age on incident dementia. More studies with long term follow up are needed to clarify the association of body weight in older age with dementia risk.

%B J Alzheimers Dis %V 70 %P S87-S99 %8 2019 %G eng %N s1 %R 10.3233/JAD-180763 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Impaired Glucose Tolerance and Reduced Plasma Insulin Precede Decreased AKT Phosphorylation and GLUT3 Translocation in the Hippocampus of Old 3xTg-AD Mice. %A Griffith, Chelsea M %A Macklin, Lauren N %A Cai, Yan %A Sharp, Andrew A %A Yan, Xiao-Xin %A Reagan, Lawrence P %A Strader, April D %A Rose, Gregory M %A Patrylo, Peter R %X

Several studies have demonstrated that mouse models of Alzheimer's disease (AD) can exhibit impaired peripheral glucose tolerance. Further, in the APP/PS1 mouse model, this is observed prior to the appearance of AD-related neuropathology (e.g., amyloid-β plaques; Aβ) or cognitive impairment. In the current study, we examined whether impaired glucose tolerance also preceded AD-like changes in the triple transgenic model of AD (3xTg-AD). Glucose tolerance testing (GTT), insulin ELISAs, and insulin tolerance testing (ITT) were performed at ages prior to (1-3 months and 6-8 months old) and post-pathology (16-18 months old). Additionally, we examined for altered insulin signaling in the hippocampus. Western blots were used to evaluate the two-primary insulin signaling pathways: PI3K/AKT and MAPK/ERK. Since the PI3K/AKT pathway affects several downstream targets associated with metabolism (e.g., GSK3, glucose transporters), western blots were used to examine possible alterations in the expression, translocation, or activation of these targets. We found that 3xTg-AD mice display impaired glucose tolerance as early as 1 month of age, concomitant with a decrease in plasma insulin levels well prior to the detection of plaques (∼14 months old), aggregates of hyperphosphorylated tau (∼18 months old), and cognitive decline (≥18 months old). These alterations in peripheral metabolism were seen at all time points examined. In comparison, PI3K/AKT, but not MAPK/ERK, signaling was altered in the hippocampus only in 18-20-month-old 3xTg-AD mice, a time point at which there was a reduction in GLUT3 translocation to the plasma membrane. Taken together, our results provide further evidence that disruptions in energy metabolism may represent a foundational step in the development of AD.

%B J Alzheimers Dis %V 68 %P 809-837 %8 2019 Mar 29 %G eng %N 2 %R 10.3233/JAD-180707 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers. %A Khoonsari, Payam Emami %A Shevchenko, Ganna %A Herman, Stephanie %A Remnestål, Julia %A Giedraitis, Vilmantas %A Brundin, RoseMarie %A Degerman Gunnarsson, Malin %A Kilander, Lena %A Zetterberg, Henrik %A Nilsson, Peter %A Lannfelt, Lars %A Ingelsson, Martin %A Kultima, Kim %X

BACKGROUND: Alzheimer's disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD.

OBJECTIVE: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects.

METHODS: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4-9 years and 21 of these converted to AD, whereas 53 remained stable.

RESULTS: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively.

CONCLUSIONS: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

%B J Alzheimers Dis %V 67 %P 639-651 %8 Jan 2019 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30614806?dopt=Abstract %R 10.3233/JAD-180855 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Inferring the Molecular Mechanisms of Noncoding Alzheimer's Disease-Associated Genetic Variants. %A Amlie-Wolf, Alexandre %A Tang, Mitchell %A Way, Jessica %A Dombroski, Beth %A Jiang, Ming %A Vrettos, Nicholas %A Chou, Yi-Fan %A Zhao, Yi %A Kuzma, Amanda %A Mlynarski, Elisabeth E %A Leung, Yuk Yee %A Brown, Christopher D %A Wang, Li-San %A Schellenberg, Gerard D %X

Most of the loci identified by genome-wide association studies (GWAS) for late-onset Alzheimer's disease (LOAD) are in strong linkage disequilibrium (LD) with nearby variants all of which could be the actual functional variants, often in non-protein-coding regions and implicating underlying gene regulatory mechanisms. We set out to characterize the causal variants, regulatory mechanisms, tissue contexts, and target genes underlying these associations. We applied our INFERNO algorithm to the top 19 non-APOE loci from the IGAP GWAS study. INFERNO annotated all LD-expanded variants at each locus with tissue-specific regulatory activity. Bayesian co-localization analysis of summary statistics and eQTL data was performed to identify tissue-specific target genes. INFERNO identified enhancer dysregulation in all 19 tag regions analyzed, significant enrichments of enhancer overlaps in the immune-related blood category, and co-localized eQTL signals overlapping enhancers from the matching tissue class in ten regions (ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, EPHA1, FERMT2, ZCWPW1). In several cases, we identified dysregulation of long noncoding RNA (lncRNA) transcripts and applied the lncRNA target identification algorithm from INFERNO to characterize their downstream biological effects. We also validated the allele-specific effects of several variants on enhancer function using luciferase expression assays. By integrating functional genomics with GWAS signals, our analysis yielded insights into the regulatory mechanisms, tissue contexts, genes, and biological processes affected by noncoding genetic variation associated with LOAD risk.

%B J Alzheimers Dis %V 72 %P 301-318 %8 2019 Oct 29 %G eng %N 1 %R 10.3233/JAD-190568 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Influx of Tau and Amyloid-β Proteins into the Blood During Hemodialysis as a Therapeutic Extracorporeal Blood Amyloid-β Removal System for Alzheimer's Disease. %A Kitaguchi, Nobuya %A Tatebe, Harutsugu %A Sakai, Kazuyoshi %A Kawaguchi, Kazunori %A Matsunaga, Shinji %A Kitajima, Tomoko %A Tomizawa, Hiroshi %A Kato, Masao %A Sugiyama, Satoshi %A Suzuki, Nobuo %A Mizuno, Masao %A Takechi, Hajime %A Nakai, Shigeru %A Hiki, Yoshiyuki %A Kushimoto, Hiroko %A Hasegawa, Midori %A Yuzawa, Yukio %A Tokuda, Takahiko %X

The accumulation of amyloid-β protein (Aβ) and tau in the brain is a major pathological change related to Alzheimer's disease. We have continued to develop Extracorporeal Blood Aβ Removal Systems (E-BARS) as a method for enhancing Aβ clearance from the brain. Our previous report revealed that dialyzers effectively remove blood Aβ and evoke large Aβ influxes into the blood, resulting in a decrease in brain Aβ accumulation after initiating hemodialysis, and that patients who underwent hemodialysis had lower brain Aβ accumulation than those who did not. Here, plasma total tau concentrations from 30 patients undergoing hemodialysis were measured using an ultrasensitive immunoassay and compared to those from 11 age-matched controls. Plasma total tau concentrations were higher in patients with renal failure regardless of whether they underwent hemodialysis, suggesting the involvement of the kidneys in tau degradation and excretion. Hemodialyzers effectively removed blood Aβ but not extracorporeal blood tau. The influx of tau into the blood was observed at around the 1 h period during hemodialysis sessions. However, the influx amount of tau was far smaller than that of Aβ. Furthermore, histopathological analysis revealed similar, not significantly less, cerebral cortex phosphorylated tau accumulation between the 17 patients who underwent hemodialysis and the 16 age-matched subjects who did not, although both groups showed sparse accumulation. These findings suggest that hemodialysis may induce both tau and Aβ migration into the blood. However, as a therapeutic strategy for Alzheimer's disease, it may only be effective for removing Aβ from the brain.

%B J Alzheimers Dis %V 69 %P 687-707 %8 2019 Jun 4 %G eng %N 3 %R 10.3233/JAD-190087 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Inhibition of Calpain Protects Against Tauopathy in Transgenic P301S Tau Mice. %A Liu, Mengyu %A Wang, Luwen %A Gao, Ju %A Dong, Qing %A Perry, George %A Ma, Xuemei %A Wang, Xinglong %X

Alzheimer's disease (AD) and other tauopathies are characterized by intracellular accumulation of microtubule-associated tau protein leading to neurodegeneration. Calpastatin is the endogenous inhibitor of calpain, a calcium-dependent cysteine protease that has been increasingly implicated in tauopathies. In this study, we generated a neuron specific calpastatin overexpressing knock-in transgenic mouse model and crossed it with the PS19 tauopathy mouse model expressing human P301S mutant tau protein. The forced expression of calpastatin in neurons significantly alleviated tau hyperphosphorylation measured by immunocytochemistry and immunoblot. The genetic inhibition of calpain by calpastatin also greatly suppressed characteristic hippocampal neuron loss and widespread astrogliosis and microgliosis in PS19 mice. Consistently, PS19 mice with neuronal calpastatin overexpression exhibited remarkably alleviated cognitive deficits, muscle weakness, skeletal muscle atrophy, and neuromuscular denervation, together implying the neuroprotective effects of neuronal calpastatin in PS19 mice of tauopathy. In sum, this study provides additional evidence supporting the pathological role of calpain in neurodegenerative diseases associated with tau pathology, and suggests that targeting calpain is likely a promising therapeutic approach for these devastating diseases.

%B J Alzheimers Dis %V 69 %P 1077-1087 %8 2019 Jun 18 %G eng %N 4 %R 10.3233/JAD-190281 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Intraneuronal Tau Misfolding Induced by Extracellular Amyloid-β Oligomers. %A Rudenko, Lauren K %A Wallrabe, Horst %A Periasamy, Ammasi %A Siller, Karsten H %A Svindrych, Zdenek %A Seward, Matthew E %A Best, Merci N %A Bloom, George S %X

Abnormal folding and aggregation of the microtubule-associated protein, tau, is a hallmark of several neurodegenerative disorders, including Alzheimer's disease (AD). Although normal tau is an intrinsically disordered protein, it does exhibit tertiary structure whereby the N- and C-termini are often in close proximity to each other and to the contiguous microtubule-binding repeat domains that extend C-terminally from the middle of the protein. Unfolding of this paperclip-like conformation might precede formation of toxic tau oligomers and filaments, like those found in AD brain. While there are many ways to monitor tau aggregation, methods to monitor changes in tau folding are not well established. Using full length human 2N4R tau doubly labeled with the Förster resonance energy transfer (FRET) compatible fluorescent proteins, Venus and Teal, on the N- and C-termini, respectively (Venus-Tau-Teal), intensity and lifetime FRET measurements were able to distinguish folded from unfolded tau in living cells independently of tau-tau intermolecular interactions. When expression was restricted to low levels in which tau-tau aggregation was minimized, Venus-Tau-Teal was sensitive to microtubule binding, phosphorylation, and pathogenic oligomers. Of particular interest is our finding that amyloid-β oligomers (AβOs) trigger Venus-Tau-Teal unfolding in cultured mouse neurons. We thus provide direct experimental evidence that AβOs convert normally folded tau into a conformation thought to predominate in toxic tau aggregates. This finding provides further evidence for a mechanistic connection between Aβ and tau at seminal stages of AD pathogenesis.

%B J Alzheimers Dis %V 71 %P 1125-1138 %8 2019 Oct 15 %G eng %N 4 %R 10.3233/JAD-190226 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Lipopolysaccharide Induced Opening of the Blood Brain Barrier on Aging 5XFAD Mouse Model. %A Barton, Shawn M %A Janve, Vaibhav A %A McClure, Richard %A Anderson, Adam %A Matsubara, Joanne A %A Gore, John C %A Pham, Wellington %X

The development of neurotherapeutics for many neurodegenerative diseases has largely been hindered by limited pharmacologic penetration across the blood-brain barrier (BBB). Previous attempts to target and clear amyloid-β (Aβ) plaques, a key mediator of neurodegenerative changes in Alzheimer's disease (AD), have had limited clinical success due to low bioavailability in the brain because of the BBB. Here we test the effects of inducing an inflammatory response to disrupt the BBB in the 5XFAD transgenic mouse model of AD. Lipopolysaccharide (LPS), a bacterial endotoxin recognized by the innate immune system, was injected at varying doses. 24 hours later, mice were injected with either thioflavin S, a fluorescent Aβ-binding small molecule or 30 nm superparamagnetic iron oxide (SPIO) nanoparticles, both of which are unable to penetrate the BBB under normal physiologic conditions. Our results showed that when pretreated with 3.0 mg/kg LPS, thioflavin S can be found in the brain bound to Aβ plaques in aged 5XFAD transgenic mice. Following the same LPS pretreatment, SPIO nanoparticles could also be found in the brain. However, when done on wild type or young 5XFAD mice, limited SPIO was detected. Our results suggest that the BBB in aged 5XFAD mouse model is susceptible to increased permeability mediated by LPS, allowing for improved delivery of the small molecule thioflavin S to target Aβ plaques and SPIO nanoparticles, which are significantly larger than antibodies used in clinical trials for immunotherapy of AD. Although this approach demonstrated efficacy for improved delivery to the brain, LPS treatment resulted in significant weight loss even at low doses, resulting from the induced inflammatory response. These findings suggest inducing inflammation can improve delivery of small and large materials to the brain for improved therapeutic or diagnostic efficacy. However, this approach must be balanced with the risks of systemic inflammation.

%B J Alzheimers Dis %V 67 %P 503-513 %8 2019 %G eng %N 2 %R 10.3233/JAD-180755 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Long-Term Trazodone Use and Cognition: A Potential Therapeutic Role for Slow-Wave Sleep Enhancers. %A La, Alice L %A Walsh, Christine M %A Neylan, Thomas C %A Vossel, Keith A %A Yaffe, Kristine %A Krystal, Andrew D %A Miller, Bruce L %A Karageorgiou, Elissaios %X

BACKGROUND: Recent studies reveal an association between slow-wave sleep (SWS), amyloid-β aggregation, and cognition.

OBJECTIVE: This retrospective study examines whether long-term use of trazodone, an SWS enhancer, is associated with delayed cognitive decline.

METHODS: We identified 25 regular trazodone users (mean age 75.4±7.5; 9 women, 16 men) who carried a diagnosis of Alzheimer's dementia, mild cognitive impairment, or normal cognition, and 25 propensity-matched trazodone non-users (mean age 74.5±8.0; 13 women, 12 men), accounting for age, sex, education, type of sleep deficit (hypersomnia, insomnia, parasomnia), diagnosis, and baseline Mini-Mental State Examination (MMSE). Longitudinal group differences in cognitive testing were evaluated through repeated measures tests over an average inter-evaluation interval of four years.

RESULTS: Trazodone non-users had 2.6-fold faster decline MMSE (primary outcome) compared to trazodone users, 0.27 (95% confidence interval [CI]: 0.07-0.48) versus 0.70 (95% CI: 0.50-0.90) points per year (p = 0.023). The observed effects were especially associated with subjective improvement of sleep complaints in post-hoc analyses (p = 0.0006). Secondary outcomes of other cognitive and functional scores had variable worsening in non-users and varied in significance when accounting for co-administered medications and multiple comparisons. Trazodone effects on MMSE remained significant within participants with AD-predicted pathology, with 2.4-fold faster decline in non-users (p = 0.038).

CONCLUSIONS: These results suggest an association between trazodone use and delayed cognitive decline, adding support for a potentially attractive and cost-effective intervention in dementia. Whether the observed relationship of trazodone to cognitive function is causal or an indirect marker of other effects, such as treated sleep disruption, and if such effects are mediated through SWS enhancement requires confirmation through prospective studies.

%B J Alzheimers Dis %V 67 %P 911-921 %8 2019 %G eng %N 3 %R 10.3233/JAD-181145 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Maintain Your Brain: Protocol of a 3-Year Randomized Controlled Trial of a Personalized Multi-Modal Digital Health Intervention to Prevent Cognitive Decline Among Community Dwelling 55 to 77 Year Olds. %A Heffernan, Megan %A Andrews, Gavin %A Fiatarone Singh, Maria A %A Valenzuela, Michael %A Anstey, Kaarin J %A Maeder, Anthony J %A McNeil, John %A Jorm, Louisa %A Lautenschlager, Nicola T %A Sachdev, Perminder S %A Ginige, Jeewani A %A Hobbs, Megan J %A Boulamatsis, Christos %A Chau, Tiffany %A Cobiac, Lynne %A Cox, Kay L %A Daniel, Kenneth %A Flood, Victoria M %A Guerrero, Yareni %A Gunn, Jane %A Jain, Nidhi %A Kochan, Nicole A %A Lampit, Amit %A Mavros, Yorgi %A Meiklejohn, Jacinda %A Noble, Yian %A O'Leary, Fiona %A Radd-Vagenas, Sue %A Walton, Courtney C %A Brodaty, Henry %X

BACKGROUND: Maintain Your Brain (MYB) is a randomized controlled trial of an online multi-modal lifestyle intervention targeting modifiable dementia risk factors with its primary aim being to reduce cognitive decline in an older age cohort.

METHODS: MYB aims to recruit 8,500 non-demented community dwelling 55 to 77 year olds from the Sax Institute's 45 and Up Study in New South Wales, Australia. Participants will be screened for risk factors related to four modules that comprise the MYB intervention: physical activity, nutrition, mental health, and cognitive training. Targeting risk factors will enable interventions to be personalized so that participants receive the most appropriate modules. MYB will run for three years and up to four modules will be delivered sequentially each quarter during year one. Upon completing a module, participants will continue to receive less frequent booster activities for their eligible modules (except for the mental health module) until the end of the trial.

DISCUSSION: MYB will be the largest internet-based trial to attempt to prevent cognitive decline and potentially dementia. If successful, MYB will provide a model for not just effective intervention among older adults, but an intervention that is scalable for broad use.

%B J Alzheimers Dis %V 70 %P S221-S237 %8 2019 %G eng %N s1 %R 10.3233/JAD-180572 %0 Journal Article %J J Alzheimers Dis %D 2019 %T The MemTrax Test Compared to the Montreal Cognitive Assessment Estimation of Mild Cognitive Impairment. %A van der Hoek, Marjanne D %A Nieuwenhuizen, Arie %A Keijer, Jaap %A Ashford, J Wesson %X

Cognitive impairment is a leading cause of dysfunction in the elderly. When mild cognitive impairment (MCI) occurs in elderly, it is frequently a prodromal condition to dementia. The Montreal Cognitive Assessment (MoCA) is a commonly used tool to screen for MCI. However, this test requires a face-to-face administration and is composed of an assortment of questions whose responses are added together by the rater to provide a score whose precise meaning has been controversial. This study was designed to evaluate the performance of a computerized memory test (MemTrax), which is an adaptation of a continuous recognition task, with respect to the MoCA. Two outcome measures are generated from the MemTrax test: MemTraxspeed and MemTraxcorrect. Subjects were administered the MoCA and the MemTrax test. Based on the results of the MoCA, subjects were divided in two groups of cognitive status: normal cognition (n = 45) and MCI (n = 37). Mean MemTrax scores were significantly lower in the MCI than in the normal cognition group. All MemTrax outcome variables were positively associated with the MoCA. Two methods, computing the average MTX score and linear regression were used to estimate the cutoff values of the MemTrax test to detect MCI. These methods showed that for the outcome MemTraxspeed a score below the range of 0.87 - 91 s-1 is an indication of MCI, and for the outcome MemTraxcorrect a score below the range of 85 - 90% is an indication for MCI.

%B J Alzheimers Dis %V 67 %P 1045-1054 %8 2019 %G eng %N 3 %R 10.3233/JAD-181003 %0 Journal Article %J J Alzheimers Dis %D 2019 %T A Meta-Analysis of Alzheimer's Disease Brain Transcriptomic Data. %A Patel, Hamel %A Dobson, Richard J B %A Newhouse, Stephen J %X

BACKGROUND: Microarray technologies have identified imbalances in the expression of specific genes and biological pathways in Alzheimer's disease (AD) brains. However, there is a lack of reproducibility across individual AD studies, and many related neurodegenerative and mental health disorders exhibit similar perturbations.

OBJECTIVE: Meta-analyze publicly available transcriptomic data from multiple brain-related disorders to identify robust transcriptomic changes specific to AD brains.

METHODS: Twenty-two AD, eight schizophrenia, five bipolar disorder, four Huntington's disease, two major depressive disorder, and one Parkinson's disease dataset totaling 2,667 samples and mapping to four different brain regions (temporal lobe, frontal lobe, parietal lobe, and cerebellum) were analyzed. Differential expression analysis was performed independently in each dataset, followed by meta-analysis using a combining p-value method known as Adaptively Weighted with One-sided Correction.

RESULTS: Meta-analysis identified 323, 435, 1,023, and 828 differentially expressed genes specific to the AD temporal lobe, frontal lobe, parietal lobe, and cerebellum brain regions, respectively. Seven of these genes were consistently perturbed across all AD brain regions with SPCS1 gene expression pattern replicating in RNA-Seq data. A further nineteen genes were perturbed specifically in AD brain regions affected by both plaques and tangles, suggesting possible involvement in AD neuropathology. In addition, biological pathways involved in the "metabolism of proteins" and viral components were significantly enriched across AD brains.

CONCLUSION: This study identified transcriptomic changes specific to AD brains, which could make a significant contribution toward the understanding of AD disease mechanisms and may also provide new therapeutic targets.

%B J Alzheimers Dis %V 68 %P 1635-1656 %8 2019 Apr 23 %G eng %N 4 %R 10.3233/JAD-181085 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Methionine Sulfoxide Reductase-B3 Risk Allele Implicated in Alzheimer's Disease Associates with Increased Odds for Brain Infarcts. %A Conner, Sarah C %A Benayoun, Laurent %A Himali, Jayandra J %A Adams, Stephanie L %A Yang, Qiong %A DeCarli, Charles %A Blusztajn, Jan K %A Beiser, Alexa %A Seshadri, Sudha %A Delalle, Ivana %X

Genome-wide association studies identified a single nucleotide polymorphism (SNP) in the MSRB3 gene encoding Methionine Sulfoxide Reductase-B3 (MsrB3) to be associated with the risk for low hippocampal volume and late onset Alzheimer's disease (AD). Subsequently, we identified AD-associated abnormal patterns of neuronal and vascular MsrB3 expression in postmortem hippocampi. The present study investigated the relationship between the MSRB3 SNP rs61921502, G (minor/risk allele) and MRI measures of brain injury including total brain volume, hippocampal volume, and white matter hyperintensities using linear regression models; the presence of brain infarcts using logistic regression models; and the incidence of stroke, dementia, and AD using Cox proportional hazards models in 2,038 Framingham Heart Study Offspring participants with MRI administered close to examination cycle 7 (1998-2001). Participants with neurological conditions that impede evaluation of vascular pathology by MRI, i.e., brain tumors, multiple sclerosis, and major head trauma, were excluded from the study. When adjusted for age and age squared at MRI exam, sex, and presence of Apolipoproteinɛ4 allele (APOE4), individuals with MSRB3 rs61921502 minor allele had increased odds for brain infarcts on MRI compared to those with no minor allele. However, in stratified analyses, MSRB3 rs61921502 minor allele was significantly associated with increased odds for MRI brain infarcts only in the absence of APOE4.

%B J Alzheimers Dis %V 68 %P 357-365 %8 2019 Mar 12 %G eng %N 1 %R 10.3233/JAD-180977 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Midlife Insulin Resistance as a Predictor for Late-Life Cognitive Function and Cerebrovascular Lesions. %A Toppala, Sini %A Ekblad, Laura L %A Lötjönen, Jyrki %A Helin, Semi %A Hurme, Saija %A Johansson, Jarkko %A Jula, Antti %A Karrasch, Mira %A Koikkalainen, Juha %A Laine, Hanna %A Parkkola, Riitta %A Viitanen, Matti %A Rinne, Juha O %X

BACKGROUND: Type 2 diabetes (T2DM) increases the risk for Alzheimer's disease (AD) but not for AD neuropathology. The association between T2DM and AD is assumed to be mediated through vascular mechanisms. However, insulin resistance (IR), the hallmark of T2DM, has been shown to associate with AD neuropathology and cognitive decline.

OBJECTIVE: To evaluate if midlife IR predicts late-life cognitive performance and cerebrovascular lesions (white matter hyperintensities and total vascular burden), and whether cerebrovascular lesions and brain amyloid load are associated with cognitive functioning.

METHODS: This exposure-to-control follow-up study examined 60 volunteers without dementia (mean age 70.9 years) with neurocognitive testing, brain 3T-MRI and amyloid-PET imaging. The volunteers were recruited from the Finnish Health 2000 survey (n = 6062) to attend follow-up examinations in 2014-2016 according to their insulin sensitivity in 2000 and their APOE genotype. The exposure group (n = 30) had IR in 2000 and the 30 controls had normal insulin sensitivity. There were 15 APOEɛ4 carriers per group. Statistical analyses were performed with multivariable linear models.

RESULTS: At follow-up the IR+group performed worse on executive functions (p = 0.02) and processing speed (p = 0.007) than the IR- group. The groups did not differ in cerebrovascular lesions. No associations were found between cerebrovascular lesions and neurocognitive test scores. Brain amyloid deposition associated with slower processing speed.

CONCLUSION: Midlife IR predicted poorer executive functions and slower processing speed, but not cerebrovascular lesions. Brain amyloid deposition was associated with slower processing speed. The association between midlife IR and late-life cognition might not be mediated through cerebrovascular lesions measured here.

%B J Alzheimers Dis %V 72 %P 215-228 %8 2019 Oct 29 %G eng %N 1 %R 10.3233/JAD-190691 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Mild Cognitive Impairment and Dementia Involving Multiple Cognitive Domains in Mexican Urbanites. %A Calderón-Garcidueñas, Lilian %A Mukherjee, Partha S %A Kulesza, Randy J %A Torres-Jardón, Ricardo %A Hernández-Luna, Jacqueline %A Ávila-Cervantes, Rodrigo %A Macías-Escobedo, Edgar %A González-González, Oscar %A González-Maciel, Angelica %A García-Hernández, Kevin %A Hernández-Castillo, Ariatna %A Villarreal-Ríos, Rodolfo %X

Exposures to fine particulate matter PM2.5 and ozone O3 are associated with Alzheimer's disease (AD) risk. Mexico City residents have lifetime exposures to PM2.5 and O3 above annual USEPA standards and their brains contain high redox, combustion, and friction-derived magnetite nanoparticles. AD pathological changes with subcortical pre-tangle stages in infancy and cortical tau pre-tangles, NFT Stages I-II, and amyloid phases 1-2 are identified by the 2nd decade. Given their AD continuum, a reliable identification of cognitive impairment is of utmost importance. The Montreal Cognitive Assessment (MoCA) was administered to 517 urbanites, age 21.60±5.88 years, with 13.69±1.28 formal education years, in Mexican PM2.5 polluted cities. MoCA score was 23.92±2.82, and 24.7% and 30.3% scored ≤24 and ≤22, respectively (MCI≤24, AD≤22). Cognitive deficits progressively targeted Visuospatial, Executive, Language, and Memory domains, body mass index (BMI) impacting total scores negatively (p = 0.0008), aging driving down Executive, Visuospatial, and Language index scores (p <  0.0001, 0.0037, and 0.0045), and males performing better in Executive tasks. Average age for AD MoCA scores was 22.38±7.7 years. Residency in polluted cities is associated with progression of multi-domain cognitive impairment affecting 55% of Mexican seemingly healthy youth. Normal BMI ought to be a neuroprotection goal. MoCA provides guidance for further mandatory neuropsychological testing in young populations. Identifying and lowering key neurotoxicants impacting neural risk trajectories in the developing brain and monitoring cognitive performance would greatly facilitate multidisciplinary early diagnosis and prevention of AD in high risk young populations. Cognitive deficits hinder development of those representing the force moving the country in future years.

%B J Alzheimers Dis %V 68 %P 1113-1123 %8 2019 Apr 8 %G eng %N 3 %R 10.3233/JAD-181208 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Mitophagy Failure in APP and Tau Overexpression Model of Alzheimer's Disease. %A Martín-Maestro, Patricia %A Gargini, Ricardo %A García, Esther %A Simón, Diana %A Avila, Jesús %A García-Escudero, Vega %X

Mitochondrial alterations and oxidative stress are common features of Alzheimer's disease brain and peripheral tissues. Moreover, mitochondrial recycling process by autophagy has been found altered in the sporadic form of the disease. However, the contribution of the main proteins involved in this pathology such as amyloid-β protein precursor (AβPP) and tau needs to be achieved. With this aim, human unmodified fibroblasts were transduced with lentivectors encoding APP and Tau and treated with CCCP to study the mitophagy process. Both AβPP and tau separately increased autophagy flux mainly by improving degradation phase. However, in the specific case of mitophagy, labeling of mitochondria by PINK1 and PARK2 to be degraded by autophagy seemed reduced, which correlates with the long-term accumulation of mitochondria. Nevertheless, the combination of tau and AβPP was necessary to cause a mitophagy functional impairment reflected in the accumulation of depolarized mitochondria labeled by PINK1. The overexpression of Tau and APP recapitulates the mitophagy failure previously found in sporadic Alzheimer's disease.

%B J Alzheimers Dis %V 70 %P 525-540 %8 2019 Jul 23 %G eng %N 2 %R 10.3233/JAD-190086 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Modifiable Risk Factors Discriminate Memory Trajectories in Non-Demented Aging: Precision Factors and Targets for Promoting Healthier Brain Aging and Preventing Dementia. %A McFall, G Peggy %A McDermott, Kirstie L %A Dixon, Roger A %X

BACKGROUND: Non-demented cognitive aging trajectories are characterized by vast level and slope differences and a spectrum of outcomes, including dementia.

OBJECTIVE: The goal of AD risk management (and its corollary, promoting healthy brain aging) is aided by two converging objectives: 1) classifying dynamic distributions of non-demented cognitive trajectories, and 2) identifying modifiable risk-elevating and risk-reducing factors that discriminate stable or normal trajectory patterns from declining or pre-impairment patterns.

METHOD: Using latent class growth analysis we classified three episodic memory aging trajectories for n = 882 older adults (baseline Mage=71.6, SD=8.9, range = 53-95, female=66%): Stable (SMA; above average level, sustained slope), Normal (NMA; average level, moderately declining slope), and Declining (DMA; below average level, substantially declining slope). Using random forest analyses, we simultaneously assessed 17 risk/protective factors from non-modifiable demographic, functional, psychological, and lifestyle domains. Within two age strata (Young-Old, Old-Old), three pairwise prediction analyses identified important discriminating factors.

RESULTS: Prediction analyses revealed that different modifiable risk predictors, both shared and unique across age strata, discriminated SMA (i.e., education, depressive symptoms, living status, body mass index, heart rate, social activity) and DMA (i.e., lifestyle activities [cognitive, self-maintenance, social], grip strength, heart rate, gait) groups.

CONCLUSION: Memory trajectory analyses produced empirical classes varying in level and slope. Prediction analyses revealed different predictors of SMA and DMA that also varied by age strata. Precision approaches for promoting healthier memory aging-and delaying memory impairment-may identify modifiable factors that constitute specific targets for intervention in the differential context of age and non-demented trajectory patterns.

%B J Alzheimers Dis %V 70 %P S101-S118 %8 2019 %G eng %N s1 %R 10.3233/JAD-180571 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Molecular Basis of Alzheimer's Disease: Focus on Mitochondria. %A Oliver, Darryll M A %A Reddy, P Hemachandra %X

Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterized by memory loss and multiple cognitive impairments. With the increased aging population, AD is a major health concern in society. Morphological and pathological studies revealed that AD is associated with the loss of synapses, defective mitochondria, and the proliferation of reactive astrocytes and microglia, in addition to the presence amyloid-β and phosphorylated tau in learning and memory regions of the brain in AD patients. AD occurs in two forms: early-onset familial and late-onset sporadic. Genetic mutations in APP, PS1, and PS2 loci cause familial AD. Multiple factors are reported to be involved in late-onset AD, including APOE4 genotype, polymorphisms in several gene loci and type 2 diabetes, traumatic brain injury, stroke, and age-related factors, including increased reactive oxygen species production and dysfunction in mitochondria. It is widely accepted that synaptic damage and mitochondrial dysfunction are early events in disease process. The purpose of this article is to highlight molecular triggers to the disease process. This article also reviews factors, including age, gender, lifestyle, epigenetic factors, and type 2 diabetes, that are involved in late-onset AD. This article also discusses recent developments in research of mitochondrial structure, function, physiology, dynamics, biogenesis, mitophagy, and mitochondrial DNA changes in healthy and diseased states.

%B J Alzheimers Dis %V 72 %P S95-S116 %8 2019 %G eng %N s1 %R 10.3233/JAD-190048 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Neurodegenerative Disease-Related Proteins within the Epidermal Layer of the Human Skin. %A Akerman, S Can %A Hossain, Shireen %A Shobo, Adeola %A Zhong, Yifei %A Jourdain, Roland %A Hancock, Mark A %A George, Kelly %A Breton, Lionel %A Multhaup, Gerhard %X

There is increasing evidence suggesting that amyloidogenic proteins might form deposits in non-neuronal tissues in neurodegenerative disorders such as Alzheimer's or Parkinson's diseases. However, the detection of these aggregation-prone proteins within the human skin has been controversial. Using immunohistochemistry (IHC) and mass spectrometry tissue imaging (MALDI-MSI), fresh frozen human skin samples were analyzed for the expression and localization of neurodegenerative disease-related proteins. While α-synuclein was detected throughout the epidermal layer of the auricular samples (IHC and MALDI-MSI), tau and Aβ34 were also localized to the epidermal layer (IHC). In addition to Aβ peptides of varying length (e.g., Aβ40, Aβ42, Aβ34), we also were able to detect inflammatory markers within the same sample sets (e.g., thymosin β-4, psoriasin). While previous literature has described α-synuclein in the nucleus of neurons (e.g., Parkinson's disease), our current detection of α-synuclein in the nucleus of skin cells is novel. Imaging of α-synuclein or tau revealed that their presence was similar between the young and old samples in our present study. Future work may reveal differences relevant for diagnosis between these proteins at the molecular level (e.g., age-dependent post-translational modifications). Our novel detection of Aβ34 in human skin suggests that, just like in the brain, it may represent a stable intermediate of the Aβ40 and Aβ42 degradation pathway.

%B J Alzheimers Dis %V 69 %P 463-478 %8 2019 May 21 %G eng %N 2 %R 10.3233/JAD-181191 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Neuronal Exosome-Derived Human Tau is Toxic to Recipient Mouse Neurons in vivo. %A Winston, Charisse N %A Aulston, Brent %A Rockenstein, Edward M %A Adame, Anthony %A Prikhodko, Olga %A Dave, Kishan N %A Mishra, Priyanka %A Rissman, Robert A %A Yuan, Shauna H %X

Progressive accumulation of aggregation-prone proteins, amyloid-β (Aβ) and hyperphosphorylated tau (p-tau), are the defining hallmarks of Alzheimer's disease (AD). The mechanisms by which Aβ and p-tau are transmitted throughout the diseased brain are not yet completely understood. Interest in exosome research has grown dramatically over the past few years, specifically due to their potential role as biomarkers for staging of neurodegenerative diseases, including AD. Despite their diagnostic utility, the pathogenic potential of exosomes has yet to be fully elucidated. In this study, we use a series of recombinant tau antibodies to characterize a new model of human tau in vivo. Exosome suspensions derived from neuronally-differentiated, human induced pluripotent stem cells that express the repeat domain of tau P301L and V337M mutations (NiPSCEs) were injected into the wild-type mouse brain and pathological changes were characterized by immunostaining at one- (1 m) and two-month (2 m) post-injection. We found that tau inclusions were present throughout the brain at 2 m post-injection, which were detectable using antibodies raised against full-length tau (K9JA) and misfolded tau (MC1). Furthermore, we found that phosphorylated tau immunoreactivity was elevated 1 m post-injection, which was surprisingly normalized after 2 m. Finally, we observed extensive degeneration of neuronal dendrites in both ipsilateral and contralateral hippocampi in NiPSCE treated mice. In summary, we demonstrate that exosomes are sufficient to cause long-distance propagation of tau pathology and neurodegeneration in vivo. These novel findings support an active role of exosomes in AD pathogenesis.

%B J Alzheimers Dis %V 67 %P 541-553 %8 2019 %G eng %N 2 %R 10.3233/JAD-180776 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Neuron-Specific Apolipoprotein E4 (1-272) Fragment Induces Tau Hyperphosphorylation and Axonopathy via Triggering Endoplasmic Reticulum Stress. %A Liang, Tao %A Xue, Feixiao %A Hang, Weijian %A Wen, Bin %A Zhang, Qianying %A Chen, Jiehui %A Liu, Xiaofeng %A Chen, Juan %X

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). It is shown that apoE4 preferentially undergoes aberrant cleavage in neurons, yielding neurotoxic C-terminal-truncated apoE4 fragment. Endoplasmic reticulum (ER) stress has also been known to be involved in the pathogenesis of AD. However, little is known about the contribution of ER stress to the neurotoxicity of apoE4 fragment. In the present study, we established the neuron-specific expression human C-terminal-truncated apoE4(1-272) fragment transgenic mice and also transfected apoE4(1-272) fragment in neuroblastoma N2a cells. We found that human apoE4(1-272) fragment could trigger ER stress as evidenced by increasing the expression of ER stress markers both in vivo and in vitro. Meanwhile, the apoE4(1-272) transgenic mice presented obviously AD-like neuropathological changes, including the impairment of spatial learning and memory, prominent axonal morphological changes, and hyperphosphorylation of tau. At the same time, we also found that glycogen synthase kinase-3 activities were significantly increased. Furthermore, these neuropathological changes, especially tau hyperphosphorylation and axonal transport impairment, were significantly rescued by the ER stress protector 4-phenylbutyric acid (4-PBA) in apoE4(1-272)-transfected N2a cells. Pretreatment with 4-PBA not only decreased the protein expression of immunoglobulin binding protein (BiP) and C/EBP-homologous protein (CHOP), but also significantly reversed these defects in axonal transport. These results suggested that the neurotoxic effects of apoE4(1-272) fragment found in AD subjects, at least in part, through triggering ER stress and inducing tau hyperphosphorylation, led to the enduring impairment of axonal transport.

%B J Alzheimers Dis %V 71 %P 597-611 %8 2019 Sep 17 %G eng %N 2 %R 10.3233/JAD-190419 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Neuropsychological Deficit Profiles, Vascular Risk Factors, and Neuropathological Findings in Hispanic Older Adults with Autopsy-Confirmed Alzheimer's Disease. %A Weissberger, Gali H %A Gollan, Tamar H %A Bondi, Mark W %A Nation, Daniel A %A Hansen, Lawrence A %A Galasko, Douglas %A Salmon, David P %X

 This study aimed to determine if patterns of neuropsychological deficits, vascular risk factors, and neuropathology differ in Hispanic and Non-Hispanic patients with autopsy-confirmed Alzheimer's disease (AD). Participants were enrolled in a longitudinal study at the Shiley-Marcos AD Research Center at the University of California, San Diego. Hispanic (n = 14) and Non-Hispanic (n = 20) patients with autopsy-confirmed AD who scored ≥95 on the Dementia Rating Scale (DRS) were included. Patient groups were matched on age, education, global mental status, and severity of functional decline; they were compared to Hispanic (n = 14) or Non-Hispanic (n = 20) cognitively-normal controls of similar age and education. Ethnicity (Hispanic, Non-Hispanic) by disease state (autopsy-confirmed AD or cognitively normal) comparisons were made for cognitive test performance and vascular risk factors. Patient groups were further compared on measures of AD (Braak stage, neuritic plaques, neurofibrillary tangles), vascular neuropathology, and performance across cognitive domains of memory, language, attention, executive functions, and visuospatial abilities after scores were z-transformed based on respective culturally-appropriate control groups. Patient groups had similar overall AD pathology burden, whereas Hispanics with AD had more small parenchymal arteriolar disease and amyloid angiopathy than Non-Hispanics with AD. Despite largely similar pathology, Hispanics with AD were less cognitively impaired (relative to respective NC groups) than Non-Hispanics with AD, and exhibited a different pattern of deficits across cognitive domains. Findings suggest that cognitive deficits that are usually prominent in AD may be less salient in Hispanic patients and this may adversely impact the ability to clinically detect the disease in mild to moderate stages.

%B J Alzheimers Dis %V 67 %P 291-302 %8 2019 %G eng %N 1 %R 10.3233/JAD-180351 %0 Journal Article %J J Alzheimers Dis %D 2019 %T NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats. %A Wilson, Edward N %A Do Carmo, Sonia %A Welikovitch, Lindsay A %A Hall, Hélène %A Aguilar, Lisi Flores %A Foret, Morgan K %A Iulita, M Florencia %A Jia, Dan Tong %A Marks, Adam R %A Allard, Simon %A Emmerson, Joshua T %A Ducatenzeiler, Adriana %A Cuello, A Claudio %X

Epidemiological, preclinical, and clinical studies have suggested a role for microdose lithium in reducing Alzheimer's disease (AD) risk by modulating key mechanisms associated with AD pathology. The novel microdose lithium formulation, NP03, has disease-modifying effects in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis at pre-plaque stages, before frank amyloid-β (Aβ) plaque deposition, during which Aβ is primarily intraneuronal. Here, we are interested in determining whether the positive effects of microdose lithium extend into early Aβ post-plaque stages. We administered NP03 (40μg Li/kg; 1 ml/kg body weight) to McGill-R-Thy1-APP transgenic rats for 12 weeks spanning the transition phase from plaque-free to plaque-bearing. The effect of NP03 on remote working memory was assessed using the novel object recognition task. Levels of human Aβ38, Aβ40, and Aβ42 as well as levels of pro-inflammatory mediators were measured in brain-extracts and plasma using electrochemiluminescent assays. Mature Aβ plaques were visualized with a thioflavin-S staining. Vesicular acetylcholine transporter (VAChT) bouton density and levels of chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-6 (IL-6), and 4-hydroxynonenal (4-HNE) were probed using quantitative immunohistochemistry. During the early Aβ post-plaque stage, we find that NP03 rescues functional deficits in object recognition, reduces loss of cholinergic boutons in the hippocampus, reduces levels of soluble and insoluble cortical Aβ42 and reduces hippocampal Aβ plaque number. In addition, NP03 reduces markers of neuroinflammation and cellular oxidative stress. Together these results indicate that microdose lithium NP03 is effective at later stages of amyloid pathology, after appearance of Aβ plaques.

%B J Alzheimers Dis %V 73 %P 723-739 %8 2020 Jan 21 %G eng %N 2 %R 10.3233/JAD-190862 %0 Journal Article %J J Alzheimers Dis %D 2019 %T O-GlcNAcylation of Amyloid-β Protein Precursor by Insulin Signaling Reduces Amyloid-β Production. %A Kwon, Oh Hoon %A Cho, Yoon Young %A Kim, Tae-Wan %A Chung, Sungkwon %X

Alzheimer's disease (AD) is caused by the accumulation of neurotoxic amyloid-β (Aβ) peptides. Aβ is derived from amyloid-β protein precursor (AβPP). In the non-amyloidogenic pathway, AβPP is cleaved by α-secretase and γ-secretase at the plasma membrane, excluding Aβ production. Alternatively, AβPP in the plasma membrane is internalized via endocytosis, and delivered to early endosomes and lysosomes, where it is cleaved by β-secretase and γ-secretase. Recent studies have shown that insulin in the periphery crosses the blood-brain barrier, and plays important roles in the brain. Furthermore, impaired insulin signaling has been linked to the progression of AD, and intranasal insulin administration improves memory impairments and cognition. However, the underlying molecular mechanisms of insulin treatment remain largely unknown. To investigate the effects of insulin on AβPP processing, we tested the effects of insulin on neuroblastoma SH-SY5Y cells overexpressing AβPP, and cultured rat cortical neurons. We found that insulin increased the level of cell surface AβPP, decreasing the endocytosis rate of AβPP. Insulin reduced Aβ generation through upregulation of AβPP O-GlcNAcylation via Akt insulin signaling. Our present data suggest that insulin affects Aβ production by regulating AβPP processing through AβPP O-GlcNAcylation. These results provide mechanistic insight into the beneficial effects of insulin, and a possible link between insulin deficient diabetes and cerebral amyloidosis in the pathogenesis of AD.

%B J Alzheimers Dis %V 69 %P 1195-1211 %8 2019 Jun 18 %G eng %N 4 %R 10.3233/JAD-190060 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Ovariectomy Influences Cognition and Markers of Alzheimer's Disease. %A Agca, Cansu %A Klakotskaia, Diana %A Stopa, Edward G %A Schachtman, Todd R %A Agca, Yuksel %X

Alzheimer's disease (AD) is one of the most devastating and costly diseases, and prevalence of AD increases with age. Furthermore, females are twice as likely to suffer from AD compared to males. The cessation of reproductive steroid hormone production during menopause is hypothesized to cause this difference. Two rodent AD models, APP21 and APP+PS1, and wild type (WT) rats underwent an ovariectomy or sham surgery. Changes in learning and memory, brain histology, amyloid-β (Aβ) deposition, levels of mRNAs involved in Aβ production and clearance, and synaptic and cognitive function were determined. Barnes maze results showed that regardless of ovariectomy status, APP+PS1 rats learned slower and had poor memory retention. Ovariectomy caused learning impairment only in the APP21 rats. High levels of Aβ42 and very low levels of Aβ40 were observed in the brain cortices of APP+PS1 rats indicating limited endogenous PS1. The APP+PS1 rats had 43-fold greater formic acid soluble Aβ42 than Aβ40 at 17 months. Furthermore, levels of formic acid soluble Aβ42 increased 57-fold in ovariectomized APP+PS1 rats between 12 and 17 months of age. The mRNA encoding Grin1 significantly decreased due to ovariectomy whereas levels of Bace1, Chat, and Prkcb all decreased with age. The expression levels of mRNAs involved in Aβ degradation and AβPP cleavage (Neprilysin, Ide, Adam9, and Psenen) were found to be highly correlated with each other as well as hippocampal Aβ deposition. Taken together, these results indicate that both ovariectomy and genotype influence AD markers in a complex manner.

%B J Alzheimers Dis %V 73 %P 529-541 %8 2020 Jan 21 %G eng %N 2 %R 10.3233/JAD-190935 %0 Journal Article %J J Alzheimers Dis %D 2019 %T The Pathology of Rapid Cognitive Decline in Clinically Diagnosed Alzheimer's Disease. %A Nance, Christin %A Ritter, Aaron %A Miller, Justin B %A Lapin, Brittany %A Banks, Sarah J %X

BACKGROUND: Variable rate of cognitive decline among individuals with Alzheimer's disease (AD) is an important consideration for disease management, but risk factors for rapid cognitive decline (RCD) are without consensus.

OBJECTIVE: To investigate demographic, clinical, and pathological differences between RCD and normal rates of cognitive decline (NCD) in AD.

METHODS: Neuropsychology test and autopsy data was pulled from the National Alzheimer's Coordinating Center database from individuals with a clinical diagnosis of AD. Individuals with average decline of 3 or more points on the Mini-Mental Status Examination (MMSE) per year over 3 years were labeled RCD; all others were NCD.

RESULTS: Sixty individuals identified as RCD; 230 as NCD. These neuropsychology tests differed at baseline (RCD versus NCD): WMS-LM Immediate Recall (4.35[3.39] versus 6.31[3.97], p < 0.001), Animal Naming (12.1[4.83] versus 13.9[4.83], p = 0.007), TMT Part B (187[86.1] versus 159[79.0], p = 0.02), WAIS-Digit Symbol (29.5[11.3] versus 29.5[11.3], p = 0.04), and the BNT (21.5[7.05] versus 23.6[5.09], p = 0.04). RCD had more thyroid disease (30% versus 16%, p = 0.01) and greater usage of AD medication at baseline (80% versus 62%, p = 0.01). RCD had more severe cerebral amyloid angiopathy (1.62(1.0) versus1.13(1.0), p = 0.002), more neocortical Lewy bodies (20% versus 10%, p = 0.04), and more atrophy (1.54[0.92] versus 1.17[0.83], p = 0.04). A model combining select variables was significant above chance (χ2 = 25.8, p = 0.002), but not to clinical utility (AUC < 0.70; 95% CI).

CONCLUSION: Individuals with RCD have more severe pathology, more comorbidities, and lower baseline neuropsychology test scores of language and executive function.

%B J Alzheimers Dis %V 70 %P 983-993 %8 2019 Aug 20 %G eng %N 4 %R 10.3233/JAD-190302 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Porphyromonas gingivalis Infection Induces Amyloid-β Accumulation in Monocytes/Macrophages. %A Nie, Ran %A Wu, Zhou %A Ni, Junjun %A Zeng, Fan %A Yu, Weixian %A Zhang, Yufeng %A Kadowaki, Tomoko %A Kashiwazaki, Haruhiko %A Teeling, Jessica L %A Zhou, Yanmin %X

Abnormal accumulation of amyloid-β (Aβ) in the brain is the most significant pathological hallmark of Alzheimer's disease (AD). We have found that chronic systemic exposure to lipopolysaccharide of Porphyromonas gingivalis (P. gingivalis) induces the accumulation of Aβ in the brain of middle-aged mice. On the other hand, recent research has shown that circulating Aβ is transferred into the brain; however, the involvement of chronic systemic P. gingivalis infection in the peripheral Aβ metabolism is unknown. We hypothesized that chronic P. gingivalis infection expands Aβ pools in peripheral inflammatory tissues and thereby contributes to the accumulation of Aβ in the brain of patients with periodontitis. We showed that the increased expression of IL-1β, AβPP770, CatB, Aβ1-42, and Aβ3-42 was mainly co-localized with macrophages in the liver of P. gingivalis infected mice. Blocking CatB and NF-κB significantly inhibited the P. gingivalis-induced expression of IL-1β, AβPP770, Aβ1-42, and Aβ3-42 in RAW264.7 cells. Aβ3-42, but not Aβ1-42, induced the significant death of macrophages, and the reduction of phagocytic abilities induced by Aβ3-42 tended to be higher than that induced by Aβ1-42. Additionally, the expression of AβPP770, CatB, Aβ1-42, and Aβ3-42 was determined in the macrophages of gingival tissues from periodontitis patients. These findings indicate that chronic systemic P. gingivalis infection induces the Aβ accumulation in inflammatory monocytes/macrophages via the activation of CatB/NF-κB signaling, thus suggesting monocytes/macrophages serve as a circulating pool of Aβ in patients with periodontitis. Taken together, CatB may be a novel therapeutic target for preventing the periodontitis-related AD initiation and pathological progression.

%B J Alzheimers Dis %V 72 %P 479-494 %8 2019 Nov 12 %G eng %N 2 %R 10.3233/JAD-190298 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Preliminary Report on the Feasibility and Efficacy of the Modified Atkins Diet for Treatment of Mild Cognitive Impairment and Early Alzheimer's Disease. %A Brandt, Jason %A Buchholz, Alison %A Henry-Barron, Bobbie %A Vizthum, Diane %A Avramopoulos, Dimitrios %A Cervenka, Mackenzie C %X

Ketone bodies, the products of fat metabolism, are a source of energy for the brain and are available even when glucose supplies are inadequate (such as with severe carbohydrate deprivation) or its metabolism is faulty (as it is in Alzheimer's disease). This phase I/II randomized clinical trial examined the feasibility of using a modified Atkins diet (MAD) to induce ketogenesis in persons with mild cognitive impairment (MCI) or early AD, and the effect of this diet on memory and other clinical outcomes. In the first 2.5 years of active recruitment, only 27 eligible and willing patients enrolled. After extensive assessment and education, they and their study partners were randomly assigned for 12 weeks to either the MAD or the National Institute on Aging (NIA) recommended diet for seniors. As of April 2018, 9 patients in the MAD arm and 5 in the NIA arm have completed the trial. In spite of extensive teaching, coaching, and monitoring, adherence to both diets was only fair. Among those in the MAD arm who generated at least trace amounts of urinary ketones, there was a large (effect size = 0.53) and statistically significant (p = 0.03) increase in Memory Composite Score between the baseline and week-6 assessment. MAD participants also reported increased energy between baseline and week-6 assessment. Despite challenges to implementing this trial, resulting in a small sample, our preliminary data suggest that the generation of even trace ketones might enhance episodic memory and patient-reported vitality in very early AD.

%B J Alzheimers Dis %V 68 %P 969-981 %8 2019 Apr 8 %G eng %N 3 %R 10.3233/JAD-180995 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Present Algorithms and Future Treatments for Alzheimer's Disease. %A Grossberg, George T %A Tong, Gary %A Burke, Anna D %A Tariot, Pierre N %X

An estimated 47 million people live with Alzheimer's disease (AD) and other forms of dementia worldwide. Although no disease-modifying treatments are currently available for AD, earlier diagnosis and proper management of the disease could have considerable impact on patient and caregiver quality of life and functioning. Drugs currently approved for AD treat the cognitive, behavioral, and functional symptoms of the disease and consist of three cholinesterase inhibitors (ChEIs) and the N-methyl-D-aspartate receptor antagonist memantine. Treatment of patients with mild to moderate AD is generally initiated with a ChEI. Patients who show progression of symptoms while on ChEI monotherapy may be switched to another ChEI and/or memantine can be added to the treatment regimen. In recent years, putative disease-modifying therapies have emerged that aim to slow the progression of AD instead of only addressing its symptoms. However, many therapies have failed in clinical trials in patients with established AD, suggesting that, once developed, disease-modifying agents may need to be deployed earlier in the course of illness. The goal of this narrative literature review is to discuss present treatment algorithms and potential future therapies in AD.

%B J Alzheimers Dis %V 67 %P 1157-1171 %8 2019 %G eng %N 4 %R 10.3233/JAD-180903 %0 Journal Article %J J Alzheimers Dis %D 2019 %T The Prevalence and Subtypes of Young Onset Dementia in Central Norway: A Population-Based Study. %A Kvello-Alme, Marte %A Bråthen, Geir %A White, Linda R %A Sando, Sigrid Botne %X

BACKGROUND: Young onset dementia poses several challenges for the individual, health care, and society that are not normally relevant for late onset dementia, but is little researched.

OBJECTIVE: To determine the prevalence and subtypes of young onset dementia in a defined catchment area in central Norway.

METHODS: The main sources of patient identification were the databases at the Department of Neurology, University Hospital of Trondheim (St. Olav's Hospital), and Department of Psychiatry, Levanger Hospital. Both departments are the main sites for referral of young onset dementia (onset before age 65 years) in the county, covering approximately 90% of the catchment area of the study. Other sources included key persons in the communities, collaborating hospital departments examining dementia, and review of hospital records of all three hospitals in the area. Included patients met the DSM-IV criteria for dementia. The prevalence of dementias was calculated by sex and age.

RESULTS: All patients identified with dementia and onset before 65 years on census date were included in the study (n = 390). Patients younger than 65 on census date were included in the calculation of prevalence, giving a result of 76.3 per 100 000 persons at risk in the age category of 30-65 years, and 163.1 per 100,000 for the category 45-64 years. Etiology was heterogeneous, but the main subtype of dementia was Alzheimer's disease.

CONCLUSIONS: Young onset dementia affects a significant number of people in central Norway. Prevalence figures are higher than previously reported from England and Japan, but are similar to a more recent study from Australia.

%B J Alzheimers Dis %V 69 %P 479-487 %8 2019 %G eng %N 2 %R 10.3233/JAD-181223 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress. %A Smith, Carr J %A Ashford, J Wesson %A Perfetti, Thomas A %X

Inheritance of a single copy of the apolipoprotein E (APOE) ɛ4 allele increases risk of Alzheimer's disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to ɛ3 allele homozygosity. There is a decreased risk associated with the APOE ɛ2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous ɛ4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily young subjects, we have reviewed a representative body of literature on ɛ4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the ɛ4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral ɛ4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing ɛ3 allele, at the expense of decreased fitness in old age, which is substantially improved by the ɛ3 allele. However, possession of the ɛ4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion.

%B J Alzheimers Dis %V 68 %P 885-923 %8 2019 Apr 8 %G eng %N 3 %R 10.3233/JAD-181089 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Quantification of Tau Protein Lysine Methylation in Aging and Alzheimer's Disease. %A Huseby, Carol J %A Hoffman, Claire N %A Cooper, Grace L %A Cocuron, Jean-Christophe %A Alonso, Ana P %A Thomas, Stefani N %A Yang, Austin J %A Kuret, Jeff %X

Tau is a microtubule-associated protein that normally interacts in monomeric form with the neuronal cytoskeleton. In Alzheimer's disease, however, it aggregates to form the structural component of neurofibrillary lesions. The transformation is controlled in part by age- and disease-associated post-translational modifications. Recently we reported that tau isolated from cognitively normal human brain was methylated on lysine residues, and that high-stoichiometry methylation depressed tau aggregation propensity in vitro. However, whether methylation stoichiometry reached levels needed to influence aggregation propensity in human brain was unknown. Here we address this problem using liquid chromatography-tandem mass spectrometry approaches and human-derived tau samples. Results revealed that lysine methylation was present in soluble tau isolated from cognitively normal elderly cases at multiple sites that only partially overlapped with the distributions reported for cognitively normal middle aged and AD cohorts, and that the quality of methylation shifted from predominantly dimethyl-lysine to monomethyl-lysine with aging and disease. However, bulk mol methylation/mol tau stoichiometries never exceeded 1 mol methyl group/mol tau protein. We conclude that lysine methylation is a physiological post-translational modification of tau protein that changes qualitatively with aging and disease, and that pharmacological elevation of tau methylation may provide a means for protecting against pathological tau aggregation.

%B J Alzheimers Dis %V 71 %P 979-991 %8 2019 Oct 1 %G eng %N 3 %R 10.3233/JAD-190604 %0 Journal Article %J J Alzheimers Dis %D 2019 %T A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Assessing Safety, Tolerability, and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer's Disease. %A Farlow, Martin R %A Thompson, Richard E %A Wei, Lee-Jen %A Tuchman, Alan J %A Grenier, Elaine %A Crockford, David %A Wilke, Susanne %A Benison, Jeffrey %A Alkon, Daniel L %X

BACKGROUND: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau.

OBJECTIVES: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer's disease (AD) patients.

METHODS: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55-85) with MMSE-2 of 4-15, randomized 1:1:1 into 20 μg and 40 μg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p < 0.1 for primary efficacy, and 2-sided, p < 0.05 for pre-specified and post hoc exploratory analyses).

RESULTS: The safety profile was similar for 20 μg treatment and placebo patients. The 40 μg patients showed safety and drop-out issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 μg bryostatin compared to placebo patients (p < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 μg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant (2-sided, p < 0.05).

CONCLUSION: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 μg compared to the placebo cohort. These promising Phase II results support further trials of 20 μg bryostatin- without memantine- to treat AD.

%B J Alzheimers Dis %V 67 %P 555-570 %8 2019 %G eng %N 2 %R 10.3233/JAD-180759 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Remembering Robert D. Terry at a Time of Change in the World of Alzheimer's Disease. %A Terry, Nickolas %A Masliah, Alberto %A Overk, Cassia %A Masliah, Eliezer %B J Alzheimers Dis %V 70 %P 621-628 %8 2019 Aug 3 %G eng %N 3 %R 10.3233/JAD-190518 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Risk Factors for and Clinical Relevance of Incident and Progression of Cerebral Small Vessel Disease Markers in an Asian Memory Clinic Population. %A Gyanwali, Bibek %A Shaik, Muhammad Amin %A Tan, Boon Yeow %A Venketasubramanian, Narayanaswamy %A Chen, Christopher %A Hilal, Saima %X

BACKGROUND: Cerebral small vessel disease (SVD) is one of the major contributors to cognitive impairment and dementia. However, data on the incidence and progression of SVD in an Asian population are lacking.

OBJECTIVE: The present study aims to investigate the incidence, progression, associated risk factors, and clinical relevance of SVD in a memory clinic setting.

METHODS: A prospective case-control study, where 346 patients underwent repeated brain MRI with a mean interval of 24.5 months, accessing white matter hyperintensities (WMH), lacunes and cerebral microbleeds (CMBs). Severity of cognitive impairment was assessed using Clinical Dementia Rating scale and change in clinical diagnosis. Data on demographics, vascular risk factors, and clinical history were collected at baseline.

RESULTS: The prevalence of significant WMH (Fazekas ≥2) was 56.6% at baseline which progressed to 59.0% at follow-up. Overall prevalence of CMBs increased from 42.2% to 47.4% (9% new cases) and lacunes increased from 31.8% to 33.2% (2.1% new cases). Hypertension was associated with WMH progression (OR: 1.78, 95% CI: 1.01, 2.99) and increasing age was associated with incident CMBs (OR: 1.04, 95% CI: 1.01, 1.08). Moreover, the use of lipid-lowering medications decreased the incidence of lacunes (OR: 0.15, 95% CI: 0.04, 0.61). The major risk factor for incident SVD was baseline SVD lesion load. WMH progression was associated with increased severity of cognitive impairment (OR: 1.95, 95% CI: 1.16, 3.23).

CONCLUSION: Vascular risk factors and baseline severity of SVD lesion load were associated with progression of SVD. Furthermore, WMH progression was linked with increased severity of cognitive impairment. Future studies should be aimed to slow cognitive deterioration by preventing SVD related brain damage by targeting vascular risk factors.

%B J Alzheimers Dis %V 67 %P 1209-1219 %8 2019 %G eng %N 4 %R 10.3233/JAD-180911 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Self and Informant Memory Reports in FINGER: Associations with Two-Year Cognitive Change. %A Vaskivuo, Laura %A Hokkanen, Laura %A Hänninen, Tuomo %A Antikainen, Riitta %A Bäckman, Lars %A Laatikainen, Tiina %A Paajanen, Teemu %A Stigsdotter-Neely, Anna %A Strandberg, Timo %A Tuomilehto, Jaakko %A Soininen, Hilkka %A Kivipelto, Miia %A Ngandu, Tiia %X

BACKGROUND: Subjective memory complaints (SMCs) may be the first sign of cognitive decline in aging.

OBJECTIVE: To examine whether SMCs reported by oneself and informant predict cognitive change over 2 years among at-risk elderly people, and to determine the relationship of different types of SMCs (prospective and retrospective memory complaints) and change in cognitive function.

METHODS: This investigation is part of the FINGER project, which is a multicenter randomized controlled trial aiming at preventing cognitive decline in cognitively healthy older adults with increased risk of dementia. A subsample of 303 control-group participants (aged 60-80 years) and their informants (n = 261) rated the frequency of SMCs, using the Prospective and Retrospective Memory Questionnaire (PRMQ). Cognitive performance was measured at baseline and at 1- and 2-year follow-up visits using a neuropsychological test battery.

RESULTS: Participants who reported more SMCs improved less in global cognition, executive function, and memory during the subsequent 2 years in the fully-adjusted analyses. Self-reported retrospective memory problems predicted less improvement in all cognitive domains, whereas prospective memory problems did not. Informant-reported memory problems were not linked to subsequent change in cognition.

CONCLUSION: Our results indicate that self-reported SMCs, measured with PRMQ, predict future cognitive change in several cognitive domains. By contrast, reports by informants were not linked to changes in cognition. Among cognitively healthy at-risk elderly individuals, the persons themselves observe more easily problems relevant for their future cognitive trajectories than their informants.

%B J Alzheimers Dis %V 71 %P 785-795 %8 2019 Oct 1 %G eng %N 3 %R 10.3233/JAD-190133 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Serum Insulin-Like Growth Factor I Deficiency Associates to Alzheimer's Disease Co-Morbidities. %A Zegarra-Valdivia, Jonathan A %A Santi, Andrea %A Fernández de Sevilla, Maria Estrella %A Nuñez, Angel %A Torres Aleman, Ignacio %X

Increasing evidence supports the notion that Alzheimer's disease (AD), a condition that presents heterogeneous pathological disturbances, is also associated to perturbed metabolic function affecting insulin and insulin-like growth factor I (IGF-I). While impaired insulin activity leading to insulin resistance has been associated to AD, whether altered IGF-I function affects the disease is not entirely clear. Despite the limitations of mouse models to mimic AD pathology, we took advantage that serum IGF-I deficient mice (LID mice) present many functional perturbations present in AD, most prominently cognitive loss, which is reversed by treatment with systemic IGF-I. We analyzed whether these mice display other pathological traits that are usual co-morbidities of AD. We found that LID mice not only display cognitive disturbances, but also show altered mood and sociability, increased susceptibility to epileptiform activity, and a disturbed sleep/wake cycle. Collectively, these data suggest that reduced IGF-I activity contributes to heterogeneous deficits commonly associated to AD. We suggest that impaired IGF-I activity needs to be taken into consideration when modeling this condition.

%B J Alzheimers Dis %V 69 %P 979-987 %8 2019 June 18 %G eng %N 4 %R 10.3233/JAD-190241 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Sirtuin 3 Mediates Tau Deacetylation. %A Li, Shiping %A Yin, Junxiang %A Nielsen, Megan %A Beach, Thomas G %A Guo, Li %A Shi, Jiong %X

BACKGROUND: Emerging evidence shows tau acetylation has been observed in Alzheimer's disease (AD) brain at early Braak stages and is involved in regulating tau early accumulation. However, the effects of deacetylase Sirtuin 3 (Sirt3) on tau acetylation and its aggregations are unclear.

OBJECTIVE: We studied the effects of Sirt3 on tau acetylation and its aggregations.

METHODS: We investigated the protein levels of Sirt3 and tangle tau in human postmortem brains slices from AD, mild cognitive impairment, and age- and education-matched cognitively normal subjects, and AD model mice. We also measured tau acetylation levels in hippocampal HT22 cells after Sirt3 knockdown or overexpression.

RESULTS: The level of Sirt3 was inversely related with tau protein in brain slices from both human being and AD model mice. Mechanistically, tau acetylation decreased dramatically with Sirt3 overexpression, while tau acetylation increased after Sirt3 knockdown in hippocampal HT22 cells.

CONCLUSIONS: Sirt3 may play a role in tau acetylation and could be a potential target for novel therapy to alleviate tau accumulation.

%B J Alzheimers Dis %V 69 %P 355-362 %8 2019 May 21 %G eng %N 2 %R 10.3233/JAD-190014 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Small Molecule Amyloid-β Protein Precursor Processing Modulators Lower Amyloid-β Peptide Levels via cKit Signaling. %A Chen, Ci-Di %A Zeldich, Ella %A Khodr, Christina %A Camara, Kaddy %A Tung, Tze Yu %A Lauder, Emma C %A Mullen, Patrick %A Polanco, Taryn J %A Liu, Yen-Yu %A Zeldich, Dean %A Xia, Weiming %A Van Nostrand, William E %A Brown, Lauren E %A Porco, John A %A Abraham, Carmela R %X

Alzheimer's disease (AD) is characterized by the accumulation of neurotoxic amyloid-β (Aβ) peptides consisting of 39-43 amino acids, proteolytically derived fragments of the amyloid-β protein precursor (AβPP), and the accumulation of the hyperphosphorylated microtubule-associated protein tau. Inhibiting Aβ production may reduce neurodegeneration and cognitive dysfunction associated with AD. We have previously used an AβPP-firefly luciferase enzyme complementation assay to conduct a high throughput screen of a compound library for inhibitors of AβPP dimerization, and identified a compound that reduces Aβ levels. In the present study, we have identified an analog, compound Y10, which also reduced Aβ. Initial kinase profiling assays identified the receptor tyrosine kinase cKit as a putative Y10 target. To elucidate the precise mechanism involved, AβPP phosphorylation was examined by IP-western blotting. We found that Y10 inhibits cKit phosphorylation and increases AβPP phosphorylation mainly on tyrosine residue Y743, according to AβPP751 numbering. A known cKit inhibitor and siRNA specific to cKit were also found to increase AβPP phosphorylation and lower Aβ levels. We also investigated a cKit downstream signaling molecule, the Shp2 phosphatase, and found that known Shp2 inhibitors and siRNA specific to Shp2 also increase AβPP phosphorylation, suggesting that the cKit signaling pathway is also involved in AβPP phosphorylation and Aβ production. We further found that inhibitors of both cKit and Shp2 enhance AβPP surface localization. Thus, regulation of AβPP phosphorylation by small molecules should be considered as a novel therapeutic intervention for AD.

%B J Alzheimers Dis %V 67 %P 1089-1106 %8 2019 Feb 12 %G eng %N 3 %R 10.3233/JAD-180923 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Social Isolation and Cognitive Function in Later Life: A Systematic Review and Meta-Analysis. %A Evans, Isobel E M %A Martyr, Anthony %A Collins, Rachel %A Brayne, Carol %A Clare, Linda %X

BACKGROUND: There is some evidence to suggest that social isolation may be associated with poor cognitive function in later life. However, findings are inconsistent and there is wide variation in the measures used to assess social isolation.

OBJECTIVE: We conducted a systematic review and meta-analysis to investigate the association between social isolation and cognitive function in later life.

METHODS: A search for longitudinal studies assessing the relationship between aspects of social isolation (including social activity and social networks) and cognitive function (including global measures of cognition, memory, and executive function) was conducted in PsycInfo, CINAHL, PubMed, and AgeLine. A random effects meta-analysis was conducted to assess the overall association between measures of social isolation and cognitive function. Sub-analyses investigated the association between different aspects of social isolation and each of the measures of cognitive function.

RESULTS: Sixty-five articles were identified by the systematic review and 51 articles were included in the meta-analysis. Low levels of social isolation characterized by high engagement in social activity and large social networks were associated with better late-life cognitive function (r = 0.054, 95% CI: 0.043, 0.065). Sub-analyses suggested that the association between social isolation and measures of global cognitive function, memory, and executive function were similar and there was no difference according to gender or number of years follow-up.

CONCLUSIONS: Aspects of social isolation are associated with cognitive function in later life. There is wide variation in approaches to measuring social activity and social networks across studies which may contribute to inconsistencies in reported findings.

%B J Alzheimers Dis %V 70 %P S119-S144 %8 2019 %G eng %N s1 %R 10.3233/JAD-180501 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Spatially Distributed Amyloid-β Reduces Glucose Metabolism in Mild Cognitive Impairment. %A Carbonell, Felix %A Zijdenbos, Alex P %A Bedell, Barry J %X

BACKGROUND: Several positron emission tomography (PET) studies have explored the relationship between amyloid-β (Aβ), glucose metabolism, and the APOEɛ4 genotype. It has been reported that APOEɛ4, and not aggregated Aβ, contributes to glucose hypometabolism in pre-clinical stages of Alzheimer's disease (AD) pathology.

OBJECTIVE: We hypothesize that typical measurements of Aβ taken either from composite regions-of-interest with relatively high burden actually cover significant patterns of the relationship with glucose metabolism. In contrast, spatially weighted measures of Aβ are more related to glucose metabolism in cognitively normal (CN) aging and mild cognitive impairment (MCI).

METHODS: We have generated a score of amyloid burden based on a joint singular value decomposition (SVD) of the cross-correlation structure between glucose metabolism, as measured by [18F]2-fluoro-2-deoxyglucose (FDG) PET, and Aβ, as measured by [18F]florbetapir PET, from the Alzheimer's Disease Neuroimaging Initiative study. This SVD-based score reveals cortical regions where a reduced glucose metabolism is maximally correlated with distributed patterns of Aβ.

RESULTS: From an older population of CN and MCI subjects, we found that the SVD-based Aβ score was significantly correlated with glucose metabolism in several cortical regions. Additionally, the corresponding Aβ network has hubs that contribute to distributed glucose hypometabolism, which, in turn, are not necessarily foci of Aβ deposition.

CONCLUSIONS: Our approach uncovered hidden patterns of the glucose metabolism-Aβ relationship. We showed that the SVD-based Aβ score produces a stronger relationship with decreasing glucose metabolism than either APOEɛ4 genotype or global measures of Aβ burden.

%B J Alzheimers Dis %V 73 %P 543-557 %8 2020 Feb 04 %G eng %N 2 %R 10.3233/JAD-190560 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Stem Cell-Derived Neurons as Cellular Models of Sporadic Alzheimer's Disease. %A Foveau, Bénédicte %A Correia, Ana Sofia %A Hébert, Sébastien S %A Rainone, Sara %A Potvin, Olivier %A Kergoat, Marie-Jeanne %A Belleville, Sylvie %A Duchesne, Simon %A LeBlanc, Andréa C %X

Alzheimer's disease (AD) occurs as either an autosomal dominant inherited disease or sporadically. While familial mutant genes can be expressed in cells or in animal models to assess dysregulated functions, sporadic AD cannot be replicated in models given our lack of understanding of causality. Furthermore, the study of sporadic forms of AD is difficult given the inaccessibility of brain tissues in living individuals and the manifestation of symptoms years after the onset of disease. Here, the objective was to assess if induced pluripotent stem cell-derived neurons from well-ascertained sporadic AD individuals could represent potential cellular models to determine the underlying molecular mechanisms of disease. We used cryopreserved peripheral blood mononuclear cells from three well-ascertained sporadic AD and three non-cognitively impaired (NCI) individuals of the CIMA-Q cohort to obtain iPSC-derived neurons. Microtubule associated protein 2 was decreased in AD neurons, whereas expression of AD-associated amyloid precursor protein, tau, and amyloid-β peptide was similar in AD and NCI individuals. RNA sequencing identified several upregulated and downregulated mRNAs in AD relative to NCI neurons. Of these, complement Factor H (CFH), signal regulatory protein beta1 (SIRPB1), and insulin like growth factor binding protein 5 (IGFBP5) were previously associated with AD. In addition, several transcription factors not previously associated with AD, but involved in neuronal proliferation and differentiation were differentially expressed. The results identify novel avenues for the study of the underlying causes of sporadic AD and support the establishment of additional lines to identify mechanisms of disease in sporadic AD individuals.

%B J Alzheimers Dis %V 67 %P 893-910 %8 2019 %G eng %N 3 %R 10.3233/JAD-180833 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Subjective Cognitive Decline May Be a Stronger Predictor of Incident Dementia in Women than in Men. %A Heser, Kathrin %A Kleineidam, Luca %A Wiese, Birgitt %A Oey, Anke %A Roehr, Susanne %A Pabst, Alexander %A Kaduszkiewicz, Hanna %A van den Bussche, Hendrik %A Brettschneider, Christian %A König, Hans-Helmut %A Weyerer, Siegfried %A Werle, Jochen %A Fuchs, Angela %A Pentzek, Michael %A Mösch, Edelgard %A Bickel, Horst %A Maier, Wolfgang %A Scherer, Martin %A Riedel-Heller, Steffi G %A Wagner, Michael %X

BACKGROUND/OBJECTIVE: Subjective cognitive decline (SCD) has often been associated with an increased risk for subsequent dementia. However, sex-specific associations are understudied until now.

METHODS: Cross-sectional and longitudinal associations over a follow-up period of up to 13 years were investigated in a sample of participants without objective cognitive impairment at baseline (n = 2,422, mean age = 79.63 years). Logistic regression and Cox proportional hazards models were conducted.

RESULTS: Women less frequently reported SCD without worries (p <  0.001), but tended to report more often SCD with worries (p = 0.082) at baseline compared to men. In models adjusted for age, education, cognitive status, and depressive symptoms, SCD at baseline increased the risk for subsequent dementia (p <  0.001), and this effect was less pronounced in males (interaction sex×SCD: p = 0.022). Stratified analyses showed that SCD increased the risk for subsequent dementia in women (HR = 1.77, p <  0.001), but not in men (HR = 1.07, p = 0.682). Similar results were found in analyses with SCD without and with worries, except that SCD with worries also predicted subsequent Alzheimer's disease (AD) in men (p = 0.037).

CONCLUSION: At baseline, men reported more SCD without worries and women tended to report more SCD with worries. SCD in women was more strongly associated with subsequent dementia. SCD without and with worries was related to incident dementia and AD in women, whereas in men only SCD with worries increased the risk for AD, but not for all-cause dementia.

%B J Alzheimers Dis %V 68 %P 1469-1478 %8 2019 Apr 23 %G eng %N 4 %R 10.3233/JAD-180981 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Tau and Amyloid-β Pathology in Japanese Forensic Autopsy Series Under 40 Years of Age: Prevalence and Association with APOE Genotype and Suicide Risk. %A Yoshida, Koji %A Hata, Yukiko %A Ichimata, Shojiro %A Nishida, Naoki %X

BACKGROUND: Aggregation of abnormal phosphorylated tau in brain stem areas may be a possible early pathological manifestation of Alzheimer's disease (AD).

OBJECTIVE: This study aimed to explore the prevalence of cases with AD-related pathology in subjects

METHOD: We conducted brain immunohistochemistry for 189 cases

RESULTS: Tau pathology was detected in 135 cases (71.4%; 13-39 years; only LC, 23 cases; only RN, 4 cases; only ErC, 35 cases; LC+RN, 3 cases; LC+ErC, 57 cases; all three regions, 10 cases). The prevalence of thread pathology was higher than that of cellular inclusions. Significantly higher prevalence of the APOEɛ2 allele were found in 10-39 years of age natural death cases (p < 0.05). Amyloid-β deposition was found in only 7 cases, along with a significantly high frequency of the ɛ4 allele (p < 0.05). While a past history of psychiatric disease was a significant risk factor for suicide, AD-related pathology was not associated with suicide.

CONCLUSIONS: Both the brain stem and entorhinal cortex was the initial site of tau pathology in many younger subjects. AD-related pathology may not be a significant accelerating factor for suicide in younger subjects.

%B J Alzheimers Dis %V 72 %P 641-652 %8 2019 Nov 12 %G eng %N 2 %R 10.3233/JAD-190196 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Tau Biology, Tauopathy, Traumatic Brain Injury, and Diagnostic Challenges. %A Castellani, Rudy J %A Perry, George %X

There is considerable interest in the pathobiology of tau protein, given its potential role in neurodegenerative diseases and aging. Tau is an important microtubule associated protein, required for the assembly of tubulin into microtubules and maintaining structural integrity of axons. Tau has other diverse cellular functions involving signal transduction, cellular proliferation, developmental neurobiology, neuroplasticity, and synaptic activity. Alternative splicing results in tau isoforms with differing microtubule binding affinity, differing representation in pathological inclusions in certain disease states, and differing roles in developmental biology and homeostasis. Tau haplotypes confer differing susceptibility to neurodegeneration. Tau phosphorylation is a normal metabolic process, critical in controlling tau's binding to microtubules, and is ongoing within the brain at all times. Tau may be hyperphosphorylated, and may aggregate as detectable fibrillar deposits in tissues, in both aging and neurodegenerative disease. The hypothesis that p-tau is neurotoxic has prompted constructs related to isomers, low-n assembly intermediates or oligomers, and the "tau prion". Human postmortem studies have elucidated broad patterns of tauopathy, with tendencies for those patterns to differ as a function of disease phenotype. However, there is extensive overlap, not only between genuine neurodegenerative diseases, but also between aging and disease. Recent studies highlight uniqueness to pathological patterns, including a pattern attributed to repetitive head trauma, although clinical correlations have been elusive. The diagnostic process for tauopathies and neurodegenerative diseases in general is challenging in many respects, and may be particularly problematic for postmortem evaluation of former athletes and military service members.

%B J Alzheimers Dis %V 67 %P 447-467 %8 2019 %G eng %N 2 %R 10.3233/JAD-180721 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Telomere Length and the Risk of Alzheimer's Disease: The Rotterdam Study. %A Fani, Lana %A Hilal, Saima %A Sedaghat, Sanaz %A Broer, Linda %A Licher, Silvan %A Arp, Pascal P %A van Meurs, Joyce B J %A Ikram, M Kamran %A Ikram, M Arfan %X

There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer's disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of Alzheimer's disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer's disease. We found a U-shaped association between telomere length and risk of Alzheimer's disease: compared to the middle tertile the adjusted hazard ratio was 1.59 (95% confidence interval (CI), 1.13-2.23) for the lowest tertile and 1.47 (1.03-2.10) for the highest tertile. Results were similarly U-shaped but slightly attenuated for all-cause dementia. In conclusion, shorter and longer telomere length are both associated with an increased risk of Alzheimer's disease in the general population.

%B J Alzheimers Dis %V 73 %P 707-714 %8 2020 Jan 21 %G eng %N 2 %R 10.3233/JAD-190759 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Telomere Shortening in the Alzheimer's Disease Neuroimaging Initiative Cohort. %A Nudelman, Kelly N H %A Lin, Jue %A Lane, Kathleen A %A Nho, Kwangsik %A Kim, Sungeun %A Faber, Kelley M %A Risacher, Shannon L %A Foroud, Tatiana M %A Gao, Sujuan %A Davis, Justin W %A Weiner, Michael W %A Saykin, Andrew J %X

BACKGROUND: Although shorter telomeres have been associated with Alzheimer's disease (AD), it is unclear whether longitudinal change in telomere length is associated with AD progression.

OBJECTIVE: To investigate the association of telomere length change with AD diagnosis and progression.

METHODS: In 653 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, T/S ratio (telomere versus single copy gene), a proxy of telomere length, was measured for up to five visits per participant (N = 1918 samples post-QC) using quantitative PCR (qPCR). T/S ratio was adjusted for batch effects and DNA storage time. A mixed effects model was used to evaluate association of telomere length with AD diagnostic group and interaction of age and diagnosis. Another mixed effects model was used to compare T/S ratio changes pre- to post-conversion to MCI or AD to telomere change in participants with stable diagnoses.

RESULTS: Shorter telomeres were associated with older age (Effect Size (ES) = -0.23) and male sex (ES = -0.26). Neither baseline T/S ratio (ES = -0.036) nor T/S ratio change (ES = 0.046) differed significantly between AD diagnostic groups. MCI/AD converters showed greater, but non-significant, telomere shortening compared to non-converters (ES = -0.186).

CONCLUSIONS: Although AD compared to controls showed small, non-significant effects for baseline T/S ratio and T/S ratio shortening, we did observe a larger, though still non-significant effect for greater telomere shortening in converters compared to non-converters. Although our results do not support telomere shortening as a robust biomarker of AD progression, further investigation in larger samples and for subgroups of participants may be informative.

%B J Alzheimers Dis %V 71 %P 33-43 %8 2019 Sep 3 %G eng %N 1 %R 10.3233/JAD-190010 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Tracking Cognitive Performance in the General Population and in Patients with Mild Cognitive Impairment with a Self-Applied Computerized Test (Brain on Track). %A Ruano, Luis %A Severo, Milton %A Sousa, Andreia %A Ruano, Catarina %A Branco, Mariana %A Barreto, Rui %A Moreira, Sandra %A Araújo, Natália %A Pinto, Paula %A Pais, Joana %A Lunet, Nuno %A Cruz, Vítor Tedim %X

Repeated measurements could be helpful to identify patients with early cognitive decline. We compare the variation of cognitive performance over one year in patients with mild cognitive impairment (MCI) and healthy individuals using the Brain on Track self-applied computerized test (BoT). The study was initiated 30 patients with probable MCI and 377 controls from a population-based cohort, who performed the BoT test from home every three months for one year. The scores were compared using a linear mixed-effects model. All participants increased their scores in the first tests, after 120 days MCI patients started to decline, with a statistically significant higher rate. The area under the curve to detect MCI was 0.94. We identified a significant decline in cognitive performance over one year in patients with MCI using BoT and the test presented a high discriminative ability.

%B J Alzheimers Dis %V 71 %P 541-548 %8 2019 Sep 17 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/31424407?dopt=Abstract %R 10.3233/JAD-190631 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Traffic-Related Air Pollution as a Risk Factor for Dementia: No Clear Modifying Effects of APOEɛ4 in the Betula Cohort. %A Oudin, Anna %A Andersson, John %A Sundström, Anna %A Nordin Adolfsson, Annelie %A Oudin Åström, Daniel %A Adolfsson, Rolf %A Forsberg, Bertil %A Nordin, Maria %X

It is widely known that the apolipoprotein E (APOE) ɛ4 allele imposes a higher risk for Alzheimer's disease (AD). Recent evidence suggests that exposure to air pollution is also a risk factor for AD, and results from a few studies indicate that the effect of air pollution on cognitive function and dementia is stronger in APOEɛ4 carriers than in non-carriers. Air pollution and interaction with APOEɛ4 on AD risk thus merits further attention. We studied dementia incidence over a 15-year period from the longitudinal Betula study in Northern Sweden. As a marker for long-term exposure to traffic-related air pollution, we used modelled annual mean nitrogen oxide levels at the residential address of the participants at start of follow-up. Nitrogen oxide correlate well with fine particulate air pollution levels in the study area. We had full data on air pollution, incidence of AD and vascular dementia (VaD), APOEɛ4 carrier status, and relevant confounding factors for 1,567 participants. As expected, air pollution was rather clearly associated with dementia incidence. However, there was no evidence for a modifying effect by APOEɛ4 on the association (p-value for interaction > 0.30 for both total dementia (AD+VaD) and AD). The results from this study do not imply that adverse effects of air pollution on dementia incidence is limited to, or stronger in, APOEɛ4 carriers than in the total population.

%B J Alzheimers Dis %V 71 %P 733-740 %8 2019 Oct 1 %G eng %N 3 %R 10.3233/JAD-181037 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Transcriptome Changes in the Alzheimer's Disease Middle Temporal Gyrus: Importance of RNA Metabolism and Mitochondria-Associated Membrane Genes. %A Piras, Ignazio S %A Krate, Jonida %A Delvaux, Elaine %A Nolz, Jennifer %A Mastroeni, Diego F %A Persico, Antonio M %A Jepsen, Wayne M %A Beach, Thomas G %A Huentelman, Matthew J %A Coleman, Paul D %X

We used Illumina Human HT-12 v4 arrays to compare RNA expression of middle temporal gyrus (MTG; BA21) in Alzheimer's disease (AD = 97) and non-demented controls (ND = 98). A total of 938 transcripts were highly differentially expressed (adj p < 0.01; log2 FC ≥ |0.500|, with 411 overexpressed and 527 underexpressed in AD. Our results correlated with expression profiling in neurons from AD and ND obtained by laser capture microscopy in MTG from an independent dataset (log2 FC correlation: r = 0.504; p = 2.2e-16). Additionally, selected effects were validated by qPCR. ANOVA analysis yielded no difference between genders in response to AD, but some gender specific genes were detected (e.g., IL8 and AGRN in males, and HSPH1 and GRM1 in females). Several transcripts were associated with Braak staging (e.g., AEBP1 and DNALI1), antemortem MMSE (e.g., AEBP1 and GFAP), and tangle density (e.g., RNU1G2, and DNALI1). At the pathway level, we detected enrichment of synaptic vesicle processes and GABAergic transmission genes. Finally, applying the Weighted Correlation Network Analysis, we identified four expression modules enriched for neuronal and synaptic genes, mitochondria-associated membrane, chemical stimulus and olfactory receptor and non-coding RNA metabolism genes. Our results represent an extensive description of MTG mRNA profiling in a large sample of AD and ND. These data provide a list of genes associated with AD, and correlated to neurofibrillary tangles density. In addition, these data emphasize the importance of mitochondrial membranes and transcripts related to olfactory receptors in AD.

%B J Alzheimers Dis %V 70 %P 691-713 %8 2019 Aug 3 %G eng %N 3 %R 10.3233/JAD-181113 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Treatment Combinations for Alzheimer's Disease: Current and Future Pharmacotherapy Options. %A Cummings, Jeffrey L %A Tong, Gary %A Ballard, Clive %X

Although Alzheimer's disease (AD) is the world's leading cause of dementia and the population of patients with AD continues to grow, no new therapies have been approved in more than a decade. Many clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy. The goal of this narrative literature review is to describe types of combination therapy, review the current clinical evidence for combination therapy regimens (both symptomatic and disease-modifying) in the treatment of AD, describe innovative clinical trial study designs that may be effective in testing combination therapy, and discuss the regulatory and drug development landscape for combination therapy. Successful combination therapies in other complex disorders, such as human immunodeficiency virus, may provide useful examples of a potential path forward for AD treatment.

%B J Alzheimers Dis %V 67 %P 779-794 %8 2019 %G eng %N 3 %R 10.3233/JAD-180766 %0 Journal Article %J J Alzheimers Dis %D 2019 %T TSPO Ligands Boost Mitochondrial Function and Pregnenolone Synthesis. %A Lejri, Imane %A Grimm, Amandine %A Hallé, François %A Abarghaz, Mustapha %A Klein, Christian %A Maitre, Michel %A Schmitt, Martine %A Bourguignon, Jean-Jacques %A Mensah-Nyagan, Ayikoe Guy %A Bihel, Frederic %A Eckert, Anne %X

 Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expression is upregulated in neuropathologies such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands based on an imidazoquinazolinone termed 2a and 2b, stimulated pregnenolone synthesis and ATP production in vitro. In the present study, we compared their effects to those of TSPO ligands described in the literature (XBD173, SSR-180,575, and Ro5-4864) by profiling the mitochondrial bioenergetic phenotype before and after treatment and investigating the protective effects of these ligands after oxidative injury in a cellular model of AD overexpressing amyloid-β (Aβ). Of note, ATP levels increased with rising pregnenolone levels suggesting that the energetic performance of mitochondria is linked to an increased production of this neurosteroid via TSPO modulation. Our results further demonstrate that the TSPO ligands 2a and 2b exerted neuroprotective effects by improving mitochondrial respiration, reducing reactive oxygen species and thereby decreasing oxidative stress-induced cell death as well as lowering Aβ levels. The compounds 2a and 2b show similar or even better functional effects than those obtained with the reference TSPO ligands XBD173 and SSR-180.575. These findings indicate that the new TSPO ligands modulate mitochondrial bioenergetic phenotype and protect against oxidative injury probably through the de novo synthesis of neurosteroids, suggesting that these compounds could be potential new therapeutic tools for the treatment of neurodegenerative disease.

%B J Alzheimers Dis %V 72 %P 1045-1058 %8 2019 Dec 12 %G eng %N 4 %R 10.3233/JAD-190127 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Two Year Outcomes, Cognitive and Behavioral Markers of Decline in Healthy, Cognitively Normal Older Persons with Global Deterioration Scale Stage 2 (Subjective Cognitive Decline with Impairment). %A Reisberg, Barry %A Torossian, Carol %A Shulman, Melanie B %A Monteiro, Isabel %A Boksay, Istvan %A Golomb, James %A Guillo Benarous, Francoise %A Ulysse, Anaztasia %A Oo, Thet %A Vedvyas, Alok %A Rao, Julia A %A Marsh, Karyn %A Kluger, Alan %A Sangha, Jaspreet %A Hassan, Mudasar %A Alshalabi, Munther %A Arain, Fauzia %A Shaikh, Naveed %A Buj, Maja %A Kenowsky, Sunnie %A Masurkar, Arjun V %A Rabin, Laura %A Noroozian, Maryam %A Sánchez-Saudinós, Mar A Belén %A Blesa, Rafael %A Auer, Stefanie %A Zhang, Yian %A de Leon, Mony %A Sadowski, Martin %A Wisniewski, Thomas %A Gauthier, Serge %A Shao, Yongzhao %X

BACKGROUND: Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2.

OBJECTIVE: Two-year interval behavioral markers were investigated herein.

METHODS: Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology "SCD(I)" for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years.

RESULTS: Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p < 0.001), with component declines in Remote memory (p < 0.01), and Functioning/self-care (p = 0.01).

CONCLUSION: SCD(I) persons decline at an annual rate of approximately 6.7% /year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.

%B J Alzheimers Dis %V 67 %P 685-705 %8 2019 Jan 22 %G eng %N 2 %R 10.3233/JAD-180341 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Ultrasensitive Detection of Plasma Amyloid-β as a Biomarker for Cognitively Normal Elderly Individuals at Risk of Alzheimer's Disease. %A Chatterjee, Pratishtha %A Elmi, Mitra %A Goozee, Kathryn %A Shah, Tejal %A Sohrabi, Hamid R %A Dias, Cintia B %A Pedrini, Steve %A Shen, Kaikai %A Asih, Prita R %A Dave, Preeti %A Taddei, Kevin %A Vanderstichele, Hugo %A Zetterberg, Henrik %A Blennow, Kaj %A Martins, Ralph N %X

BACKGROUND: Aberrant amyloid-β (Aβ) deposition in the brain occurs two decades prior to the manifestation of Alzheimer's disease (AD) clinical symptoms and therefore brain Aβ load measured using PET serves as a gold standard biomarker for the early diagnosis of AD. However, the uneconomical nature of PET makes blood markers, that reflect brain Aβ deposition, attractive candidates for investigation as surrogate markers.

OBJECTIVE: Investigation of plasma Aβ as a surrogate marker for brain Aβ deposition in cognitively normal elderly individuals.

METHODS: Plasma Aβ40 and Aβ42 concentrations were measured using the ultrasensitive Single Molecule Array (Simoa) assay in 95 cognitively normal elderly individuals, who have all undergone PET to assess brain Aβ deposition. Based on the standard uptake value ratios (SUVR) obtained from PET imaging, using the tracer 18F-Florbetaben, plasma Aβ was compared between 32 participants assessed to have low brain Aβ load (Aβ-, SUVR <1.35) and 63 assessed to have high brain Aβ load (Aβ+, SUVR ≥1.35).

RESULTS: Plasma Aβ42/Aβ40 ratios were lower in the Aβ+ group compared to the Aβ-group. Plasma Aβ40 and Aβ42 levels were not significantly different between Aβ-and Aβ+ groups, although a trend of higher plasma Aβ40 was observed in the Aβ+ group. Additionally, plasma Aβ42/Aβ40 ratios along with the known AD risk factors, age and APOEɛ4 status, resulted in Aβ+ participants being distinguished from Aβ-participants based on an area under the receiver operating characteristic curve shown to be 78%.

CONCLUSION: Plasma Aβ ratios in this study are a potential biomarker for brain Aβ deposition and therefore, for preclinical AD. However, this method to measure plasma Aβ needs further development to increase the accuracy of this promising AD blood biomarker.

%B J Alzheimers Dis %V 71 %P 775-783 %8 2019 Oct 1 %G eng %N 3 %R 10.3233/JAD-190533 %0 Journal Article %J J Alzheimers Dis %D 2019 %T An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults. %A Yang, Hyun-Sik %A Chhatwal, Jasmeer P %A Xu, Jishu %A White, Charles C %A Hanseeuw, Bernard %A Rabin, Jennifer S %A Papp, Kathryn V %A Buckley, Rachel F %A Schultz, Aaron P %A Properzi, Michael J %A Gatchel, Jennifer R %A Amariglio, Rebecca E %A Donovan, Nancy J %A Mormino, Elizabeth C %A Hedden, Trey %A Marshall, Gad A %A Rentz, Dorene M %A Johnson, Keith A %A De Jager, Philip L %A Sperling, Reisa A %X

BACKGROUND: The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele's effect on hippocampal neurodegeneration needs to be examined.

OBJECTIVE: To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adults.

METHODS: We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n = 174). Linear mixed effect models were used to examine the effect of rs3846455G on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-β (Aβ) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455G and greater PACC decline through a mediation analysis.

RESULTS: rs3846455G was associated with greater PACC decline (β= -0.087/year, 95% CI -0.169 to -0.005, p = 0.039) after controlling for baseline Aβ. Further, rs3846455G predicted accelerated hippocampal atrophy after controlling for baseline Aβ (β= -57.3 mm3/year, 95% CI -102.8 to -11.9, p = 0.014). The association between rs3846455G and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale) = -0.014, 95% CI -0.032 to -6.0×10-4, p = 0.039).

CONCLUSION: UNC5C rs3846455G predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults.

%B J Alzheimers Dis %V 68 %P 1161-1170 %8 2019 Apr 8 %G eng %N 3 %R 10.3233/JAD-180788 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Understanding the Amyloid Hypothesis in Alzheimer's Disease. %A Paroni, Giulia %A Bisceglia, Paola %A Seripa, Davide %X

The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-β (Aβ) peptides production and AP formation is a physiological aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aβ peptides act as neurotoxic molecules, but only above a critical concentration [Aβ]c. A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c. In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing Aβ anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or Aβ catabolism/clearance could contribute to exceed the threshold [Aβ]c, being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.

%B J Alzheimers Dis %V 68 %P 493-510 %8 2019 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/30883346?dopt=Abstract %R 10.3233/JAD-180802 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Upregulation of Thioredoxin-Interacting Protein in Brain of Amyloid-β Protein Precursor/Presenilin 1 Transgenic Mice and Amyloid-β Treated Neuronal Cells. %A Wang, Yiran %A Wang, Ying %A Bharti, Veni %A Zhou, Hong %A Hoi, Vanessa %A Tan, Hua %A Wu, Zijian %A Nagakannan, Pandian %A Eftekharpour, Eftekhar %A Wang, Jun-Feng %X

Oxidative stress has been hypothesized to play a role in the pathophysiology of Alzheimer's disease (AD). Previously, we found that total nitrosylated protein levels were increased in the brain of amyloid-β protein precursor (AβPP) and presenilin 1 (PS1) double transgenic mice, an animal model for AD, suggesting that cysteine oxidative protein modification may contribute to this disease. Thioredoxin (Trx) is a major oxidoreductase that can reverse cysteine oxidative modifications such as sulfenylation and nitrosylation, and inhibit oxidative stress. Thioredoxin-interacting protein (Txnip) is an endogenous Trx inhibitor. To understand the involvement of Trx and Txnip in AD development, we investigated Trx and Txnip in the brain of AβPP/PS1 mice. Using immunoblotting analysis, we found that although Trx protein levels were not changed, Txnip protein levels were significantly increased in hippocampus and frontal cortex of 9- and 12-month-old AβPP/PS1 mice when compared to wild-type mice. Txnip protein levels were also increased by amyloid-β treatment in primary cultured mouse cerebral cortical neurons and HT22 mouse hippocampal cells. Using biotin switch and dimedone conjugation methods, we found that amyloid-β treatment increased protein nitrosylation and sulfenylation in HT22 cells. We also found that downregulation of Txnip, using CRISPR/Cas9 method in HT22 cells, attenuated amyloid-β-induced protein nitrosylation and sulfenylation. Our findings suggest that amyloid-β may increase Txnip levels, subsequently inhibiting Trx reducing capability and enhancing protein cysteine oxidative modification. Our findings also indicate that Txnip may be a potential target for the treatment of AD.

%B J Alzheimers Dis %V 72 %P 139-150 %8 2019 Oct 29 %G eng %N 1 %R 10.3233/JAD-190223 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Vascular Burden Score Impacts Cognition Independent of Amyloid PET and MRI Measures of Alzheimer's Disease and Vascular Brain Injury. %A DeCarli, Charles %A Villeneuve, Sylvia %A Maillard, Pauline %A Harvey, Danielle %A Singh, Baljeet %A Carmichael, Owen %A Fletcher, Evan %A Olichney, John %A Farias, Sarah %A Jagust, William %A Reed, Bruce %A Mungas, Dan %X

BACKGROUND/OBJECTIVE: To determine the impact of vascular burden on rates of decline in episodic memory and executive function. We hypothesize that greater vascular burden will have an additive negative impact on cognition after accounting for baseline cognitive impairment, positron emission tomography (PET) amyloid burden, and magnetic resonance imaging (MRI) measures.

METHODS: Individuals were followed an average of 5 years with serial cognitive assessments. Predictor variables include vascular burden score (VBS), quantitative brain MRI assessment, and amyloid imaging. Subjects consisted of 65 individuals, 53% of whom were male, aged 73.2±7.2 years on average with an average of 15.5±3.3 years of educational achievement.

RESULTS: Baseline cognitive impairment was significantly associated poorer episodic memory (p < 0.0001), smaller hippocampal volume (p < 0.0001), smaller brain volume (p = 0.0026), and greater global Pittsburg Imaging Compound B (PiB) index (p = 0.0008). Greater amyloid burden was associated with greater decline in episodic memory over time (β= -0.20±0.07, p < 0.005). VBS was significantly associated with the level of executive function performance (β= -0.14±0.05, p < 0.005) and there was a significant negative interaction between VBS, cognitive impairment, and PiB index (β= -0.065±0.03, p = 0.03).

CONCLUSIONS: Our results find a significant influence of VBS independent of standard MRI measures and cerebral amyloid burden on executive function. In addition, VBS reduced the amount of cerebral amyloid burden needed to result in cognitive impairment. We conclude that the systemic effects of vascular disease as reflected by the VBS independently influence cognitive ability.

%B J Alzheimers Dis %V 68 %P 187-196 %8 2019 Mar 12 %G eng %N 1 %R 10.3233/JAD-180965 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Vascular Mild Cognitive Impairment: Identifying Disease in Community-Dwelling Older Adults, Reducing Risk Factors, and Providing Support. The Osaki-Tajiri and Kurihara Projects. %A Meguro, Kenichi %A Dodge, Hiroko H %X

Vascular mild cognitive impairment (MCI) is a critical disease. Its prognosis includes not only onset of vascular dementia, but also death by cardiovascular disease. The vascular risk factors for vascular MCI are treatable, and appropriate treatment can prevent or delay the progression to dementia. Therefore, this group is an excellent candidate for secondary prevention. However, community-dwelling older adults with vascular MCI are often undetected and are not clinically identified until they develop frank dementia. Furthermore, older adults with undetected vascular MCI often have decreased ability to follow their medication regimens and this poor medication adherence worsens their vascular comorbidities. This vicious cycle needs to be prevented through community-based interventions. There is evidence that treatment of hypertension or diabetes mellitus could lead to a reduced incidence of vascular MCI and dementia. In this review article, we first explain the background and etiology of vascular MCI. We then summarize phenotype of subcortical vascular dementia which is often unrecognized or "hidden" in the community. Then we introduce the Osaki-Tajiri and Kurihara Projects which have been conducted in Northern Japan, as an example of prevention projects aimed to identify early-stage vascular MCI in the community, reduce the risk factors and facilitate their treatment. Early identification of vascular MCI in the community could lead to a large reduction in the dementia burden worldwide. The outreach efforts presented here could be useful in developing secondary prevention strategies targeted to vascular MCI.

%B J Alzheimers Dis %V 70 %P S293-S302 %8 2019 %G eng %N s1 %R 10.3233/JAD-180899 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Vital Exhaustion and Incidence of Dementia: Results from the Copenhagen City Heart Study. %A Islamoska, Sabrina %A Ishtiak-Ahmed, Kazi %A Hansen, Åse Marie %A Grynderup, Matias Brødsgaard %A Mortensen, Erik Lykke %A Garde, Anne Helene %A Gyntelberg, Finn %A Prescott, Eva Irene Bossano %A Török, Eszter %A Waldemar, Gunhild %A Nabe-Nielsen, Kirsten %X

BACKGROUND: Psychological distress is potentially linked to the risk of dementia through neurologic and cardiovascular mechanisms. Vital exhaustion (VE) is a mental state of psychological distress, which could be a risk factor for dementia.

OBJECTIVE: To investigate whether VE is a risk factor for dementia in later life.

METHODS: We used data from 6,807 participants attending the third survey of the Copenhagen City Heart Study in 1991-1994. VE was assessed by 17 symptoms (score: 0-17) from the Maastricht Questionnaire. Information on dementia was obtained from national registers. Risk time for dementia was counted from five years after VE assessment for participants > 55 years at the time of VE assessment. For younger participants, risk time for dementia was counted from the year they turned 60 years and onwards. Participants were followed until 2016. We used Poisson regression to calculate incidence rate ratios (IRR) and their 95% confidence intervals (CI).

RESULTS: During an average follow-up of 10 years, 872 participants were registered with dementia. We found a dose-response relation between the number of VE symptoms and the incidence of dementia. For every additional VE symptom, the dementia incidence increased by 2% (IRR = 1.024; 95% CI: 1.004-1.043). Adjustment for socio-demographic and health-related factors did not change the results substantially. Neither did stratification by age, sex, educational level, and marital status.

CONCLUSION: We found evidence that VE is a risk factor for dementia. Our sensitivity analyses supported that this association was not only due to VE being a potential prodromal sign of dementia.

%B J Alzheimers Dis %V 67 %P 369-379 %8 2019 %G eng %N 1 %R 10.3233/JAD-180478 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Why Is Amyloid-β PET Requested After Performing Cerebrospinal Fluid Biomarkers? %A Reimand, Juhan %A Groot, Colin %A Teunissen, Charlotte E %A Windhorst, Albert D %A Boellaard, Ronald %A Barkhof, Frederik %A Nazarenko, Sergei %A van der Flier, Wiesje M %A van Berckel, Bart N M %A Scheltens, Philip %A Ossenkoppele, Rik %A Bouwman, Femke %X

BACKGROUND: Amyloid-β PET and cerebrospinal fluid (CSF) Aβ42 are considered interchangeable for clinical diagnosis of Alzheimer's disease.

OBJECTIVE: To explore the clinical reasoning for requesting additional amyloid-β PET after performing CSF biomarkers.

METHODS: We retrospectively identified 72 memory clinic patients who underwent amyloid-β PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-β PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-β PET.

RESULTS: Mean patient age was 62.0 (SD = 8.1) and mean Mini-Mental State Exam score was 23.6 (SD = 3.8). CSF analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-β PET scan (n = 53, 74%), followed by incongruent MRI (n = 16, 22%), unusual clinical presentation (n = 11, 15%) and young age (n = 8, 11%). An amyloid-β PET scan was rarely (n = 5, 7%) requested in patients with a CSF Aβ+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n = 11 (15%) cases, the reason that the clinician requested amyloid-β was not covered by AUC. This happened most often (n = 7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-β PET.

CONCLUSION: In this single-center study, the main reason for requesting an amyloid-β PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aβ/tau results.

%B J Alzheimers Dis %V 73 %P 559-569 %8 2020 Jan 21 %G eng %N 2 %R 10.3233/JAD-190836 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A 10-Year Follow-Up of Adiposity and Dementia in Swedish Adults Aged 70 Years and Older. %A Arnoldussen, Ilse A C %A Sundh, Valter %A Bäckman, Kristoffer %A Kern, Silke %A Östling, Svante %A Blennow, Kaj %A Zetterberg, Henrik %A Skoog, Ingmar %A Kiliaan, Amanda J %A Gustafson, Deborah R %X

BACKGROUND: Adiposity measured in mid- or late-life and estimated using anthropometric measures such as body mass index (BMI) and waist-to-hip ratio (WHR), or metabolic markers such as blood leptin and adiponectin levels, is associated with late-onset dementia risk. However, during later life, this association may reverse and aging- and dementia-related processes may differentially affect adiposity measures.

OBJECTIVE: We explored associations of concurrent BMI, WHR, and blood leptin and high molecular weight adiponectin levels with dementia occurrence.

METHODS: 924 Swedish community-dwelling elderly without dementia, aged 70 years and older, systematically-sampled by birth day and birth year population-based in the Gothenburg city region of Sweden. The Gothenburg Birth Cohort Studies are designed for evaluating risk and protective factors for dementia. All dementias diagnosed after age 70 for 10 years were identified. Multivariable logistic regression models were used to predict dementia occurrence between 2000-2005, 2005-2010, and 2000-2010 after excluding prevalent baseline (year 2000) dementias. Baseline levels of BMI, WHR, leptin, and adiponectin were used.

RESULTS: Within 5 years of baseline, low BMI (<20 kg/m2) was associated with higher odds of dementia compared to those in the healthy BMI category (≥ 20-24.9 kg/m2). Compared to the lowest quartile, leptin levels in the second quartile were associated with lower odds of dementia in women (p < 0.05).

CONCLUSION: In late-life, anthropometric and metabolic adiposity measures appear to be differentially associated with dementia risk. While BMI and leptin levels are highly positively correlated, our results show that their association with dementia at age ≥70 years, is asynchronous. These data suggest that with aging, the complexity of the adiposity exposure may increase and suggests metabolic dysregulation. Additional studies are needed to better understand this complexity.

%B J Alzheimers Dis %V 63 %P 1325-1335 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758945?dopt=Abstract %R 10.3233/JAD-180099 %0 Journal Article %J J Alzheimers Dis %D 2018 %T 11C-CFT-PET in Presymptomatic FTDP-17: A Potential Biomarker Predicting Onset. %A Wu, Liyong %A Liu, Jia %A Feng, Xueyan %A Dong, Jing %A Qin, Wei %A Liu, Yang %A Wang, Jingjuan %A Lu, Jie %A Chen, Kewei %A Wang, Yuping %A Jia, Jianping %K Adult %K Biomarkers %K Brain %K Carbon Radioisotopes %K Female %K Frontotemporal Dementia %K Heterozygote %K Humans %K Male %K Middle Aged %K Mutation %K Parkinsonian Disorders %K Pedigree %K Positron-Emission Tomography %K tau Proteins %X

Frontotemporal dementia with parkinsonism-linked to chromosome 17 (FTDP-17) is a rare autosomal dominant neurodegenerative disorder. Most patients with FTDP-17 carry the mutation in the microtubule-associated protein tau (MAPT) gene. Striatum is predominantly and early affected in FTDP-17. Five family members (two symptomatic patients and three presymptomatic mutation carriers) from a Chinese pedigree of FTDP-17 with N279K mutation in MAPT were enrolled. Parkinsonism was the initial symptom for symptomatic patients. 2b-carbomethoxy-3b-(4-trimethylstannylphenyl) tropane (11C-CFT) uptake was obviously affected in the putamen of two presymptomatic mutation carriers. Presymptomatic case 3, whose 11C-CFT uptake in the right putamen was normal at baseline, was still free of parkinsonism during follow-up. In conclusion, 11C-CFT-positron emission tomography could be a potential biomarker for the presymptomatic stage of FTDP-17 to predict the disease onset.

%B J Alzheimers Dis %V 61 %P 613-618 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226866?dopt=Abstract %R 10.3233/JAD-170561 %0 Journal Article %J J Alzheimers Dis %D 2018 %T 18F-FDG PET for Prediction of Conversion to Alzheimer's Disease Dementia in People with Mild Cognitive Impairment: An Updated Systematic Review of Test Accuracy. %A Smailagic, Nadja %A Lafortune, Louise %A Kelly, Sarah %A Hyde, Chris %A Brayne, Carol %X

BACKGROUND: A previous Cochrane systematic review concluded there is insufficient evidence to support the routine use of 18F-FDG PET in clinical practice in people with mild cognitive impairment (MCI).

OBJECTIVES: To update the evidence and reassess the accuracy of 18F-FDG-PET for detecting people with MCI at baseline who would clinically convert to Alzheimer's disease (AD) dementia at follow-up.

METHODS: A systematic review including comprehensive search of electronic databases from January 2013 to July 2017, to update original searches (1999 to 2013). All key review steps, including quality assessment using QUADAS 2, were performed independently and blindly by two review authors. Meta-analysis could not be conducted due to heterogeneity across studies.

RESULTS: When all included studies were examined across all semi-quantitative and quantitative metrics, exploratory analysis for conversion of MCI to AD dementia (n = 24) showed highly variable accuracy; half the studies failed to meet four or more of the seven sets of QUADAS 2 criteria. Variable accuracy for all metrics was also found across eleven newly included studies published in the last 5 years (range: sensitivity 56-100%, specificity 24-100%). The most consistently high sensitivity and specificity values (approximately ≥80%) were reported for the sc-SPM (single case statistical parametric mapping) metric in 6 out of 8 studies.

CONCLUSION: Systematic and comprehensive assessment of studies of 18FDG-PET for prediction of conversion from MCI to AD dementia reveals many studies have methodological limitations according to Cochrane diagnostic test accuracy gold standards, and shows accuracy remains highly variable, including in the most recent studies. There is some evidence, however, of higher and more consistent accuracy in studies using computer aided metrics, such as sc-SPM, in specialized clinical settings. Robust, methodologically sound prospective longitudinal cohort studies with long (≥5 years) follow-up, larger consecutive samples, and defined baseline threshold(s) are needed to test these promising results. Further evidence of the clinical validity and utility of 18F-FDG PET in people with MCI is needed.

%B J Alzheimers Dis %V 64 %P 1175-1194 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010119?dopt=Abstract %R 10.3233/JAD-171125 %0 Journal Article %J J Alzheimers Dis %D 2018 %T 18F-Flortaucipir Binding in Choroid Plexus: Related to Race and Hippocampus Signal. %A Lee, Christopher M %A Jacobs, Heidi I L %A Marquié, Marta %A Becker, John A %A Andrea, Nicolas V %A Jin, David S %A Schultz, Aaron P %A Frosch, Matthew P %A Gómez-Isla, Teresa %A Sperling, Reisa A %A Johnson, Keith A %X

BACKGROUND: On target 18F-Flortaucipir (FTP) binding of Alzheimer's disease tau aggregates and off-target binding of melanocytes have been demonstrated with autoradiography.

OBJECTIVE: We aimed to investigate the hypothesis that if binding in choroid plexus (CP) is due to melanocytes, the signal would be elevated in Black/African American (B/AA) compared to White (W) participants. In addition, we examined whether CP signal affects measurements in adjacent regions, and whether correcting for spill-in effects has an influence on associations between hippocampus (HC) FTP and amyloid or cognition.

METHODS: FTP race differences in 147 Harvard Aging Brain Study participants (23 B/AA, 124W) were examined in CP, HC, HC covaried for CP, amygdala, inferior temporal gyrus, entorhinal cortex, and fusiform regions. Associations between CP FTP and other regions-of-interest (ROIs) were probed to assess spill-in effects. A statistical regression approach to attenuate CP spill-in was tested by relating adjusted HC SUVR residuals and unadjusted HC SUVR to race, cognition and amyloid. All analyses were covaried for age, sex, education and amyloid deposition, and Bonferroni-corrected for multiple comparisons.

RESULTS: B/AA individuals had elevated CP and HC SUVR (p < 0.007), whereas other ROI SUVR and HC SUVR covaried for CP SUVR did not show race differences (p > 0.05). CP SUVR was associated with HC SUVR (p < 10-14), but with no other ROI SUVR (p > 0.05). When adjusting HC SUVR for CP SUVR, no race differences in residual HC SUVR were detected, and relationships with amyloid and memory became apparent.

CONCLUSION: Melanocyte FTP binding may account partially for high CP signal. This off-target binding affects mainly HC FTP measurements, which should be interpreted with caution.

%B J Alzheimers Dis %V 62 %P 1691-1702 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614677?dopt=Abstract %R 10.3233/JAD-170840 %0 Journal Article %J J Alzheimers Dis %D 2018 %T [18F]-Flutemetamol Uptake in Cortex and White Matter: Comparison with Cerebrospinal Fluid Biomarkers and [18F]-Fludeoxyglucose. %A Kalheim, Lisa Flem %A Fladby, Tormod %A Coello, Christopher %A Bjørnerud, Atle %A Selnes, Per %X

Flutemetamol (18F-Flut) is an [18F]-labelled amyloid PET tracer with increasing availability. The main objectives of this study were to investigate 1) cerebrospinal fluid (CSF) Aβ 1-42 (Aβ42) concentrations associated with regional 18F-Flut uptake, 2) associations between cortical 18F-Flut and [18F]-fludeoxyglucose (18F-FDG)-PET, and 3) the potential use of 18F-Flut in WM pathology. Cognitively impaired, nondemented subjects were recruited (n = 44). CSF was drawn, and 18F-Flut-PET, 18F-FDG-PET, and MRI performed. Our main findings were: 1) Different Alzheimer's disease predilection areas showed increased 18F-Flut retention at different CSF Aβ42 concentrations (posterior regions were involved at higher concentrations). 2) There were strong negative correlations between regional cortical 18F-Flut and 18F-FDG uptake. 3) Increased 18F-Flut uptake were observed in multiple subcortical regions in amyloid positive subjects, including investigated reference regions. However, WM hyperintensity 18F-Flut standardized uptake value ratios (SUVr) were not significantly different, thus we cannot definitely conclude that the higher uptake in 18F-Flut(+) is due to amyloid deposition. In conclusion, our findings support clinical use of CSF Aβ42, putatively relate decreasing CSF Aβ42 concentrations to a sequence of regional amyloid deposition, and associate amyloid pathology to cortical hypometabolism. However, we cannot conclude that 18F-Flut-PET is a suitable marker for WM pathology due to high aberrant WM uptake.

%B J Alzheimers Dis %V 62 %P 1595-1607 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504529?dopt=Abstract %R 10.3233/JAD-170582 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The 20-Year Voyage Aboard the Journal of Alzheimer's Disease: Docking at 'Type 3 Diabetes', Environmental/Exposure Factors, Pathogenic Mechanisms, and Potential Treatments. %A de la Monte, Suzanne M %A Tong, Ming %A Wands, Jack R %X

The Journal of Alzheimer's Disease (JAD), founded in 1998, played a pivotal role in broadening the field of research on Alzheimer's disease (AD) by publishing a diverse range of clinical, pathological, molecular, biochemical, epidemiological, experimental, and review articles from its birth. This article recounts my own journey as an author who contributed articles to JAD over the 20 years of the journal's existence. In retrospect, it seems remarkable that a considerable body of work that originated from our group marks a trail that began with studies of vascular, stress, and mitochondrial factors in AD pathogenesis, exploded into the concept of 'Type 3 Diabetes', and continued with the characterization of how environmental, exposure, and lifestyle factors promote neurodegeneration and which therapeutic strategies could reverse the neurodegeneration cascade.

%B J Alzheimers Dis %V 62 %P 1381-1390 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562538?dopt=Abstract %R 10.3233/JAD-170829 %0 Journal Article %J J Alzheimers Dis %D 2018 %T ABC Transporters Are Key Players in Alzheimer's Disease. %A Pereira, Cátia D %A Martins, Filipa %A Wiltfang, Jens %A da Cruz E Silva, Odete A B %A Rebelo, Sandra %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K ATP-Binding Cassette Transporters %K Blood-Brain Barrier %K Humans %X

Human ATP-binding cassette (ABC) transporters mediate a critical function in the cell, namely the transport of molecules across lipid membranes. Associated to their ubiquitous tissue distribution, they are key players in cellular homeostasis but also potential causative or contributing factors for many pathologies, including Alzheimer's disease (AD). In the central nervous system (CNS), numerous ABC transporters are present throughout the brain parenchyma and especially at the blood-brain barrier (BBB). AD is a neurodegenerative disorder mainly characterized by extracellular deposition of amyloid-β (Aβ) peptides and intracellular accumulation of hyperphosphorylated forms of tau protein. Besides being degraded via proteolytic and phagocytic processes mediated by brain parenchymal cells, a major mechanism for eliminating cerebral Aβ is through its transport across the BBB into the peripheral blood. In fact, many AD cases are associated with impaired Aβ clearance. Consistently, several studies have recently uncovered important roles for ABC transporters in AD pathophysiology. Hence, this review focuses on the relevance of ABC transporters in CNS homeostasis by highlighting AD as a strong example of the deleterious consequences that might result from the former's altered expression and/or activity in the brain. The potentiality of human ABC transporters as novel pharmacological targets for both the diagnosis and therapeutics of AD is emphasized.

%B J Alzheimers Dis %V 61 %P 463-485 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171999?dopt=Abstract %R 10.3233/JAD-170639 %0 Journal Article %J J Alzheimers Dis %D 2018 %T ABCA7 Downregulation Modifies Cellular Cholesterol Homeostasis and Decreases Amyloid-β Peptide Efflux in an in vitro Model of the Blood-Brain Barrier. %A Lamartinière, Yordenca %A Boucau, Marie-Christine %A Dehouck, Lucie %A Krohn, Markus %A Pahnke, Jens %A Candela, Pietra %A Gosselet, Fabien %A Fenart, Laurence %X

The role of ABCA7 in brain homeostasis and Alzheimer's disease (AD) is currently under intense scrutiny, since it has been reported that polymorphisms in the Abca7 gene and a loss of function of the protein are closely linked to excessive accumulation of amyloid peptides and disturbed cholesterol homeostasis. The blood-brain barrier (BBB), which isolates the brain from the blood compartment, is involved in both of these processes. We therefore hypothesized that ABCA7 downregulation might affect cholesterol and amyloid exchanges at the BBB. Using siRNA and primary cultures of mouse endothelial cells purified from brain microvessels and seeded on Transwell ® inserts, we investigated the role of ABCA7 in cholesterol and amyloid exchanges across the BBB. Our results showed that a decrease in ABCA7 expression at the BBB provokes in vitro a reduction in ABCA1 expression and a decrease in APOE secretion. In vitro, these decreases reduce cholesterol exchange across the BBB, particularly for high-density lipoproteins and ApoA-I particles. When ABCA7 was absent, we observed a reduction in Aβ peptide basolateral-to-apical transport in the presence of ApoA-I, with non-significant changes in the expression levels of Rage, Lrp1, Abcb1, Abcc1, and Abcg2. Our study in murine BBB model highlighted a putative new role for ABCA7 in AD via the protein's involvement in cholesterol metabolism and amyloid clearance at the BBB.

%B J Alzheimers Dis %V 64 %P 1195-1211 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010117?dopt=Abstract %R 10.3233/JAD-170883 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Aberrant Cortical Event-Related Potentials During Associative Learning in Rat Models for Presymptomatic Stages of Alzheimer's Disease. %A Nouriziabari, Bardia %A Sarkar, Susmita %A Tanninen, Stephanie E %A Dayton, Robert D %A Klein, Ronald L %A Takehara-Nishiuchi, Kaori %X

Trace eyeblink conditioning is a hippocampus-dependent associative learning paradigm which is impaired in patients with Alzheimer's disease (AD) and animal AD models. Learning in this paradigm accompanies changes in oscillatory activity in forebrain regions, some of which are loci of pathogenic changes in prodromal AD stages. These observations motivated us to examine how cortical event-related potentials (ERPs) during this paradigm are affected by two features of the asymptomatic, AD-related brain abnormality, entorhinal tau accumulation and mild cholinergic deficit. Adult rats received viral overexpression of P301L mutant human tau in the entorhinal cortex, low-dose scopolamine treatment, or both. Electroencephalograms were recorded with epidural electrodes on the surface of the frontal, parietal, and temporal cortices during differential and reversal trace eyeblink conditioning. All rats developed conditioned responses to one of two stimuli (auditory or visual) paired with mild eyelid shock (CS+), but not to the other stimulus presented alone (CS-). They were also able to adjust the response when the stimulus contingency was reversed. With learning, the amplitude of several ERP components in the frontal and temporal cortices came to differentiate the CS+ from CS-. Scopolamine affected the learning-related change in temporal P2 and other learning-unrelated components in three regions. Entorhinal tau overexpression primary affected the amplitude of temporal visual ERPs and learning-unrelated frontal and temporal auditory ERP components. The double manipulation only affected two components of temporal auditory ERPs. Thus, cortical ERPs during differential associative learning are sensitive to asymptomatic brain abnormality associated with AD.

%B J Alzheimers Dis %V 63 %P 725-740 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660939?dopt=Abstract %R 10.3233/JAD-171033 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Abnormal Functional Brain Networks in Mild Cognitive Impairment and Alzheimer's Disease: A Minimum Spanning Tree Analysis. %A Wang, Bin %A Miao, Liwen %A Niu, Yan %A Cao, Rui %A Li, Dandan %A Yan, Pengfei %A Guo, Hao %A Yan, Tianyi %A Wu, Jinglong %A Xiang, Jie %X

Alzheimer's disease (AD) disrupts the topological architecture of whole-brain connectivity. Minimum spanning tree (MST), which captures the most important connections in a network, has been considered an unbiased method for brain network analysis. However, the alterations in the MST of functional brain networks during the progression of AD remain unclear. Here, we performed an MST analysis to examine the alterations in functional networks among normal controls (NCs), mild cognitive impairment (MCI) patients, and AD patients. We identified substantial differences in the connections among the three groups. The maximum betweenness centrality, leaf number, and tree hierarchy of the MSTs showed significant group differences, indicating a more star-like topology in the MCI patients and a more line-like topology in the NCs and AD patients. These findings may correspond to changes in the core of the functional brain networks. For nodal properties (degree and betweenness centrality), we determined that brain regions around the cingulate gyrus, occipital lobes, subcortex, and inferior temporal gyrus showed significant differences among the three groups and contributed to the global topological alterations. The leaf number and tree hierarchy, as well as the nodal properties, were significantly correlated with clinical features in the MCI and AD patients, which demonstrated that more star-to-line topology changes were associated with worse cognitive performance in these patients. These findings indicated that MST properties could capture slight alterations in network topology, particularly for the differences between NCs and MCI patients, and may be applicable as neuroimaging markers of the early stage of AD.

%B J Alzheimers Dis %V 65 %P 1093-1107 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149457?dopt=Abstract %R 10.3233/JAD-180603 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Abnormalities of Resting State Cortical EEG Rhythms in Subjects with Mild Cognitive Impairment Due to Alzheimer's and Lewy Body Diseases. %A Babiloni, Claudio %A Del Percio, Claudio %A Lizio, Roberta %A Noce, Giuseppe %A Lopez, Susanna %A Soricelli, Andrea %A Ferri, Raffaele %A Pascarelli, Maria Teresa %A Catania, Valentina %A Nobili, Flavio %A Arnaldi, Dario %A Famá, Francesco %A Aarsland, Dag %A Orzi, Francesco %A Buttinelli, Carla %A Giubilei, Franco %A Onofrj, Marco %A Stocchi, Fabrizio %A Vacca, Laura %A Stirpe, Paola %A Fuhr, Peter %A Gschwandtner, Ute %A Ransmayr, Gerhard %A Garn, Heinrich %A Fraioli, Lucia %A Pievani, Michela %A Frisoni, Giovanni B %A D'Antonio, Fabrizia %A de Lena, Carlo %A Güntekin, Bahar %A Hanoğlu, Lutfu %A Başar, Erol %A Yener, Görsev %A Emek-Savaş, Derya Durusu %A Triggiani, Antonio Ivano %A Franciotti, Raffaella %A Taylor, John Paul %A De Pandis, Maria Francesca %A Bonanni, Laura %X

The present study tested the hypothesis that cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and dementia with Lewy bodies (DLBMCI) as compared to cognitively normal elderly (Nold) subjects. Clinical and rsEEG data in 30 ADMCI, 23 DLBMCI, and 30 Nold subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) score was matched between the ADMCI and DLBMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROCC) classified these sources across individuals. Compared to Nold, IAF showed marked slowing in DLBMCI and moderate in ADMCI. Furthermore, the posterior alpha 2 and alpha 3 source activities were more abnormal in the ADMCI than the DLBMCI group, while widespread delta source activities were more abnormal in the DLBMCI than the ADMCI group. The posterior delta and alpha sources correlated with the MMSE score and correctly classified the Nold and MCI individuals (area under the ROCC >0.85). In conclusion, the ADMCI and DLBMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test the clinical validity of these rsEEG markers.

%B J Alzheimers Dis %V 62 %P 247-268 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439335?dopt=Abstract %R 10.3233/JAD-170703 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Accuracy of Inferred APOE Genotypes for a Range of Genotyping Arrays and Imputation Reference Panels. %A Lupton, Michelle K %A Medland, Sarah E %A Gordon, Scott D %A Goncalves, Tabatha %A MacGregor, Stuart %A Mackey, David A %A Young, Terri L %A Duffy, David L %A Visscher, Peter M %A Wray, Naomi R %A Nyholt, Dale R %A Bain, Lisa %A Ferreira, Manuel A %A Henders, Anjali K %A Wallace, Leanne %A Montgomery, Grant W %A Wright, Margaret J %A Martin, Nicholas G %X

Cohort studies investigating aging and dementia require APOE genotyping. We compared directly measured APOE genotypes to 'hard-call' genotypes derived from imputing genome-wide genotyping data from a range of platforms using several imputation panels. Older GWAS arrays imputed to 1000 Genomes Project (1KGP) phases and the Haplotype Reference Consortium (HRC) reference panels were able to achieve concordance rates of over 98% with stringent quality control (hard-call-threshold 0.8). However, this resulted in high levels of missingness (>12% with 1KGP and 5% with HRC). With recent GWAS arrays, concordance of 99% could be obtained with relatively lenient QC, resulting in no missingness.

%B J Alzheimers Dis %V 64 %P 49-54 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865051?dopt=Abstract %R 10.3233/JAD-171104 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Acute Stroke Care in Dementia: A Cohort Study from the Swedish Dementia and Stroke Registries. %A Zupanic, Eva %A Kåreholt, Ingemar %A Norrving, Bo %A Secnik, Juraj %A von Euler, Mia %A Winblad, Bengt %A Religa, Dorota %A Kramberger, Milica Gregoric %A Johnell, Kristina %A Eriksdotter, Maria %A Garcia-Ptacek, Sara %X

BACKGROUND: Previous studies have shown that patients with dementia receive less testing and treatment for stroke.

OBJECTIVES: Our aim was to investigate hospital management of acute ischemic stroke in patients with and without dementia.

METHODS: Retrospective analysis of prospectively collected data 2010-2014 from the Swedish national dementia registry (SveDem) and the Swedish national stroke registry (Riksstroke). Patients with dementia who suffered an acute ischemic stroke (AIS) (n = 1,356) were compared with matched non-dementia AIS patients (n = 6,755). Outcomes included length of stay in a stroke unit, total length of hospitalization, and utilization of diagnostic tests and assessments.

RESULTS: The median age at stroke onset was 83 years. While patients with dementia were equally likely to be directly admitted to a stroke unit as their non-dementia counterparts, their stroke unit and total hospitalization length were shorter (10.5 versus 11.2 days and 11.6 versus 13.5, respectively, p < 0.001). Dementia patients were less likely to receive carotid ultrasound (OR 0.36, 95% CI [0.30-0.42]) or undergo assessments by the interdisciplinary team members (physiotherapists, speech therapists, occupational therapists; p < 0.05 for all adjusted models). However, a similar proportion of patients received CT imaging (97.4% versus 98.6%, p = 0.001) and a swallowing assessment (90.7% versus 91.8%, p = 0.218).

CONCLUSIONS: Patients with dementia who suffer an ischemic stroke have equal access to direct stroke unit care compared to non-dementia patients; however, on average, their stay in a stroke unit and total hospitalization are shorter. Dementia patients are also less likely to receive specific diagnostic tests and assessments by the interdisciplinary stroke team.

%B J Alzheimers Dis %V 66 %P 185-194 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30248059?dopt=Abstract %R 10.3233/JAD-180653 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Added Diagnostic Value of Cerebrospinal Fluid Biomarkers for Differential Dementia Diagnosis in an Autopsy-Confirmed Cohort. %A Niemantsverdriet, Ellis %A Feyen, Bart F E %A Le Bastard, Nathalie %A Martin, Jean-Jacques %A Goeman, Johan %A De Deyn, Peter Paul %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

BACKGROUND: Differential dementia diagnosis remains a challenge due to overlap of clinical profiles, which often results in diagnostic doubt.

OBJECTIVE: Determine the added diagnostic value of cerebrospinal fluid (CSF) biomarkers for differential dementia diagnosis as compared to autopsy-confirmed diagnosis.

METHODS: Seventy-one dementia patients with autopsy-confirmed diagnoses were included in this study. All neuropathological diagnoses were established according to standard neuropathological criteria and consisted of Alzheimer's disease (AD) or other dementias (NONAD). CSF levels of Aβ1 - 42, T-tau, and P-tau181 were determined and interpreted based on the IWG-2 and NIA-AA criteria, separately. A panel of three neurologists experienced with dementia made clinical consensus dementia diagnoses. Clinical and CSF biomarker diagnoses were compared to the autopsy-confirmed diagnoses.

RESULTS: Forty-two patients (59%) had autopsy-confirmed AD, whereas 29 patients (41%) had autopsy-confirmed NONAD. Of the 24 patients with an ambiguous clinical dementia diagnosis, a correct diagnosis would have been established in 67% of the cases applying CSF biomarkers in the context of the IWG-2 or the NIA-AA criteria respectively.

CONCLUSION: AD CSF biomarkers have an added diagnostic value in differential dementia diagnosis and can help establishing a correct dementia diagnosis in case of ambiguous clinical dementia diagnoses.

%B J Alzheimers Dis %V 63 %P 373-381 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614653?dopt=Abstract %R 10.3233/JAD-170927 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Added Value of Diffusion-Weighted MRI-Derived Structural Connectome in Evaluating Mild Cognitive Impairment: A Multi-Cohort Validation1. %A Wang, Qi %A Guo, Lei %A Thompson, Paul M %A Jack, Clifford R %A Dodge, Hiroko %A Zhan, Liang %A Zhou, Jiayu %X

T1-weighted MRI has been extensively used to extract imaging biomarkers and build classification models for differentiating Alzheimer's disease (AD) patients from healthy controls, but only recently have brain connectome networks derived from diffusion-weighted MRI been used to model AD progression and various stages of disease such as mild cognitive impairment (MCI). MCI, as a possible prodromal stage of AD, has gained intense interest recently, since it may be used to assess risk factors for AD. Little work has been done to combine information from both white matter and gray matter, and it is unknown how much classification power the diffusion-weighted MRI-derived structural connectome could provide beyond information available from T1-weighted MRI. In this paper, we focused on investigating whether diffusion-weighted MRI-derived structural connectome can improve differentiating healthy controls subjects from those with MCI. Specifically, we proposed a novel feature-ranking method to build classification models using the most highly ranked feature variables to classify MCI with healthy controls. We verified our method on two independent cohorts including the second stage of Alzheimer's Disease Neuroimaging Initiative (ADNI2) database and the National Alzheimer's Coordinating Center (NACC) database. Our results indicated that 1) diffusion-weighted MRI-derived structural connectome can complement T1-weighted MRI in the classification task; 2) the feature-rank method is effective because of the identified consistent T1-weighted MRI and network feature variables on ADNI2 and NACC. Furthermore, by comparing the top-ranked feature variables from ADNI2, NACC, and combined dataset, we concluded that cross-validation using independent cohorts is necessary and highly recommended.

%B J Alzheimers Dis %V 64 %P 149-169 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865049?dopt=Abstract %R 10.3233/JAD-171048 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Advanced Circadian Timing and Sleep Fragmentation Differentially Impact on Memory Complaint Subtype in Subjective Cognitive Decline. %A Manousakis, Jessica E %A Scovelle, Anna J %A Rajaratnam, Shantha M W %A Naismith, Sharon L %A Anderson, Clare %X

BACKGROUND: Increased sleep fragmentation and advanced circadian timing are hallmark phenotypes associated with increased age-related cognitive decline. Subjective cognitive decline (SCD) is considered a prodromal stage of neurodegeneration and dementia; however, little is known about how sleep and circadian timing impact on memory complaints in SCD.

OBJECTIVE: To determine how sleep and circadian timing impact on memory complaint subtypes in older adults with SCD.

METHODS: Twenty-five older adults with SCD (mean age = 69.97, SD = 5.33) completed the Memory Functioning Questionnaire to characterize their memory complaints. They also underwent neuropsychological assessment, and completed 1 week of at-home monitoring of sleep with actigraphy and sleep diaries. This was followed by a two-night laboratory visit with overnight polysomnography and a dim light melatonin onset assessment to measure circadian timing.

RESULTS: Advanced circadian timing was associated with greater memory complaints, specifically poorer memory of past events (r = -0.688, p = 0.002), greater perceived decline over time (r = -0.568, p = 0.022), and increased reliance on mnemonic tools (r = -0.657, p = 0.004). Increased sleep fragmentation was associated with reduced self-reported memory decline (r = 0.529, p = 0.014), and reduced concern about everyday forgetfulness (r = 0.435, p = 0.038).

CONCLUSION: Advanced circadian timing was associated with a number of subjective memory complaints and symptoms. By contrast, sleep fragmentation was linked to lowered perceptions of cognitive decline, and less concern about memory failures. As circadian disruption is apparent in both MCI and Alzheimer's disease, and plays a key role in cognitive function, our findings further support a circadian intervention as a potential therapeutic tool for cognitive decline.

%B J Alzheimers Dis %V 66 %P 565-577 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320584?dopt=Abstract %R 10.3233/JAD-180612 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Age-Dependent Changes in the Sarkosyl-Insoluble Proteome of APPSWE/PS1ΔE9 Transgenic Mice Implicate Dysfunctional Mitochondria in the Pathogenesis of Alzheimer's Disease. %A Thygesen, Camilla %A Metaxas, Athanasios %A Larsen, Martin R %A Finsen, Bente %X

BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia, is characterized by the intra- and extracellular aggregation and accumulation of proteins. The major molecular hallmark is the aggregation of amyloid-β (Aβ) and hyperphosphorylated tau proteins into plaques and tangles, respectively. Evidence points to the pre-fibrillary states of protein aggregates harboring the greatest neurotoxicity.

OBJECTIVE: This study was designed to identify and quantify pre-fibrillary protein species enriched by their insolubility in the detergent sarkosyl in the APPSWE/PS1ΔE9 (APP/PS1) transgenic mouse model of AD. Sarkosyl insoluble fractions were isolated from the brains of APP/PS1 and littermate wild type (Wt) mice to identify pre-fibrillary protein species associated with AD.

METHODS: Pre-fibrillary protein species were isolated from the brains of 3- and 24-month-old APP/PS1 and littermate Wt mice using sarkosyl extraction and subjected to quantitative proteomics analysis by the use of isobaric tags for relative and absolute quantitation (iTRAQ).

RESULTS: The sarkosyl-insoluble pre-fibrillary proteome showed differential age- and genotype-induced effects. In addition to Aβ and tau, old APP/PS1 mice showed significant enrichment in proteins in the sarkosyl fraction involved in oxidative phosphorylation and mitochondrial function.

CONCLUSION: The results of this study implicate dysfunctional mitochondria as playing a key role of Aβ- and potentially tau-induced pathological events in the APP/PS1 transgenic mouse model of AD.

%B J Alzheimers Dis %V 64 %P 1247-1259 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29991132?dopt=Abstract %R 10.3233/JAD-180197 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Age-Dependent Changes to Sphingolipid Balance in the Human Hippocampus are Gender-Specific and May Sensitize to Neurodegeneration. %A Couttas, Timothy A %A Kain, Nupur %A Tran, Collin %A Chatterton, Zac %A Kwok, John B %A Don, Anthony S %X

The greatest risk factor for developing Alzheimer's disease (AD) is aging. The major genetic risk factor for AD is the ɛ4 allele of the APOE gene, encoding the brain's major lipid transport protein, apolipoprotein E (ApoE). The research community is yet to decipher why the ApoE4 variant pre-disposes to AD, and how aging causes the disease. Studies have shown deregulated levels of sphingolipids, including decreased levels of the neuroprotective signaling lipid sphingosine 1-phosphate (S1P), and increased ceramide content, in brain tissue and serum of people with pre-clinical or very early AD. In this study we investigated whether sphingolipid levels are affected as a function of age or APOE genotype, in the hippocampus of neurologically normal subjects over the age of 65. Lipids were quantified in 80 postmortem tissue samples using liquid chromatography tandem mass spectrometry (LC-MS/MS). Sphingolipid levels were not significantly affected by the presence of one ɛ4 or ɛ2 allele. However, ceramide, sphingomyelin, and sulfatide content was very significantly correlated with age in the hippocampus of males. On the other hand, S1P, normalized to its non-phosphorylated precursor sphingosine, was inversely correlated with age in females. Our results therefore establish gender-specific differences in sphingolipid metabolism in the aging human brain. Ceramide is a pro-apoptotic lipid, and heavily implicated as a driver of insulin resistance in metabolic tissues. S1P is a neuroprotective lipid that supports glutamatergic neurotransmission. Increasing ceramide and decreasing S1P levels may contribute significantly to a pro-neurodegenerative phenotype in the aging brain.

%B J Alzheimers Dis %8 2018 Apr 11 %G eng %R 10.3233/JAD-171054 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Age-Dependent Decrease of Mitochondrial Complex II Activity in a Familial Mouse Model for Alzheimer's Disease. %A Emmerzaal, Tim L %A Rodenburg, Richard J %A Tanila, Heikki %A Verweij, Vivienne %A Kiliaan, Amanda J %A Kozicz, Tamas %X

Alzheimer's disease (AD) is a severe neurodegenerative disorder for which the exact etiology is largely unknown. An increasingly recognized and investigated notion is the pathogenic role of mitochondrial dysfunction in AD. We assessed mitochondrial oxidative-phosphorylation (OXPHOS) enzyme activities in the APPswe/PS1ΔE9 mouse model from 4.5 to 14 months of age. We show an age-dependent decrease in mitochondrial complex-II activity starting at 9 months in APP/PS1 mice. Other enzymes of the OXPHOS do not show any alterations. Since amyloid-β (Aβ) plaques are already present from 4 months of age, mitochondrial dysfunction likely occurs downstream of Aβ pathology in this mouse model.

%B J Alzheimers Dis %V 66 %P 75-82 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30248054?dopt=Abstract %R 10.3233/JAD-180337 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Age-Related Changes in the Spatial Frequency Threshold of Male and Female 3xTg-AD Mice Using OptoMotry. %A King, Jillian L %A Wong, Aimée A %A Brown, Richard E %K Aging %K Alzheimer Disease %K Animals %K Disease Models, Animal %K Female %K Humans %K Male %K Maze Learning %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Sex Characteristics %K tau Proteins %K Vision, Ocular %X

Visual impairments and retinal abnormalities occur in patients with Alzheimer's disease (AD) and in mouse models of AD. It is important to know the visual ability of mouse models of AD to ensure that age-related cognitive deficits are not confounded by visual impairments. Using OptoMotry, the spatial frequency thresholds of male and female 3xTg-AD mice did not differ from their B6129SF2 wildtype controls between 1-18 months of age, but females had higher spatial frequency thresholds than males. However, the differences were quite small, and the visual ability of all mice was comparable to that of C57BL/6 mice.

%B J Alzheimers Dis %V 62 %P 591-596 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480178?dopt=Abstract %R 10.3233/JAD-170805 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Aging without Dementia is Achievable: Current Evidence from Epidemiological Research. %A Qiu, Chengxuan %A Fratiglioni, Laura %X

Both the incidence and the prevalence of dementia increase exponentially with increasing age. This raises the question of whether dementia is an inevitable consequence of aging or whether aging without dementia is achievable. In this review article, we sought to summarize the current evidence from epidemiological and neuropathological studies that investigated this topic. Epidemiological studies have shown that dementia could be avoided even at extreme old ages (e.g., centenarians or supercentenarians). Furthermore, clinico-neuropathological studies found that nearly half of centenarians with dementia did not have sufficient brain pathology to explain their cognitive symptoms, while intermediate-to-high Alzheimer pathology was present in around one-third of very old people without dementia or cognitive impairment. This suggests that certain compensatory mechanisms (e.g., cognitive reserve or resilience) may play a role in helping people in extreme old ages escape dementia syndrome. Finally, evidence has been accumulating in recent years indicating that the incidence of dementia has declined in Europe and North America, which supports the view that the risk of dementia in late life is modifiable. Evidence has emerged that intervention strategies that promote general health, maintain vascular health, and increase cognitive reserve are likely to help preserve cognitive function till late life, thus achieving the goal of aging without dementia.

%B J Alzheimers Dis %V 62 %P 933-942 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562544?dopt=Abstract %R 10.3233/JAD-171037 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Aging-Related Calcium Dysregulation in Rat Entorhinal Neurons Homologous with the Human Entorhinal Neurons in which Alzheimer's Disease Neurofibrillary Tangles First Appear. %A Gant, John C %A Kadish, Inga %A Chen, Kuey-Chu %A Thibault, Olivier %A Blalock, Eric M %A Porter, Nada M %A Landfield, Philip W %X

Aging is the leading risk factor for idiopathic Alzheimer's disease (AD), indicating that normal aging processes promote AD and likely are present in the neurons in which AD pathogenesis originates. In AD, neurofibrillary tangles (NFTs) appear first in entorhinal cortex, implying that aging processes in entorhinal neurons promote NFT pathogenesis. Using electrophysiology and immunohistochemistry, we find pronounced aging-related Ca2 + dysregulation in rat entorhinal neurons homologous with the human neurons in which NFTs originate. Considering that humans recapitulate many aspects of animal brain aging, these results support the hypothesis that aging-related Ca2 + dysregulation occurs in human entorhinal neurons and promotes NFT pathogenesis.

%B J Alzheimers Dis %V 66 %P 1371-1378 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412490?dopt=Abstract %R 10.3233/JAD-180618 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Albuminuria and Microalbuminuria as Predictors of Cognitive Performance in a General Population: An 11-Year Follow-Up Study. %A Ekblad, Laura L %A Toppala, Sini %A Johansson, Jouni K %A Koskinen, Seppo %A Sundvall, Jouko %A Rinne, Juha O %A Puukka, Pauli %A Viitanen, Matti %A Jula, Antti %K Adult %K Aged %K Albuminuria %K Cognition %K Cognitive Dysfunction %K Creatinine %K Cross-Sectional Studies %K Female %K Finland %K Follow-Up Studies %K Humans %K Kidney %K Linear Models %K Male %K Middle Aged %K Multivariate Analysis %K Neuropsychological Tests %K Risk Factors %X

Microalbuminuria, defined as urine albumin-to-creatinine ratio (UACR)>3.0 mg/mmol and ≤ 30 mg/mmol, is an early marker of endothelial damage of the renal glomeruli. Recent research suggests an association among microalbuminuria, albuminuria (UACR > 3.0 mg/mmol), and cognitive impairment. Previous studies on microalbuminuria, albuminuria, and cognition in the middle-aged have not provided repeated cognitive testing at different time-points. We hypothesized that albuminuria (micro- plus macroalbuminuria) and microalbuminuria would predict cognitive decline independently of previously reported risk factors for cognitive decline, including cardiovascular risk factors. In addition, we hypothesized that UACR levels even below the cut-off for microalbuminuria might be associated with cognitive functioning. These hypotheses were tested in the Finnish nationwide, population-based Health 2000 Survey (n = 5,921, mean age 52.6, 55.0% women), and its follow-up, Health 2011 (n = 3,687, mean age at baseline 49.3, 55.6% women). Linear regression analysis was used to determine the associations between measures of albuminuria and cognitive performance. Cognitive functions were assessed with verbal fluency, word-list learning, word-list delayed recall (at baseline and at follow-up), and with simple and visual choice reaction time tests (at baseline only). Here, we show that micro- plus macroalbuminuria associated with poorer word-list learning and a slower reaction time at baseline, with poorer word-list learning at follow-up, and with a steeper decline in word-list learning during 11 years after multivariate adjustments. Also, higher continuous UACR consistently associated with poorer verbal fluency at levels below microalbuminuria. These results suggest that UACR might have value in evaluating the risk for cognitive decline.

%B J Alzheimers Dis %V 62 %P 635-648 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480195?dopt=Abstract %R 10.3233/JAD-170972 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Allocentric and Egocentric Spatial Processing in Middle-Aged Adults at High Risk of Late-Onset Alzheimer's Disease: The PREVENT Dementia Study. %A Ritchie, Karen %A Carrière, Isabelle %A Howett, David %A Su, Li %A Hornberger, Michael %A O'Brien, John T %A Ritchie, Craig W %A Chan, Dennis %X

Impairments in spatial processing due to hippocampal degeneration have been observed in the years immediately preceding the diagnosis of Alzheimer's disease (AD) dementia. The demonstration of changes in spatial processing in preceding decades would provide a cognitive marker for pre-clinical AD and an outcome measure for early intervention trials. The present study examined allocentric and egocentric spatial processing in relation to future dementia risk in a middle-aged cohort. The CAIDE Dementia Risk Score (DRS) was calculated for 188 persons aged 40 to 59, of whom 94 had a parent with dementia. Participants underwent the Four Mountains Test (4MT) of allocentric spatial processing, the Virtual Reality Supermarket Trolley Task (VRSTT) of egocentric spatial processing, and 3T MRI scans. A significant negative association was found between the DRS and 4MT (Spearman correlation - 0.26, p = 0.0006), but not with the VRSTT. The 4MT was also found to be a better predictor of risk than tests of episodic memory, verbal fluency, or executive functioning. The results suggest that allocentric rather than egocentric processing may be a potential indicator of risk for late-onset AD, consistent with the hypothesis that the earliest cognitive changes in AD are driven by tau-related degeneration in the medial temporal lobe rather than amyloid-only deposition in the medial parietal lobe.

%B J Alzheimers Dis %V 65 %P 885-896 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103333?dopt=Abstract %R 10.3233/JAD-180432 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alterations in Acrolein Metabolism Contribute to Alzheimer's Disease. %A Tsou, Han-Hsing %A Hsu, Wen-Chin %A Fuh, Jong-Ling %A Chen, Shih-Pin %A Liu, Tsung-Yun %A Wang, Hsiang-Tsui %K Acetylcysteine %K Acrolein %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Creatinine %K Disease Progression %K Early Diagnosis %K Female %K Humans %K Male %K Middle Aged %X

Alzheimer's disease (AD) is a detrimental neurodegenerative disease, and early diagnosis appears to be the key to successful treatment. Acrolein, a byproduct of lipid peroxidation, has been shown to contribute to the pathological process of AD. This study recruited 118 elderly subjects consisting of 58 non-demented control subjects and 62 AD patients. We analyzed the acrolein-related metabolites in the plasma, cerebrospinal fluid (CSF), and urine of all subjects. We found that the levels of acrolein-conjugated protein (Acr-PC) in the plasma (p = 0.00012) and CSF (p = 0.00161) of AD patients were significantly higher than those of control subjects, whereas the levels of a urinary acrolein metabolite, 3-hydroxypropyl mercapturic acid (3-HPMA), were markedly decreased (p = 0.00882) in AD patients. These data suggest that deregulated acrolein metabolism may be correlated with neuronal damage in AD patients, which might provide further insights into the disease progression and early diagnosis of AD.

%B J Alzheimers Dis %V 61 %P 571-580 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226874?dopt=Abstract %R 10.3233/JAD-170736 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alterations in the Plasma Levels of Specific Choline Phospholipids in Alzheimer's Disease Mimic Accelerated Aging. %A Dorninger, Fabian %A Moser, Ann B %A Kou, Jianqiu %A Wiesinger, Christoph %A Forss-Petter, Sonja %A Gleiss, Andreas %A Hinterberger, Margareta %A Jungwirth, Susanne %A Fischer, Peter %A Berger, Johannes %X

Alzheimer's disease (AD) is the most common neurodegenerative disease and of continuously rising prevalence. The identification of easy-to-measure biomarkers capable to assist in the prediction and early diagnosis of AD is currently a main research goal. Lipid metabolites in peripheral blood of human patients have recently gained major attention in this respect. Here, we analyzed plasma of 174 participants (not demented at baseline; mean age: 75.70±0.44 years) of the Vienna Transdanube Aging (VITA) study, a longitudinal, population-based birth cohort study, at baseline and after 90 months or at diagnosis of probable AD. We determined the levels of specific choline phospholipids, some of which have been suggested as potential biomarkers for the prediction of AD. Our results show that during normal aging the levels of lysophosphatidylcholine, choline plasmalogen, and lyso-platelet activating factor increase significantly. Notably, we observed similar but more pronounced changes in the group that developed probable AD. Thus, our results imply that, in terms of choline-containing plasma phospholipids, the conversion to AD mimics an accelerated aging process. We conclude that age, even in the comparatively short time frame between 75 and 82.5 years, is a crucial factor in the quest for plasma lipid biomarkers for AD that must be carefully considered in future studies and trials.

%B J Alzheimers Dis %V 62 %P 841-854 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480199?dopt=Abstract %R 10.3233/JAD-171036 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alterations of Effective Connectivity Patterns in Mild Cognitive Impairment: An MEG Study. %A Gómez, Carlos %A Juan-Cruz, Celia %A Poza, Jesús %A Ruiz-Gómez, Saúl J %A Gomez-Pilar, Javier %A Núñez, Pablo %A García, María %A Fernández, Alberto %A Hornero, Roberto %X

Neuroimaging techniques have demonstrated over the years their ability to characterize the brain abnormalities associated with different neurodegenerative diseases. Among all these techniques, magnetoencephalography (MEG) stands out by its high temporal resolution and noninvasiveness. The aim of the present study is to explore the coupling patterns of resting-state MEG activity in subjects with mild cognitive impairment (MCI). To achieve this goal, five minutes of spontaneous MEG activity were acquired with a 148-channel whole-head magnetometer from 18 MCI patients and 26 healthy controls. Inter-channel relationships were investigated by means of two complementary coupling measures: coherence and Granger causality. Coherence is a classical method of functional connectivity, while Granger causality quantifies effective (or causal) connectivity. Both measures were calculated in the five conventional frequency bands: delta (δ, 1-4 Hz), theta (θ, 4-8 Hz), alpha (α, 8-13 Hz), beta (β, 13-30 Hz), and gamma (γ, 30-45 Hz). Our results showed that connectivity values were lower for MCI patients than for controls in all frequency bands. However, only Granger causality revealed statistically significant differences between groups (p-values < 0.05, FDR corrected Mann-Whitney U-test), mainly in the beta band. Our results support the role of MCI as a disconnection syndrome, which elicits early alterations in effective connectivity patterns. These findings can be helpful to identify the neural substrates involved in prodromal stages of dementia.

%B J Alzheimers Dis %V 65 %P 843-854 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103032?dopt=Abstract %R 10.3233/JAD-170475 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Altered Expression of Circulating Cdc42 in Frontotemporal Lobar Degeneration. %A Saraceno, Claudia %A Catania, Marcella %A Paterlini, Anna %A Fostinelli, Silvia %A Ciani, Miriam %A Zanardini, Roberta %A Binetti, Giuliano %A Di Fede, Giuseppe %A Caroppo, Paola %A Benussi, Luisa %A Ghidoni, Roberta %A Bolognin, Silvia %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Case-Control Studies %K cdc42 GTP-Binding Protein %K Female %K Frontotemporal Lobar Degeneration %K Humans %K Male %K Middle Aged %X

The term frontotemporal lobar degeneration (FTLD) defines a group of heterogeneous conditions histologically characterized by neuronal degeneration, inclusions of various proteins, and synaptic loss. However, the molecular mechanisms contributing to these alterations are still unknown. As the Rho-GTPase family member Cell division cycle 42 (Cdc42) plays a key role in the regulation of actin cytoskeleton dynamics and spine formation, we investigated whether Cdc42 protein levels were altered in the disease. Cdc42 was increased in the frontal cortex of FTLD patients compared to age-matched controls, but also in Alzheimer's disease (AD) patients included in the data-set. On the other hand, the pool of circulating Cdc42 in the plasma was altered in FTLD but not in AD patients. Interestingly, the stratification of the FTLD patients according to the different clinical variants showed a specific decrease of Cdc42 expression in the behavioral subgroup. This data support a role of Cdc42 in FTLD and specifically in the behavioral variant.

%B J Alzheimers Dis %V 61 %P 1477-1483 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376863?dopt=Abstract %R 10.3233/JAD-170722 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Altered Expression of Urea Cycle Enzymes in Amyloid-β Protein Precursor Overexpressing PC12 Cells and in Sporadic Alzheimer's Disease Brain. %A Jęśko, Henryk %A Lukiw, Walter J %A Wilkaniec, Anna %A Cieślik, Magdalena %A Gąssowska-Dobrowolska, Magdalena %A Murawska, Emilia %A Hilgier, Wojciech %A Adamczyk, Agata %X

Urea cycle enzymes may play important yet poorly characterized roles in Alzheimer's disease (AD). Our previous results showed that amyloid-β (Aβ) affects urea cycle enzymes in rat pheochromocytoma (PC12) cells. The aim of the present study was to investigate the changes in arginases, other urea cycle enzymes, and nitric oxide synthases (NOSs) in PC12 cells transfected with AβPP bearing the double 'Swedish' mutation (APPsw, K670M/N671L) and in postmortem sporadic AD brain hippocampus; the mutation intensifies Aβ production and strongly associates with AD neuropathology. mRNA expression was analyzed using real-time PCR in cell cultures and DNA microarrays in hippocampal CA1 area of human AD brains. Arginase activity was measured spectrophotometrically, and arginine, ornithine, and citrulline levels by high-performance liquid chromatography. Our data demonstrated that the expression and activity of arginases (Arg1 and Arg2), as well as the expression of argininosuccinate synthase (Ass) were significantly reduced in APPsw cells compared to control. However, argininosuccinate lyase (Asl) was upregulated in APPsw cells. Real-time PCR analysis revealed significant elevation of neuronal nitric oxide synthase (Nnos) mRNA in APPsw cells, without changes in the endothelial Enos, whereas inducible Inos was undetectable. The changes were found to follow closely those observed in the human hippocampal CA1 region of sporadic AD brains. The changes in enzyme expression were accompanied in APPsw cells by significantly elevated citrulline, ornithine, and arginine. Our findings demonstrate that AβPP/Aβ alters arginine metabolism and induces a shift of cellular homeostasis that may support the oxidative/nitrosative stress observed in AD.

%B J Alzheimers Dis %V 62 %P 279-291 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439324?dopt=Abstract %R 10.3233/JAD-170427 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Altered microRNA, mRNA, and Protein Expression of Neurodegeneration-Related Biomarkers and Their Transcriptional and Epigenetic Modifiers in a Human Tau Transgenic Mouse Model in Response to Developmental Lead Exposure. %A Masoud, Anwar M %A Bihaqi, Syed W %A Alansi, Bothaina %A Dash, Miriam %A Subaiea, Gehad M %A Renehan, William E %A Zawia, Nasser H %X

Amyloid deposits originating from the amyloid-β protein precursor (AβPP) and aggregates of the microtubule associated protein tau (MAPT) are the hallmarks of Alzheimer's disease (AD). Animal studies have demonstrated a link between early life exposure to lead (Pb) and latent overexpression of the AβPP and MAPT genes and their products via epigenetic reprogramming. The present study monitored APP gene and epigenetic mediators and transcription factors known to regulate it. Western blot analysis and quantitative polymerase chain reaction (qPCR) were used to study the mRNA, miRNA, and proteins levels of AβPP, specificity protein 1 (SP1; a transcriptional regulator of amyloid and tau pathway), and epigenetic intermediates namely: DNA methyltransferase (DNMT) 1, DNMT3a and Methyl- CpG protein binding 2 (MeCP2) in the cerebral cortex of transgenic mice (Knock-in for human MAPT). These transgenic mice were developmentally exposed to Pb and the impact on mRNA, miRNA, and protein levels was scrutinized on postnatal days (PND) 20 and 50. The data revealed a consistent inverse relationship between miRNA and protein levels for SP1 and AβPP both in the basal and exposed conditions, which may influence the levels of their corresponding proteins. On the other hand, the relationship between miRNA and protein levels was not correlative for DNMT1 and DNMT3a. MeCP2 miRNA protein levels corresponded only following environmental exposure. These results suggest that developmental exposure to Pb and subsequent AβPP protein levels may be controlled through transcriptional regulators and epigenetic mechanisms that mainly involve miRNA regulation.

%B J Alzheimers Dis %V 63 %P 273-282 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614648?dopt=Abstract %R 10.3233/JAD-170824 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-β Burden in Down Syndrome. %A Lao, Patrick J %A Handen, Ben L %A Betthauser, Tobey J %A Mihaila, Iulia %A Hartley, Sigan L %A Cohen, Annie D %A Tudorascu, Dana L %A Bulova, Peter D %A Lopresti, Brian J %A Tumuluru, Rameshwari V %A Murali, Dhanabalan %A Mathis, Chester A %A Barnhart, Todd E %A Stone, Charles K %A Price, Julie C %A Devenny, Darlynne A %A Johnson, Sterling C %A Klunk, William E %A Christian, Bradley T %K Adult %K Alzheimer Disease %K Amyloid beta-Peptides %K Down Syndrome %K Female %K Fluorodeoxyglucose F18 %K Gray Matter %K Humans %K Linear Models %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Positron-Emission Tomography %K Radiopharmaceuticals %K United States %X

BACKGROUND: The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer's disease (AD).

OBJECTIVE: The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD.

METHODS: Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest.

RESULTS: Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume.

CONCLUSIONS: In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.

%B J Alzheimers Dis %V 61 %P 631-644 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254096?dopt=Abstract %R 10.3233/JAD-170720 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Amyloid-β is an Antimicrobial Peptide: A Review of the Evidence. %A Gosztyla, Maya L %A Brothers, Holly M %A Robinson, Stephen R %X

The amyloid-β (Aβ) peptide has long been considered to be the driving force behind Alzheimer's disease (AD). However, clinical trials that have successfully reduced Aβ burden in the brain have not slowed the cognitive decline, and in some instances, have resulted in adverse outcomes. While these results can be interpreted in different ways, a more nuanced picture of Aβ is emerging that takes into account the facts that the peptide is evolutionarily conserved and is present throughout life in cognitively normal individuals. Recent evidence indicates a role for Aβ as an antimicrobial peptide (AMP), a class of innate immune defense molecule that utilizes fibrillation to protect the host from a wide range of infectious agents. In humans and in animal models, infection of the brain frequently leads to increased amyloidogenic processing of the amyloid-β protein precursor (AβPP) and resultant fibrillary aggregates of Aβ. Evidence from in vitro and in vivo studies demonstrates that Aβ oligomers have potent, broad-spectrum antimicrobial properties by forming fibrils that entrap pathogens and disrupt cell membranes. Importantly, overexpression of Aβ confers increased resistance to infection from both bacteria and viruses. The antimicrobial role of Aβ may explain why increased rates of infection have been observed in some of the AD clinical trials that depleted Aβ. Perhaps progress toward a cure for AD will accelerate once treatment strategies begin to take into account the likely physiological functions of this enigmatic peptide.

%B J Alzheimers Dis %V 62 %P 1495-1506 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504537?dopt=Abstract %R 10.3233/JAD-171133 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease: A Journey from Amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies-Gains from AIBL and DIAN Cohort Studies. %A Martins, Ralph N %A Villemagne, Victor %A Sohrabi, Hamid R %A Chatterjee, Pratishtha %A Shah, Tejal M %A Verdile, Giuseppe %A Fraser, Paul %A Taddei, Kevin %A Gupta, Veer B %A Rainey-Smith, Stephanie R %A Hone, Eugene %A Pedrini, Steve %A Lim, Wei Ling %A Martins, Ian %A Frost, Shaun %A Gupta, Sunil %A O'Bryant, Sid %A Rembach, Alan %A Ames, David %A Ellis, Kathryn %A Fuller, Stephanie J %A Brown, Belinda %A Gardener, Samantha L %A Fernando, Binosha %A Bharadwaj, Prashant %A Burnham, Samantha %A Laws, Simon M %A Barron, Anna M %A Goozee, Kathryn %A Wahjoepramono, Eka J %A Asih, Prita R %A Doecke, James D %A Salvado, Olivier %A Bush, Ashley I %A Rowe, Christopher C %A Gandy, Samuel E %A Masters, Colin L %X

Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer's disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ɛ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aβ.

%B J Alzheimers Dis %V 62 %P 965-992 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562546?dopt=Abstract %R 10.3233/JAD-171145 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease: Advances in Drug Development. %A Piton, Morgane %A Hirtz, Christophe %A Desmetz, Caroline %A Milhau, Jacqueline %A Lajoix, Anne Dominique %A Bennys, Karim %A Lehmann, Sylvain %A Gabelle, Audrey %X

As of 2018, Alzheimer's disease (AD) is the most common form of neurodegenerative dementia. It contributes to a progressive neuron loss, deterioration of memory, and cognitive impairment. Current therapies may provide a symptomatic benefit, but do not treat the underlying process. Ongoing researches focus on understanding the causal mechanisms and finding neuropathological hallmarks of AD. Therapeutic approaches targeting senile plaques or neurofibrillary tangles have not yet resulted in a significant cognitive improvement. However, recent data according to the analysis of AD clinical trials (clinicaltrials.gov database) show promising results. This literature review aims at summarizing the recent advances and at highlighting the most promising results of the ongoing researches. It compares the merits of small-molecules, antibodies, cell, and gene-based therapies and emphasizes the need for treatment at earlier stages of the disease.

%B J Alzheimers Dis %V 65 %P 3-13 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040716?dopt=Abstract %R 10.3233/JAD-180145 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog): Modifications and Responsiveness in Pre-Dementia Populations. A Narrative Review. %A Kueper, Jacqueline K %A Speechley, Mark %A Montero-Odasso, Manuel %X

The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) was developed in the 1980s to assess the level of cognitive dysfunction in Alzheimer's disease. Advancements in the research field have shifted focus toward pre-dementia populations, and use of the ADAS-Cog has extended into these pre-dementia studies despite concerns about its ability to detect important changes at these milder stages of disease progression. If the ADAS-Cog cannot detect important changes, our understanding of pre-dementia disease progression may be compromised and trials may incorrectly conclude that a novel treatment approach is not beneficial. The purpose of this review was to assess the performance of the ADAS-Cog in pre-dementia populations, and to review all modifications that have been made to the ADAS-Cog to improve its measurement performance in dementia or pre-dementia populations. The contents of this review are based on bibliographic searches of electronic databases to locate all studies using the ADAS-Cog in pre-dementia samples or subsamples, and to locate all modified versions. Citations from relevant articles were also consulted. Overall, our results suggest the original ADAS-Cog is not an optimal outcome measure for pre-dementia studies; however, given the prominence of the ADAS-Cog, care must be taken when considering the use of alternative outcome measures. Thirty-one modified versions of the ADAS-Cog were found. Modification approaches that appear most beneficial include altering scoring methodology or adding tests of memory, executive function, and/or daily functioning. Although modifications improve the performance of the ADAS-Cog, this is at the cost of introducing heterogeneity that may limit between-study comparison.

%B J Alzheimers Dis %V 63 %P 423-444 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660938?dopt=Abstract %R 10.3233/JAD-170991 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease Biomarkers Have Distinct Associations with Specific Hippocampal Subfield Volumes. %A Müller-Ehrenberg, Lisa %A Riphagen, Joost M %A Verhey, Frans R J %A Sack, Alexander T %A Jacobs, Heidi I L %X

Measures of amyloid-β (Aβ) and phosphorylated tau (p-tau) concentrations in cerebrospinal fluid are extensively used for diagnostic and research purposes in Alzheimer's disease (AD) as correlates of cortical thinning and cognitive outcomes. The present study investigated the relationship of Aβ and p-tau with hippocampal subfield volumes Cornu Ammonis (CA) 1-4, dentate gyrus (DG), and subiculum. Subfields were segmented from T1-weighted images from the ADNI-population using FreeSurfer v6. Linear and polynomial regression models revealed distinct associations of Aβ and p-tau with subfield volumes. Aβ had a quadratic relationship with all hippocampal subfield volumes and the inflection point was higher than the validated cut-off for Aβ. For p-tau the relationships were linear, except for CA3, in which it was quadratic. For the CA1 and CA3, these quadratic relationships with Aβ were only observed when p-tau was low. Amyloid and p-tau contributed equally to the explained variance in CA4 and DG volume. Subicular volume was best explained by Aβ alone. These biomarker relationships with hippocampal subfield volumes seem to mirror the hippocampal-specific topography of Aβ and tau reported in neuropathological staging models. In addition, using continuous values of Aβ reveals positive patterns with imaging markers for individuals around the positivity threshold that would be masked when using dichotomized biomarker groups, which can be important for early detection and accurate inclusion of potential participants at risk for AD in clinical trials.

%B J Alzheimers Dis %V 66 %P 811-823 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320590?dopt=Abstract %R 10.3233/JAD-180676 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease Can Be Spared by Nonsteroidal Anti-Inflammatory Drugs. %A McGeer, Patrick L %A Guo, Jian Ping %A Lee, Moonhee %A Kennedy, Krista %A McGeer, Edith G %X

Alzheimer's disease (AD) is characterized by deposits of amyloid-β protein (Aβ) in brain which become foci of inflammation. Neurons are destroyed by this inflammatory process, leading to the cognitive deficits which define AD clinical onset. Epidemiological studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) can ameliorate this destructive process if they are started well before clinical signs develop. Biomarker studies indicate that the disease process starts at least a decade before cognitive deficits appear. This pre-clinical onset explains the NSAID effect. It also opens a window of opportunity for preventive treatment that can be met with a simple diagnostic test. Salivary levels of Aβ42 may fulfill that need. They can be measured by a simple ELISA test we have developed using commercially available reagents. By this ELISA test, normal controls, who are not at risk for AD, have levels of Aβ42 close to 20 pg/ml. AD cases, as well as high level controls, secrete levels in the range of 40-85 pg/ml. Widespread application of this test to detect high level controls, followed by NSAID consumption, could substantially reduce the prevalence of AD.

%B J Alzheimers Dis %V 62 %P 1219-1222 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103042?dopt=Abstract %R 10.3233/JAD-170706 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease Computer-Aided Diagnosis: Histogram-Based Analysis of Regional MRI Volumes for Feature Selection and Classification. %A Ruiz, Elena %A Ramírez, Javier %A Górriz, Juan Manuel %A Casillas, Jorge %X

This paper proposes a novel fully automatic computer-aided diagnosis (CAD) system for the early detection of Alzheimer's disease (AD) based on supervised machine learning methods. The novelty of the approach, which is based on histogram analysis, is twofold: 1) a feature extraction process that aims to detect differences in brain regions of interest (ROIs) relevant for the recognition of subjects with AD and 2) an original greedy algorithm that predicts the severity of the effects of AD on these regions. This algorithm takes account of the progressive nature of AD that affects the brain structure with different levels of severity, i.e., the loss of gray matter in AD is found first in memory-related areas of the brain such as the hippocampus. Moreover, the proposed feature extraction process generates a reduced set of attributes which allows the use of general-purpose classification machine learning algorithms. In particular, the proposed feature extraction approach assesses the ROI image separability between classes in order to identify the ones with greater discriminant power. These regions will have the highest influence in the classification decision at the final stage. Several experiments were carried out on segmented magnetic resonance images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) in order to show the benefits of the overall method. The proposed CAD system achieved competitive classification results in a highly efficient and straightforward way.

%B J Alzheimers Dis %V 65 %P 819-842 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966190?dopt=Abstract %R 10.3233/JAD-170514 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease in Systemic Sclerosis Patients: A Nationwide Population-Based Cohort Study. %A Watad, Abdulla %A Bragazzi, Nicola L %A Tiosano, Shmuel %A Yavne, Yarden %A Comaneshter, Doron %A Cohen, Arnon D %A Amital, Howard %X

BACKGROUND: Neurological features are often overlooked in systemic sclerosis (SSc) patients and little is known about the link between dementia and SSc.

OBJECTIVES: We sought to investigate whether an association exists between Alzheimer's disease (AD) and SSc, as well as assess the impact of a dual diagnosis on mortality rates, by performing an extensive data analysis on a large subject sample.

METHODS: We utilized the medical database of the Clalit-Health-Services in a case-control study. Patients with SSc were compared with age- and sex-matched controls with regard to the prevalence of AD and its impact on their mortality.

RESULTS: Our study included 2,431 SSc patients and 12,377 age- and sex-matched controls. The mean age of the study population was 63.32±18.06 years and the female to male ratio was 4.5:1. 134 (5.5%) cases had AD as a co-morbidity in comparison with 749 (5.9%) of the controls. The mortality rate was 12.5% among controls and 26.2% among SSc cases. On the Cox multivariate survival analysis, diagnosis of SSc and AD demonstrated significant HRs (2.35 (95% CI 2.05-2.69, p < 0.0001) and 2.19 (95% CI 1.94-2.48, p < 0.0001), respectively). SSc patients with AD had a relative risk of death of 2.35 (95% CI: 1.44-3.83) in comparison with SSc patients without AD.

CONCLUSION: AD is a predictor of death in SSc and therefore preemptive screening may be warranted. Further studies are needed to evaluate whether improvements in the medical regimen for SSc may lead to a reduction in AD development and possibly to increased survival as well.

%B J Alzheimers Dis %V 65 %P 117-124 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040736?dopt=Abstract %R 10.3233/JAD-180516 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease, Oligomers, and Inflammation. %A Forloni, Gianluigi %A Balducci, Claudia %X

The production of soluble amyloid-β oligomers (AβOs) and the activation of inflammation are two important early steps in the pathogenesis of Alzheimer's disease (AD). The central role of oligomers as responsible for the neuronal dysfunction associated with the clinical features has been extended to the other protein misfolding disorders definable, on this basis, as oligomeropathies. In AD, recent evidence indicates that the mechanism of inflammation as a consequence of neurodegeneration must be assessed in favor of a more direct role of glial activation in the alteration of synaptic function. Our own experimental models demonstrate the efficacy of anti-inflammatory treatments in preventing the cognitive deficits induced acutely by AβOs applied directly in the brain. Moreover, some promising clinical tools are based on immunological activation reducing the presence of cerebral Aβ deposits. However, the strategies based on the control of inflammatory factors as well as the amyloid aggregation show poor or non-therapeutic efficacy. Numerous studies have examined inflammatory factors in biological fluids as possible markers of the neuroinflammation in AD. In some cases, altered levels of cytokines or other inflammatory markers in cerebrospinal fluid correlate with the severity of the disease. Here we propose, according to the precision medicine principles, innovative therapeutic approaches to AD based on the patient's inflammatory profile/state. The earlier intervention and a multifactor approach are two other elements considered essential to improve the chances of effective therapy in AD.

%B J Alzheimers Dis %V 62 %P 1261-1276 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562537?dopt=Abstract %R 10.3233/JAD-170819 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease Progression: Factors Influencing Cognitive Decline. %A Ferrari, Camilla %A Lombardi, Gemma %A Polito, Cristina %A Lucidi, Giulia %A Bagnoli, Silvia %A Piaceri, Irene %A Nacmias, Benedetta %A Berti, Valentina %A Rizzuto, Debora %A Fratiglioni, Laura %A Sorbi, Sandro %K Aged %K Aged, 80 and over %K Alleles %K Alzheimer Disease %K Apolipoprotein E4 %K Aspirin %K Cognitive Dysfunction %K Disease Progression %K Female %K Heterozygote %K Humans %K Italy %K Male %K Middle Aged %K Neuropsychological Tests %K Retrospective Studies %K Secondary Prevention %X

BACKGROUND: Alzheimer's disease (AD) patients present high variability in the rate of cognitive decline. Despite the wide knowledge on factors influencing dementia risk, little is known on what accounts for AD progression. Previous studies on this topic have mainly analyzed each factor separately without taking into account the interaction between genetic and non-genetic factors.

OBJECTIVE: The aim of the present study is to evaluate the role of demographic, clinical, therapeutic, and genetic factors and their interaction on cognitive decline among newly diagnosed AD patients.

METHODS: We retrospectively selected 160 AD patients diagnosed at the Neurology Unit of Careggi University Hospital of Florence. We evaluated the occurrence of rapid cognitive changes defined as the worsening of more than four points at the Mini-Mental State Examination after 2-year follow up period.

RESULTS: Among the 160 AD patients, 50% presented rapid disease progression. Extrapyramidal signs at disease onset were predictors of worse outcome (OR 2.2), especially among Apolipoprotein E (APOE) ɛ4 allele carriers, while the presence of family history for dementia decreased the risk of rapid progression by about 50%. Higher educated ɛ4-carriers showed a slower AD progression. We identified the chronic use of aspirin as potential secondary preventative strategy for the non ɛ4-carriers.

CONCLUSION: At dementia onset, some clinical and demographic data can be predictors of future progression. The outcomes of the present study support the already hypothesized interaction between genetic and non-genetic factors during disease course and suggest genetic-based approaches.

%B J Alzheimers Dis %V 61 %P 785-791 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226870?dopt=Abstract %R 10.3233/JAD-170665 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines. %A Zádori, Dénes %A Veres, Gábor %A Szalárdy, Levente %A Klivenyi, Peter %A Vecsei, Laszlo %K Alzheimer Disease %K Animals %K Central Nervous System %K Disease Models, Animal %K Energy Metabolism %K Glutamic Acid %K Humans %K Immunity, Innate %K Inflammation %K Kynurenine %K Mitochondria %K Quinolinic Acid %K Reactive Oxygen Species %K Receptors, Glutamate %K Signal Transduction %X

The pathomechanism of Alzheimer's disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport, act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. Neuroinflammation in AD is predominantly linked to central players of the innate immune system, with central nervous system (CNS)-resident microglia, astroglia, and perivascular macrophages having been implicated at the cellular level. Several abnormalities have been described regarding the activation of certain steps of the kynurenine (KYN) pathway of tryptophan metabolism in AD. First of all, the activation of indolamine 2,3-dioxygenase, the first and rate-limiting step of the pathway, is well-demonstrated. 3-Hydroxy-L-KYN and its metabolite, 3-hydroxy-anthranilic acid have pro-oxidant, antioxidant, and potent immunomodulatory features, giving relevance to their alterations in AD. Another metabolite, quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathway-related alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options.

%B J Alzheimers Dis %V 62 %P 523-547 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480191?dopt=Abstract %R 10.3233/JAD-170929 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease rs11767557 Variant Regulates EPHA1 Gene Expression Specifically in Human Whole Blood. %A Liu, Guiyou %A Zhang, Yan %A Wang, Longcai %A Xu, Jianyong %A Chen, Xiaoyun %A Bao, Yunjuan %A Hu, Yang %A Jin, Shuilin %A Tian, Rui %A Bai, Weiyang %A Zhou, Wenyang %A Wang, Tao %A Han, Zhifa %A Zong, Jian %A Jiang, Qinghua %K Alzheimer Disease %K Case-Control Studies %K China %K Gene Expression %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %K Receptor, EphA1 %K Risk Assessment %X

Large-scale genome-wide association studies have reported EPHA1 rs11767557 variant to be associated with Alzheimer's disease (AD) risk in the European population. However, it is still unclear how this variant functionally contributes to the underlying disease pathogenesis. The rs11767557 variant is located approximately 3 kb upstream of EPHA1 gene. We think that rs11767557 may modify the expression of nearby genes such as EPHA1 and further cause AD risk. Until now, the potential association between rs11767557 and the expression of nearby genes has not been reported in previous studies. Here, we evaluate the potential expression association between rs11767557 and EPHA1 using multiple large-scale eQTLs datasets in human brain tissues and the whole blood. The results show that rs11767557 variant could significantly regulate EPHA1 gene expression specifically in human whole blood. These findings may further provide important supplementary information about the regulating mechanisms of rs11767557 variant in AD risk.

%B J Alzheimers Dis %V 61 %P 1077-1088 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332039?dopt=Abstract %R 10.3233/JAD-170468 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease, Visual Search, and Instrumental Activities of Daily Living: A Review and a New Perspective on Attention and Eye Movements. %A Ramzaoui, Hanane %A Faure, Sylvane %A Spotorno, Sara %X

Many instrumental activities of daily living (IADLs), like cooking and managing finances and medications, involve finding efficiently and in a timely manner one or several objects within complex environments. They may thus be disrupted by visual search deficits. These deficits, present in Alzheimer's disease (AD) from its early stages, arise from impairments in multiple attentional and memory mechanisms. A growing body of research on visual search in AD has examined several factors underlying search impairments in simple arrays. Little is known about how AD patients search in real-world scenes and in real settings, and about how such impairments affect patients' functional autonomy. Here, we review studies on visuospatial attention and visual search in AD. We then consider why analysis of patients' oculomotor behavior is promising to improve understanding of the specific search deficits in AD, and of their role in impairing IADL performance. We also highlight why paradigms developed in research on real-world scenes and real settings in healthy individuals are valuable to investigate visual search in AD. Finally, we indicate future research directions that may offer new insights to improve visual search abilities and autonomy in AD patients.

%B J Alzheimers Dis %V 66 %P 901-925 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400086?dopt=Abstract %R 10.3233/JAD-180043 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Amsterdam Dementia Cohort: Performing Research to Optimize Care. %A van der Flier, Wiesje M %A Scheltens, Philip %X

The Alzheimer center of the VU University Medical Center opened in 2000 and was initiated to combine both patient care and research. Together, to date, all patients forming the Amsterdam Dementia Cohort number almost 6,000 individuals. In this cohort profile, we provide an overview of the results produced based on the Amsterdam Dementia Cohort. We describe the main results over the years in each of these research lines: 1) early diagnosis, 2) heterogeneity, and 3) vascular factors. Among the most important research efforts that have also impacted patients' lives and/or the research field, we count the development of novel, easy to use diagnostic measures such as visual rating scales for MRI and the Amsterdam IADL Questionnaire, insight in different subgroups of AD, and findings on incidence and clinical sequelae of microbleeds. Finally, we describe in the outlook how our research endeavors have improved the lives of our patients.

%B J Alzheimers Dis %V 62 %P 1091-1111 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562540?dopt=Abstract %R 10.3233/JAD-170850 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Amyloid Accumulation and Cognitive Decline in Clinically Normal Older Individuals: Implications for Aging and Early Alzheimer's Disease. %A Mormino, Elizabeth C %A Papp, Kathryn V %X

 The aberrant accumulation of the amyloid protein is a critical and early event in the Alzheimer's disease (AD) cascade. Given the early involvement of this pathological process, it is not surprising that many clinically normal (CN) older individuals demonstrate evidence of abnormal Aβ at postmortem examination and in vivo using either CSF or PET imaging. Converging evidence across multiple research groups suggests that the presence of abnormal Aβ among CN individuals is associated with elevated risk of future clinical impairment and cognitive decline. Amyloid positivity in conjunction with biomarkers of neuronal injury offers further insight into which CN are most at risk for short-term decline. Although in its infancy, tau PET has demonstrated early increases among Aβ+ that will likely be an important indicator of risk among CN. Overall, the detection of early Aβ among CN individuals has provided an important opportunity to understand the contributions of this pathology to age-related cognitive decline and to explore early intervention with disease modifying strategies.

%B J Alzheimers Dis %V 64 %P S633-S646 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782318?dopt=Abstract %R 10.3233/JAD-179928 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Amyloid and FDG PET of Successful Cognitive Aging: Global and Cingulate-Specific Differences. %A Baran, Timothy M %A Lin, Feng Vankee %X

BACKGROUND: Some individuals, called Supernormals (SN), maintain excellent memory in old age. While brain structural and functional integrity in SN seem to be aging-resistant, their amyloidosis and neural injury status has not been well studied.

OBJECTIVE: The goal of this study was to compare cortical amyloid deposition and glucose metabolism between SN and older adults with normal cognition (NC), amnestic mild cognitive impairment (MCI), and Alzheimer's disease (AD).

METHODS: Subjects from the ADNI database were included if they received T1-weighted MRI, amyloid PET, FDG-PET, and cognitive testing within a 6-month period, yielding 27 AD, 69 MCI, 172 NC, and 122 SN. PET standardized uptake value ratios (SUVrs) were calculated for the whole cortex and 68 regions of interest, with whole cerebellum serving as reference.

RESULTS: SN had lower whole cortex amyloid than MCI, and higher glucose metabolism than all others. Regional analysis revealed that amyloid burden and glucose metabolism in the right isthmus cingulate cortex differed in SN compared to others, while SN glucose metabolism also differed from others in several frontal and temporal regions.

CONCLUSION: Preserved cortical glucose metabolism, and lower levels of amyloidosis and glucose hypometabolism in the right isthmus cingulate cortex, contributes to the Supernormal phenomenon. These findings may be informative for development of early screening biomarkers and therapeutic targets for modification of cognitive trajectories.

%B J Alzheimers Dis %V 66 %P 307-318 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282358?dopt=Abstract %R 10.3233/JAD-180360 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Amyloid-Mediated Cholinergic Dysfunction in Motor Impairment Related to Alzheimer's Disease. %A Schirinzi, Tommaso %A Di Lorenzo, Francesco %A Sancesario, Giulia Maria %A Di Lazzaro, Giulia %A Ponzo, Viviana %A Pisani, Antonio %A Mercuri, Nicola Biagio %A Koch, Giacomo %A Martorana, Alessandro %X

BACKGROUND: Although motor disturbances parallel the course of dementia, worsening both quality of life and social costs, the pathogenesis remains still unclear.

OBJECTIVE: Through the combination of cerebrospinal fluid (CSF) biomarkers assessment and transcranial magnetic stimulation (TMS) protocols, here we provided a cross-sectional study to understand pathogenic mechanisms of Alzheimer's disease (AD)-related early motor disturbances.

METHODS: The motor phenotype, as defined with Unified Parkinson's Disease Rating Scale (UPDRS) part 2-3, Rating Scale for Gait Evaluation in Cognitive Deterioration (RSEGCD) and Tinetti scale, together with CSF profile of amyloid-β 42 (Aβ42), total-tau, and phosphorylated-tau were determined in 37 AD patients and compared to 18 patients with vascular dementia (VaD). A TMS protocol of short afferent inhibition (SAI) was further applied on a subset of AD patients. Clinical, biochemical, and neurophysiological data were then compared and correlated in order to find significant associations.

RESULTS: AD patients exhibited subtle locomotor impairment and slight extrapyramidal signs. Main motor features (UPDRS part 3, RSGECD, and Tinetti scale scores) correlate with Aβ42 levels but not with t-tau and p-tau. AD patients also presented SAI impairment directly related to UPDRS part 3 score and Aβ42 levels. Motor disturbances of VaD group did not differ statistically from AD and did not correlate with CSF biomarkers.

CONCLUSIONS: The association of motor disturbances with low Aβ42 CSF levels and individual SAI suggests that amyloid-mediated degeneration of cholinergic system may account for early AD-related motor impairment, providing interesting insights either for frailty stratification of patients or personalized therapies.

%B J Alzheimers Dis %V 64 %P 525-532 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914023?dopt=Abstract %R 10.3233/JAD-171166 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Amyloid-β and Tau in Alzheimer's Disease: Novel Pathomechanisms and Non-Pharmacological Treatment Strategies. %A Nisbet, Rebecca M %A Götz, Jürgen %X

Accumulation of the peptide amyloid-β (Aβ) and the protein tau in Alzheimer's disease (AD) brains is a gradual process that involves the post-translational modification and assembly of monomeric forms into larger structures that eventually form fibrillar inclusions. This process is thought to both drive and initiate AD. However, why the axonally enriched tau in the course of AD accumulates in the somatodendritic domain is not fully understood. We discuss new data that provide a possible explanation that involves de novo protein synthesis, induced by Aβ and mediated through the kinase Fyn. We further discuss how in a pathological state, tau, being a scaffolding protein, impairs nuclear and mitochondrial functions and reduces action potential generation at the axon initial segment. Pathological tau can further be packaged into exosomes, released by one neuron and taken up by another, contributing to its pathogenicity. We also present our new work that suggests ultrasound as a new treatment modality to clear pathological Aβ and tau. We put this work into perspective, discussing current vaccination strategies and improved brain delivery methods involving antibody engineering and viral approaches. We propose that rather than reducing post-translational modifications of tau, its levels and de novo synthesis need to be reduced. We anticipate a surge in combinatorial strategies, simultaneously targeting multiple pathologies, and an improved drug delivery to the brain facilitated by emerging technologies such as ultrasound.

%B J Alzheimers Dis %V 64 %P S517-S527 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562514?dopt=Abstract %R 10.3233/JAD-179907 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Amyloid-β Induces AMPA Receptor Ubiquitination and Degradation in Primary Neurons and Human Brains of Alzheimer's Disease. %A Zhang, Yanmin %A Guo, Ouyang %A Huo, Yuda %A Wang, Guan %A Man, Heng-Ye %X

As the primary mediator for synaptic transmission, AMPA receptors (AMPARs) are crucial for synaptic plasticity and higher brain functions. A downregulation of AMPAR expression has been indicated as one of the early pathological molecular alterations in Alzheimer's disease (AD), presumably via amyloid-β (Aβ). However, the molecular mechanisms leading to the loss of AMPARs remain less clear. We report that in primary neurons, application of Aβ triggers AMPAR internalization accompanied with a decrease in cell-surface AMPAR expression. Importantly, in both Aβ-treated neurons and human brain tissue from AD patients, we observed a significant decrease in total AMPAR amount and an enhancement in AMPAR ubiquitination. Consistent with facilitated receptor degradation, AMPARs show higher turnover rates in the presence of Aβ. Furthermore, AD brain lysates and Aβ-incubated neurons show increased expression of the AMPAR E3 ligase Nedd4 and decreased expression of AMPAR deubiquitinase USP46. Changes in these enzymes are responsible for the Aβ-dependent AMPAR reduction. These findings indicate that AMPAR ubiquitination acts as the key molecular event leading to the loss of AMPARs and thus suppressed synaptic transmission in AD.

%B J Alzheimers Dis %V 62 %P 1789-1801 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614651?dopt=Abstract %R 10.3233/JAD-170879 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade. %A Cline, Erika N %A Bicca, Maíra Assunção %A Viola, Kirsten L %A Klein, William L %X

The amyloid-β oligomer (AβO) hypothesis was introduced in 1998. It proposed that the brain damage leading to Alzheimer's disease (AD) was instigated by soluble, ligand-like AβOs. This hypothesis was based on the discovery that fibril-free synthetic preparations of AβOs were potent CNS neurotoxins that rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death (Lambert et al., 1998). The mechanism was attributed to disrupted signaling involving the tyrosine-protein kinase Fyn, mediated by an unknown toxin receptor. Over 4,000 articles concerning AβOs have been published since then, including more than 400 reviews. AβOs have been shown to accumulate in an AD-dependent manner in human and animal model brain tissue and, experimentally, to impair learning and memory and instigate major facets of AD neuropathology, including tau pathology, synapse deterioration and loss, inflammation, and oxidative damage. As reviewed by Hayden and Teplow in 2013, the AβO hypothesis "has all but supplanted the amyloid cascade." Despite the emerging understanding of the role played by AβOs in AD pathogenesis, AβOs have not yet received the clinical attention given to amyloid plaques, which have been at the core of major attempts at therapeutics and diagnostics but are no longer regarded as the most pathogenic form of Aβ. However, if the momentum of AβO research continues, particularly efforts to elucidate key aspects of structure, a clear path to a successful disease modifying therapy can be envisioned. Ensuring that lessons learned from recent, late-stage clinical failures are applied appropriately throughout therapeutic development will further enable the likelihood of a successful therapy in the near-term.

%B J Alzheimers Dis %V 64 %P S567-S610 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843241?dopt=Abstract %R 10.3233/JAD-179941 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Amyloid-β25-35 Upregulates Endogenous Neuroprotectant Neuroglobin via NFκB Activation in vitro. %A Liu, Ning %A Yu, Zhanyang %A Xun, Yu %A Shu, Pan %A Yue, Yiwei %A Yuan, Shishan %A Jiang, Yinghua %A Huang, Zixuan %A Yang, Xiaoping %A Feng, Xing %A Xiang, Shuanglin %A Wang, Xiaoying %X

Neuroglobin (Ngb) has been reported to be increased in early and moderately advanced Alzheimer's disease (AD) stages but declined in the severe stage. However, its regulatory mechanisms and pathophysiological roles in the disease remain to be defined. In this study, we found that Ngb expression was significantly upregulated by low dose Aβ25-35, the neurotoxic fragment of Aβ1 - 40 and Aβ1 - 42, but was not further increased by a higher dose of Aβ25-35. Mutation analysis and supershift assay demonstrated that transcription factor Nuclear Factor κB (NFκB), κB2 and κB3 sites located in mouse Ngb promoter region were involved in dynamic regulation of Ngb expression in response to different doses of Aβ25-35 stimulation. In addition, we found that suppression of endogenous Ngb expression exacerbated Aβ25-35-induced neuronal cell death and mitochondrial dysfunction. Our results indicate that endogenous Ngb expression may be upregulated by low dose Aβ25-35, which is responsible for protecting against Aβ25-35-mediated neurotoxicity. These experimental findings suggest that upregulation of endogenous Ngb expression might be an effective intervention approach for AD.

%B J Alzheimers Dis %V 64 %P 1163-1174 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010125?dopt=Abstract %R 10.3233/JAD-180163 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Amyloid-β/Drug Interactions from Computer Simulations and Cell-Based Assays. %A Nguyen, Phuong H %A Del Castillo-Frias, Maria P %A Berthoumieux, Olivia %A Faller, Peter %A Doig, Andrew J %A Derreumaux, Philippe %X

Targeting the early oligomers formed by the amyloid-β (Aβ) peptide of 40 and 42 amino acids is considered one promising therapeutic approach for Alzheimer's disease (AD). In vitro experiments and computer simulations are often used in synergy to reveal the modes of interactions of drugs. In this account, we present our contribution to understanding how small molecules bind to Aβ40/Aβ42 peptides, based either on extensive coarse-grained and all-atom simulations, or a variety of experimental techniques. We conclude by offering several perspectives on the future of this field to design more efficient drugs.

%B J Alzheimers Dis %V 64 %P S659-S672 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562512?dopt=Abstract %R 10.3233/JAD-179902 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Analyses of Clinical Features and Investigations on Potential Mechanisms in Patients with Alzheimer's Disease and Olfactory Dysfunction. %A Zuo, Li-Jun %A Guo, Peng %A Liu, Li %A Yu, Shu-Yang %A Lian, Teng-Hong %A Yu, Qiu-Jin %A Hu, Yang %A Jin, Zhao %A Wang, Rui-Dan %A Piao, Ying-Shan %A Li, Li-Xia %A Wang, Ya-Jie %A Wang, Xiao-Min %A Zhang, Wei %X

BACKGROUND: OD is common in patients with Alzheimer's disease (AD). However, the relationship between OD and clinical symptoms and the potential mechanisms of OD in AD patients are still unknown.

OBJECTIVE: To explore the relationship between OD and clinical symptoms and the potential mechanisms of OD in AD patients.

METHODS: We evaluated OD using the Hyposmia Rating Scale (HRS), classified patients into AD with OD (AD-OD) and AD with no OD (AD-NOD) groups, and detected the levels of free radicals and inflammatory factors, including hydroxyl radical (•OH), hydrogen peroxide (H2O2), nitric oxide, interleukin-1β, interleukin-6, tumor necrosis factor-α, and prostaglandin E2 in serum from AD patients.

RESULTS: It was shown that the scores of the Mini-Mental State Examination, Animal Fluency Test, Boston Naming Test (BNT), and Auditory Verbal Learning Test-delayed recall were all significantly lower and the score of overall activity of daily living (ADL) and instrumental ADL were significantly higher in AD-OD group than those in AD-NOD group. Compared with AD-NOD group, •OH level in serum was prominently elevated, and H2O2 level was dramatically declined in AD-OD group. In the correlation analysis, HRS score was significantly and positively correlated with the score of BNT, and negatively correlated with •OH level in serum.

CONCLUSIONS: AD-OD patients suffered from severe cognitive impairment in the domain of language. Oxidative stress might be correlated with AD-OD featured by the drastically increased •OH level in serum.

%B J Alzheimers Dis %V 66 %P 789-799 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30347619?dopt=Abstract %R 10.3233/JAD-180425 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Analysis of Brain Donors' Demographic and Medical Characteristics to Facilitate the Construction of a Human Brain Bank in China. %A Zhang, Hanlin %A Chen, Kang %A Wang, Naili %A Zhang, Di %A Yang, Qian %A Zhang, Qing %A Liu, Pan %A Wan, Mengyao %A Gong, Changlin %A Hong, Xinyu %A Qiu, Wenying %A Qian, Xiaojing %A Chen, Yongmei %A Ma, Chao %X

The Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS/PUMC) Human Brain Bank was established in December 2012 and had accomplished 197 brain donations by November 2017. The brain bank was based on a large-scale willed body donation program in CAMS/PUMC starting from 1999. Demographic and medical characteristic analysis of brain donors was conducted to facilitate the construction of the brain bank. The average postmortem delay of brain donors was 17.7 h and 77.7% of these donors died less than 15 km away from the brain bank. Donors were predominantly with higher-level education (p < 0.001) and at an older age when registration (p < 0.001) and donation (p < 0.001) occurred. Our results elucidated the characteristics of donors in the CAMS/PUMC Human Brain Bank, which may provide useful information to target potential donors and improve the quality and quantity of brain specimens. The current study may pave the way for the construction of a nationwide network of standardized human brain banks in China.

%B J Alzheimers Dis %V 66 %P 1245-1254 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412500?dopt=Abstract %R 10.3233/JAD-180779 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Antemortem-Postmortem Correlation of Florbetapir (18F) PET Amyloid Imaging with Quantitative Biochemical Measures of Aβ42 but not Aβ40. %A Beach, Thomas G %A Maarouf, Chera L %A Intorcia, Anthony %A Sue, Lucia I %A Serrano, Geidy E %A Lu, Ming %A Joshi, Abhinay %A Pontecorvo, Michael J %A Roher, Alex E %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloidosis %K Aniline Compounds %K Autopsy %K Brain %K Ethylene Glycols %K Humans %K Linear Models %K Peptide Fragments %K Plaque, Amyloid %K Positron-Emission Tomography %X

Amyloid imaging demonstrates the in vivo presence of amyloid-β (Aβ) deposits in the aging human brain but it is still unknown which structural forms and modifications of Aβ are detected. In Alzheimer's disease, most amyloid deposits are predominantly composed of Aβ ending at amino acid residues Val40 or Ala42. It has been reported that Aβ40 is largely restricted to neuritic plaques while Aβ42 may be deposited in amyloid plaques of all types, and is often the sole component of diffuse plaques. The distinction is important as it is mainly the neuritic plaques that correlate with cognitive impairment while diffuse plaques may be the initial type of Aβ deposited. Whether PET amyloid ligands such as florbetapir-18F (Amyvid) are partially or wholly selective for brain deposits of Aβ40 or Aβ42 is currently unknown. We compared antemortem florbetapir PET cortical/cerebellar signal intensity (SUVr) of 55 subjects with postmortem biochemical (ELISA) measurements employing specific antibodies against Aβ40 and Aβ42. Spearman's univariable correlations were significant for both Aβ40 and Aβ42, but were much stronger for Aβ42. Multiple linear regression showed significance only for Aβ42. These results suggest that florbetapir binds only weakly, if at all, to Aβ40. This may be in part due to the higher likelihood for Aβ42 to be present in a β-pleated sheet tertiary structure, or to differences between Aβ40 and Aβ42 in β-pleated sheet tertiary or quaternary structure.

%B J Alzheimers Dis %V 61 %P 1509-1516 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376867?dopt=Abstract %R 10.3233/JAD-170762 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Antibodies to Multiple Receptors are Associated with Neuropsychiatric Symptoms and Mortality in Alzheimer's Disease: A Longitudinal Study. %A Giil, Lasse M %A Aarsland, Dag %A Hellton, Kristoffer %A Lund, Anders %A Heidecke, Harald %A Schulze-Forster, Kai %A Riemekasten, Gabriela %A Vik-Mo, Audun Osland %A Kristoffersen, Einar K %A Vedeler, Christian A %A Nordrehaug, Jan Erik %X

BACKGROUND: Endogenous antibodies to signaling molecules and receptors (Abs) are associated with Alzheimer's disease (AD).

OBJECTIVES: To investigate the association of 33 Abs to dopaminergic, serotoninergic, muscarinic, adrenergic, vascular, and immune receptors with cognitive, neuropsychiatric, and mortality outcomes.

METHODS: Ninety-one patients with mild AD were followed annually for 5 years with the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI; composite outcomes: "psychosis" (item 1 + 2), "mood" (item 4 + 5 + 7), and "agitation" (item 3 + 8 + 9)). Abs were quantified in sera obtained at baseline by ELISA and reduced to principal components (PCs). Associations between Abs and outcomes were assessed by a mixed model (MMSE decline), zero-inflated fixed effects count models (composite NPI scores), and Cox regression (mortality). The resulting p-values were adjusted for multiple testing according to a false discovery rate of 0.05 (Benjamini-Hochberg).

RESULTS: The measured levels of the 33 Abs formed four PCs. PC1 (dopaminergic and serotonergic Abs) was associated with increased mortality (Hazard ratio 2.57, p < 0.001), PC2 (serotonergic, immune, and vascular Abs) with decreased agitation symptoms (β - 0.19, p < 0.001), and PC3 (cholinergic receptor Abs) with increased mood symptoms (β 0.04, p = 0.002), over time. There were no associations between Abs and MMSE decline.

CONCLUSION: The associations between Abs, mortality, and neuropsychiatric symptoms reported in this cohort are intriguing. They cannot, however, be generalized. Validation in independent sample sets is required.

%B J Alzheimers Dis %V 64 %P 761-774 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914018?dopt=Abstract %R 10.3233/JAD-170882 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Anticholinergic Burden and Risk of Stroke and Death in People with Different Types of Dementia. %A Tan, Edwin C K %A Eriksdotter, Maria %A Garcia-Ptacek, Sara %A Fastbom, Johan %A Johnell, Kristina %X

BACKGROUND: Anticholinergic burden is associated with poorer cognitive and functional outcomes in people with dementia. However, the impact of anticholinergics on significant adverse outcomes such as stroke has not been studied previously.

OBJECTIVE: To investigate the association between total anticholinergic cognitive burden (ACB) and risk of stroke and death in people with different dementia subtypes.

METHODS: This was a cohort study of 39,107 people with dementia and no prior history of stroke registered in the Swedish Dementia Registry (SveDem) from 2008-2014. Data were extracted from the Swedish Prescribed Drug Register, the Swedish National Patient Register, and the Swedish Total Population Register. Competing risk regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between time-varying ACB score and risk of stroke and all-cause mortality.

RESULTS: During a mean follow-up period of 2.31 (standard deviation 1.66) years, 11,224 (28.7%) individuals had a stroke or died. Compared with non-users of anticholinergic medications, ACB score of 1 (HR 1.09, 95% CI 1.04-1.14) and ACB score of ≥2 (HR 1.20, 95% CI 1.14-1.26) increased the risk of developing the composite outcome of stroke and death. When stratifying by dementia disorder, the association remained significant in Alzheimer's disease, mixed dementia, and vascular dementia.

CONCLUSIONS: The use of anticholinergic medicines may be associated with an increased risk of stroke and death in people with dementia. A dose-response relationship was observed. Careful consideration should be made when prescribing medications with anticholinergic properties to people with dementia.

%B J Alzheimers Dis %V 65 %P 589-596 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056424?dopt=Abstract %R 10.3233/JAD-180353 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Anti-Tau Monoclonal Antibodies Derived from Soluble and Filamentous Tau Show Diverse Functional Properties in vitro and in vivo. %A Vandermeeren, Marc %A Borgers, Marianne %A Van Kolen, Kristof %A Theunis, Clara %A Vasconcelos, Bruno %A Bottelbergs, Astrid %A Wintmolders, Cindy %A Daneels, Guy %A Willems, Roland %A Dockx, Koen %A Delbroek, Lore %A Marreiro, André %A Ver Donck, Luc %A Sousa, Cristiano %A Nanjunda, Rupesh %A Lacy, Eilyn %A Van De Casteele, Tom %A Van Dam, Debby %A De Deyn, Peter Paul %A Kemp, John A %A Malia, Thomas J %A Mercken, Marc H %X

The tau spreading hypothesis provides rationale for passive immunization with an anti-tau monoclonal antibody to block seeding by extracellular tau aggregates as a disease-modifying strategy for the treatment of Alzheimer's disease (AD) and potentially other tauopathies. As the biochemical and biophysical properties of the tau species responsible for the spatio-temporal sequences of seeding events are poorly defined, it is not yet clear which epitope is preferred for obtaining optimal therapeutic efficacy. Our internal tau antibody collection has been generated by immunizations with different tau species: aggregated- and non-aggregated tau and human postmortem AD brain-derived tau fibrils. In this communication, we describe and characterize a set of these anti-tau antibodies for their biochemical and biophysical properties, including binding, tissue staining by immunohistochemistry, and epitope. The antibodies bound to different domains of the tau protein and some were demonstrated to be isoform-selective (PT18 and hTau56) or phospho-selective (PT84). Evaluation of the antibodies in cellular- and in vivo seeding assays revealed clear differences in maximal efficacy. Limited proteolysis experiments support the hypothesis that some epitopes are more exposed than others in the tau seeds. Moreover, antibody efficacy seems to depend on the structural properties of fibrils purified from tau Tg mice- and postmortem human AD brain.

%B J Alzheimers Dis %V 65 %P 265-281 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040731?dopt=Abstract %R 10.3233/JAD-180404 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Aortic Stiffness is Associated with Increased Risk of Incident Dementia in Older Adults. %A Cui, Chendi %A Sekikawa, Akira %A Kuller, Lewis H %A Lopez, Oscar L %A Newman, Anne B %A Kuipers, Allison L %A Mackey, Rachel H %X

Cardiovascular disease risk factors, including age, hypertension, and diabetes, contribute to aortic stiffness and subclinical cardiovascular and brain disease, increasing dementia risk. Aortic stiffness, measured by carotid-femoral pulse wave velocity (cfPWV), reduces the buffering of pulsatile blood flow, exposing cerebral small arteries to microvascular damage. High cfPWV is related to white matter hyperintensities and brain amyloid deposition, and to cognitive decline, but it is unclear whether cfPWV independently predicts incident dementia. Therefore, we tested the hypothesis that cfPWV predicts incident dementia in older adults, independent of potential confounders. The Cardiovascular Health Study Cognition Study followed 532 non-demented older adults with annual cognitive exams from 1998-99 through 2013. CfPWV was measured on 356 (mean age = 78, 59% women) between 1996-2000. Over 15 years, 212 (59.6%) developed dementia (median time from cfPWV measurement = 4 years). In age and sex-adjusted Cox models, cfPWV was significantly associated with increased risk of dementia, but systolic blood pressure, mean arterial pressure and pulse pressure were not. CfPWV (transformed as - 1/cfPWV) remained significantly associated with dementia risk when further adjusted for education, race, APOEɛ4, diabetes, body mass index, mean arterial pressure, and anti-hypertensive medication (hazard ratio = 1.60, 95% CI = 1.02, 2.51). Results were similar when further adjusted for baseline global cognition, subclinical brain measures, and coronary artery calcification. Finally, higher cfPWV was related to lower physical activity intensity and higher systolic blood pressure, heart rate, and waist circumference measured 5 years prior. An important unanswered question is whether interventions to slow arterial stiffening can reduce the risk of dementia.

%B J Alzheimers Dis %V 66 %P 297-306 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282361?dopt=Abstract %R 10.3233/JAD-180449 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Aphasia in Progressive Supranuclear Palsy: As Severe as Progressive Non-Fluent Aphasia. %A Burrell, James R %A Ballard, Kirrie J %A Halliday, Glenda M %A Hodges, John R %K Aged %K Aged, 80 and over %K Case-Control Studies %K Cognition %K Female %K Humans %K Language Tests %K Male %K Middle Aged %K Primary Progressive Nonfluent Aphasia %K Semantics %K Speech %K Supranuclear Palsy, Progressive %X

BACKGROUND: Adynamic speech is characteristic of progressive supranuclear palsy (PSP), but higher language deficits have been reported inconsistently, in the context of clinical and pathological overlaps with progressive non-fluent aphasia (PNFA).

OBJECTIVE: The present study tested two hypotheses: 1) PSP and PNFA display impaired single word repetition, object naming, semantic knowledge, and syntactic comprehension; and 2) PSP have reduced speed on timed cognitive tasks.

METHODS: Structured clinical and neuropsychological assessments of language were performed on patients with clinically defined PSP and PNFA. Language was tested using the Sydney Language Battery (SYDBAT) and the Test of Reception of Grammar (TROG).

RESULTS: In total, 144 participants were studied (PSP 22, PNFA 29, and Control 93). PSP patients had prominent eye movement abnormalities, parkinsonism, and falls. All 4 PSP patients who underwent postmortem examination had 4-Repeat tauopathy, with PSP pathology in 3. The frequency and severity of impairment on the SYDBAT (naming, word comprehension, semantic association), and TROG (syntactic comprehension) did not differ between PSP and PNFA, but PSP were significantly slower on timed non-language cognitive tests.

CONCLUSION: Tested formally, aphasia may be seen in PSP, with a severity similar to that seen in PNFA.

%B J Alzheimers Dis %V 61 %P 705-715 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254097?dopt=Abstract %R 10.3233/JAD-170743 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Apparent Cognitive Decline as Revealed by an Executive Function Test within a Cohort of Elderly Individuals Self-Reporting Normal Cognitive Performance. %A Shea, Thomas B %A Remington, Ruth %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition %K Cognitive Dysfunction %K Cohort Studies %K Executive Function %K Female %K Humans %K Male %K Memory %K Neuropsychological Tests %K Self Report %X

Alzheimer's disease (AD) can be preceded by subtle memory decline that can last a decade or more before progressing to what would be diagnosed as the mild cognitive impairment stage. During this early stage of decline, individuals and even their caregivers can fail to perceive any serious difficulty or need to consult a physician. Herein, we present evidence in support of these concerns, and demonstrate how this can interfere not only with clinical trials of AD but also those involving cognitive performance of elderly individuals without intentional reference to AD.

%B J Alzheimers Dis %V 61 %P 913-915 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332053?dopt=Abstract %R 10.3233/JAD-170794 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Application of Weighted Gene Co-Expression Network Analysis to Explore the Key Genes in Alzheimer's Disease. %A Liang, Jia-Wei %A Fang, Zheng-Yu %A Huang, Yong %A Liuyang, Zhen-Yu %A Zhang, Xiao-Lin %A Wang, Jing-Lin %A Wei, Hui %A Wang, Jian-Zhi %A Wang, Xiao-Chuan %A Zeng, Ji %A Liu, Rong %X

BACKGROUND: Weighted co-expression network analysis (WGCNA) is a powerful systems biology method to describe the correlation of gene expression based on the microarray database, which can be used to facilitate the discovery of therapeutic targets or candidate biomarkers in diseases.

OBJECTIVE: To explore the key genes in the development of Alzheimer's disease (AD) by using WGCNA.

METHODS: The whole gene expression data GSE1297 from AD and control human hippocampus was obtained from the GEO database in NCBI. Co-expressed genes were clustered into different modules. Modules of interest were identified through calculating the correlation coefficient between the module and phenotypic traits. GO and pathway enrichment analyses were conducted, and the central players (key hub genes) within the modules of interest were identified through network analysis. The expression of the identified key genes was confirmed in AD transgenic mice through using qRT-PCR.

RESULTS: Two modules were found to be associated with AD clinical severity, which functioning mainly in mineral absorption, NF-κB signaling, and cGMP-PKG signaling pathways. Through analysis of the two modules, we found that metallothionein (MT), Notch2, MSX1, ADD3, and RAB31 were highly correlated with AD phenotype. Increase in expression of these genes was confirmed in aged AD transgenic mice.

CONCLUSION: WGCNA analysis can be used to analyze and predict the key genes in AD. MT1, MT2, MSX1, NOTCH2, ADD3, and RAB31 are identified to be the most relevant genes, which may be potential targets for AD therapy.

%B J Alzheimers Dis %V 65 %P 1353-1364 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30124448?dopt=Abstract %R 10.3233/JAD-180400 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Argyrophilic Grain Pathology in Frontotemporal Lobar Degeneration: Demographic, Clinical, Neuropathological, and Genetic Features. %A Gil, María José %A Manzano, María Sagrario %A Cuadrado, María Luz %A Fernández, Cristina %A Góméz, Elena %A Matesanz, Carmen %A Calero, Miguel %A Rábano, Alberto %X

Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically, and genetically heterogeneous group of disorders that affect the frontal and temporal lobes of the brain. FTLD classification distinguishes three main neuropathological groups: FTLD-tau, FTLD-TDP, and FTLD-FUS. As a four-repeat tauopathy, argyrophilic grain disease (AGD) is included in the FTLD-tau group. AGD may also appear in association with other neuropathological disorders. We describe the demographic, clinical, neuropathological, and genetic characteristics of a series of FTLD cases presenting with AGD. For this purpose, a clinico-pathological study of 71 autopsy-confirmed FTLD cases from different tissue banks was performed. AGD was found in 52.1% of FTLD cases. The presence of AGD increased with the increasing age (up to 88.9% in cases older than 80 years; p < 0.001) and was associated with higher ages at onset (p < 0.001) and death (p < 0.001). In AGD cases, progressive supranuclear palsy (PSP) was the most frequent clinical diagnosis (29.7%) and gait disturbance was the most common symptom (64.5%); behavioral and language symptoms were less frequent as compared with non-AGD cases (p = 0.055; p = 0.012). PSP was the most frequent neuropathological diagnosis among cases with AGD (32.4%). This group also showed less brain atrophy (p = 0.094) and higher prevalence of Alzheimer (p = 0.002) and vascular pathology (p = 0.047) as compared to the non-AGD group. We also observed that H1/H1 genotype was overrepresented in AGD cases (p = 0.018) and that there was no association with any specific APOE allele. A subanalysis of PSP cases according to the AGD status was carried out, yielding no significant differences.

%B J Alzheimers Dis %V 63 %P 1109-1117 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758948?dopt=Abstract %R 10.3233/JAD-171115 %0 Journal Article %J J Alzheimers Dis %D 2018 %T An Aspartyl Cathepsin Targeted PET Agent: Application in an Alzheimer's Disease Mouse Model. %A Snir, Jonatan A %A Suchy, Mojmir %A Bindseil, Geron A %A Kovacs, Michael %A Chronik, Blaine A %A Hudson, Robert H E %A Pasternak, Stephen H %A Bartha, Robert %K Alzheimer Disease %K Animals %K Brain %K Cathepsin D %K Contrast Media %K Disease Models, Animal %K Female %K Fluorodeoxyglucose F18 %K Glucose %K Mice %K Mice, Transgenic %K Positron-Emission Tomography %X

BACKGROUND: Early detection of Alzheimer's disease (AD) pathology is a serious challenge for both diagnosis and clinical trials. The aspartyl protease, Cathepsin D (CatD), is overexpressed in AD and could be a biomarker of disease. We have previously designed a unique contrast agent (CA) for dual-optical and magnetic resonance imaging of the activity of the CatD class of enzymes.

OBJECTIVE: To compare the uptake and retention of a novel, more sensitive, and clinically-translatable 68Ga PET tracer targeting CatD activity in 5XFAD mice and non-Tg littermates.

METHODS: The targeted CA consisted of an HIV-1 Tat cell penetrating peptide (CPP) conjugated to a specialized cleavage sequence targeting aspartyl cathepsins and a DOTA conjugate chelating 68Ga. PET images were acquired using a Siemens Inveon preclinical microPET in female Tg AD mice and non-Tg age matched female littermates (n = 5-8) following intravenous CA administration at 2, 6, and 9 months of age. Additionally, 18F fluorodeoxyglucose (FDG) PET imaging was performed at 10 months to measure glucose uptake.

RESULTS: The Tg mice showed significantly higher relative uptake rate of the targeting CA in the forebrain relative to hindbrain at all ages compared to controls, consistent with histology. In contrast, no differences were seen in CA uptake in other organs. Additionally, the Tg mice did not show any differences in relative uptake of FDG at 10 months of age in the forebrain relative to the hindbrain compared to age matched non-Tg controls.

CONCLUSIONS: Elevated aspartryl cathepsin activity was detected in vivo in the 5XFAD mouse model of AD using a novel targeted PET contrast agent.

%B J Alzheimers Dis %V 61 %P 1241-1252 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332035?dopt=Abstract %R 10.3233/JAD-170115 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Assay of Plasma Phosphorylated Tau Protein (Threonine 181) and Total Tau Protein in Early-Stage Alzheimer's Disease. %A Yang, Che-Chuan %A Chiu, Ming-Jang %A Chen, Ta-Fu %A Chang, Hui-Ling %A Liu, Bing-Hsien %A Yang, Shieh-Yueh %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Case-Control Studies %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Phosphorylation %K tau Proteins %X

The feasibility of assaying plasma phosphorylated tau protein (threonine 181), denoted p-tau181, using immunomagnetic reduction (IMR) is explored. The reagent for assaying p-tau181 with IMR was synthesized, and its analytic performances were characterized. Seventy-three subjects were recruited. Each participant was examined with neuropsychological tests, magnetic resonance imaging, and IMR assay for plasma p-tau181. Using commercially available IMR kits, the plasma total tau protein (T-tau) of each subject was assayed. The dynamic range for assaying p-tau181 using IMR was 1.96×10-2 pg/ml to 104 pg/ml. There was no significant interference from total tau protein in the assay of p-tau181. The measured concentrations of plasma p-tau181 were 2.46±1.09 pg/ml for healthy controls, 4.41±1.85 pg/ml for MCI due to AD, and 6.14±1.59 pg/ml for very mild AD. Meanwhile, the measured concentrations of plasma T-tau were 18.85±10.16 pg/ml for healthy controls, 32.98±10.18 pg/ml for MCI due to AD, and 37.54±12.29 pg/ml for very mild AD. A significant difference in plasma p-tau181 was observed between healthy controls and MCI due to AD (p < 0.001) and between MCI due to AD and very mild AD (p < 0.001). However, for the plasma T-tau concentration, a significant difference existed only between healthy controls and MCI due to AD (p < 0.001). This implies that the plasma p-tau181 level is correlated more to AD severity than plasma T-tau is. Additionally, p-tau181 was observed as approximately 14% of T-tau in human plasma.

%B J Alzheimers Dis %V 61 %P 1323-1332 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376870?dopt=Abstract %R 10.3233/JAD-170810 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Assessing Mild Behavioral Impairment with the Mild Behavioral Impairment-Checklist in People with Mild Cognitive Impairment. %A Mallo, Sabela C %A Ismail, Zahinoor %A Pereiro, Arturo X %A Facal, David %A Lojo-Seoane, Cristina %A Campos-Magdaleno, María %A Juncos-Rabadán, Onésimo %X

BACKGROUND: Neuropsychiatric symptoms (NPS) are non-cognitive, behavioral, or psychiatric symptoms, common in mild cognitive impairment (MCI) and associated with a higher risk of dementia. Mild behavioral impairment (MBI) is a validated diagnostic entity, that describes the emergence of later life NPS in pre-dementia states. The Mild Behavioral Impairment Checklist (MBI-C) is the first measure developed to assess MBI.

OBJECTIVE: To estimate the prevalence of MBI in people with MCI and to study the score distribution, sensitivity, specificity, diagnostic utility of the MBI-C, and its correlations with neuropsychological tests.

METHODS: One hundred eleven MCI participants were evaluated with the Questionnaire for Subjective Memory Complaints (QSMC), Mini-Mental State Examination, Cambridge Cognitive Assessment-Revised, Neuropsychiatric Inventory-Questionnaire (NPI-Q), Geriatric Depression Scale-15 items (GDS-15), Lawton and Brody Index, and the MBI-C, which was administered by phone to participants' informants. Descriptive, logistic regression, ROC curve, and bivariate correlations analyses were performed.

RESULTS: MBI diagnosis prevalence was 14.2%. The total MBI-C score differentiated people with MBI at a cutoff-point of 6.5, optimizing sensitivity and specificity. MBI-C total score correlated positively with NPI-Q, QSMC, GDS-15, and Lawton and Brody Index.

CONCLUSION: The total MBI-C score, obtained by phone administration, is sensitive for detecting MBI in people with MCI. The MBI-C scores indicated that MCI participants had subtle NPS that were correlated to their subjective memory complaints reported by informants, depressive symptoms, and negatively with Instrumental Activities of Daily Living. Further research should be done to clarify the predictive role of NPS in MCI for incident dementia.

%B J Alzheimers Dis %V 66 %P 83-95 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30175974?dopt=Abstract %R 10.3233/JAD-180131 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Assessing Mild Cognitive Impairment Progression using a Spherical Brain Mapping of Magnetic Resonance Imaging. %A Martinez-Murcia, Francisco Jesus %A Górriz, Juan Manuel %A Ramírez, Javier %A Segovia, Fermín %A Salas-Gonzalez, Diego %A Castillo-Barnes, Diego %A Ortiz, Andrés %X

BACKGROUND: The early diagnosis of Alzheimer's Disease (AD), particularly in its prodromal stage, mild cognitive impairment (MCI), still remains a challenge. Many computational tools have been developed to successfully explore and predict the disease progression. In this context, the Spherical Brain Mapping (SBM) proved its ability in detecting differences between AD and aged subjects without symptoms of dementia. Being a very visual tool, its application in predicting MCI conversion to AD could be of great help to understand neurodegeneration and the disease progression.

OBJECTIVE: In this work, we aim at predicting the conversion of MCI affected subjects to AD more than 6 months in advance of their conversion session and understanding the progression of the disease by predicting neuropsychological test outcomes from MRI data.

METHODS: In order to do so, SBM is applied to a series of MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The resulting spherical brain maps show statistical and morphological information of the brain in a bidimensional plane, performing at the same time a significant feature reduction that provides a feature vector used in classification analysis.

RESULTS: The study achieves up to 92.3% accuracy in the AD versus normal controls (CTL) detection, and up to a 77.6% in detection a of MCI conversions when trained with AD and CTL subjects. The prediction of neuropsychological test outcomes achieved R2 rates up to more than 0.5. Significant regions according to t-test and correlation analysis match reported brain areas in the literature.

CONCLUSION: The results prove that Spherical Brain Mapping offers good ability to predict conversion patterns and cognitive state, at the same time that provides an additional aid for visualizing a two-dimensional abstraction map of the brain.

%B J Alzheimers Dis %V 65 %P 713-729 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29630547?dopt=Abstract %R 10.3233/JAD-170403 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Assessing the Limitations and Biases in the Current Understanding of Chronic Traumatic Encephalopathy. %A Schwab, Nicole %A Hazrati, Lili-Naz %X

Chronic traumatic encephalopathy (CTE) is considered to be a progressive neurodegenerative disease caused by mild traumatic brain injury (mTBI). Recently there has been a significant amount of media attention surrounding the commonness of CTE in professional athletes, particularly American football, based on several postmortem case series. However, despite the persuasive claims made by the media about CTE, research on the disease and the effects of mTBI in general remain in its infancy. Commonly cited case series studying CTE are limited by methodological biases, pathological inconsistencies, insufficient clinical data, and a reliance on inherently biased postmortem data. These case series do not allow for the collection of any epidemiological data and are not representative of the general population. The exaggerated assumptions and assertions taken from these studies run the risk of creating a self-fulfilling prophecy for individuals who believe they are at risk and have the potential to negatively influence sports-related policymaking. This review outlines the status and limitations of recent CTE case series and calls for future prospective, longitudinal studies to further characterize the pathological and clinical hallmarks of CTE.

%B J Alzheimers Dis %V 64 %P 1067-1076 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010133?dopt=Abstract %R 10.3233/JAD-180373 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Assessing Working Memory in Mild Cognitive Impairment with Serial Order Recall. %A Emrani, Sheina %A Libon, David J %A Lamar, Melissa %A Price, Catherine C %A Jefferson, Angela L %A Gifford, Katherine A %A Hohman, Timothy J %A Nation, Daniel A %A Delano-Wood, Lisa %A Jak, Amy %A Bangen, Katherine J %A Bondi, Mark W %A Brickman, Adam M %A Manly, Jennifer %A Swenson, Rodney %A Au, Rhoda %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Executive Function %K Female %K Humans %K Male %K Memory Disorders %K Memory, Short-Term %K Mental Recall %K Neuropsychological Tests %K Regression Analysis %K Serial Learning %X

BACKGROUND: Working memory (WM) is often assessed with serial order tests such as repeating digits backward. In prior dementia research using the Backward Digit Span Test (BDT), only aggregate test performance was examined.

OBJECTIVE: The current research tallied primacy/recency effects, out-of-sequence transposition errors, perseverations, and omissions to assess WM deficits in patients with mild cognitive impairment (MCI).

METHODS: Memory clinic patients (n = 66) were classified into three groups: single domain amnestic MCI (aMCI), combined mixed domain/dysexecutive MCI (mixed/dys MCI), and non-MCI where patients did not meet criteria for MCI. Serial order/WM ability was assessed by asking participants to repeat 7 trials of five digits backwards. Serial order position accuracy, transposition errors, perseverations, and omission errors were tallied.

RESULTS: A 3 (group)×5 (serial position) repeated measures ANOVA yielded a significant group×trial interaction. Follow-up analyses found attenuation of the recency effect for mixed/dys MCI patients. Mixed/dys MCI patients scored lower than non-MCI patients for serial position 3 (p < 0.003) serial position 4 (p < 0.002); and lower than both group for serial position 5 (recency; p < 0.002). Mixed/dys MCI patients also produced more transposition errors than both groups (p < 0.010); and more omissions (p < 0.020), and perseverations errors (p < 0.018) than non-MCI patients.

CONCLUSIONS: The attenuation of a recency effect using serial order parameters obtained from the BDT may provide a useful operational definition as well as additional diagnostic information regarding working memory deficits in MCI.

%B J Alzheimers Dis %V 61 %P 917-928 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254087?dopt=Abstract %R 10.3233/JAD-170555 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Assessment of the Genetic Architecture of Alzheimer's Disease Risk in Rate of Memory Decline. %A Del-Aguila, Jorge L %A Fernández, Maria Victoria %A Schindler, Suzanne %A Ibanez, Laura %A Deming, Yuetiva %A Ma, Shengmei %A Saef, Ben %A Black, Kathleen %A Budde, John %A Norton, Joanne %A Chasse, Rachel %A Harari, Oscar %A Goate, Alison %A Xiong, Chengjie %A Morris, John C %A Cruchaga, Carlos %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Dementia %K Disease Progression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heterozygote %K Humans %K Longitudinal Studies %K Male %K Membrane Glycoproteins %K Memory Disorders %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Immunologic %K Risk Assessment %X

Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β= 0.146, p = 0.03). In the case of rare variants, TREM2 (β= 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.

%B J Alzheimers Dis %V 62 %P 745-756 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480181?dopt=Abstract %R 10.3233/JAD-170834 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Assessment of the Mid-Life Demographic and Lifestyle Risk Factors of Dementia Using Data from the Framingham Heart Study Offspring Cohort. %A Li, Jinlei %A Ogrodnik, Matthew %A Kolachalama, Vijaya B %A Lin, Honghuang %A Au, Rhoda %X

BACKGROUND: Dementia is the leading cause of dependence and disability in the elderly population worldwide. However, currently there is no effective medication for dementia treatment. Therefore, identifying lifestyle-related risk factors including some that are modifiable may provide important strategies for reducing risk of dementia.

OBJECTIVE: This study aims to highlight associations between easily obtainable lifestyle risk factors in mid-life and dementia in later adulthood.

METHODS: Using data from the Framingham Heart Study Offspring cohort, we leveraged well-known classification models (decision tree classifier and random forests) to associate demographic and lifestyle behavioral data with dementia status. We then evaluated model performance by computing area under receiver operating characteristic (ROC) curve.

RESULTS: As expected, age was strongly associated with dementia. The analysis also identified 'widowed' marital status, lower BMI, and less sleep at mid-life as risk factors of dementia. The areas under the ROC curves were 0.79 for the decision tree, and 0.89 for the random forest model.

CONCLUSION: Demographic and lifestyle factors that are non-invasive and inexpensive to implement can be assessed in midlife and used to potentially modify the risk of dementia in late adulthood. Classification models can help identify associations between dementia and midlife lifestyle risk factors. These findings inform further research, in order to help public health officials develop targeted programs for dementia prevention.

%B J Alzheimers Dis %V 63 %P 1119-1127 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710704?dopt=Abstract %R 10.3233/JAD-170917 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association between Alzheimer's Disease and Oral and Gut Microbiota: Are Pore Forming Proteins the Missing Link? %A Aguayo, Sebastian %A Schuh, Christina Maria Anna Pia %A Vicente, Benjamin %A Aguayo, Luis Gerardo %X

Alzheimer's disease (AD) is a neurodegenerative condition affecting millions of people worldwide. It is associated with cerebral amyloid-β (Aβ) plaque deposition in the brain, synaptic disconnection, and subsequent progressive neuronal death. Although considerable progress has been made to elucidate the pathogenesis of AD, the specific causes of the disease remain highly unknown. Recent research has suggested a potential association between certain infectious diseases and dementia, either directly due to bacterial brain invasion and toxin production, or indirectly by modulating the immune response. Therefore, in the present review we focus on the emerging issues of bacterial infection and AD, including the existence of antimicrobial peptides having pore-forming properties that act in a similar way to pores formed by Aβ in a variety of cell membranes. Special focus is placed on oral bacteria and biofilms, and on the potential mechanisms associating bacterial infection and toxin production in AD. The role of bacterial outer membrane vesicles on the transport and delivery of toxins as well as porins to the brain is also discussed. Aβ has shown to possess antimicrobial activity against several bacteria, and therefore could be upregulated as a response to bacteria and bacterial toxins in the brain. Although further research is needed, we believe that the control of biofilm-mediated diseases could be an important potential prevention mechanism for AD development.

%B J Alzheimers Dis %V 65 %P 29-46 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040725?dopt=Abstract %R 10.3233/JAD-180319 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Association Between Body Mass Index, and Cognitive, Functional, and Behavioral Declines for Incident Dementia. %A Michaud, Tzeyu L %A Siahpush, Mohammad %A Farazi, Paraskevi A %A Kim, Jungyoon %A Yu, Fang %A Su, Dejun %A Murman, Daniel L %X

BACKGROUND: Association between high adiposity and the clinical progression of dementia remains puzzling.

OBJECTIVE: To separately examine the association between body mass index (BMI) and cognitive, functional, and behavioral declines before, at, and after diagnosis of dementia, and further stratified by age groups, and sex.

METHODS: A total of 1,141 individuals with incident dementia were identified from the Uniform Data Set of the National Alzheimer's Coordinating Center. Cognitive function was evaluated by Mini-Mental State Exam, functional abilities were assessed using Functional Activities Questionnaire, and behavioral symptoms were captured by Neuropsychiatric Inventory Questionnaire at each follow-up visit. We used separate linear-mixed effects models to examine the association.

RESULTS: Compared to moderate baseline BMI, high baseline BMI was associated with 0.30-point slower annual progression rates in functional decline. For individuals aged 76 and over, high baseline BMI was associated with 0.42-point faster progression rates in cognitive decline annually. A U-shaped association between baseline BMI and cognitive decline was observed among men.

CONCLUSION: BMI levels before dementia diagnosis may facilitate the identification of different risk profiles for progression rates of cognitive and functional declines in individuals who developed dementia.

%B J Alzheimers Dis %V 66 %P 1507-1517 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412484?dopt=Abstract %R 10.3233/JAD-180278 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Association Between Frontotemporal Lobar Degeneration and Bullous Pemphigoid. %A Katisko, Kasper %A Kokkonen, Nina %A Krüger, Johanna %A Hartikainen, Päivi %A Koivisto, Anne M %A Helisalmi, Seppo %A Korhonen, Ville E %A Kokki, Merja %A Tuusa, Jussi %A Herukka, Sanna-Kaisa %A Solje, Eino %A Haapasalo, Annakaisa %A Tasanen, Kaisa %A Remes, Anne M %X

Recent studies have shown an epidemiological and immunological association between bullous pemphigoid (BP) and several neurological or psychiatric diseases. Here, our aim was for the first time to specify whether an association exists between BP and frontotemporal lobar degeneration (FTLD). Medical histories of FTLD patients (N = 196) were screened for clinical comorbidity, and BP180 and BP230 autoantibodies were analyzed in the sera of FTLD patients (N = 70, including 24 C9orf72 repeat expansion carriers) by BP180-NC16A-ELISA and BP230-ELISA. One FTLD patient (C9orf72 repeat expansion carrier) had a comorbid diagnosis of BP. Increased levels of serum BP180 autoantibodies (cutoff value >9 U/ml) were detected more often in FTLD patients (10.0%) than in controls (4.9%). Moreover, elevated levels of both BP180 and BP230 autoantibodies were found more often in C9orf72 repeat expansion-carrying FTLD than non-carrying patients or controls. However, none of these differences reached a statistical significance likely due to our limited cohort size. In conclusion, our findings suggest that subset of FTLD patients especially with the C9orf72 repeat expansion may have an immunological association with BP.

%B J Alzheimers Dis %V 66 %P 743-750 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320585?dopt=Abstract %R 10.3233/JAD-180624 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association between Hippocampal Shape, Neuroinflammation, and Cognitive Decline in Alzheimer's Disease. %A Cabinio, Monia %A Saresella, Marina %A Piancone, Federica %A LaRosa, Francesca %A Marventano, Ivana %A Guerini, Franca %A Nemni, Raffaello %A Baglio, Francesca %A Clerici, Mario %X

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition characterized by memory impairment and general decrease in cognitive functions and daily living competences, that leads to a complete loss of autonomy. The pathogenesis of AD is characterized by the deposition of amyloid-β plaques (Aβ plaques) and neurofibrillary tangles, initially involving cortical and hippocampal structures, and neuroinflammation. To date, no studies have investigated the topological association between neuroinflammation and hippocampal shape in AD.

OBJECTIVE: The aim of the present study is to assess the association between hippocampal shape, cognitive profile, and neuroinflammation in a group of AD patients in the mild stage of the disease.

METHODS: Thirty-one patients with typical onset AD (mild stage) underwent MRI examination (1.5T scanner); hippocampal structures were segmented using a vertex-wise analysis (FSL-FIRST). Immune parameters were evaluated on peripheral blood mononuclear cells by flow-cytometry. Correlation analyses were performed between hippocampal shape and both cognitive profile (ADAS-Cog and MMSE scores), and neuro-inflammatory variables (i.e., circulating monocytes, cytokines).

RESULTS: Statistically significant correlations (p < 0.05FWE) between right hippocampal shape and cognitive measurements and between left hippocampal shape and inflammatory indices were detected. The hippocampal field mostly involved was the lateral portion of bilateral hippocampi, mainly overlapping with Cornu Ammonis, extending along the entire longitudinal axis.

CONCLUSIONS: A topological relationship between hippocampal atrophy and both cognitive profile and neuroinflammation is found; the association with neuroinflammatory indices is in line with the pattern of AD-associated neuronal death, whereas the association with cognitive test might account for residual cognitive functions.

%B J Alzheimers Dis %V 66 %P 1131-1144 %8 2018 Nov 23 %G eng %N 3 %R 10.3233/JAD-180250 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association between Neuropsychiatric Improvement and Neurocognitive Change in Alzheimer's Disease: Analysis of the CATIE-AD Study. %A Nagata, Tomoyuki %A Shinagawa, Shunichiro %A Nakajima, Shinichiro %A Mimura, Masaru %A Shigeta, Masahiro %X

BACKGROUND/OBJECTIVE: To assess associations between improvements in neuropsychiatric symptoms (NPS) and neurocognitive change in patients with Alzheimer's disease (AD) during treatment using the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer Disease (CATIE-AD) dataset.

METHODS: AD outpatients with NPS who needed pharmacological treatment (n = 421) were followed up with antipsychotics, citalopram, or placebo for up to 36 weeks (mean±SD = 252±52 days). The study aim was to investigate associations between improvement in each NPS evaluating scale (by Clinical Global Impression of Change [CGI-C], Neuropsychiatric Inventory [NPI], or Brief Psychiatric Scale [BPRS]) at endpoint (week 36 or early termination [ET], n = 340) and neurocognitive change (change score in the Mini-Mental State Examination [MMSE] between endpoint and baseline during the treatment). Multiple logistic regression analyses were performed on the associations between each NPS improvement and neurocognitive change as well as socio-clinico-demographic variables of interest.

RESULTS: At endpoint, NPS improvement rates were 76.1%, 70.8%, and 58.1% in CGI-C, NPI, and BPRS, respectively, while MMSE score change was -2.3±3.8. NPS improvement was significantly related to more severe psychotic symptoms at baseline and preserved levels of neurocognition (smaller MMSE score change) among several variables.

CONCLUSIONS: Our findings suggested that neurocognitive preservation may be associated with attaining optimal benefits from any treatment against NPSs in a longitudinal treatment course of patients with AD.

%B J Alzheimers Dis %V 66 %P 139-148 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30248052?dopt=Abstract %R 10.3233/JAD-180304 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association between Peripheral Leptin and Adiponectin Levels and Cognitive Decline in Patients with Neurocognitive Disorders ≥65 Years. %A Gilbert, Thomas %A Roche, Sylvain %A Blond, Emilie %A Bar, Jean-Yves %A Drai, Jocelyne %A Cuerq, Charlotte %A Haution-Bitker, Marine %A Ecochard, René %A Bonnefoy, Marc %X

BACKGROUND: There is evidence that adipokines have roles in brain functioning and cognitive decline.

OBJECTIVE: Assess the role of leptin and adiponectin levels in predicting changes in neuro-cognitive disorders (NCD).

METHODS: The study included 205 patients over 65 years of age presenting for a one-day hospitalization for current assessment of cognitive function. Peripheral blood leptin and adiponectin levels were measured at admission. Demographic variables, body mass index (BMI), and history of hypertension were also recorded. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) at admission and at later scheduled visits over a median follow-up period of 14.5 months. Conventional univariate comparisons were made between diagnosis groups (Alzheimer's disease (AD), mild NCD, vascular/mixed dementia). Changes in MMSE scores over time were examined with regard to the above variables using a linear mixed model.

RESULTS: The mean BMI was significantly lower (by 2 kg/m2, p = 0.01) in patients with AD than in patients with either mild-NCD or vascular/mixed dementia. Leptin levels were significantly higher (p = 0.043) and adiponectin levels significantly lower (p = 0.045) in patients with mild-NCD than in patients with major-NCD (AD or vascular/mixed dementia). However, the mixed model suggested no influence of the baseline levels of these two biomarkers on the course of cognitive decline.

CONCLUSION: The present study confirms the associations between leptin and adiponectin and AD or AD-related disorders but did not confirm that these peptides may be used as predictive biomarkers of cognitive decline.

%B J Alzheimers Dis %V 66 %P 1255-1264 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400097?dopt=Abstract %R 10.3233/JAD-180533 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association between Plasma Levels of PAI-1, tPA/PAI-1 Molar Ratio, and Mild Cognitive Impairment in Chinese Patients with Type 2 Diabetes Mellitus. %A Wang, Jiaqi %A Yuan, Yang %A Cai, Rongrong %A Huang, Rong %A Tian, Sai %A Lin, Hongyan %A Guo, Dan %A Wang, Shaohua %X

BACKGROUND: Plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (tPA) are involved in the complications of type 2 diabetes mellitus (T2DM) and early pathology of Alzheimer's disease.

OBJECTIVE: This study aimed to investigate the association between plasma PAI-1, tPA/PAI-1 molar ratio, and mild cognitive impairment (MCI) in Chinese T2DM patients.

METHODS: A total of 162 Chinese T2DM patients were recruited and divided into two groups according to the Montreal Cognitive Assessment score. Demographic data were collected, plasma PAI-1 and tPA levels were measured through enzyme-linked immunosorbent assay, tPA/PAI-1 molar ratio was calculated, and neuropsychological test results were examined. The association between PAI-1, tPA/PAI-1 molar ratio, and cognition was analyzed.

RESULTS: There were 66 diabetic MCI patients and 96 healthy cognition participants (controls). T2DM patients with MCI displayed significantly increased plasma PAI-1 levels (p = 0.016) and decreased tPA/PAI-1 molar ratio (p = 0.021) compared with the controls. High PAI-1 levels and low tPA/PAI-1 molar ratio were associated with MCI in T2DM patients, e.g., plasma level of PAI-1 were negatively correlated (r = -0.343, p = 0.007) with logic memory in T2DM patients with MCI. Linear regression analysis further revealed that PAI-1 concentration was an independent factor of diabetic MCI (p = 0.001).

CONCLUSIONS: High PAI-1 levels and low tPA/PAI-1 molar ratio were significantly correlated with T2DM-associated cognitive impairment, especially memory function, in Chinese patients.

%B J Alzheimers Dis %V 63 %P 835-845 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689724?dopt=Abstract %R 10.3233/JAD-171038 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Association between Social Engagement, Loneliness, and Risk of Dementia: A Systematic Review and Meta-Analysis. %A Penninkilampi, Ross %A Casey, Anne-Nicole %A Singh, Maria Fiatarone %A Brodaty, Henry %X

It has been reported that social engagement may be associated with dementia risk. We searched PubMed, EMBASE, PsycINFO, CINAHL, LILACS, Biomed Central, Scopus, and Web of Science from January 2012 - May 2017, supplemented by extraction from previous reviews. We included cohort and case-control studies examining the association between social engagement or loneliness and dementia risk, pooling data using a random-effects model. Registered: PROSPERO (CRD42017067074). We included 31 cohort and 2 case-control studies comprising 2,370,452 participants. Poor social engagement indices were associated with increased dementia risk, including having a poor social network (RR = 1.59, 95% CI 1.31-1.96; I2 = 0.00%) and poor social support (RR = 1.28, 95% CI 1.01-1.62; I2 = 55.51%). In long-term studies (≥10 years), good social engagement was modestly protective (RR = 0.88, 95% CI 0.80-0.96; I2 = 0.00%). Loneliness was non-significantly associated with increased risk (RR = 1.38, 95% CI 0.98-1.94; I2 = 45.32). Our findings encourage interventions targeting social isolation and disengagement for dementia prevention.

%B J Alzheimers Dis %V 66 %P 1619-1633 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30452410?dopt=Abstract %R 10.3233/JAD-180439 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association Between the Use of Antihyperglycemic Drugs and Dementia Risk: A Case-Control Study. %A Bohlken, Jens %A Jacob, Louis %A Kostev, Karel %X

BACKGROUND: There is a conflicting literature on the association between the use of antihyperglycemic drugs and dementia risk.

OBJECTIVE: The goal of this case-control study was to analyze the association between the use of antihyperglycemic drugs and dementia risk in patients followed in general practices in Germany.

METHODS: This study included patients with type 2 diabetes mellitus who had received a first dementia diagnosis in 972 general practices in Germany between January 2013 and December 2017 (index date). Controls without dementia were matched (1:1) to cases by age, gender, index year, and physician. Two multivariate regression models were used to study the association between the use of antihyperglycemic drugs and dementia risk. Model 1 included all antihyperglycemic drugs prescribed to patients regardless of the prescription duration, whereas Model 2 only included the longest therapy prescribed to each patient.

RESULTS: There were 8,276 diabetes patients with dementia and 8,276 diabetes patients without dementia included in this study. In Model 1, glitazones were associated with a decreased dementia risk (odds ratio [OR] = 0.80), whereas insulin was associated with an increased risk of developing the condition (OR = 1.34). In Model 2, metformin, prescribed as monotherapy (OR = 0.71) or as dual therapy with sulfonylureas (OR = 0.90), was associated with a decrease in the likelihood of subsequently being diagnosed with dementia. By contrast, the combination of basal insulin and bolus insulin (OR = 1.47) and premix insulin (OR = 1.33) were risk factors for dementia.

CONCLUSION: Metformin and glitazones were negatively associated with dementia, while insulin was positively associated with dementia.

%B J Alzheimers Dis %V 66 %P 725-732 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320593?dopt=Abstract %R 10.3233/JAD-180808 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association between α-Klotho and Deep White Matter Lesions in the Brain: A Pilot Case Control Study Using Brain MRI. %A Kuriyama, Nagato %A Ozaki, Etsuko %A Mizuno, Toshiki %A Ihara, Masafumi %A Mizuno, Shigeto %A Koyama, Teruhide %A Matsui, Daisuke %A Watanabe, Isao %A Akazawa, Kentaro %A Takeda, Kazuo %A Takada, Akihiro %A Inaba, Masaaki %A Yamada, Shinsuke %A Motoyama, Koka %A Takeshita, Wakiko %A Iwai, Komei %A Hashiguchi, Kanae %A Kobayashi, Daiki %A Kondo, Masaki %A Tamura, Aiko %A Yamada, Kei %A Nakagawa, Masanori %A Watanabe, Yoshiyuki %K Aged %K Aged, 80 and over %K Apolipoprotein E4 %K Brain %K C-Reactive Protein %K Case-Control Studies %K Cognition Disorders %K Female %K Glucuronidase %K Humans %K Image Processing, Computer-Assisted %K Leukoencephalopathies %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Pilot Projects %K Severity of Illness Index %X

BACKGROUND: The anti-aging protein, α-Klotho, may be involved in cognitive decline and has potential as a surrogate marker that reflects dementia. However, the role of α-Klotho in the brain has not been sufficiently investigated.

OBJECTIVE: Here, we investigated the association between α-Klotho and cognitive decline that is associated with cerebral deep white matter lesions (DWMLs).

METHODS: Two hundred-eighty participants (187 males and 93 females, mean age: 70.8 years old) were evaluated for DWMLs, and the Fazekas scale (Grade) was assessed following brain magnetic resonance imaging. A questionnaire concerning lifestyle and neuropsychological tests was administered, and their associations with the blood α-Klotho level were retrospectively investigated.

RESULTS: The α-Klotho level was 685.1 pg/mL in Grade 0 (68 subjects), 634.1 in G1 (134), 596.0 in G2 (62), and 571.6 in G3 (16), showing that the level significantly decreased with advanced grades. Significant correlations were noted between the α-Klotho level and higher brain function tests including the Mini-Mental State Examination and word fluency tests (p < 0.05). When a 90th percentile value of the level in the G0 group (400 pg/mL) or lower was defined as a low α-Klotho level, the odds ratio of the high-grade G3 group was 2.9 (95% confidence interval: 1.4-7.8) (after correction for age, sex, hypertension, and chronic kidney disease), which was significant.

CONCLUSION: A reduced blood α-Klotho level was correlated with grading of cerebral DWMLs and was accompanied by cognitive decline as an independent risk factor. The α-Klotho level may serve as a useful clinical index of vascular cognitive impairment.

%B J Alzheimers Dis %V 61 %P 145-155 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154273?dopt=Abstract %R 10.3233/JAD-170466 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease. %A Geijselaers, Stefan L C %A Aalten, Pauline %A Ramakers, Inez H G B %A De Deyn, Peter Paul %A Heijboer, Annemieke C %A Koek, Huiberdina L %A OldeRikkert, Marcel G M %A Papma, Janne M %A Reesink, Fransje E %A Smits, Lieke L %A Stehouwer, Coen D A %A Teunissen, Charlotte E %A Verhey, Frans R J %A van der Flier, Wiesje M %A Biessels, Geert Jan %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Brain %K Cognition Disorders %K Female %K Humans %K Insulin %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Signal Transduction %K tau Proteins %X

BACKGROUND: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD).

OBJECTIVE: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype.

METHODS: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau.

RESULTS: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029).

CONCLUSION: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

%B J Alzheimers Dis %V 61 %P 309-320 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154275?dopt=Abstract %R 10.3233/JAD-170522 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of Low-Level Ozone with Cognitive Decline in Older Adults. %A Cleary, Ekaterina Galkina %A Cifuentes, Manuel %A Grinstein, Georges %A Brugge, Doug %A Shea, Thomas B %K Age Distribution %K Aged %K Aged, 80 and over %K Aging %K Air Pollutants %K Cognitive Dysfunction %K Female %K Humans %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Ozone %K Regression Analysis %K Retrospective Studies %K United States %X

Increasing evidence points to an association of airborne pollutant exposure with respiratory, cardiovascular, and neurological pathology. We examined whether or not ground-level ozone or fine particulate matter ≤ 2.5 μm in diameter (PM2.5) was associated with accelerated cognitive decline. Using repeated measures mixed regression modeling, we analyzed cognitive performance of a geographically diverse sampling of individuals from the National Alzheimer's Coordinating Center between 2004-2008. Ambient air concentrations of ozone and PM2.5 were established using a space-time Hierarchical Bayesian Model that statistically merged air monitor data and modeled air quality estimates. We then compared the ambient regional concentrations of ozone and PM2.5 with the rate of cognitive decline in residents within those regions. Increased levels of ozone correlated with an increased rate of cognitive decline, following adjustment for key individual and community-level risk factors. Furthermore, individuals harboring one or more APOE4 alleles exhibited a faster rate of cognitive decline. The deleterious association of ozone was confined to individuals with normal cognition who eventually became cognitively impaired as opposed to those who entered the study with baseline impairment. In contrast to ozone, we did not observe any correlation between ambient PM2.5 and cognitive decline at regulatory limits set by the Environmental Protection Agency. Our findings suggest that prolonged exposure to ground-level ozone may accelerate cognitive decline during the initial stages of dementia development.

%B J Alzheimers Dis %V 61 %P 67-78 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103040?dopt=Abstract %R 10.3233/JAD-170658 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Association of Mid- and Late-Life Systemic Inflammation with Brain Amyloid Deposition: The ARIC-PET Study. %A Walker, Keenan A %A Windham, B Gwen %A Brown, Charles H %A Knopman, David S %A Jack, Clifford R %A Mosley, Thomas H %A Selvin, Elizabeth %A Wong, Dean F %A Hughes, Timothy M %A Zhou, Yun %A Gross, Alden L %A Gottesman, Rebecca F %X

BACKGROUND: Although inflammation has been implicated in the pathogenesis of Alzheimer's disease, the effects of systemic inflammation on brain amyloid deposition remain unclear.

OBJECTIVE: We examined the association of midlife and late-life systemic inflammation with late-life brain amyloid levels in a community sample of non-demented older adults from the Atherosclerosis Risk in Communities (ARIC) - PET Study.

METHODS: 339 non-demented participants (age: 75 [SD 5]) were recruited from the ARIC Study to undergo florbetapir PET (amyloid) imaging. Blood levels of high sensitivity C-reactive protein (CRP), a marker of systemic inflammation, were measured 22 years (Visit 2), 16 years (Visit 4), and up to 2 years before PET imaging (Visit 5). Elevated brain amyloid deposition (standardized uptake value ratio >1.2) was the primary outcome.

RESULTS: Our primary analyses found no association of midlife and late-life CRP with late-life brain amyloid levels. However, in secondary stratified analyses, we found that higher midlife (Visit 2) CRP was associated with elevated amyloid among males (OR 1.65, 95% CI: 1.13-2.42), and among white (OR 1.33, 95% CI: 1.02-1.75), but not African American, participants (p-interactions<0.05). Among male participants, those who maintained high CRP levels (≥3 mg/L) throughout mid- and late-life were most likely to have elevated brain amyloid (OR, 8.81; 95% CI: 1.23, 62.91).

CONCLUSIONS: Although our primary analysis does not support an association between systemic inflammation and brain amyloid deposition, we found evidence for sex- and race-dependent associations. However, findings from subgroup analyses should be interpreted with caution.

%B J Alzheimers Dis %V 66 %P 1041-1052 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400093?dopt=Abstract %R 10.3233/JAD-180469 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of Motoric Cognitive Risk Syndrome with Cardiovascular Disease and Risk Factors: Results from an Original Study and Meta-Analysis. %A Beauchet, Olivier %A Sekhon, Harmehr %A Barden, John %A Liu-Ambrose, Teresa %A Chester, Victoria L %A Szturm, Tony %A Grenier, Sébastien %A Léonard, Guillaume %A Bherer, Louis %A Allali, Gilles %X

BACKGROUND: Motoric cognitive risk (MCR) syndrome, a recently described pre-dementia syndrome, has been associated with cardiovascular disease and their risk factors (CVDRF).

OBJECTIVE: To determine whether MCR syndrome was associated with CVDRF in French community-dwelling older adults, and to quantitatively evaluate, with a systematic review and meta-analysis, the association of MCR syndrome with CVDRF.

METHODS: Based on a cross-sectional design, 238 older adults without dementia were selected from the French GAIT study. An English and French systematic Medline and Embase search (without limiting date of publication) was also conducted in February 2017 using the terms "motoric cognitive risk syndrome" OR "motoric cognitive risk" OR "motoric risk". The systematic review and meta-analysis included 8 studies. CVDRF were defined as cardiovascular diseases, hypertension, diabetes, stroke, obesity and abnormal waist-hip ratio (WHR).

RESULTS: The prevalence of MCR syndrome in the current original study was 16.8%. MCR syndrome was associated with abnormalWHR(Odds ratio [OR] >2.8 with p < 0.020) and high blood pressure (OR >2.5 with p < 0.025). Of the 202 originally identified abstracts, 7 (3.5%) were selected for the systematic review. The meta-analysis showed that all pooled OR were significant with a p-value <0.001 (OR = 1.41 for cardiovascular diseases, 1.21 for hypertension, 1.44 for diabetes, 2.05 for stroke, and 1.34 for obesity). When pooling all CVDRF, the overall OR was 1.38 (95% CI, 1.33-1.45) with p-value <0.001.

CONCLUSION: MCR syndrome is significantly associated with CVDRF. These findings suggest that a vascular mechanism may underlie the pathophysiology of MCR syndrome.

%B J Alzheimers Dis %V 64 %P 875-887 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966199?dopt=Abstract %R 10.3233/JAD-180203 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of Plasma Neurofilament Light Chain with Neocortical Amyloid-β Load and Cognitive Performance in Cognitively Normal Elderly Participants. %A Chatterjee, Pratishtha %A Goozee, Kathryn %A Sohrabi, Hamid R %A Shen, Kaikai %A Shah, Tejal %A Asih, Prita R %A Dave, Preeti %A ManYan, Candice %A Taddei, Kevin %A Chung, Roger %A Zetterberg, Henrik %A Blennow, Kaj %A Martins, Ralph N %X

BACKGROUND: The disruption of neurofilament, an axonal cytoskeletal protein, in neurodegenerative conditions may result in neuronal damage and its release into the cerebrospinal fluid and blood. In Alzheimer's disease (AD), neurofilament light chain (NFL), a neurofilament subunit, is elevated in the cerebrospinal fluid and blood.

OBJECTIVE: Investigate the association of plasma NFL with preclinical-AD features, such as high neocortical amyloid-β load (NAL) and subjective memory complaints, and cognitive performance in cognitively normal older adults.

METHODS: Plasma NFL concentrations were measured employing the single molecule array platform in participants from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort, aged 65- 90 years. Participants underwent a battery of neuropsychological testing to evaluate cognitive performance and were categorized as low NAL (NAL-, n = 65) and high NAL (NAL+, n = 35) assessed via PET, and further stratified into subjective memory complainers (SMC; nNAL- = 51, nNAL+ = 25) and non-SMC (nNAL- = 14, nNAL+ = 10) based on the Memory Assessment Clinic- Questionnaire.

RESULTS: Plasma NFL inversely correlated with cognitive performance. No significant difference in NFL was observed between NAL+ and NAL- participants; however, within APOEɛ4 non-carriers, higher NAL was observed in individuals with NFL concentrations within quartiles 3 and 4 (versus quartile 1). Additionally, within the NAL+ participants, SMC had a trend of higher NFL compared to non-SMC.

CONCLUSION: Plasma NFL is inversely associated with cognitive performance in elderly individuals. While plasma NFL may not reflect NAL in individuals with normal global cognition, the current observations indicate that onset of axonal injury, reflected by increased plasma NFL, within the preclinical phase of AD may contribute to the pathogenesis of AD.

%B J Alzheimers Dis %V 63 %P 479-487 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29630554?dopt=Abstract %R 10.3233/JAD-180025 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of the New Variant Tyr424Asp at TBK1 Gene with Amyotrophic Lateral Sclerosis and Cognitive Decline. %A Piaceri, Irene %A Bessi, Valentina %A Matà, Sabrina %A Polito, Cristina %A Tedde, Andrea %A Berti, Valentina %A Bagnoli, Silvia %A Braccia, Arianna %A Del Mastio, Monica %A Pignone, Alberto Moggi %A Pupi, Alberto %A Sorbi, Sandro %A Nacmias, Benedetta %K Aged %K Amyotrophic Lateral Sclerosis %K Aspartic Acid %K C9orf72 Protein %K Cognitive Dysfunction %K DNA Mutational Analysis %K Female %K Fluorodeoxyglucose F18 %K Genetic Association Studies %K Genetic Predisposition to Disease %K Humans %K Italy %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Mutation %K Neuropsychological Tests %K Positron-Emission Tomography %K Protein-Serine-Threonine Kinases %K Tyrosine %X

A new risk gene associated with amyotrophic lateral sclerosis (ALS) has recently been identified: the Tank-binding kinase 1 (TBK1) gene. Up to now, 90 TBK1 variants have been described in ALS patients with or without frontotemporal dementia (FTD), thus making TBK1 the third or fourth most frequent genetic cause of ALS and FTD. A point mutation analysis in a cohort of 69 Italian ALS patients was performed in order to analyze the frequency of TBK1 mutations and the correlation with clinical phenotypes. The analysis identified the novel variant p.Tyr424Asp in a patient with a rapid progression of the disease. Our data supports the implication of TBK1 in ALS pathogenesis in Italy.

%B J Alzheimers Dis %V 61 %P 41-46 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103041?dopt=Abstract %R 10.3233/JAD-170694 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Associations between the Frailty Index and Brain Atrophy: The Treviso Dementia (TREDEM) Registry. %A Gallucci, Maurizio %A Piovesan, Cinzia %A Di Battista, Maria Elena %X

BACKGROUND: Frailty is a condition which is characterized by a reduction in the homeostatic reserves of the individual and which entails an increased vulnerability to stressful endogenous and exogenous agents. The Frailty Index (FI), proposed by Rockwood, was designed following an accumulation of deficits model: the greater the number of deficits in a given individual, the greater the degree of frailty.

OBJECTIVE: The aim of this study was to verify the existence of associations between FI and cerebral atrophy.

METHODS: The TREDEM Register (Treviso Dementia) provided retrospective observational data from 1,584 patients. The FI was calculated based on 50 variables comprising diseases, disability, behavioral disturbances, and blood chemistry parameters. The severity of atrophy in the cortical and subcortical regions, such as the amplitude of the lateral ventricles, were detected by computerized axial tomography (CAT). Multiple logistic regression models using the stepwise backward method were used to analyze possible associations between FI and atrophy.

RESULTS: For each increment of one hundredth of the FI, the probability of cortical atrophy increases by 2%. The female gender is a protective factor for cortical and subcortical atrophy. At each increase of one percent of the FI, the probability of a severe degree of cortical atrophy increases by 3%. The FI was significantly associated with frontal and temporal cortical atrophy. The relationship between overall subcortical atrophy and the FI was not significant, whereas it was the one with the severe degree of subcortical atrophy. The FI is significantly associated with the atrophy of the peri-insular subcortical region. Similar associations were found considering only demented patients.

CONCLUSION: The FI is associated with the presence, degree, and some localization of cerebral atrophy in a population of cognitive-decline patients.

%B J Alzheimers Dis %V 62 %P 1623-1634 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504533?dopt=Abstract %R 10.3233/JAD-170938 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Associations between Use of Specific Analgesics and Concentrations of Amyloid-β 42 or Phospho-Tau in Regions of Human Cerebral Cortex. %A Flanagan, Margaret E %A Larson, Eric B %A Walker, Rod L %A Keene, C Dirk %A Postupna, Nadia %A Cholerton, Brenna %A Sonnen, Joshua A %A Dublin, Sascha %A Crane, Paul K %A Montine, Thomas J %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Analgesics %K Analgesics, Opioid %K Anti-Inflammatory Agents, Non-Steroidal %K Autopsy %K Cerebral Cortex %K Female %K Humans %K Logistic Models %K Male %K Peptide Fragments %K Prospective Studies %K tau Proteins %X

Analgesics are commonly used by older adults, raising the question of whether their use might contribute to dementia risk and neuropathologic changes of Alzheimer's disease (AD). The Adult Changes in Thought (ACT) study is a population-based study of brain aging and incident dementia among people 65 years or older who are community dwelling and not demented at entry. Amyloid-β (Aβ)42 and phospho-tau were quantified using Histelide in regions of cerebral cortex from 420 brain autopsies. Total standard daily doses of prescription opioid and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) exposure during a defined 10-year exposure window were identified using automated pharmacy dispensing data and used to classify people as having no/low, intermediate, or high exposure. People with high NSAID exposure had significantly greater Aβ42 concentration in middle frontal gyrus and superior and middle temporal gyri, but not inferior parietal lobule; no Aβ42 regional concentration was associated with prescription opioid usage. People with high opioid usage had significantly greater concentration of phospho-tau in middle frontal gyrus than people with little-to-no opioid usage. Consistent with our previous studies, findings suggest that high levels of NSAID use in older individuals may promote Aβ42 accumulation in cerebral cortex.

%B J Alzheimers Dis %V 61 %P 653-662 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226863?dopt=Abstract %R 10.3233/JAD-170414 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Associations of Angiotensin Converting Enzyme-1 and Angiotensin II Blood Levels and Cognitive Function. %A Yasar, Sevil %A Varma, Vijay R %A Harris, Gregory C %A Carlson, Michelle C %X

BACKGROUND: Emerging evidence suggests a possible role of the renin angiotensin system in the pathophysiologic process of Alzheimer's disease, of which angiotensin converting enzyme-1 (ACE-1) and angiotensin II (ANGII) are important proteins. Few studies evaluated associations between blood ACE-1 and none between ANGII levels, and cognition.

OBJECTIVE: Our pilot study was aimed to examine associations between blood ACE-1 and ANG II levels and cognitive function in non-demented participants at baseline and over a 1-year period.

METHODS: 56 participants were included from the Brain Health Substudy of the Baltimore Experience Corps Study. Linear regression analysis, adjusting for confounders, was used to determine associations between baseline ACE-1 and ANGII, and baseline and 1-year follow-up measures of psychomotor and processing speed, executive function, verbal learning memory and working memory, and whether these associations were mediated by blood pressure.

RESULTS: Participants were predominantly female (75%), African-American (93%), with mean age of 67.8 years and education of 14.3 years. There were no associations between baseline ACE-1 or ANGII levels and cognitive function; however, there were significant association between baseline ACE-1 levels and 1-year follow-up Trail Making Test, Part A (β= 0.003, p = 0.04) and Digit Span (β= -0.001, p = 0.02).

CONCLUSIONS: In this cognitively intact sample, elevated ACE-1 levels were associated with worse processing speed and working memory after 1 year. Findings from this pilot study suggest that changes in the RAS are associated with alterations in cognitive function warranting further assessment of the role of RAS in neurodegenerative disorders.

%B J Alzheimers Dis %V 63 %P 655-664 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660936?dopt=Abstract %R 10.3233/JAD-170944 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Associations of Dietary Protein and Fiber Intake with Brain and Blood Amyloid-β. %A Fernando, W M A D Binosha %A Rainey-Smith, Stephanie R %A Gardener, Samantha L %A Villemagne, Victor L %A Burnham, Samantha C %A Macaulay, S Lance %A Brown, Belinda M %A Gupta, Veer Bala %A Sohrabi, Hamid R %A Weinborn, Michael %A Taddei, Kevin %A Laws, Simon M %A Goozee, Kathryn %A Ames, David %A Fowler, Christopher %A Maruff, Paul %A Masters, Colin L %A Salvado, Olivier %A Rowe, Christopher C %A Martins, Ralph N %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Australia %K Biomarkers %K Brain %K Cognition %K Cohort Studies %K Cross-Sectional Studies %K Dietary Fiber %K Dietary Proteins %K Female %K Humans %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %X

Accumulating evidence suggests a diet high in protein and fiber may confer some protection against Alzheimer's disease (AD). However, no human studies to-date have assessed the relationship between protein and fiber intake, and plasma and brain amyloid-β (Aβ). Consequently, this cross-sectional study, investigated the association of self-reported dietary intakes of protein and fiber, with plasma and brain Aβ burden (n = 541, and n = 162 respectively), in a well-characterized cohort of cognitively normal older adults, drawn from the larger Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. We observed 12.59 and 8.43 higher odds of 'high' brain Aβ burden (PiB PET SUVR≥1.5) if protein intake fell in the lowest and middle tertile, respectively, compared to the highest tertile (p = 0.008; p = 0.013). Thus, in this cohort, the more protein consumed, the less likelihood of 'high' Aβ burden in the brain. No other significant associations were observed. The results of this study highlight the potentially protective impact of high dietary protein intake on brain Aβ burden in older adults, before objective memory decline is apparent. While longitudinal validation is required, these findings may assist in the development of dietary approaches aimed at preventing or delaying AD onset.

%B J Alzheimers Dis %V 61 %P 1589-1598 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376865?dopt=Abstract %R 10.3233/JAD-170742 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Associations of Genetic Susceptibility to Alzheimer's Disease with Adiposity and Cardiometabolic Risk Factors among Children in a 2-Year Follow-up Study. %A Haapala, Eero A %A Paananen, Jussi %A Hiltunen, Mikko %A Lakka, Timo A %X

We investigated the associations of genetic risk score (GRS) for Alzheimer's disease and apolipoprotein E (APOE) ɛ variant with cardiometabolic risk factors during 2-year follow-up in children and whether body fat percentage (BF%) modify these associations. A population-based sample of 469 children (246 boys, 223 girls) at baseline and 398 children (201 boys, 197 girls) at 2-year follow-up participated in the study. Genotyping was performed using the Illumina Custom Infinium CardioMetabo BeadChip and the Illumina Infinium HumanCoreExome BeadChip. The GRS was calculated using information on nine independent gene variants available in our genomic data. We assessed BF%, waist circumference, insulin, glucose, triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and systolic and diastolic blood pressure. We computed a cardiometabolic risk score and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). In boys, the GRS was not associated with cardiometabolic risk factors. In girls, GRS was directly associated with LDL cholesterol (β= 0.133, 95% CI = 0.002 to 0.262) at baseline and with a higher cardiometabolic risk score (β= 0.154, 95% CI = 0.015 to 0.294), glucose (β= 0.143, 95% CI = 0.003 to 0.284), and HOMA-IR (β= 0.141, 95% CI = 0.004 to 0.278) at 2-year follow-up. GRS was directly associated with a cardiometabolic risk score at baseline and 2-year follow-up among girls in the highest third of BF% at baseline, but not in other girls (p < 0.05 for interaction). Children with the APOEɛ3/3 genotype had higher LDL cholesterol at and 2-year follow-up than those with the APOEɛ2/3 genotype. In conclusion, GRS was associated with increased cardiometabolic risk in girls and especially those with higher BF%.

%B J Alzheimers Dis %V 64 %P 587-595 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914036?dopt=Abstract %R 10.3233/JAD-180216 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Atherosclerosis, Hypertension, and Diabetes in Alzheimer's Disease, Vascular Dementia, and Mixed Dementia: Prevalence and Presentation. %A Javanshiri, Keivan %A Waldö, Maria Landqvist %A Friberg, Niklas %A Sjövall, Fredrik %A Wickerström, Karin %A Haglund, Mattias %A Englund, Elisabet %X

BACKGROUND: Alzheimer's disease (AD) is the most prevalent cause of dementia with vascular dementia (VaD) being second alongside with mixed AD and VaD, according to some. For some time, it has been proposed that cardiovascular disease (CaVD), hypertension, and diabetes mellitus (DM), which are known risk factors for VaD, also are associated with and contribute to the development of AD.

OBJECTIVE: The aim of this study was to investigate the prevalence of these proposed general risk factors, and to document presence of CaVD as evidenced from clinical records or from autopsy findings, further to correlate these with the diagnoses AD, VaD and mixed AD-VaD (MD), respectively.

METHODS: Autopsy reports at the Clinical Department of Pathology in Lund from 1992-2017 were analyzed. All cases with a complete autopsy report and a neuropathologically diagnosed dementia disorder (AD, VaD, or MD) were selected on the condition of a clinical diagnosis of dementia. Clinical data were retrieved through medical records and the Swedish National Diabetes Register (NDR). A total of 268 subjects were included.

RESULTS: In AD, there was less CaVD as significantly less organ/tissue findings (p < 0.05), significantly less hypertension (p < 0.001), and likewise significantly less DM (p = 0.0014) than in VaD, with the MD group results being set between these two in all aspects studied.

CONCLUSION: AD and VaD exhibit such different profiles of organ and vascular damage as well as of hypertension and DM that they clearly point toward different pathogenic origin with low likelihood of shared risk factors.

%B J Alzheimers Dis %V 65 %P 1247-1258 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149459?dopt=Abstract %R 10.3233/JAD-180644 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Atrophy in Distributed Networks Predicts Cognition in Alzheimer's Disease and Type 2 Diabetes. %A Buss, Stephanie S %A Padmanabhan, Jaya %A Saxena, Sadhvi %A Pascual-Leone, Alvaro %A Fried, Peter J %X

BACKGROUND: Alzheimer's disease (AD) and type 2 diabetes (T2DM) are common causes of cognitive decline among older adults and share strong epidemiological links. Distinct patterns of cortical atrophy are observed in AD and T2DM, but robust comparisons between structure-function relationships across these two disease states are lacking.

OBJECTIVE: To compare how atrophy within distributed brain networks is related to cognition across the spectrum of cognitive aging.

METHODS: The relationship between structural MRI changes and cognition was studied in 22 mild-to-moderate AD, 28 T2DM, and 27 healthy participants. Cortical thickness measurements were obtained from networks of interest (NOIs) matching the limbic, default, and frontoparietal resting-state networks. Composite cognitive scores capturing domains of global cognition, memory, and executive function were created. Associations between cognitive scores and the NOIs were assessed using linear regression, with age as a covariate. Within-network General Linear Model (GLM) analysis was run in Freesurfer 6.0 to visualize differences in patterns of cortical atrophy related to cognitive function in each group. A secondary analysis examined hemispheric differences in each group.

RESULTS: Across all groups, cortical atrophy within the limbic NOI was significantly correlated with Global Cognition (p = 0.009) and Memory Composite (p = 0.002). Within-network GLM analysis and hemispheric analysis revealed qualitatively different patterns of atrophy contributing to cognitive dysfunction between AD and T2DM.

CONCLUSION: Brain network atrophy is related to cognitive function across AD, T2DM, and healthy participants. Differences in cortical atrophy patterns were seen between AD and T2DM, highlighting neuropathological differences.

%B J Alzheimers Dis %V 65 %P 1301-1312 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149455?dopt=Abstract %R 10.3233/JAD-180570 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Automated Multi-Atlas Segmentation of Hippocampal and Extrahippocampal Subregions in Alzheimer's Disease at 3T and 7T: What Atlas Composition Works Best? %A Xie, Long %A Shinohara, Russell T %A Ittyerah, Ranjit %A Kuijf, Hugo J %A Pluta, John B %A Blom, Kim %A Kooistra, Minke %A Reijmer, Yael D %A Koek, Huiberdina L %A Zwanenburg, Jaco J M %A Wang, Hongzhi %A Luijten, Peter R %A Geerlings, Mirjam I %A Das, Sandhitsu R %A Biessels, Geert Jan %A Wolk, David A %A Yushkevich, Paul A %A Wisse, Laura E M %X

BACKGROUND: Multi-atlas segmentation, a popular technique implemented in the Automated Segmentation of Hippocampal Subfields (ASHS) software, utilizes multiple expert-labelled images ("atlases") to delineate medial temporal lobe substructures. This multi-atlas method is increasingly being employed in early Alzheimer's disease (AD) research, it is therefore becoming important to know how the construction of the atlas set in terms of proportions of controls and patients with mild cognitive impairment (MCI) and/or AD affects segmentation accuracy.

OBJECTIVE: To evaluate whether the proportion of controls in the training sets affects the segmentation accuracy of both controls and patients with MCI and/or early AD at 3T and 7T.

METHODS: We performed cross-validation experiments varying the proportion of control subjects in the training set, ranging from a patient-only to a control-only set. Segmentation accuracy of the test set was evaluated by the Dice similarity coeffiecient (DSC). A two-stage statistical analysis was applied to determine whether atlas composition is linked to segmentation accuracy in control subjects and patients, for 3T and 7T.

RESULTS: The different atlas compositions did not significantly affect segmentation accuracy at 3T and for patients at 7T. For controls at 7T, including more control subjects in the training set significantly improves the segmentation accuracy, but only marginally, with the maximum of 0.0003 DSC improvement per percent increment of control subject in the training set.

CONCLUSION: ASHS is robust in this study, and the results indicate that future studies investigating hippocampal subfields in early AD populations can be flexible in the selection of their atlas compositions.

%B J Alzheimers Dis %V 63 %P 217-225 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614654?dopt=Abstract %R 10.3233/JAD-170932 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Aβ42/Aβ40 and Aβ42/Aβ38 Ratios Are Associated with Measures of Gait Variability and Activities of Daily Living in Mild Alzheimer's Disease: A Pilot Study. %A Koychev, Ivan %A Galna, Brook %A Zetterberg, Henrik %A Lawson, Jennifer %A Zamboni, Giovanna %A Ridha, Basil H %A Rowe, James B %A Thomas, Alan %A Howard, Robert %A Malhotra, Paresh %A Ritchie, Craig %A Lovestone, Simon %A Rochester, Lynn %X

Gait disturbances are some of the earliest changes in dementia and their monitoring presents an opportunity for early diagnosis. The exact relationship between gait and well-established biomarkers of Alzheimer's disease (AD) remains to be clarified. In this study we compared gait-related measures with cerebrospinal fluid (CSF) markers of AD pathology. We recruited seventeen participants with mild AD in a multi-site study and performed gait assessment as well as lumbar punctures to obtain CSF. CSF Aβ42/Aβ40 and Aβ42/Aβ38 correlated positively with measures of variability (step time and step length) in the clinic-based assessments. This was driven by a negative relationship between gait variability and Aβ40 and Aβ38 but not Aβ42.The amyloid ratios and gait variability measures were also associated with more severe functional impairment. We interpret these data as an indication that increasing amyloid production (i.e., increasing Aβ40 and Aβ38) is associated with diminishing cognitive-motor control of gait. These preliminary results suggest that the two amyloid ratios may be a marker of the earliest disturbances in the interplay between cognitive and motor control which characterize dementia.

%B J Alzheimers Dis %V 65 %P 1377-1383 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30198873?dopt=Abstract %R 10.3233/JAD-180622 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Behavioral and Neuropsychiatric Disorders in Alzheimer's Disease. %A Cortés, Nicole %A Andrade, Víctor %A Maccioni, Ricardo B %X

Alzheimer's disease (AD) is the most frequent type of dementia in the elderly, severely affecting functional and executive skills of subjects suffering from this disease. Moreover, the distress of caregivers as well as the social implications constitute a critical issue for families. Furthermore, cognitive impairment, along with behavioral disorders and neuropsychiatric symptoms are characteristics of AD. Although these are present with variations in prevalence, intensity, and progression, an important core of them is visible before cognitive impairment, especially depression and apathy, which affect at least 50% of patients. The most updated literature shows that depression and/or behavioral and neuropsychiatric symptoms (BNS) are part of the initial phase of the disease rather than just a risk factor. Thus, mood disorders are associated with anomalies in specific brain regions that disturb the normal balance of neurotransmission. This in turn is linked with an inflammatory pathway that leads to microglial activation and aggregated neurofibrillary tangle formation, finally triggering neuronal loss, according to our neuroimmunomodulation theory. Altogether, inflammation and tau aggregation are observed in preclinical stages, preceding the BNS of patients, which in turn are exhibited earlier than cognitive and functional impairment detected in AD. This review is focused on the latest insights of cellular and molecular processes associated with BNS in asymptomatic early-onset stages of AD. An important medical research focus is to improve quality of life of patients, through prevention and treatments of AD, and the study of behavioral disorders and early event in AD pathogenesis has a major impact.

%B J Alzheimers Dis %8 2018 Apr 25 %G eng %R 10.3233/JAD-180005 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) Scale: Comprehensive Assessment of Psychopathology in Down Syndrome. %A Dekker, Alain D %A Sacco, Silvia %A Carfi, Angelo %A Benejam, Bessy %A Vermeiren, Yannick %A Beugelsdijk, Gonny %A Schippers, Mieke %A Hassefras, Lyanne %A Eleveld, José %A Grefelman, Sharina %A Fopma, Roelie %A Bomer-Veenboer, Monique %A Boti, Mariángeles %A Oosterling, G Danielle E %A Scholten, Esther %A Tollenaere, Marleen %A Checkley, Laura %A Strydom, Andre %A Van Goethem, Gert %A Onder, Graziano %A Blesa, Rafael %A Zu Eulenburg, Christine %A Coppus, Antonia M W %A Rebillat, Anne-Sophie %A Fortea, Juan %A De Deyn, Peter P %X

People with Down syndrome (DS) are prone to develop Alzheimer's disease (AD). Behavioral and psychological symptoms of dementia (BPSD) are core features, but have not been comprehensively evaluated in DS. In a European multidisciplinary study, the novel Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) scale was developed to identify frequency and severity of behavioral changes taking account of life-long characteristic behavior. 83 behavioral items in 12 clinically defined sections were evaluated. The central aim was to identify items that change in relation to the dementia status, and thus may differentiate between diagnostic groups. Structured interviews were conducted with informants of persons with DS without dementia (DS, n = 149), with questionable dementia (DS+Q, n = 65), and with diagnosed dementia (DS+AD, n = 67). First exploratory data suggest promising interrater, test-retest, and internal consistency reliability measures. Concerning item relevance, group comparisons revealed pronounced increases in frequency and severity in items of anxiety, sleep disturbances, agitation & stereotypical behavior, aggression, apathy, depressive symptoms, and eating/drinking behavior. The proportion of individuals presenting an increase was highest in DS+AD, intermediate in DS+Q, and lowest in DS. Interestingly, among DS+Q individuals, a substantial proportion already presented increased anxiety, sleep disturbances, apathy, and depressive symptoms, suggesting that these changes occur early in the course of AD. Future efforts should optimize the scale based on current results and clinical experiences, and further study applicability, reliability, and validity. Future application of the scale in daily care may aid caregivers to understand changes, and contribute to timely interventions and adaptation of caregiving.

%B J Alzheimers Dis %V 63 %P 797-819 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689719?dopt=Abstract %R 10.3233/JAD-170920 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Behavioral Variant Frontotemporal Dementia Performance on a Range of Saccadic Tasks. %A Douglass, Amanda %A Walterfang, Mark %A Velakoulis, Dennis %A Abel, Larry %X

BACKGROUND: Saccadic paradigms display changes across a number of degenerative conditions reflecting changes in the oculomotor pathway which in some conditions have been linked to disease presentation.

OBJECTIVE: To examine a novel range of saccadic paradigms in behavioral variant frontotemporal dementia (bvFTD).

METHODS: Prosaccade, predictive, self-paced, memory-guided, and anti-saccade tasks were examined in bvFTD patients and controls.

RESULTS: A significant increase in latency for the bvFTD group was seen in all tasks. Self-paced saccades are reduced in number, memory-guided saccades display an increase in errors. Predictive saccades show an increased latency that does not remain when prosaccade latency changes are accounted for. While changes were seen across a range of paradigms, no individual task completely separated bvFTD from control participants.

CONCLUSION: bvFTD patients as a group display a number of changes on saccadic testing which may reflect the frontal lobe changes seen in this condition.

%B J Alzheimers Dis %V 65 %P 231-242 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040708?dopt=Abstract %R 10.3233/JAD-170797 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Beneficial Effects of Sideritis scardica and Cichorium spinosum against Amyloidogenic Pathway and Tau Misprocessing in Alzheimer's Disease Neuronal Cell Culture Models. %A Chalatsa, Ioanna %A Arvanitis, Demetrios A %A Mikropoulou, Eleni V %A Giagini, Athina %A Papadopoulou-Daifoti, Zeta %A Aligiannis, Nektarios %A Halabalaki, Maria %A Tsarbopoulos, Anthony %A Skaltsounis, Leandros A %A Sanoudou, Despina %X

BACKGROUND: Natural products are a significantly underutilized source of potential treatments against human disease. Alzheimer's disease (AD) is a prime example of conditions that could be amenable to such treatments as suggested by recent findings.

OBJECTIVE: Aiming to identify novel potentially therapeutic approaches against AD, we assessed the effects of Cichorium spinosum and Sideritis scardica extracts, both distinct components of the Mediterranean diet.

METHODS/RESULTS: After the detailed characterization of the extracts' composition using LC-HRMS methods, they were evaluated on two AD neuronal cell culture models, namely the AβPP overexpressing SH-SY5Y-AβPP and the hyperphosphorylated tau expressing PC12-htau. Initially their effect on cell viability of SH-SY5Y and PC12 cells was examined, and subsequently their downstream effects on AβPP and tau processing pathways were investigated in the SH-SY5Y-AβPP and PC12-htau cells. We found that the S. scardica and C. spinosum extracts have similar effects on tau, as they both significantly decrease total tau, the activation of the GSK3β, ERK1 and/or ERK2 kinases of tau, as well as tau hyperphosphorylation. Furthermore, both extracts appear to promote AβPP processing through the alpha, non-amyloidogenic pathway, albeit through partly different mechanisms.

CONCLUSIONS: These findings suggest that C. spinosum and S. scardica could have a notable potential in the prevention and/or treatment of AD, and merit further investigations at the in vivo level.

%B J Alzheimers Dis %V 64 %P 787-800 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914017?dopt=Abstract %R 10.3233/JAD-170862 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Berberine Alleviates Tau Hyperphosphorylation and Axonopathy-Associated with Diabetic Encephalopathy via Restoring PI3K/Akt/GSK3β Pathway. %A Wang, Shanshan %A He, Benhong %A Hang, Weijian %A Wu, NingHua %A Xia, Liangtao %A Wang, Xu %A Zhang, Qianying %A Zhou, Xinwen %A Feng, Zuohua %A Chen, Qingjie %A Chen, Juan %X

BACKGROUND: Axonopathy is closely linked to the development of diabetic encephalopathy induced by type II diabetes (T2D). Berberine has been shown to cross the blood-brain barrier and holds promising effect for neuronal damage in diabetes.

OBJECTIVE: The present study investigated the protective effect and the underlying mechanism of berberine on neuronal axonopathy in both in vitro and in vivo models.

METHODS: High glucose/high fat diet and streptozotocin injection-induced T2D rat model was used. Berberine was administered p.o. to T2D rat model for 10 weeks. Morris water maze test, in vivo neuronal tracing, immunohistochemistry, and western blot analysis were performed to evaluate the protective effects of berberine in T2D-induced diabetic encephalopathy rats. Primary cultured neurons were used to further explore the underlying mechanisms in vitro.

RESULTS: Berberine dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Berberine significantly attenuated memory impairment, axonopathy, and tau hyperphosphorylation, and also restored PI3K/Akt/GSK3β signaling pathway in T2D rats. In vitro, berberine induced an increase in the phosphorylation of PI3K/Akt as well as GSK3β in high glucose-treated primary neurons. Furthermore, berberine-induced PI3K/Akt activation also resulted in the dephosphorylation of tau protein, which could improve axonal transport impairment in high glucose-treated primary neurons. Pretreated neurons with LY294002, an inhibitor of PI3K, partially blocked berberine-inhibited tau phosphorylation and berberine-activated PI3K/Akt signaling pathway.

CONCLUSIONS: Berberine exerts the protective effect against cognitive deficits by improving tau hyperphosphorylation and the axonal damage through restoring PI3K/Akt/GSK3β signaling pathway.

%B J Alzheimers Dis %V 65 %P 1385-1400 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30175975?dopt=Abstract %R 10.3233/JAD-180497 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Biallelic Loss of Function of SORL1 in an Early Onset Alzheimer's Disease Patient. %A Le Guennec, Kilan %A Tubeuf, Hélène %A Hannequin, Didier %A Wallon, David %A Quenez, Olivier %A Rousseau, Stéphane %A Richard, Anne-Claire %A Deleuze, Jean-François %A Boland, Anne %A Frebourg, Thierry %A Gaildrat, Pascaline %A Campion, Dominique %A Martins, Alexandra %A Nicolas, Gaël %K Alzheimer Disease %K Case-Control Studies %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genetic Variation %K Humans %K LDL-Receptor Related Proteins %K Male %K Membrane Transport Proteins %K Middle Aged %K Risk Factors %X

Heterozygous SORL1 protein truncating variants (PTV) are a strong risk factor for early-onset Alzheimer's disease (EOAD). In case control studies performed at the genome-wide level, PTV definition is usually straightforward. Regarding splice site variants, only those affecting canonical sites are typically included. Some other variants, not annotated as PTV, could, however, affect splicing and hence result in a loss of SORL1 function. We took advantage of the whole exome sequencing data from the 9/484 patients with a previously reported SORL1 PTV in the French EOAD series and searched for a second variant which may affect splicing and eventually result in more than 50% loss of function overall. We found that one patient, known to carry a variant predicted to disrupt the canonical 5' splice site of exon 8, also carried a second novel intronic variant predicted to affect SORL1 splicing of exon 29. Segregation analysis showed that the second variant was located in trans from the known PTV. We performed ex vivo minigene splicing assays and showed that both variants led to the generation of transcripts containing a premature stop codon. This is therefore the first evidence of a human carrying biallelic SORL1 PTV. This patient had a family history of dementia in both maternal and paternal lineages with later ages of onset than the proband himself. However, his 55 years age at onset was in the same ranges as previously published SORL1 heterozygous PTV carriers. This suggests that biallelic loss of SORL1 function is an extremely rare event that was not associated with a dramatically earlier age at onset than heterozygous SORL1 loss-of-function variant carriers, in this single patient.

%B J Alzheimers Dis %V 62 %P 821-831 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480197?dopt=Abstract %R 10.3233/JAD-170981 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Bi-directional Association of Cerebrospinal Fluid Immune Markers with Stage of Alzheimer's Disease Pathogenesis. %A Meyer, Pierre-François %A Savard, Mélissa %A Poirier, Judes %A Labonte, Anne %A Rosa-Neto, Pedro %A Weitz, Tara M %A Town, Terrence %A Breitner, John %X

Immune mechanisms may be important in the pathogenesis of Alzheimer's disease (AD). Yet, studies comparing cerebrospinal fluid (CSF) and plasma immune marker levels of healthy and demented individuals have yielded conflicting results. We analyzed CSF from 101 members of the parental history-positive PREVENT-AD cohort of healthy aging adults, and 237 participants without dementia from the initial cohort of the Alzheimer's Disease Neuroimaging Initiative (ADNI-1). Following recent practice, we used the biomarkers total-tau and amyloid-β1-42 to allocate participants from each study into four stages of AD pathogenesis: Stage 0 (no abnormality), Stage 1 (reduced amyloid-β1-42), Stage 2 (reduced amyloid-β1-42 and increased total-tau), or "Suspected Non-Alzheimer Pathology" (elevated total-tau only). Investigating the PREVENT-AD participants' CSF assay results for 19 immune/inflammatory markers, we found six that showed a distinct bi-directional relationship with pathogenetic stage. Relative to Stage 0, these were diminished at Stage 1 but strongly increased at Stage 2. Among the ADNI participants (90 healthy controls and 147 with mild cognitive impairment), we found that 23 of 83 available CSF markers also showed this distinct pattern. These results support recent observations that immune activation may become apparent only after the onset of both amyloid and tau pathologies. Unexpectedly, they also suggest that immune marker activity may diminish along with earliest appearance of amyloid-β plaque pathology. These findings may explain discordant results from past studies, and suggest the importance of characterizing the extent of AD pathology when comparing clinical groups.

%B J Alzheimers Dis %V 63 %P 577-590 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660934?dopt=Abstract %R 10.3233/JAD-170887 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Bioactive Food Abates Metabolic and Synaptic Alterations by Modulation of Gut Microbiota in a Mouse Model of Alzheimer's Disease. %A Syeda, Tauqeerunnisa %A Sanchez-Tapia, Mónica %A Pinedo-Vargas, Laura %A Granados, Omar %A Cuervo-Zanatta, Daniel %A Rojas-Santiago, Eleazar %A Díaz-Cintra, Sof A %A Torres, Nimbe %A Perez-Cruz, Claudia %X

Recent investigations have demonstrated an important role of gut microbiota (GM) in the pathogenesis of Alzheimer's disease (AD). GM modulates a host's health and disease by production of several substances, including lipopolysaccharides (LPS) and short-chain fatty acids (SCFAs), among others. Diet can modify the composition and diversity of GM, and ingestion of a healthy diet has been suggested to lower the risk to develop AD. We have previously shown that bioactive food (BF) ingestion can abate neuroinflammation and oxidative stress and improve cognition in obese rats, effects associated with GM composition. Therefore, BF can impact the gut-brain axis and improved behavior. In this study, we aim to explore if inclusion of BF in the diet may impact central pathological markers of AD by modulation of the GM. Triple transgenic 3xTg-AD (TG) female mice were fed a combination of dried nopal, soy, chia oil, and turmeric for 7 months. We found that BF ingestion improved cognition and reduced Aβ aggregates and tau hyperphosphorylation. In addition, BF decreased MDA levels, astrocyte and microglial activation, PSD-95, synaptophysin, GluR1 and ARC protein levels in TG mice. Furthermore, TG mice fed BF showed increased levels of pGSK-3β. GM analysis revealed that pro-inflammatory bacteria were more abundant in TG mice compared to wild-type, while BF ingestion was able to restore the GM's composition, LPS, and propionate levels to control values. Therefore, the neuroprotective effects of BF may be mediated, in part, by modulation of GM and the release of neurotoxic substances that alter brain function.

%B J Alzheimers Dis %V 66 %P 1657-1682 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30475761?dopt=Abstract %R 10.3233/JAD-180556 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Biological Factors Contributing to the Response to Cognitive Training in Mild Cognitive Impairment. %A Peter, Jessica %A Schumacher, Lena V %A Landerer, Verena %A Abdulkadir, Ahmed %A Kaller, Christoph P %A Lahr, Jacob %A Klöppel, Stefan %K Aged %K Aged, 80 and over %K Analysis of Variance %K Apolipoproteins E %K Biological Factors %K Cognitive Behavioral Therapy %K Cognitive Dysfunction %K Entorhinal Cortex %K Female %K Follow-Up Studies %K Functional Laterality %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Recall %K Middle Aged %K Neuropsychological Tests %K Reaction Time %K Spatial Navigation %K Treatment Outcome %X

In mild cognitive impairment (MCI), small benefits from cognitive training were observed for memory functions but there appears to be great variability in the response to treatment. Our study aimed to improve the characterization and selection of those participants who will benefit from cognitive intervention. We evaluated the predictive value of disease-specific biological factors for the outcome after cognitive training in MCI (n = 25) and also considered motivation of the participants. We compared the results of the cognitive intervention group with two independent control groups of MCI patients (local memory clinic, n = 20; ADNI cohort, n = 302). The primary outcome measure was episodic memory as measured by verbal delayed recall of a 10-word list. Episodic memory remained stable after treatment and slightly increased 6 months after the intervention. In contrast, in MCI patients who did not receive an intervention, episodic memory significantly decreased during the same time interval. A larger left entorhinal cortex predicted more improvement in episodic memory after treatment and so did higher levels of motivation. Adding disease-specific biological factors significantly improved the prediction of training-related change compared to a model based simply on age and baseline performance. Bootstrapping with resampling (n = 1000) verified the stability of our finding. Cognitive training might be particularly helpful in individuals with a bigger left entorhinal cortex as individuals who did not benefit from intervention showed 17% less volume in this area. When extended to alternative treatment options, stratification based on disease-specific biological factors is a useful step towards individualized medicine.

%B J Alzheimers Dis %V 61 %P 333-345 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154279?dopt=Abstract %R 10.3233/JAD-170580 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Biological, Neuroimaging, and Neurophysiological Markers in Frontotemporal Dementia: Three Faces of the Same Coin. %A Borroni, Barbara %A Benussi, Alberto %A Premi, Enrico %A Alberici, Antonella %A Marcello, Elena %A Gardoni, Fabrizio %A Di Luca, Monica %A Padovani, Alessandro %X

Frontotemporal dementia (FTD) is a heterogeneous clinical, genetic, and neuropathological disorder. Clinical diagnosis and prediction of neuropathological substrates are hampered by heterogeneous pictures. Diagnostic markers are key in clinical trials to differentiate FTD from other neurodegenerative dementias. In the same view, identifying the neuropathological hallmarks of the disease is key in light of future disease-modifying treatments. The aim of the present review is to unravel the progress in biomarker discovery, discussing the potential applications of available biological, imaging, and neurophysiological markers.

%B J Alzheimers Dis %V 62 %P 1113-1123 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171998?dopt=Abstract %R 10.3233/JAD-170584 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Blood Glucose Levels May Exacerbate Executive Function Deficits in Older Adults with Cognitive Impairment. %A Pappas, Colleen %A Small, Brent J %A Andel, Ross %A Laczó, Jan %A Pařízková, Martina %A Ondrej, Lerch %A Hort, Jakub %X

BACKGROUND: Identifying protective factors that promote healthy cognitive aging is of importance due to the growing older adult population. Preventing chronic hyperglycemia may be one such way to preserve cognitive abilities, as high blood glucose levels have been associated with cognitive impairment and decline.

OBJECTIVE: To evaluate the influence of blood glucose levels on cognition among older adults using common neuropsychological tests and a spatial navigation task.

METHODS: The association between cognitive performance and blood glucose levels was assessed among 117 older adults classified as cognitively healthy, subjective cognitive decline, amnestic mild cognitive impairment, or Alzheimer's disease dementia from the Czech Brain Aging Study. Cognitive abilities were measured by tests of verbal memory, nonverbal memory, working memory, visuospatial skills, and executive function. A test of spatial navigation known as the Hidden Goal Task was also used. Blood glucose levels were measured by glycosylated hemoglobin A1c (HbA1c). Analyses were performed using multiple linear regression controlling for age, gender, education, depressive symptoms, diabetes, and cognitive status.

RESULTS: A significant relationship was observed for HbA1c and executive function performance (beta = -2.46, SE = 0.92, p = 0.008). Following moderation analysis, this relationship was significant only among those with cognitive impairment (beta = -4.37, SE = 1.28, p = 0.001, 95% CI [-6.91, -1.83]). Associations between HbA1c and other cognitive domains were not significant (ps >  0.05).

CONCLUSIONS: Higher HbA1c was associated with poorer executive function among persons with cognitive impairment, but not with performance on other cognitive domains. Maintaining proper glucoregulation may help preserve executive function performance among cognitively impaired older adults.

%B J Alzheimers Dis %8 2018 Nov 22 %G eng %R 10.3233/JAD-180693 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Blood Inflammatory Mediators and Cognitive Decline in Alzheimer's Disease: A Two Years Longitudinal Study. %A Julian, Adrien %A Rioux-Bilan, Agnès %A Ragot, Stéphanie %A Krolak-Salmon, Pierre %A Berrut, Gilles %A Dantoine, Thierry %A Hommet, Caroline %A Hanon, Olivier %A Page, Guylène %A Paccalin, Marc %X

Peripheral inflammatory processes are involved in Alzheimer's disease (AD). We aimed to determine whether plasma inflammatory mediator levels at diagnosis are associated with cognitive decline through a 2-year follow-up in AD patients. Patients (n = 109, mean age 79.44 (6.82) years) were included at diagnosis with MMSE scores between 16 and 25, with C-reactive protein <10 mg/L, and without any acute or chronic inflammation status. Plasma IL-1β, IL-6, TNF-α, and CCL5 were measured using Luminex X-MAP technology at baseline, and after one year and two years of follow-up. The mean values of IL-1β, IL-6, TNF-α, and CCL5 at diagnosis were 0.3, 1.94, 6.57, and 69,615.81 pg/mL, respectively. Mean cognitive decline in MMSE was 3.35 points. No correlation between plasmatic value of IL-1β, IL-6, TNF-α, or CCL5 at diagnosis and cognitive decline during the two years of follow-up was found. Cognitive decline in AD does not appear to be predictable by the tested inflammatory mediators.

%B J Alzheimers Dis %V 63 %P 87-92 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614665?dopt=Abstract %R 10.3233/JAD-171131 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Blood Test for Alzheimer's Disease: Progress, Challenges, and Recommendations. %A Kiddle, Steven J %A Voyle, Nicola %A Dobson, Richard J B %X

Ever since the discovery of APOEɛ4 around 25 years ago, researchers have been excited about the potential of a blood test for Alzheimer's disease (AD). Since then researchers have looked for genetic, protein, metabolite, and/or gene expression markers of AD and related phenotypes. However, no blood test for AD is yet being used in the clinical setting. We first review the trends and challenges in AD blood biomarker research, before giving our personal recommendations to help researchers overcome these challenges. While some degree of consistency and replication has been seen across independent studies, several high-profile studies have seemingly failed to replicate. Partly due to academic incentives, there is a reluctance in the field to report predictive ability, to publish negative findings, and to independently replicate the work of others. If this can be addressed, then we will know sooner whether a blood test for AD or related phenotypes with clinical utility can be developed.

%B J Alzheimers Dis %V 64 %P S289-S297 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614671?dopt=Abstract %R 10.3233/JAD-179904 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Bone-Marrow-Derived Microglia-Like Cells Ameliorate Brain Amyloid Pathology and Cognitive Impairment in a Mouse Model of Alzheimer's Disease. %A Kawanishi, Shohei %A Takata, Kazuyuki %A Itezono, Shouma %A Nagayama, Hiroko %A Konoya, Sayaka %A Chisaki, Yugo %A Toda, Yuki %A Nakata, Susumu %A Yano, Yoshitaka %A Kitamura, Yoshihisa %A Ashihara, Eishi %X

Microglia, the primary immune cells in the brain, sense pathogens and tissue damage, stimulate cytokine production, and phagocytosis to maintain homeostasis. Accumulation of amyloid-β peptides (Aβ) in the brain triggers the onset of Alzheimer's disease (AD). Accordingly, promotion of Aβ clearance represents a promising strategy for AD therapy. We previously demonstrated that primary-cultured rat microglia phagocytose Aβ, and that transplantation of these cells ameliorates the Aβ burden in brains of Aβ-injected rats. In this study, we demonstrate that stimulation with colony-stimulating factor-1 efficiently differentiates mouse bone marrow cells into bone marrow-derived microglia-like (BMDML) cells that express markers for microglia, including the recently identified transmembrane protein 119. BMDML cells effectively phagocytose Aβ in vitro, with effects comparable to primary-cultured mouse microglia and greater than peritoneal macrophages. RT-qPCR analysis for cytokine mRNA levels revealed that BMDML cells polarize to a relatively anti-inflammatory state under non-stimulated and inflammatory conditions but exert a pro-inflammatory reaction after lipopolysaccharide treatment. Moreover, BMDML cells hippocampally injected into a mouse model of AD are morphologically similar to the ramified and amoeboid types of residential microglia. Comparisons with simulations assuming a uniform distribution of cells suggest that BMDML cells migrate directionally toward Aβ plaques. We also detected Aβ phagocytosis by BMDML cells, concomitant with a reduction in the number and area of Aβ plaques. Finally, we observed amelioration of cognitive impairment in a mouse model of AD after hippocampal injection of BMDML cells. Our results suggest that BMDML cells have potential as a cell-based disease-modifying therapy against AD.

%B J Alzheimers Dis %V 64 %P 563-585 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914020?dopt=Abstract %R 10.3233/JAD-170994 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Brain Aging and Late-Onset Alzheimer's Disease: A Matter of Increased Amyloid or Reduced Energy? %A Mecocci, Patrizia %A Baroni, Marta %A Senin, Umberto %A Boccardi, Virginia %X

Alzheimer's disease (AD) represents the most common form of dementia in old age subjects, and despite decades of studies, the underlying etiopathogenetic mechanisms remain unsolved. The definition of AD has changed over the past years, offering an ever more detailed definition of pre-morbid and pre-clinical status, but without a similar strong emphasis on the role of aging as the main risk factor. In fact, while early-onset AD is a clear consequence of gene mutations, late-onset AD is more likely due to a gradual accumulation of age-related damages. The pathogenetic amyloid cascade hypothesis has been recently questioned due to multiple clinical failures. Furthermore, several studies reported that cognitively normal elderly have a high amyloid deposition in the brain comparable to the levels observed in old age subjects with AD. This suggests that amyloid accumulation enters into the normal process of aging and what really triggers neuronal death and clinical manifestation in late-onset AD still needs further explanation. In this context, 'normal brain aging' and AD might represent a different pathway of successful or failed capability to adapt brain structures and cerebral functions. Cellular senescence and age-related changes affecting the brain may be considered as biologic manifestations of increasing entropy. Bioenergetic deficits due to mitochondrial dysfunction may lead to progressive neuronal death and clinical expression of dementia. So, increased amyloid in the brain of old age subjects may represent the downstream event expression of a biological system that is cooling down because of its exhaustion and not the core causative factor of late-onset dementia.

%B J Alzheimers Dis %V 64 %P S397-S404 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562513?dopt=Abstract %R 10.3233/JAD-179903 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Brain Amyloid Contribution to Cognitive Dysfunction in Early-Stage Parkinson's Disease: The PPMI Dataset. %A Fiorenzato, Eleonora %A Biundo, Roberta %A Cecchin, Diego %A Frigo, Anna Chiara %A Kim, Jinhee %A Weis, Luca %A Strafella, Antonio P %A Antonini, Angelo %X

BACKGROUND: The pathological processes underlying cognitive impairment in Parkinson's disease (PD) are heterogeneous and the contribution of cerebral amyloid deposits is poorly defined, particularly in the early stages of the disease.

OBJECTIVE: To investigate regional [18F]florbetaben binding to amyloid-β (Aβ) and its contribution to cognitive dysfunction in early stage PD.

METHODS: A multicenter cohort of 48 PD patients from the Parkinson's Progression Marker Initiative (PPMI) underwent [18F]florbetaben positron emission tomography (PET) scanning. Clinical features, including demographic characteristics, motor severity, cerebrospinal fluid (CSF), and cognitive testing were systematically assessed according to the PPMI study protocol. For the purpose of this study, we analyzed various neuropsychological tests assessing all cognitive functions.

RESULTS: There were 10/48 (21%) amyloid positive PD patients (PDAβ+). Increased [18F]florbetaben uptake in widespread cortical and subcortical regions was associated with poorer performance on global cognition, as assessed by Montreal Cognitive Assessment (MoCA), and impaired performance on Symbol Digit Modality test (SDMT). Further, we found that PDAβ+ patients had higher CSF total-tau/Aβ1 - 42 (p = 0.001) and phosphorylated-tau/Aβ1 - 42 in (p = 0.002) compared to amyloid-negative PD.

CONCLUSION: These findings suggest that multiple disease processes are associated with PD cognitive impairment and amyloid deposits may be observed already in early stages. However, prevalence of amyloid positivity is in the range of literature age-matched control population. Increased cortical and subcortical amyloid is associated with poor performance in attentive-executive domains while cognitive deficits at MoCA and SDMT may identify amyloid-related dysfunction in early PD.

%B J Alzheimers Dis %V 66 %P 229-237 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282359?dopt=Abstract %R 10.3233/JAD-180390 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Brain Inflammation Connects Cognitive and Non-Cognitive Symptoms in Alzheimer's Disease. %A Selles, M Clara %A Oliveira, Mauricio M %A Ferreira, Sergio T %X

Alzheimer's disease (AD) is the main form of dementia in the elderly and affects greater than 47 million people worldwide. Care for AD patients poses very significant personal and economic demands on individuals and society, and the situation is expected to get even more dramatic in the coming decades unless effective treatments are found to halt the progression of the disease. Although AD is most commonly regarded as a disease of the memory, the entire brain is eventually affected by neuronal dysfunction or neurodegeneration, which brings about a host of other behavioral disturbances. AD patients often present with apathy, depression, eating and sleeping disorders, aggressive behavior, and other non-cognitive symptoms, which deeply affect not only the patient but also the caregiver's health. These symptoms are usually associated with AD pathology but are often neglected as part of disease progression due to the early and profound impact of disease on memory centers such as the hippocampus and entorhinal cortex. Yet, a collection of findings offers biochemical insight into mechanisms underlying non-cognitive symptoms in AD, and indicate that, at the molecular level, such symptoms share common mechanisms. Here, we review evidence indicating mechanistic links between memory loss and non-cognitive symptoms of AD. We highlight the central role of the pro-inflammatory activity of microglia in behavioral alterations in AD patients and in experimental models of the disease. We suggest that a deeper understanding of non-cognitive symptoms of AD may illuminate a new beginning in AD research, offering a fresh approach to elucidate mechanisms involved in disease progression and potentially unveiling yet unexplored therapeutic targets.

%B J Alzheimers Dis %V 64 %P S313-S327 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710716?dopt=Abstract %R 10.3233/JAD-179925 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Brains for Dementia Research: Evolution in a Longitudinal Brain Donation Cohort to Maximize Current and Future Value. %A Francis, Paul T %A Costello, Helen %A Hayes, Gillian M %X

Brain banking has a long and distinguished past, contributing greatly to our understanding of human neurological and psychiatric conditions. Brain banks have been operationally diverse, collecting primarily end stage disease, with variable quality clinical data available, yet it is now recognized the most informative brain donations are from those in longitudinally studied cohorts. The Brains for Dementia Research (BDR) cohort and program was for planned brain donation across five UK brain banks and one donation point, with standardized operating procedures, following longitudinal clinical and psychometric assessments for people with no cognitive impairment as well as those with dementia. Lay representatives with experience of dementia were involved from inception of BDR and 74.5% of all enquiries about participation came through routes that were directly attributable to or influenced by lay representatives. Ten years after inception, this ongoing project has received over 700 brain donations from the recruited cohort of 3,276 potential brain donors. At cohort census for this paper, 72.2% of the living cohort have no cognitive impairment by assessment, whereas only 28.3% of the donated cohort were without cognitive impairment. It is important that brain banks are agile and reflect the changing needs of the research community, given that 'big data', readiness cohorts, and GWAS demand large sample numbers of highly characterized individuals to facilitate new approaches and understanding of pathological processes in dementia.

%B J Alzheimers Dis %V 66 %P 1635-1644 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30452415?dopt=Abstract %R 10.3233/JAD-180699 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Brazilian Green Propolis Prevents Cognitive Decline into Mild Cognitive Impairment in Elderly People Living at High Altitude. %A Zhu, Aiqin %A Wu, Zhou %A Zhong, Xin %A Ni, Junjun %A Li, Yinglan %A Meng, Jie %A Du, Can %A Zhao, Xue %A Nakanishi, Hiroshi %A Wu, Shizheng %X

BACKGROUND: Systemic inflammation is known as a risk factor of cognitive decline.

OBJECTIVE: To investigate the effects of propolis on cognitive decline and systemic inflammation in elderly people living at high altitude.

METHODS: Sixty participants (average 72.8 years) living at altitude (2,260 meters) were randomized to receive propolis (0.83 g, n = 30) or placebo (n = 30) for 24 months. Cognitive outcomes were assessed using MMSE and serum cytokine levels were measured for 24 months in a double-blind study.

RESULTS: MMSE scores were 26.17 at baseline and 23.87 at 24 months in placebo group. Compared to placebo group, improvements of MMSE scores were significant in propolis-treated subjects (p = 0.007) with a response emerging over time (time points×group interaction, p = 0.016). In addition, the serum IL-1β and IL-6 levels were significantly different across treatments (p < 0.0001) showing upward and downward trends in placebo- and propolis-treated subjects, respectively (p < 0.0001). Serum levels of TNF-α were not significantly different across treatment (p = 0.0528) but with a response emerging over time (time points×group interaction, p = 0.016). In contrast, serum levels of TGFβ1 were significantly different across treatments (p < 0.0001) showing downward and upward trends in placebo- and propolis-treated subjects, respectively. Serum levels of IL-10 were significant for the effect of groups (p = 0.0411). Furthermore, MMSE scores correlated with the decrease in IL-1β and the increase in TGFβ1 in serum.

CONCLUSION: Elderly people living at high altitude developed to MCI in 24 months with exacerbation of systemic inflammation. Ingestion of propolis (>12 months) protected against cognitive decline after systemic inflammation was reduced.

%B J Alzheimers Dis %V 63 %P 551-560 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29630549?dopt=Abstract %R 10.3233/JAD-170630 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Brimapitide Reduced Neuronal Stress Markers and Cognitive Deficits in 5XFAD Transgenic Mice. %A Gourmaud, Sarah %A Thomas, Priscilla %A Thomasseau, Sylvie %A Tible, Marion %A Abadie, Claire %A Paquet, Claire %A Hugon, Jacques %X

Alzheimer's disease (AD) is characterized by accumulations of amyloid-β (Aβ42) and hyperphosphorylated tau proteins, associated with neuroinflammation, synaptic loss, and neuronal death. Several studies indicate that c-Jun N-terminal kinase (JNK) is implicated in the pathological features of AD. We have investigated in 5XFAD mice, the therapeutic effects of Brimapitide, a JNK-specific inhibitory peptide previously tested with higher concentrations in another AD model (TgCRND8). Three-month-old 5XFAD and wild-type littermate mice were treated by intravenous injections of low doses (10 mg/kg) of Brimapitide every 3 weeks, for 3 or 6 months (n = 6-9 per group). Cognitive deficits and brain lesions were assessed using Y-maze, fear-conditioning test, and histological and biochemical methods. Chronic treatment of Brimapitide for 3 months resulted in a reduction of Aβ plaque burden in the cortex of 5XFAD treated mice. After 6 months of treatment, cognitive deficits were reduced but also a significant reduction of cell death markers and the pro-inflammatory IL-1β cytokine in treated mice were detected. The Aβ plaque burden was not anymore modified by the 6 months of treatment. In addition to modulating cognition and amyloid plaque accumulation, depending on the treatment duration, Brimapitide seems experimentally to reduce neuronal stress in 5XFAD mice.

%B J Alzheimers Dis %V 63 %P 665-674 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660941?dopt=Abstract %R 10.3233/JAD-171099 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Call for a Uniform Strategy of Collecting Alzheimer's Disease Costs: A Review and Meta-Analysis. %A Maresova, Petra %A Dolejš, Josef %A Kuca, Kamil %X

BACKGROUND: There is now a general attempt in developed countries to implement strategic plans to fight against Alzheimer's disease and other dementia disorders. Among others, attention is paid to the issues of registers and calculations of economic burden. Currently available calculations of costs are difficult to compare. The problem is a different breakdown of cost categories and non-unified monitoring of cost types.

OBJECTIVE: The aim of this paper is to note the problem of poor availability and inconsistencies in cost monitoring. Furthermore, the intersection of cost items that are comparable and consistently monitored in expert studies are specified.

METHODS: The Web of Science, Elsevier Science Direct, PubMed, and Scopus databases are used in a systematic review. Two independent reviewers screened the identified records and selected relevant articles published in the period from 2010 to 2016. A meta-analysis of costs is performed in four categories related to patients suffering from Alzheimer's disease.

RESULTS: The resulting estimation of total costs per patient per month through meta-analysis is € 3,896, with 95% CI [2078, 5713]. The highest costs arise from informal care following non-medical and medical care.

CONCLUSION: The results confirm assumption that inconsistencies in cost monitoring of the treatment and care of people with dementia exists in Europe. Homogeneity could be assumed only in the medical costs of severe patients. Heterogeneity is assumed in non-medical costs, informal costs. Cost items should be defined and collected more precisely for future more precise monitoring of the economic burden.

%B J Alzheimers Dis %V 63 %P 227-238 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578487?dopt=Abstract %R 10.3233/JAD-171028 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Calpain I Activation Causes GLUT3 Proteolysis and Downregulation of O-GlcNAcylation in Alzheimer's Disease Brain. %A Gu, Jianlan %A Jin, Nana %A Ma, Denglei %A Chu, Dandan %A Iqbal, Khalid %A Gong, Cheng-Xin %A Liu, Fei %X

Impairment of cerebral glucose uptake/metabolism in individuals with Alzheimer's disease (AD) is believed to lead to downregulation of protein O-GlcNAcylation, which contributes to tau pathogenesis through tau hyperphosphorylation. Level of glucose transporter 3 (GLUT3), a neuronal specific glucose transporter, is decreased in AD brain, which may contribute to impaired brain glucose uptake/metabolism. However, what causes the reduction of GLUT3 in AD brain is not fully understood. Here, we report 1) that decrease of GLUT3 is associated with the reduction of protein O-GlcNAcylation in AD brain, 2) that GLUT3 level is negatively correlated with calpain I activation in human brain, 3) that calpain I proteolyzes GLUT3 at the N-terminus in vitro, and 4) that activation of calpain I is negatively correlated with protein O-GlcNAcylation in AD brain. Furthermore, we found that overexpression of GLUT3 enhances protein O-GlcNAcylation in N2a cells. Overexpression of calpain I suppresses protein O-GlcNAcylation in these cells. These findings suggest a novel mechanism by which calpain I overactivation leads to GLUT3 degradation and the consequent down-regulation of protein O-GlcNAcylation in AD brain.

%B J Alzheimers Dis %V 62 %P 1737-1746 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614685?dopt=Abstract %R 10.3233/JAD-171047 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Can 11C-PiB-PET Relative Delivery R1 or 11C-PiB-PET Perfusion Replace 18F-FDG-PET in the Assessment of Brain Neurodegeneration? %A Oliveira, Francisco P M %A Moreira, Ana Paula %A de Mendonça, Alexandre %A Verdelho, Ana %A Xavier, Carolina %A Barroca, Dalila %A Rio, Joana %A Cardoso, Eva %A Cruz, Ângela %A Abrunhosa, Antero %A Castelo-Branco, Miguel %X

BACKGROUND: Pittsburgh Compound B (PiB) positron emission tomography (PET) is used to visualize in vivo amyloid plaques in the brain. Frequently the PiB examinations are complemented with a fluorodeoxyglucose (FDG) PET scan to further assess neurodegeneration.

OBJECTIVE: Our goal is to identify alternative correlates of FDG images by assessing which kinetic methods originate PiB derived relative delivery ratio (R1) images that can be correlated with the FDG images, and to compare them with PiB perfusion (pPiB) images obtained from the early-phase of PiB acquisition.

METHODS: We selected 52 patients with cognitive impairment who underwent a dynamic PiB and FDG acquisitions. To compute the R1 images, two simplified reference tissue models (SRTM and SRTM2) and two multi-linear reference tissue models (MRTM and MRTM2) were used. The pPiB images were obtained in two different time intervals.

RESULTS: All six types of images were of good quality and highly correlated with the FDG images (mean voxelwise within-subjects r > 0.92). The higher correlation was found for FDG-R1(MRTM). Regarding the voxelwise regional correlation, the higher mean all brain correlations was r = 0.825 for FDG-R1(MRTM) and statistically significant in the whole brain analysis.

CONCLUSION: All R1 and pPiB images here tested have potential to assess the metabolic impact of neurodegeneration almost as reliably as the FDG images. However, this is not enough to validate these images for a single-subject analysis compared with the FDG image, and thus they cannot yet be used clinically to replace the FDG image before such evaluation.

%B J Alzheimers Dis %V 65 %P 89-97 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056421?dopt=Abstract %R 10.3233/JAD-180274 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Can a Novel High-Density EEG Approach Disentangle the Differences of Visual Event Related Potential (N170), Elicited by Negative Facial Stimuli, in People with Subjective Cognitive Impairment? %A Lazarou, Ioulietta %A Adam, Katerina %A Georgiadis, Kostas %A Tsolaki, Anthoula %A Nikolopoulos, Spiros %A Yiannis Kompatsiaris, Ioannis %A Tsolaki, Magda %X

BACKGROUND: Studies on subjective cognitive impairment (SCI) and neural activation report controversial results.

OBJECTIVE: To evaluate the ability to disentangle the differences of visual N170 ERP, generated by facial stimuli (Anger & Fear) as well as the cognitive deterioration of SCI, mild cognitive impairment (MCI), and Alzheimer's disease (AD) compared to healthy controls (HC).

METHOD: 57 people took part in this study. Images corresponding to facial stimuli of "Anger" and "Fear" were presented to 12 HC, 14 SCI, 17 MCI and 14 AD participants. EEG data were recorded by using a HD-EEG HydroCel with 256 channels.

RESULTS: Results showed that the amplitude of N170 can contribute in distinguishing the SCI group, since statistically significant differences were observed with the HC (p < 0.05) and the MCI group from HC (p < 0.001), as well as AD from HC (p = 0.05) during the processing of facial stimuli. Noticeable differences were also observed in the topographic distribution of the N170 amplitude, while localization analysis by using sLORETA images confirmed the activation of superior, middle-temporal, and frontal lobe brain regions. Finally, in the case of "Fear", SCI and HC demonstrated increased activation in the orbital and inferior frontal gyrus, respectively, MCI in the inferior temporal gyrus, and AD in the lingual gyrus.

CONCLUSION: These preliminary findings suggest that the amplitude of N170 elicited after negative facial stimuli could be modulated by the decline related to pathological cognitive aging and can contribute in distinguishing HC from SCI, MCI, and AD.

%B J Alzheimers Dis %V 65 %P 543-575 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103320?dopt=Abstract %R 10.3233/JAD-180223 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cannabinoid Receptor 2-Deficiency Ameliorates Disease Symptoms in a Mouse Model with Alzheimer's Disease-Like Pathology. %A Schmöle, Anne-Caroline %A Lundt, Ramona %A Toporowski, Gregor %A Hansen, Jan N %A Beins, Eva %A Halle, Annett %A Zimmer, Andreas %X

It is widely accepted that the endocannabinoid system (ECS) is a modulator of neuroinflammation associated with neurodegenerative disorders, including Alzheimer's disease (AD). Thus, expression of the cannabinoid receptor 2 (CB2) is induced in plaque-associated microglia and astrocytes in brain tissues from AD patients and in genetic mouse models expressing pathogenic variants of the amyloid precursor protein (APP). However, the exact mechanism of CB2 signaling in this mouse model remains elusive, because the genetic deletion of CB2 and the pharmacological activation of CB2 both reduced neuroinflammation. Here, we demonstrate that CB2 deletion also improved cognitive and learning deficits in APP/PS1*CB2-/- mice. This was accompanied by reduced neuronal loss and decreased plaque levels and coincided with increased expression of Aβ degrading enzymes. Interestingly, plaque-associated microglia in APP/PS1*CB2-/- mice showed a less activated morphology, while plaques were smaller and more condensed than in APP/PS1 mice. Taken together, these results indicate a beneficial effect of CB2-deficiency in APP transgenic mice. CB2 appears to be part of a protective system that may be detrimental when engaged continuously.

%B J Alzheimers Dis %V 64 %P 379-392 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865078?dopt=Abstract %R 10.3233/JAD-180230 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cardiorespiratory Fitness and Cognitive Function are Positively Related Among Participants with Mild and Subjective Cognitive Impairment. %A Stuckenschneider, Tim %A Askew, Christopher David %A Rüdiger, Stefanie %A Polidori, Maria Cristina %A Abeln, Vera %A Vogt, Tobias %A Krome, Andreas %A Olde Rikkert, Marcel %A Lawlor, Brian %A Schneider, Stefan %X

BACKGROUND: By 2030, about 74 million people will be diagnosed with dementia, and many more will experience subjective (SCI) or mild cognitive impairment (MCI). As physical inactivity has been identified to be a strong modifiable risk factor for dementia, exercise and physical activity (PA) may be important parameters to predict the progression from MCI to dementia, but might also represent disease trajectory modifying strategies for SCI and MCI.

OBJECTIVE: A better understanding of the relationship between activity, fitness, and cognitive function across the spectrum of MCI and SCI would provide an insight into the potential utility of PA and fitness as early markers, and treatment targets to prevent cognitive decline.

METHODS: 121 participants were stratified into three groups, late MCI (LMCI), early MCI (EMCI), and SCI based on the Montreal Cognitive Assessment (MoCA). Cognitive function assessments also included the Trail Making Test A+B, and a verbal fluency test. PA levels were evaluated with an interviewer-administered questionnaire (LAPAQ) and an activity monitor. An incremental exercise test was performed to estimate cardiorespiratory fitness and to determine exercise capacity relative to population normative data.

RESULTS: ANCOVA revealed that LMCI subjects had the lowest PA levels (LAPAQ, p = 0.018; activity monitor, p = 0.041), and the lowest exercise capacity in relation to normative values (p = 0.041). Moreover, a modest correlation between MoCA and cardiorespiratory fitness (r = 0.25; p < 0.05) was found.

CONCLUSION: These findings suggest that during the earliest stages of cognitive impairment PA and exercise capacity might present a marker for the risk of further cognitive decline. This finding warrants further investigation using longitudinal cohort studies.

%B J Alzheimers Dis %V 62 %P 1865-1875 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614659?dopt=Abstract %R 10.3233/JAD-170996 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cardiorespiratory Fitness and White Matter Neuronal Fiber Integrity in Mild Cognitive Impairment. %A Ding, Kan %A Tarumi, Takashi %A Zhu, David C %A Tseng, Benjamin Y %A Thomas, Binu P %A Turner, Marcel %A Repshas, Justin %A Kerwin, Diana R %A Womack, Kyle B %A Lu, Hanzhang %A Cullum, C Munro %A Zhang, Rong %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Anisotropy %K Cardiorespiratory Fitness %K Case-Control Studies %K Cognition %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Executive Function %K Female %K Humans %K Linear Models %K Male %K Memory %K Middle Aged %K Nerve Fibers, Myelinated %K Neuropsychological Tests %K Texas %K White Matter %X

BACKGROUND: Mounting evidence showed the self-reported levels of physical activity are positively associated with white matter (WM) integrity and cognitive performance in normal adults and patients with mild cognitive impairment (MCI). However, the objective measure of cardiorespiratory fitness (CRF) was not used in these studies.

OBJECTIVE: To determine the associations of CRF measured by maximal oxygen uptake (VO2max) with WM fiber integrity and neurocognitive performance in older adults with MCI.

METHODS: Eighty-one participants (age = 65±7 years, 43 women), including 26 cognitively normal older adults and 55 amnestic MCI patients, underwent VO2max test to measure CRF, diffusion tensor imaging (DTI) to assess WM fiber integrity, and neurocognitive assessment focused on memory and executive function. DTI data were analyzed by the tract-based spatial statistics and region-of-interest approach.

RESULTS: Cognitively normal older adults and MCI patients were not different in global WM fiber integrity and VO2max. VO2max was associated positively with DTI metrics of fractional anisotropy in ∼54% WM fiber tracts, and negatively with mean and radial diffusivities in ∼46% and ∼56% of the WM fiber tracts. The associations of VO2max with DTI metrics remained statistically significant after adjustment of age, sex, body mass index, WM lesion burden, and MCI status. The DTI metrics obtained from the area that correlated to VO2max were associated with executive function performance in MCI patients.

CONCLUSIONS: Higher levels of CRF are associated with better WM fiber integrity, which in turn is correlated with better executive function performance in MCI patients.

%B J Alzheimers Dis %V 61 %P 729-739 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226864?dopt=Abstract %R 10.3233/JAD-170415 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cardiovascular Response to Mental Stress in Mild Cognitive Impairment and its Association with Cerebral Perfusion. %A Henley, Brandon C %A Shokouhi, Mahsa %A Mahajan, Anushree Y %A Inan, Omer T %A Hajjar, Ihab %X

Mental stress has been linked to various chronic diseases including Alzheimer's disease, but the mechanisms underlying cognitive decline with mental stress are unknown. Reduced cardiovascular response to stress is associated with cardiovascular disease, and the latter is associated with cognitive impairment. We measured electrodermal activity, blood pressure, and cardiac hemodynamics in cognitively normal and mild cognitive impairment (MCI) adults (n = 76, mean age = 58 years, 46% MCI) during rest, a math test, and face-name recall tasks to derive the following cardiovascular indicators: mean arterial pressure, heart rate, stroke volume and cardiac output. These indicators were compared between the two groups. Cerebral blood perfusion via arterial spin-labeling MRI was measured in a subgroup who underwent an MRI scan (n = 30). Following exposure to mental stress, a decrease in stroke volume (p = 0.024) and cardiac output (p = 0.005) was found in the MCI group, but an increase in both parameters in the cognitively normal group. This difference was largest during face-name recall (standardized difference in stroke volume = -0.50, p = 0.029, and in cardiac output = -0.52, p = 0.023). Cardiac output during mental stress, but not at rest, decreased with cerebral perfusion (normal: p = 0.078, β= 1.97, R2 = 0.090; MCI: p = 0.007, β= 2.02, R2 = 0.008). No significant difference was found between the two groups at rest. This preliminary study suggests that individuals with MCI have an insufficient cardiac output, and in turn lower cerebral perfusion in response to mental stress.

%B J Alzheimers Dis %8 2018 Apr 11 %G eng %R 10.3233/JAD-180036 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Caregiving and Caregiver Burden in Dementia Home Care: Results from the Prospective Dementia Registry (PRODEM) of the Austrian Alzheimer Society. %A Ransmayr, Gerhard %A Hermann, Philipp %A Sallinger, Katharina %A Benke, Thomas %A Seiler, Stephan %A Dal-Bianco, Peter %A Marksteiner, Josef %A Defrancesco, Michaela %A Sanin, Günter %A Struhal, Walter %A Guger, Michael %A Vosko, Milan %A Hagenauer, Karin %A Lehner, Riccarda %A Futschik, Andreas %A Schmidt, Reinhold %X

BACKGROUND: Comprehensive studies on caregiver burden (CB) of persons caring for dementia patients differ methodologically and show variable results.

OBJECTIVE: Analysis of known and hypothesized factors of CB in home care of dementia patients.

METHODS: Multicenter longitudinal study comprising 585 persons caring mostly for Alzheimer's disease patients (age median 77.25 years, Mini-Mental State Examination raw score median 23) using the Zarit Caregiver Burden Interview (CBI). Known patient-related determinants of CB were studied, such as dementia severity (Clinical Dementia Rating, CDR), neuropsychological deficits (CERAD-Plus), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), disability (Disability Assessment for Dementia, DAD), dependency (Dependency Scale, DS), and moreover, unclarified potential factors (age, sex, education of patients; age, sex, occupational status of the caregivers; family relationship). Psychological and somatic effects of CB were analyzed (factor analysis).

RESULTS: Caregiver age was median 61. Female caregivers prevailed (67.8%). Median CBI sum score (CBIss) was 16 at baseline. After two years, CBIss was 22 and 37% of the caregivers reported mild to moderate (CBIss 21-40), 16.8% moderate to severe or severe (≥41), and 46.2% absent to little CB (CBIss ≤ 20). CB correlated positively with NPI, CDR, DS scores, disability (DAD), years of education of the patients, and proximity of patient and caregiver sex (female), and negatively with caregiver age. Caregivers reported restrictions of time, health problems, and negative emotions.

CONCLUSION: The findings are applicable to identify persons at risk for substantial CB and its consequences. There is demand for personal, psychological, and medical support of caregivers and increasing male participation.

%B J Alzheimers Dis %V 63 %P 103-114 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614643?dopt=Abstract %R 10.3233/JAD-170657 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Ceftriaxone Improves Cognitive Function and Upregulates GLT-1-Related Glutamate-Glutamine Cycle in APP/PS1 Mice. %A Fan, ShuJuan %A Xian, XiaoHui %A Li, Li %A Yao, XiaoGuang %A Hu, YuYan %A Zhang, Min %A Li, WenBin %X

Alzheimer's disease (AD) is characterized by progressive impairment of learning, memory, and cognitive deficits. Glutamate is the major excitatory neurotransmitter in the central nervous system and plays an important role in learning, memory, and cognition. The homeostasis and reutilization of glutamate are dependent on astrocytic uptake by glutamate transporter-1 (GLT-1) and the subsequent glutamate-glutamine cycle. Increasing evidence showed impairments in GLT-1 expression and uptake activity and glutamate-glutamine cycle in AD. Ceftriaxone (Cef) has been reported to upregulate the expression and uptake of GLT-1. Therefore, the present study was undertaken to explore whether Cef can improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating GLT-1 expression, and then promoting the glutamate-glutamine cycle. It was shown that Cef treatment significantly alleviated the cognitive deficits measured by Morris water maze test and upregulated GLT-1 protein expression in the hippocampus of APP/PS1 mice. Particularly, the activity of glutamine synthetase (GS) and the protein expression of system N glutamine transporter 1 (SN1), which are the key factors involved in the glutamate-glutamine cycle, were significantly upregulated as well after the Cef treatment. Furthermore, inhibition of GLT-1 uptake activity by dihydrokainic acid, an inhibitor of GLT-1, blocked the Cef-induced improvement on the cognitive deficits, GS activity, and SN1 expression. The above results suggested that Cef could improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating the GLT-1 expression, GS activity, and SN1 expression, which would lead to stimulating the glutamate-glutamine cycle.

%B J Alzheimers Dis %V 66 %P 1731-1743 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30452416?dopt=Abstract %R 10.3233/JAD-180708 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Ceramide Accumulation Is Associated with Declining Verbal Memory in Coronary Artery Disease Patients: An Observational Study. %A Chan, Parco %A Saleem, Mahwesh %A Herrmann, Nathan %A Mielke, Michelle M %A Haughey, Norman J %A Oh, Paul I %A Kiss, Alexander %A Lanctôt, Krista L %X

BACKGROUND: Biomarkers in cognitively vulnerable populations, like those with coronary artery disease (CAD), may inform earlier intervention in vascular neurodegeneration. Circulating ceramide C18:0 (CerC18:0) is associated with changes in verbal memory in early neurodegeneration and CAD progression.

OBJECTIVE: To investigate whether plasma CerC18:0 accumulation is associated with longitudinal declines in verbal memory performance in CAD.

METHODS: In addition to total CerC18:0, we assessed its relative abundance to its precursors as ratios: CerC18:0 to monohexosylceramide C18:0 (MHxCer18:0), CerC18:0 to sphingomyelin C18:0 (SM18:0), and CerC18:0 to sphingosine-1-phosphate (S1P). Verbal memory was assessed using the California Verbal Learning Test 2nd Ed. Using mixed models in 60 CAD participants, we evaluated associations between baseline CerC18:0 ratios and changes in verbal memory performance, adjusting for age, body mass index, and education. Given that cognitive decline is more rapid following onset of deficits, these associations were compared between those with possible mild vascular neurocognitive disorder (MVND).

RESULTS: Increased baseline CerC18:0 concentrations correlated with worse verbal memory performance over time (b[SE] = - 0.91[0.30], p = 0.003). Increased baseline CerC18:0/SM18:0 (b[SE] = - 1.11[`], p = 0.03) were associated with worse verbal memory performance over time. These associations were not mediated by whether or not patients had possible MVND at baseline.

CONCLUSION: These findings support aberrant CerC18:0 metabolism as an early neurobiological change in vascular neurodegeneration. Future studies should measure enzymes responsible for conversion of sphingolipid precursors into CerC18:0 to assess enzymatic activity.

%B J Alzheimers Dis %V 64 %P 1235-1246 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010121?dopt=Abstract %R 10.3233/JAD-180030 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebral Amyloid Angiopathy and Cerebral Amyloid Angiopathy-Related Inflammation: Comparison of Hemorrhagic and DWI MRI Features. %A Renard, Dimitri %A Tatu, Lavinia %A Collombier, Laurent %A Wacongne, Anne %A Ayrignac, Xavier %A Charif, Mahmoud %A Boukriche, Yassine %A Chiper, Laura %A Fourcade, Genevieve %A Azakri, Souhayla %A Gaillard, Nicolas %A Mercier, Erick %A Lehmann, Sylvain %A Thouvenot, Eric %X

BACKGROUND: Cerebral amyloid angiopathy (CAA) can be associated with primary vasculitis of small/medium-sized leptomeningeal and cortical arteries, called CAA-related inflammation (CAA-ri).

OBJECTIVE: To compare hemorrhagic and diffusion-weighted imaging (DWI) MRI features in CAA and CAA-ri.

METHODS: We prospectively scored in a consecutive CAA and CAA-ri cohort: presence/number of chronic intracerebral hemorrhage (ICH), cerebral microbleeds (CMB), and cortical superficial siderosis (CSS) on initial T2*-weighted imaging, and DWI lesions on both initial and follow-up imaging. In a subgroup, ApoE, CSF, and 18F-florbetaben-positron emission tomography (FBB-PET) were also analyzed.

RESULTS: In CAA-ri, CMB presence was more frequent (100% versus 40%, p < 0.001) and CMB numbers higher (mean 137 versus 8, p < 0.001). No difference was observed for chronic ICH or CSS. DWI lesions were more frequent in acute compared to chronic CAA-ri (p = 0.025), whereas no such difference was observed between acute and chronic CAA (p = 0.18). Both ApoE4 (genotyping available in 22 CAA-ri and 48 CAA patients) carriers and homozygosity were more frequent in CAA-ri (48% versus 19% [p = 0.014] and 32% versus 2% [p < 0.001] respectively). CSF biomarker analyses (performed in 20 CAA-ri and 45 CAA patients) showed lower Aβ42 levels in CAA-ri compared to CAA (median 312 versus 422 pg/mL, p = 0.0032). FBB-PET (performed in 11 CAA-ri and 20 CAA patients) showed higher standardized uptake value ratios in CAA-ri compared with CAA, only significant when the pons was used as reference (p = 0.037).

CONCLUSION: Compared to CAA, CAA-ri was associated with higher CMB numbers, more frequent ApoE4 carriers and homozygotes, lower CSF Aβ42 levels, and more severe amyloid load on FBB-PET.

%B J Alzheimers Dis %V 64 %P 1113-1121 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010128?dopt=Abstract %R 10.3233/JAD-180269 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebral Amyloid Angiopathy: Similarity in African-Americans and Caucasians with Alzheimer's Disease. %A Kamara, Dennis M %A Gangishetti, Umesh %A Gearing, Marla %A Willis-Parker, Monica %A Zhao, Liping %A Hu, William T %A Walker, Lary C %X

Cerebral amyloid angiopathy (CAA) of the Aβ type is variably present in the brains of patients with Alzheimer's disease (AD). CAA contributes to cognitive decline and increases the risk of lobar hemorrhage; because both AD-typical dementia and lobar hemorrhage are more common in African-Americans than in Caucasians, we postulated that African-Americans with AD might be particularly susceptible to CAA. To test this hypothesis, we analyzed CAA histopathologically in the large vessels and capillaries of autopsy-derived frontal, temporal, parietal, and occipital cortical samples from African-Americans (n = 18) and Caucasians (n = 19) with end-stage AD. In the combined cohort of 37 subjects, 22% of the subjects had severe CAA in large vessels, and 11% had severe CAA in capillaries. However, the prevalence and histopathologic characteristics of CAA were similar in the African-Americans and Caucasians. This conclusion was substantiated in an independent sample from the National Alzheimer's Coordinating Center database, in which the degree of CAA was comparable in 1,554 Caucasians and 68 African-Americans with end-stage AD. These findings support a growing consensus that the fundamental histopathologic features of AD are largely impartial to the race of the afflicted.

%B J Alzheimers Dis %V 62 %P 1815-1826 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614657?dopt=Abstract %R 10.3233/JAD-170954 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebral White Matter Lesions have Low Impact on Cognitive Function in a Large Elderly Memory Clinic Population. %A Claus, Jules J %A Coenen, Mirthe %A Staekenborg, Salka S %A Schuur, Jacqueline %A Tielkes, Caroline E M %A Koster, Pieter %A Scheltens, Philip %X

BACKGROUND: Evidence suggests that cerebral white matter lesions (WML) play a role in cognitive decline.

OBJECTIVE: To assess the impact of cerebral WML on cognitive function relative to absence or presence of medial temporal atrophy (MTA) in a large single-center memory clinic population.

METHODS: Patients included had subjective cognitive impairment (SCI, n = 333), mild cognitive impairment (MCI, n = 492) and Alzheimer's disease (AD, n = 832). The relationships between visually rated WML (Fazekas scale, 0-3) on brain Computed Tomography and CAMCOG memory and non-memory function were investigated with regression analysis adjusted for age, gender and education in combined patient groups. We assessed possible interaction versus addition effects of these relationships with visually rated MTA (Scheltens scale).

RESULTS: The highly statistical significant relationship between WML and memory function was no longer significant when MTA was taken into account. However, the strong significant relationship between WML and non-memory function remained significant after adjustment for MTA, but the explained variance attributed to WML was only 1.3%. There was no interaction between WML and MTA on CAMCOG test scores. In addition, shown by a 2×2 factorial model by presence versus absence of WML and MTA, WML affected non-memory function only in the presence of MTA.

CONCLUSION: Our data suggest that presence of WML is associated with lower non-memory cognitive function but this effect is conditional on the presence of pre-existing MTA. The very small explained variance suggests little impact of WML to the clinical profile of a memory clinic patient.

%B J Alzheimers Dis %8 2018 Apr 27 %G eng %R 10.3233/JAD-171111 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Amyloid-β Levels are Increased in Patients with Insomnia. %A Chen, Dong-Wan %A Wang, Jun %A Zhang, Li-Li %A Wang, Yan-Jiang %A Gao, Chang-Yue %K Adult %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Female %K Humans %K Male %K Middle Aged %K Phosphorylation %K Sleep Initiation and Maintenance Disorders %K tau Proteins %X

Previous studies demonstrate that patients with sleep disorders are at risk of developing Alzheimer's disease (AD), with the mechanism unknown. It is suggested that acute sleep deprivation induces an increase of amyloid-β (Aβ), the major pathological agent in AD, in the cerebrospinal fluid (CSF). In the present study, we recruited 23 patients with chronic insomnia aged between 46 to 67 years and 23 healthy controls aged between 43 to 67 years. We investigated the CSF levels of Aβ and tau, another pathological hallmark in the AD pathogenesis. We found that CSF Aβ42 levels were significantly increased in insomnia patients. However, no significant difference was found in Aβ40, total tau (t-Tau), and phosphorylated tau (p-Tau) between the two groups. Furthermore, we found that CSF Aβ40 and Aβ42 levels are significantly correlated with the sleep quality, as reflected by the Pittsburgh Sleep Quality Index (PSQI) scores. But no significant correlation was found in CSF t-Tau and p-Tau levels with PSQI. Our results indicate that chronic sleep disorders may induce the disruption of Aβ metabolism in the brain, thus increase the risk for developing AD.

%B J Alzheimers Dis %V 61 %P 645-651 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29278891?dopt=Abstract %R 10.3233/JAD-170032 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer's Disease Pathology and Neuronal Damage. %A Bettcher, Brianne M %A Johnson, Sterling C %A Fitch, Ryan %A Casaletto, Kaitlin B %A Heffernan, Kate S %A Asthana, Sanjay %A Zetterberg, Henrik %A Blennow, Kaj %A Carlsson, Cynthia M %A Neuhaus, John %A Bendlin, Barbara B %A Kramer, Joel H %X

Inflammatory markers have been shown to predict neurocognitive outcomes in aging adults; however, the degree to which peripheral markers mirror the central nervous system remains unknown. We investigated the association between plasma and cerebrospinal fluid (CSF) markers of inflammation, and explored whether these markers independently predict CSF indicators of Alzheimer's disease (AD) pathology or neuronal damage. Plasma and CSF samples were analyzed for inflammatory markers in a cohort of asymptomatic older adults (n = 173). CSF samples were analyzed for markers of AD pathology (Aβ42, phosphorylated tau [p-tau], sAβPPβ) or neuronal damage (total tau; neurofilament light chain) (n = 147). Separate linear models for each analyte were conducted with CSF and plasma levels entered simultaneously as predictors and markers of AD pathology or neuronal damage as outcome measures. Strong associations were noted between CSF and plasma MIP-1β levels, and modest associations were observed for remaining analytes. With respect to AD pathology, higher levels of plasma and CSF IL-8, CSF MIP-1β, and CSF IP-10 were associated with higher levels of p-tau. Higher levels of CSF IL-8 were associated with higher levels of CSF Aβ42. Higher CSF sAβPPβ levels were associated with higher plasma markers only (IL-8; MCP-1). In terms of neuronal injury, higher levels of plasma and CSF IL-8, CSF IP-10, and CSF MIP-1β were associated with higher levels of CSF total tau. Exploratory analyses indicated that CSF Aβ42 modifies the relationship between plasma inflammatory levels and CSF tau levels. Results suggest that both plasma and CSF inflammatory markers independently relay integral information about AD pathology and neuronal damage.

%B J Alzheimers Dis %V 62 %P 385-397 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439331?dopt=Abstract %R 10.3233/JAD-170602 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Biomarkers are Differentially Related to Structural and Functional Changes in Dementia of the Alzheimer's Type. %A Malpas, Charles B %A Saling, Michael M %A Velakoulis, Dennis %A Desmond, Patricia %A Hicks, Rodney J %A Zetterberg, Henrik %A Blennow, Kaj %A O'Brien, Terence J %X

The two cardinal pathologies of Alzheimer's disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimer's type. Interrelationships were analyzed between cerebrospinal fluid biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18F]-FDG-PET. Amyloid-related pathology was preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings support the hypothesis that tau- and amyloid-pathology exert differential effects on structurofunctional changes in the AD brain. These findings have implications for future therapeutic trials and hint at a more complex relationship between the cardinal pathologies and disruption of brain networks.

%B J Alzheimers Dis %V 62 %P 417-427 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439322?dopt=Abstract %R 10.3233/JAD-170250 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Biomarkers for Early and Differential Alzheimer's Disease Diagnosis. %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

An accurate and early diagnosis of Alzheimer's disease (AD) is important to select optimal patient care and is critical in current clinical trials targeting core AD neuropathological features. The past decades, much progress has been made in the development and validation of cerebrospinal fluid (CSF) biomarkers for the biochemical diagnosis of AD, including standardization and harmonization of (pre-) analytical procedures. This has resulted in three core CSF biomarkers for AD diagnostics, namely the 42 amino acid long amyloid-beta peptide (Aβ1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181). These biomarkers have been incorporated into research diagnostic criteria for AD and have an added value in the (differential) diagnosis of AD and related disorders, including mixed pathologies, atypical presentations, and in case of ambiguous clinical dementia diagnoses. The implementation of the CSF Aβ1-42/Aβ1-40 ratio in the core biomarker panel will improve the biomarker analytical variability, and will also improve early and differential AD diagnosis through a more accurate reflection of pathology. Numerous biomarkers are being investigated for their added value to the core AD biomarkers, aiming at the AD core pathological features like the amyloid mismetabolism, tau pathology, or synaptic or neuronal degeneration. Others aim at non-AD neurodegenerative, vascular or inflammatory hallmarks. Biomarkers are essential for an accurate identification of preclinical AD in the context of clinical trials with potentially disease-modifying drugs. Therefore, a biomarker-based early diagnosis of AD offers great opportunities for preventive treatment development in the near future.

%B J Alzheimers Dis %V 62 %P 1199-1209 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562530?dopt=Abstract %R 10.3233/JAD-170680 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Biomarkers in Alzheimer's Disease: An Invaluable Tool for Clinical Diagnosis and Trial Enrichment. %A Parnetti, Lucilla %A Eusebi, Paolo %X

Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting around 35 million people worldwide. Cerebrospinal fluid (CSF) biomarkers entered the diagnostic criteria as support for early diagnosis. The classical biochemical signature of AD includes total tau (T-tau), phosphorylated tau (P-tau), and the 42 amino acid peptide (Aβ42) of amyloid-β. Recent observations suggest that the use of CSF Aβ42:Aβ40 ratio rather than CSF Aβ42 alone could contribute to reduce inter-laboratory variation in Aβ values and increasing diagnostic performance of the CSF AD biomarkers in routine practice. However, research efforts aimed at enriching the CSF biomarker panel are ongoing. The CSF AD signature is also crucial for the design of clinical trials for AD, since it best guarantees AD pathology as the cause of cognitive impairment. Accordingly, CSF biomarkers have been now reported in the inclusion criteria of Phase I, Phase II, and Phase III clinical trials as enrichment strategy. So far, one of the most important reasons for the failure of AD clinical trials was the inclusion of participants with unlikely AD pathology. In order to implement the use of CSF biomarkers in AD routine diagnostic work-up and as accepted strategy for enriching trial populations, inter-laboratory variability should be minimized. Increasing efforts should also be devoted to promote data sharing practices, encouraging individual participant data meta-analyses.

%B J Alzheimers Dis %V 64 %P S281-S287 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562517?dopt=Abstract %R 10.3233/JAD-179910 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Biomarkers in Patients with Frontotemporal Dementia Spectrum: A Single-Center Study. %A Abu-Rumeileh, Samir %A Mometto, Nicola %A Bartoletti-Stella, Anna %A Polischi, Barbara %A Oppi, Federico %A Poda, Roberto %A Stanzani-Maserati, Michelangelo %A Cortelli, Pietro %A Liguori, Rocco %A Capellari, Sabina %A Parchi, Piero %X

Cerebrospinal fluid (CSF) neurofilament light chain protein (NfL) and Alzheimer's disease (AD) core biomarker levels have been evaluated in cohorts of patients with frontotemporal dementia spectrum (FTD), but the distribution of values across the different clinical syndromes and underlying proteinopathies, and the relative diagnostic accuracy appear discordant among studies. We measured CSF NfL, total (t)-tau, phosphorylated (p)-tau, and amyloid-β (Aβ)42 in healthy controls (n = 38) and subjects with a clinical, genetic, CSF biomarker-based, and/or neuropathological diagnosis of FTD (n = 141) or AD (n = 60). Sub-analyses were conducted in a proportion of subjects with definite and/or probable frontotemporal lobar degeneration with tau (FTLD-TAU) (n = 42) or TDP43 pathology (FTLD-TDP) (n = 36). Both FTD and AD groups showed significantly increased CSF NfL levels in comparison to controls (p < 0.001). CSF NfL levels were significantly higher in FTD patients than in AD (p < 0.001), reaching the highest values in amyotrophic lateral sclerosis associated with FTD. Patients with probable and definite FTLD-TDP had significantly higher NfL levels (p < 0.001) and lower p-tau/t-tau values (p < 0.001) in comparison with probable and definite FTLD-TAU cases. NfL showed good diagnostic accuracy in the distinction between FTD and controls (AUC 0.862±0.027) and yielded an accuracy (AUC 0.861±0.045) comparable to that of the p-tau/t-tau ratio (AUC 0.814±0.050), with 80.0% sensitivity and 81.0% specificity, in the discrimination between probable/definite FTLD-TAU and FTLD-TDP. Our data further validate CSF NfL as a surrogate biomarker of neurodegeneration and disease severity in patients with FTD spectrum. Moreover, they demonstrate a good diagnostic value for NfL and p-tau/t-tau ratio in the discrimination between FTLD-TAU and FTLD-TDP.

%B J Alzheimers Dis %V 66 %P 551-563 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320576?dopt=Abstract %R 10.3233/JAD-180409 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid C-C Motif Chemokine Ligand 2 Correlates with Brain Atrophy and Cognitive Impairment in Alzheimer's Disease. %A Kimura, Akio %A Yoshikura, Nobuaki %A Hayashi, Yuichi %A Inuzuka, Takashi %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Atrophy %K Biomarkers %K Chemokine CCL2 %K Cognitive Dysfunction %K Disease Progression %K Female %K Gray Matter %K Humans %K Linear Models %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K tau Proteins %K Temporal Lobe %X

BACKGROUND: Chronic neuroinflammation has been implicated in Alzheimer's disease (AD) pathology.

OBJECTIVE: To investigate the association between cytokine and anti-amyloid-β (Aβ) autoantibody levels and the degree of brain atrophy and cognitive impairment in AD patients.

METHODS: Cerebrospinal fluid (CSF) levels of C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8, C-X-C motif chemokine ligand 10, interleukin 6, and anti-Aβ autoantibody were evaluated in 69 AD patients. Serum levels of CCL2 and anti-Aβ autoantibody were also examined. The degree of brain atrophy was assessed using the voxel-based specific regional analysis system for AD, which targets the volumes of interest (VOI) in medial temporal structures. Cognitive function was evaluated by neuropsychological testing, including the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB).

RESULTS: CSF CCL2 levels correlated significantly with the severity (p = 0.023) and the extent (p = 0.022) of VOI atrophy, and with the extent of gray matter atrophy (p = 0.039) in AD patients. CSF anti-Aβ autoantibody levels were inversely correlated with the severity of VOI atrophy (p = 0.020), the extent of VOI atrophy (p = 0.015), and the ratio of VOI/GM atrophy (r = -0.358, p = 0.004). CSF CCL2 levels were also inversely correlated with MMSE (p = 0.0497) and FAB scores (p = 0.016).

CONCLUSIONS: CSF CCL2 levels are associated with the degree of medial temporal lobe and gray matter atrophy, and cognitive decline in AD.

%B J Alzheimers Dis %V 61 %P 581-588 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171996?dopt=Abstract %R 10.3233/JAD-170519 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Levels of Angiotensin-Converting Enzyme Are Associated with Amyloid-β42 Burden in Alzheimer's Disease. %A Rocha, Natalia P %A Toledo, Andre %A Corgosinho, Laiane T S %A de Souza, Leonardo C %A Guimarães, Henrique C %A Resende, Elisa P F %A Braz, Nayara F T %A Gomes, Karina B %A Simoes E Silva, Ana C %A Caramelli, Paulo %A Teixeira, Antônio L %X

This study was designed to determine whether the levels of renin-angiotensin system (RAS) components are associated with Alzheimer's disease (AD) pathology. Cerebrospinal fluid levels of Angiotensin (Ang) II, Ang-(1-7), angiotensin-converting enzyme (ACE), ACE2, Amyloid-β (Aβ)40, Aβ42, total tau (hTau), and phospho-tau (pTau) were measured in 18 patients with AD and 10 controls. Patients with AD presented decreased levels of ACE when compared with controls. We found a significant positive correlation between ACE and Aβ42 levels among patients. Our results strengthen the hypothesis that ACE is associated with Aβ pathology in AD.

%B J Alzheimers Dis %V 64 %P 1085-1090 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040721?dopt=Abstract %R 10.3233/JAD-180282 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid, MRI, and Florbetaben-PET in Cerebral Amyloid Angiopathy-Related Inflammation. %A Renard, Dimitri %A Collombier, Laurent %A Demattei, Christophe %A Wacongne, Anne %A Charif, Mahmoud %A Ayrignac, Xavier %A Azakri, Souhayla %A Gaillard, Nicolas %A Boudousq, Vincent %A Lehmann, Sylvain %A Menjot de Champfleur, Nicolas %A Thouvenot, Eric %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Aniline Compounds %K Biomarkers %K Brain %K Cerebral Amyloid Angiopathy %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Multivariate Analysis %K Positron-Emission Tomography %K Prospective Studies %K Stilbenes %K tau Proteins %K Vasculitis, Central Nervous System %X

BACKGROUND: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is associated with a cerebrospinal fluid (CSF) biomarker profile similar to that observed in CAA. Few CAA-ri patients have been studied by fibrillar amyloid-β (Aβ) imaging (using 11C-Pittsburgh compound B and 18F-florbetapir, but not 18F-florbetaben).

OBJECTIVE: To describe CSF biomarkers, magnetic resonance imaging (MRI), and 18F-florbetaben (FBB)-positron emission tomography (PET) changes in CAA-ri patients.

METHODS: CSF levels of total tau, phosphorylated tau, Aβ1-42, and Aβ1-40, MRI (cerebral microbleeds count on susceptibility-weighted imaging and semi-quantitative analysis of fluid-attenuation inversion recovery white matter hyperintensities), and FBB-PET (using both cerebellar cortex and pons to calculate standardized uptake value ratios) were analyzed in nine consecutive CAA-ri patients.

RESULTS: A median number of 769 cerebral microbleeds/patient were counted on MRI. When using the pons as reference region, amyloid load on FBB-PET was very strongly correlated to CSF Aβ1-40 levels (rho = -0.83, p = 0.008) and moderately correlated to cerebral microbleed numbers in the occipital lobes (rho = 0.59, p = 0.001), while comparisons with other CSF biomarkers were not statistically significant (total tau, rho = -0.63, p = 0.076; phosphorylated tau, rho = -0.68, p = 0.05; Aβ1-42, rho = -0.59, p = 0.09). All correlations were weaker, and not statistically significant, when using the cerebellum as reference region. A non-significant correlation (rho = -0.50, p = 0.18) was observed between CSF Aβ1-40 levels and cerebral microbleed numbers.

CONCLUSION: In CAA-ri, CSF Aβ1-40 levels correlated well with amyloid load assessed by FBB-PET when the pons was used as reference, and to a lesser degree with cerebral microbleeds count on MRI. This confirms earlier data on CSF Aβ1-40 as an in vivo marker for CAA and CAA-ri.

%B J Alzheimers Dis %V 61 %P 1107-1117 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254099?dopt=Abstract %R 10.3233/JAD-170843 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Orexin Levels and Nocturnal Sleep Disruption in Alzheimer's Disease Patients Showing Neuropsychiatric Symptoms. %A Liguori, Claudio %A Mercuri, Nicola Biagio %A Nuccetelli, Marzia %A Izzi, Francesca %A Bernardini, Sergio %A Placidi, Fabio %X

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. It is characterized by a progressive deterioration of cognition, frequently associated with neuropsychiatric symptoms (NPS). Among NPS, sleep disturbances often affect AD patients. Orexinergic system dysregulation has been associated with sleep impairment in AD patients.

OBJECTIVE: The present study investigated CSF orexin levels in AD patients and their relationship with both NPS, measured by the neuropsychiatric inventory (NPI), and sleep, measured via polysomnography.

METHODS: This is a secondary analysis of a previous study investigating CSF biomarkers, sleep impairment and cognitive decline in AD patients. AD patients completing the NPI were included in this analysis and distributed in two groups based on the presence (NPI score ≥4, AD/NPS+) or absence (NPI score <4, AD/NPS-) of NPS.

RESULTS: Twenty-two AD patients constituted the AD/NPS+ group and 20 patients constituted the AD/NPS-group. We observed higher CSF orexin levels in AD/NPS+ than AD/NPS-patients. Moreover, AD/NPS+ showed a more fragmented and the reduction of REM sleep compared to AD/NPS-patients. Notably, higher NPI scores correlated with a more altered sleep structure, higher CSF orexin levels and lower MMSE scores.

CONCLUSION: This study documented that AD patients showing NPS present a more fragmented sleep coupled with higher CSF orexin levels compared to AD patients not affected by NPS. This finding showing the increased orexinergic tone in AD patients affected by NPS suggests the possible influence of the orexinergic system dysregulation not only on sleep impairment but also on neurobehavioral disturbances.

%B J Alzheimers Dis %V 66 %P 993-999 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30372684?dopt=Abstract %R 10.3233/JAD-180769 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrovascular Disease and Neurodegeneration in Alzheimer's Disease with and without a Strong Family History: A Pilot Magnetic Resonance Imaging Study in Dominican Republic. %A Piriz, Angel %A Reyes, Dolly %A Narkhede, Atul %A Guzman, Vanessa A %A Viqar, Fawad %A Meier, Irene B %A Budge, Mariana %A Mena, Pedro %A Dashnaw, Stephen %A Lee, Joseph %A Reitz, Christiane %A Gutierrez, Jose %A Campos, Luis %A Medrano, Martin %A Lantigua, Rafael %A Mayeux, Richard %A Brickman, Adam M %X

The incidence and prevalence of Alzheimer's disease (AD) dementia are higher among Caribbean Hispanics than among non-Hispanic Whites. The causes of this health disparity remain elusive, partially because of the relative limited capacity for biomedical research in the developing countries that comprise Caribbean Latin America. To begin to address this issue, we were awarded a Development Research Award from the US NIH and Fogarty International Center in order to establish the local capacity to integrate magnetic resonance imaging (MRI) into studies of cognitive aging and dementia in Dominican Republic, establish collaborations with Dominican investigators, and conduct a pilot study on the role of cerebrovascular markers in the clinical expression of AD. Ninety older adult participants with and without AD dementia and with and without a strong family history of AD dementia received MRI scans and clinical evaluation. We quantified markers of cerebrovascular disease (white matter hyperintensities [WMH], presence of infarct, and presence of microbleed) and neurodegeneration (entorhinal cortex volume) and compared them across groups. Patients with AD dementia had smaller entorhinal cortex and greater WMH volumes compared with controls, regardless of family history status. This study provides evidence for the capacity to conduct MRI studies of cognitive aging and dementia in Dominican Republic. The results are consistent with the hypothesis that small vessel cerebrovascular disease represents a core feature of AD dementia, as affected participants had elevated WMH volumes irrespective of family history status.

%B J Alzheimers Dis %V 66 %P 1519-1528 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412503?dopt=Abstract %R 10.3233/JAD-180807 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrovascular Hemodynamics on Transcranial Doppler Ultrasonography and Cognitive Decline in Mild Cognitive Impairment. %A Lim, Eun-Ye %A Yang, Dong-Won %A Cho, A-Hyun %A Shim, Yong S %X

BACKGROUND/OBJECTIVE: Vascular risk factors and neurovascular dysfunction may be closely related to cognitive impairment and dementia. In this study, we evaluated the association between hemodynamic markers and longitudinal cognitive changes in patients with mild cognitive impairment (MCI). Furthermore, we investigated whether hemodynamic markers could predict the risk of progression to Alzheimer's disease (AD) in patients with MCI.

METHODS: A total of 68 subjects with amnestic MCI were recruited. Using transcranial Doppler (TCD) ultrasonography, cerebrovascular reactivity was evaluated with a breath-holding test (breath holding index; BHI) in addition to the mean flow velocity (MFV) and pulsatility index (PI) of the middle cerebral artery. We followed subjects for 24 months and each subject underwent neuropsychological testing and TCD ultrasonography, annually. According to the follow-up neuropsychological studies and clinical interviews at 12 months, we divided the patients with MCI into two groups: patients with stable cognitive performance and patients who progressed to AD.

RESULTS: Lower BHI and higher PI were observed in patients who progressed to AD. The changes of MMSE score over the first 12 months correlated with lower baseline MMSE score and changes of MFV and BHI. The changes of MMSE score over 24 months were closely related to higher baseline resistance index and PI values. Multivariate logistic regression showed that abnormal baseline BHI value could predict a conversion from MCI to AD.

CONCLUSIONS: We confirmed there is a close association between hemodynamic changes represented by TCD markers and cognitive decline, supporting the clinical value of hemodynamic markers in predicting MCI patients who will progress to AD.

%B J Alzheimers Dis %V 65 %P 651-657 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103317?dopt=Abstract %R 10.3233/JAD-180026 %0 Journal Article %J J Alzheimers Dis %D 2018 %T CFH and ARMS2 Polymorphisms Interact with Zinc Supplements in Cognitive Impairment in the Women's Health Initiative Hormone Trial. %A Kustra, Rafal %A Awh, Carl C %A Rojas-Fernandez, Carlos %A Zanke, Brent %X

BACKGROUND: An interaction between genetic variants in complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) and high-dose zinc supplementation on progression to advanced age-related macular degeneration (AMD) exists. Because cognitive impairment (CI) is associated with AMD, we used data from the Women's Health Initiative (WHI) to search for a zinc/genetics interaction.

OBJECTIVE: To study the interaction of chronic zinc supplementation with genetic variants in CFH and ARMS2 on the development of CI.

BACKGROUND: Zinc dietary supplements, CFH and ARMS2 genotypes, and serial mental status was analyzed in participants with available genetic data (n = 7,483). Cognition was assessed using the Modified Mini-Mental State Examination. The development of CI over 5 years was analyzed by genotype and zinc intake using a repeated measures logistic regression model.

RESULTS: Zinc supplementation of approximately 15 mg/day was associated with decreased development of CI in women with 1 or 2 CFH and no ARMS2 risk alleles (OR = 0.46: 1 CFH risk allele; 0.20: 2 CFH risk alleles; p = 0.002).

CONCLUSION: Low-dose zinc (approximately 15 mg) is associated with reduced CI in women with 2 CFH and 0 ARMS2 AMD risk alleles. This interaction is opposite in direction to that observed in AMD, where patients with 2 CFH and 0 ARMS2 risk alleles had increased progression to neovascular AMD if treated with 80 mg/day of zinc. This may be due to a zinc dose-response or to a fundamental difference in the role of zinc in the progression of early CI versus advanced AMD.

%B J Alzheimers Dis %V 66 %P 707-715 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320589?dopt=Abstract %R 10.3233/JAD-180673 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Change in Fitness and the Relation to Change in Cognition and Neuropsychiatric Symptoms After Aerobic Exercise in Patients with Mild Alzheimer's Disease. %A Sobol, Nanna A %A Dall, Christian Have %A Høgh, Peter %A Hoffmann, Kristine %A Frederiksen, Kristian Steen %A Vogel, Asmus %A Siersma, Volkert %A Waldemar, Gunhild %A Hasselbalch, Steen G %A Beyer, Nina %X

BACKGROUND: Physical activity has the potential to improve physical function in patients with Alzheimer's disease (AD) and may contribute to modify disease processes and cognitive function.

OBJECTIVE: The aim of this study was to investigate 1) the effect of moderate-high-intensity aerobic exercise on cardiorespiratory fitness, i.e., peak oxygen uptake (VO2peak) determined by direct breath-by-breath cardiopulmonary exercise test, and 2) the association between changes in VO2peak and changes in cognition and neuropsychiatric symptoms in patients with mild AD.

METHODS: The study is based on secondary outcome analyses from the large single-blinded multi-center study ADEX (Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise). A preselected sub-group of 55 participants (age 52-83 years), 29 from the intervention group (IG) and 26 from the control group (CG), was included. IG performed 16 weeks of supervised moderate-to-high intensity aerobic exercise. Assessments of VO2peak, mental speed and attention (Symbol Digit Modalities Test, SDMT), and neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI) were performed at baseline and at 16 weeks.

RESULT: VO2peak increased 13% in the IG and a between-group difference in mean change (3.92 ml/kg/min, 95% CI 6.34-1.51, p = 0.003) was present in favor of the IG. Combined data from IG and CG showed positive associations between changes in VO2peak and changes in NPI (Rho = - 0.41, p = 0.042) and changes in SDMT (Rho = 0.36, p = 0.010), respectively.

CONCLUSION: Aerobic exercise improves VO2peak in community-dwelling patients with mild AD. Furthermore, changes in VO2peak appear to be associated to changes in cognition and neuropsychiatric symptoms.

%B J Alzheimers Dis %V 65 %P 137-145 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040719?dopt=Abstract %R 10.3233/JAD-180253 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Change of Amyloid-β 1-42 Toxic Conformer Ratio After Cerebrospinal Fluid Diversion Predicts Long-Term Cognitive Outcome in Patients with Idiopathic Normal Pressure Hydrocephalus. %A Akiba, Chihiro %A Nakajima, Madoka %A Miyajima, Masakazu %A Ogino, Ikuko %A Motoi, Yumiko %A Kawamura, Kaito %A Adachi, Satoshi %A Kondo, Akihide %A Sugano, Hidenori %A Tokuda, Takahiko %A Irie, Kazuhiro %A Arai, Hajime %X

BACKGROUND: Alzheimer's disease (AD) pathology in idiopathic normal pressure hydrocephalus (iNPH) contributes to poor shunt responses. Amyloid-β 1- 42 (Aβ42) toxic conformer was recently identified with features of rapid oligomerization, strong neurotoxicity and synaptotoxicity.

OBJECTIVE: This observational study points to Aβ42 toxic conformer as a biomarker for AD pathology and for poor postoperative prognosis in patients with iNPH.

METHODS: The first cohort consisted of patients with AD (n = 17) and iNPH (n = 17), and cognitively normal individuals (CN, n = 12). The second cohort, consisted of 51 patients with iNPH, was divided into two groups according to phosphorylated Tau (pTau) level (low- and high-pTau groups); the low-pTau group was further subdivided according to one-year postoperative change in Aβ42 toxic conformer ratio (%) [Aβ42 toxic conformer/Aβ42×100] (decreased- and increased-conformer subgroups). Enzyme-linked immunosorbent assay was used to measure pTau, Aβ42, and Aβ42 toxic conformer in cerebrospinal fluid. Outcomes were evaluated using neuropsychological tests one- and two-years postoperatively.

RESULTS: In the first cohort, Aβ42 toxic conformer ratio in the iNPH group (10.8%) was significantly higher than that in the CN group (6.3%) and significantly lower than that in the AD group (17.2%). In the second cohort, the high-pTau group showed cognitive decline two-years postoperatively compared to baseline. However, the low-pTau group showed favorable outcomes one-year postoperatively; furthermore, the increased-conformer subgroup showed cognitive decline two-years postoperatively while the decreased-conformer subgroup maintained the improvement.

CONCLUSIONS: Change in Aβ42 toxic conformer ratio predicts long-term cognitive outcome in iNPH, even in the low-pTau group.

%B J Alzheimers Dis %V 63 %P 989-1002 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710721?dopt=Abstract %R 10.3233/JAD-180059 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Changes in Expression Profiles Revealed by Transcriptomic Analysis in Peripheral Blood Mononuclear Cells of Alzheimer's Disease Patients. %A Leandro, Giovana Silva %A Evangelista, Adriane Feijó %A Lobo, Romulo Rebouças %A Xavier, Danilo Jordão %A Moriguti, Julio César %A Sakamoto-Hojo, Elza Tiemi %X

Alzheimer's disease (AD) is an age-related neurodegenerative pathology associated with accumulation of DNA damage. Inflammation and cell cycle alterations seem to be implicated in the pathogenesis of AD, although the molecular mechanisms have not been thoroughly elucidated to date. The aim of the present study was to evaluate whether peripheral blood mononuclear cells (PBMCs) of AD patients display alterations in gene expression profiles, focusing on finding markers that might improve the diagnosis of AD. Blood samples were collected from 22 AD patients and 13 healthy individuals to perform genome-wide mRNA expression. We found 593 differentially expressed genes in AD compared to controls, from which 428 were upregulated, and 165 were downregulated. By performing a gene set enrichment analysis, we observed pathways involved in inflammation, DNA damage response, cell cycle, and neuronal processes. Moreover, functional annotation analyses indicated that differentially expressed genes are strongly related to pathways associated with the cell cycle and the immune system. The results were compared with those of an independent study on hippocampus samples, and a number of genes in common between both studies were identified as potential peripheral biomarkers for AD, including DUSP1, FOS, SLC7A2, RGS1, GFAP, CCL2, ANGPTL4, and SSPN. Taken together, our results demonstrate that PBMCs of AD patients do present alterations in gene expression profiles, and these results are comparable to those previously reported in the literature for AD neurons, supporting the hypothesis that blood peripheral mononuclear cells express molecular changes that occur in the neurons of AD patients.

%B J Alzheimers Dis %V 66 %P 1483-1495 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400085?dopt=Abstract %R 10.3233/JAD-170205 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Characteristics of Cognitively Normal Mexican-Americans with Cognitive Complaints. %A Hall, James R %A Wiechmann, April %A Johnson, Leigh A %A Edwards, Melissa %A O'Bryant, Sid E %K Aged %K Biomarkers %K Cognition %K Cognitive Dysfunction %K Executive Function %K Female %K Humans %K Male %K Mexican Americans %K Middle Aged %K Neuropsychological Tests %K Risk Factors %K Texas %X

BACKGROUND: Subjective cognitive complaints in cognitively normal adults have been linked to later cognitive decline and dementia. Research on the characteristics of this group has been conducted on a variety of clinical and community-based populations. The current study focuses on the rapidly expanding population of Mexican-American elders.

OBJECTIVE: The objective of the study is the determination of characteristics of cognitively normal Mexican-Americans with cognitive complaints.

METHODS: Data on 319 cognitively normal participants in a large-scale community-based study of elderly Mexican-Americans (HABLE) were analyzed comparing those with cognitive complaints with those without on clinical characteristics, affective status, neuropsychological functioning, and proteomic markers.

RESULTS: Those expressing concern about cognitive decline scored lower on the MMSE, were more likely to have significantly more affective symptoms, higher levels of diabetic markers, poorer performance on attention and executive functioning, and a different pattern of inflammatory markers.

CONCLUSION: Although longitudinal research is needed to determine the impact of these differences on later cognition, possible targets for early intervention with Mexican-Americans were identified.

%B J Alzheimers Dis %V 61 %P 1485-1492 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376872?dopt=Abstract %R 10.3233/JAD-170836 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Characterization of Music and Photograph Evoked Autobiographical Memories in People with Alzheimer's Disease. %A Baird, Amee %A Brancatisano, Olivia %A Gelding, Rebecca %A Thompson, William Forde %X

BACKGROUND: Music evoked autobiographical memories (MEAMs) have been documented in people with Alzheimer's disease (AD), but it is unclear whether music is more effective than other familiar stimuli at evoking memories.

OBJECTIVE: To explore the frequency and specificity of memories in response to famous songs compared with photographs of famous events (photograph evoked autobiographical memories, PEAMs), and whether stimuli from the period of the reminiscence bump (10-30 years of age) were more likely to elicit memories.

METHODS: 10 participants with AD and 10 aged-matched healthy elderly people reported memories following exposure to 2 songs (longest time at number one in Australian music charts) and 2 photographs (of prominent famous events) from each decade from 1930 to 2010.

RESULTS: PEAMs were more frequent than MEAMs in healthy elderly (p < 0.05), but no such differences were observed among people with AD. There was no difference in the frequency of MEAMs between groups, but people with AD showed a significant decline in the frequency of PEAMs. In both groups, MEAMs were typically less specific than PEAMs and comprised semantic knowledge or repeated/extended events. Stimuli from when participants were aged 10-30 years triggered more frequent memories compared with stimuli from later decades, but this was only statistically significant for MEAMs.

CONCLUSION: Our findings indicate a preserved mnemonic effect of music relative to pictures in this patient population, corroborating suggestions that MEAMs represent an island of preservation during the progression of AD.

%B J Alzheimers Dis %V 66 %P 693-706 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320586?dopt=Abstract %R 10.3233/JAD-180627 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Childhood Lead Exposure and Adult Neurodegenerative Disease. %A Reuben, Aaron %X

Millions of Americans now entering midlife and old age were exposed to high levels of lead, a neurotoxin, as children. Evidence from animal-model and human observational studies suggest that childhood lead exposure may raise the risk of adult neurodegenerative disease, particularly dementia, through a variety of possible mechanisms including epigenetic modification, delayed cardiovascular and kidney disease, direct degenerative CNS injury from lead remobilized from bone, and lowered neural and cognitive reserve. Within the next ten years, the generation of children with the highest historical lead exposures, those born in the 1960s, 1970s, and 1980s, will begin to enter the age at which dementia symptoms tend to emerge. Many will also enter the age in which lead stored in the skeleton may be remobilized at greater rates, particularly for women entering menopause and men and women experiencing osteoporosis. Should childhood lead exposure prove pro-degenerative, the next twenty years will provide the last opportunities for possible early intervention to forestall greater degenerative disease burden across the aging lead-exposed population. More evidence is needed now to characterize the nature and magnitude of the degenerative risks facing adults exposed to lead as children and to identify interventions to limit long-term harm.

%B J Alzheimers Dis %V 64 %P 17-42 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865081?dopt=Abstract %R 10.3233/JAD-180267 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Chinese Herbal Medicine for Vascular Dementia: A Systematic Review and Meta-Analysis of High-Quality Randomized Controlled Trials. %A Xu, Qing-Qing %A Shan, Chun-Shuo %A Wang, Yong %A Shi, Yi-Hua %A Zhang, Qi-Hao %A Zheng, Guo-Qing %X

BACKGROUND: Vascular dementia (VaD) is the second common form of dementia and Chinese herbal medicine (CHM) has been used for aging-related disorders for thousands of years. However, there is still a lack of scientific evidence using CHM for VaD.

OBJECTIVE: To conduct a systematic review to assess the current evidence available for the effectiveness and safety of CHM for VaD.

METHODS: Six databases were searched for high-quality randomized-controlled clinical trials that met the requirements of at least 4 of the 7 domains of the Cochrane risk of bias tool from their inception to February 2017. RevMan 5.3 was applied for data analysis.

RESULTS: Forty studies with 42 comparisons and 3,572 individuals were included. The studies investigated the CHM versus placebo (n = 4), CHM versus western conventional treatment (WCT) (n = 36), and CHM plus WCT versus WCT (n = 2). Meta-analysis showed that CHM for VaD could improve Mini-Mental State Examination (MMSE), the Activities of Daily Living, Hasegawa's dementia scale, and clinical effective rate but had statistically similar effect based on Blessed Behavior Scale (BBS) outcome when compared with WCTs. When compared with placebo, CHMs were more beneficial in improving MMSE but showed no significant difference in BBS scores. CHM as adjuvant therapy exerted an additive anti-VaD benefit on MMSE scores. The participants of CHM group had fewer adverse events than that of the placebo group or WCT group.

CONCLUSION: The findings of the present study support, at least to an extent, that CHM can be recommended for routine use for treatment of VaD.

%B J Alzheimers Dis %V 62 %P 429-456 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439346?dopt=Abstract %R 10.3233/JAD-170856 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Chinese Herbal Medicine Xueshuantong Enhances Cerebral Blood Flow and Improves Neural Functions in Alzheimer's Disease Mice. %A Huang, Yangmei %A Guo, Baihong %A Shi, Bihua %A Gao, Qingtao %A Zhou, Qiang %X

Reduced cerebral blood flow in Alzheimer's disease (AD) may occur in early AD, which contributes to the pathogenesis and/or pathological progression of AD. Reversing this deficit may have therapeutic potential. Certain traditional Chinese herbal medicines (e.g., Saponin and its major component Xueshuantong [XST]) increase blood flow in humans, but whether they could be effective in treating AD patients has not been tested. We found that systemic XST injection elevated cerebral blood flow in APP/PS1 transgenic mice using two-photon time-lapse imaging in the same microvessels before and after injection. Subchronic XST treatment led to improved spatial learning and memory and motor performance in the APP/PS1 mice, suggesting improved neural plasticity and functions. Two-photon time lapse imaging of the same plaques revealed a reduction in plaque size after XST treatment. In addition, western blots experiments showed that XST treatment led to reduced processing of amyloid-β protein precursor (AβPP) and enhanced clearance of amyloid-β (Aβ) without altering the total level of AβPP. We also found increased synapse density in the immediate vicinity of amyloid plaques, suggesting enhanced synaptic function. We conclude that targeting cerebral blood flow can be an effective strategy in treating AD.

%B J Alzheimers Dis %V 63 %P 1089-1107 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710701?dopt=Abstract %R 10.3233/JAD-170763 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Chronic Lithium Treatment Increases Telomere Length in Parietal Cortex and Hippocampus of Triple-Transgenic Alzheimer's Disease Mice. %A Cardillo, Giancarlo de Mattos %A De-Paula, Vanessa de Jesus Rodrigues %A Ikenaga, Eliza Hiromi %A Costa, Luciana Rodrigues %A Catanozi, Sergio %A Schaeffer, Evelin Lisete %A Gattaz, Wagner Farid %A Kerr, Daniel Shikanai %A Forlenza, Orestes Vicente %X

Telomere length (TL) is a biomarker of cell aging, and its shortening has been linked to several age-related diseases. In Alzheimer's disease (AD), telomere shortening has been associated with neuroinflammation and oxidative stress. The majority of studies on TL in AD were based on leucocyte DNA, with little information about its status in the central nervous system. In addition to other neuroprotective effects, lithium has been implicated in the maintenance of TL. The present study aims to determine the effect of chronic lithium treatment on TL in different regions of the mouse brain, using a triple-transgenic mouse model (3xTg-AD). Eighteen transgenic and 22 wild-type (Wt) male mice were treated for eight months with chow containing 1.0 g (Li1) or 2.0 g (Li2) of lithium carbonate/kg, or standard chow (Li0). DNA was extracted from parietal cortex, hippocampus and olfactory epithelium and TL was quantified by real-time PCR. Chronic lithium treatment was associated with longer telomeres in the hippocampus (Li2, p = 0.0159) and in the parietal cortex (Li1, p = 0.0375) of 3xTg-AD compared to Wt. Our findings suggest that chronic lithium treatment does affect telomere maintenance, but the magnitude and nature of this effect depend on the working concentrations of lithium and characteristics of the tissue. This effect was observed when comparing 3xTg-AD with Wt mice, suggesting that the presence of AD pathology was required for the lithium modulation of TL.

%B J Alzheimers Dis %V 63 %P 93-101 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614649?dopt=Abstract %R 10.3233/JAD-170838 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Chronic Traumatic Encephalopathy and Neurodegeneration in Contact Sports and American Football. %A Zuckerman, Scott L %A Brett, Benjamin L %A Jeckell, Aaron %A Yengo-Kahn, Aaron M %A Solomon, Gary S %X

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by the presence of abnormally phosphorylated tau protein in the depths of one or more cortical sulci. Controversy over the risk of CTE and neurologic disorders later in life among contact sport athletes has taken hold in the public spotlight, most notably in American football. Players, parents, coaches, and legislators have taken action based on the commonly held notion that contact sports invariably lead to neurodegenerative disorders. However, to fully understand the science behind this assumed association, a critical appraisal of the evidence is warranted. With regards to CTE in sports, the objectives of the current report are to: 1) describe the history of CTE, 2) review current CTE definitions, 3) critically evaluate the empiric data, divided into all contact sports and exclusively American football, and 4) summarize notable themes for future research.

%B J Alzheimers Dis %V 66 %P 37-55 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30223396?dopt=Abstract %R 10.3233/JAD-180218 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Circulating, Cell-Free Micro-RNA Profiles Reflect Discordant Development of Dementia in Monozygotic Twins. %A Mengel-From, Jonas %A Rønne, Mette E %A Carlsen, Anting L %A Skogstrand, Kristin %A Larsen, Lisbeth A %A Tan, Qihua %A Christiansen, Lene %A Christensen, Kaare %A Heegaard, Niels H H %X

We aim to examine if circulating micro-RNA and cytokine levels associate with dementia diagnosis and cognitive scores. To test our hypothesis, we use plasma donated from 48 monozygotic twin pairs in 1997 and 46 micro-RNAs and 10 cytokines were quantified using microfluidic RT-qPCR and multiplex solid-phase immunoassays, respectively. Micro-RNA and cytokine profiling were examined for associations with dementia diagnoses in a longitudinal registry study or with cognitive scores at baseline. Thirty-six micro-RNAs and all cytokines were detected consistently. Micro-RNA profiles associate with diagnoses and cognitive scores at statistically significant levels while cytokine only showed trends pointing at chronic inflammation in twins having or developing dementia. The most notable findings were decreased miR-106a and miR-210, and increased miR-106b expression in twins with a dementia diagnosis. This pioneering evaluation of micro-RNA and cytokine and dementia diagnosis suggests micro-RNA targets in vasculogenesis, lipoprotein transport, and amyloid precursor protein genes.

%B J Alzheimers Dis %V 63 %P 591-601 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660943?dopt=Abstract %R 10.3233/JAD-171163 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Circulating miR-127-3p as a Potential Biomarker for Differential Diagnosis in Frontotemporal Dementia. %A Piscopo, Paola %A Grasso, Margherita %A Puopolo, Maria %A D'Acunto, Emanuela %A Talarico, Giuseppina %A Crestini, Alessio %A Gasparini, Marina %A Campopiano, Rosa %A Gambardella, Stefano %A Castellano, Anna Elisa %A Bruno, Giuseppe %A Denti, Michela A %A Confaloni, Annamaria %X

Given the heterogeneous nature of frontotemporal dementia (FTD), sensitive biomarkers are greatly needed for the accurate diagnosis of this neurodegenerative disorder. Circulating miRNAs have been reported as promising biomarkers for neurodegenerative disorders and processes affecting the central nervous system, especially in aging. The objective of the study was to evaluate if some circulating miRNAs linked with apoptosis (miR-29b-3p, miR-34a-5p, miR-16-5p, miR-17-5p, miR-107, miR-19b-3p, let-7b-5p, miR-26b-5p, and 127-3p) were able to distinguish between FTD patients and healthy controls. For this study, we enrolled 127 subjects, including 54 patients with FTD, 20 patients with Alzheimer's disease (AD), and 53 healthy controls. The qRT-PCR analysis showed a downregulation of miR-127-3p in FTD compared to controls, while the levels of other miRNAs remained unchanged. Then, miR-127-3p expression was also analyzed in AD patients, finding a different expression between two patient groups. A receiver operating characteristic curve was then created for miR-127-3p to discriminate FTD versus AD (AUC: 0.8986), and versus healthy controls (AUC: 0.8057). In conclusion, miR-127-3p could help to diagnose FTD and to distinguish it from AD.

%B J Alzheimers Dis %V 65 %P 455-464 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056425?dopt=Abstract %R 10.3233/JAD-180364 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Circulating Plasma microRNAs are Altered with Amyloidosis in a Mouse Model of Alzheimer's Disease. %A Ryan, Margaret M %A Guévremont, Diane %A Mockett, Bruce G %A Abraham, Wickliffe C %A Williams, Joanna M %X

Pathological changes underlying Alzheimer's disease (AD) begin decades before the classical symptoms of memory loss become evident. As microRNAs are released from neurons and enter the bloodstream, circulating microRNAs may be reflective of AD progression and are ideal candidates as biomarkers for early-stage disease detection. Here, we provide a novel, in-depth analysis of how plasma microRNAs alter with aging, the most prominent risk factor for AD, and with development of amyloid-β (Aβ) plaque deposition. We assessed the circulating microRNAs in APPswe/PSEN1dE9 transgenic mice and wild-type controls at 4, 8 and 15 m (n = 8-10) using custom designed Taqman arrays representing 185 neuropathology-related microRNAs. We performed a linear mixed-effects model to investigate the effects of age and genotype on plasma microRNAs expression. Following this analysis, we found 8 microRNAs were significantly affected by age alone in wild-type animals and 12 microRNAs altered in APPswe/PSEN1dE9 mice, either prior to Aβ plaque deposition (4 m) or during the development of AD-like pathogenesis (8 m or 15 m). Importantly, we found that differing sets of microRNAs were identified at each time point. Functional analysis of these data revealed that while common biological pathways, such as Inflammatory Response, were enriched throughout the disease process, Free Radical Scavenging, Immunological Disease, and Apoptosis Signaling were specifically enriched later in the disease process. Overall, this study reinforces that distinct biological processes underpin the early versus late stages of AD-like pathogenesis and highlights potential pre-symptomatic microRNAs biomarkers of neurodegeneration.

%B J Alzheimers Dis %V 66 %P 835-852 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30347618?dopt=Abstract %R 10.3233/JAD-180385 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Circulating Progenitor Cells Correlate with Memory, Posterior Cortical Thickness, and Hippocampal Perfusion. %A Nation, Daniel A %A Tan, Alick %A Dutt, Shubir %A McIntosh, Elissa C %A Yew, Belinda %A Ho, Jean K %A Blanken, Anna E %A Jang, Jung Yun %A Rodgers, Kathleen E %A Gaubert, Aimée %K Aged %K Aged, 80 and over %K Antigens, CD %K Apolipoproteins E %K Cerebral Cortex %K Cognitive Dysfunction %K Female %K Flow Cytometry %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Perfusion %K Stem Cells %K White Matter %X

BACKGROUND: Bone marrow-derived progenitor cells survey the vasculature and home to sites of tissue injury where they can promote repair and regeneration. It has been hypothesized that these cells may play a protective role neurodegenerative and vascular cognitive impairment.

OBJECTIVE: To evaluate progenitor cell levels in older adults with and without mild cognitive impairment (MCI), and to relate circulating levels to memory, brain volume, white matter lesion volume, and cerebral perfusion.

METHOD: Thirty-two older adults, free of stroke and cardiovascular disease, were recruited from the community and evaluated for diagnosis of MCI versus cognitively normal (CN). Participants underwent brain MRI and blood samples were taken to quantify progenitor reserve using flow cytometry (CD34+, CD34+CD133+, and CD34+CD133+CD309+ cells).

RESULTS: Participants with MCI (n = 10) exhibited depletion of all CPC markers relative to those who were CN (n = 22), after controlling for age, sex, and education. Post-hoc age, sex, and education matched comparisons (n = 10 MCI, n = 10 CN) also revealed the same pattern of results. Depletion of CD34+ cells correlated with memory performance, left posterior cortical thickness, and bilateral hippocampal perfusion. Participants exhibited low levels of vascular risk and white matter lesion burden that did not correlate with progenitor levels.

CONCLUSIONS: Circulating progenitor cells are associated with cognitive impairment, memory, cortical atrophy, and hippocampal perfusion. We hypothesize that progenitor depletion contributes to, or is triggered by, cognitive decline and cortical atrophy. Further study of progenitor cell depletion in older adults may benefit efforts to prevent or delay dementia.

%B J Alzheimers Dis %V 61 %P 91-101 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103037?dopt=Abstract %R 10.3233/JAD-170587 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Circulatory Levels of Toxic Metals (Aluminum, Cadmium, Mercury, Lead) in Patients with Alzheimer's Disease: A Quantitative Meta-Analysis and Systematic Review. %A Xu, Lin %A Zhang, Wenchao %A Liu, Xianchen %A Zhang, Cuili %A Wang, Pin %A Zhao, Xiulan %X

BACKGROUND: Environmental exposure to toxic metals has been postulated to play a role in the pathophysiological processes of Alzheimer's disease (AD). However, the circulatory levels of toxic metals in AD patients are not consistent in previous studies.

OBJECTIVE: To systematically assess levels of toxic metals (aluminum, mercury, cadmium, lead) in the circulation (blood, serum/plasma) of AD patients and controls.

METHODS: PubMed, Web of Science, Science Direct, Cochrane Library, and the China National Knowledge Infrastructure (CNKI) were systematically searched to identify studies published up to January 1, 2017. Meta-analyses were performed using random-effects models and the pooled standardized mean difference (SMD) were reported with 95% confidence intervals (CI).

RESULTS: We identified 17, 7, 8, and 10 studies for aluminum, mercury, cadmium, and lead, respectively. Meta-analyses showed significantly elevated circulatory levels of aluminum (SMD = 1.08, 95% CI: 0.66, 1.50), mercury (SMD = 0.55, 95% CI, 0.15, 0.95), and cadmium (SMD = 0.62, 95% CI: 0.12, 1.11), whereas lower levels of lead (SMD = -0.23, 95% CI: -0.38, -0.07) in AD patients than in controls. Publication bias was only observed for aluminum studies, but the "trim and fill" analysis showed that the publication bias did not alter the direction of the effect. Sensitivity analyses showed no studies from the pooled analysis changed the results.

CONCLUSION: Compared to controls, circulatory levels of aluminum, mercury, and cadmium are significantly higher but the levels of lead were reduced in AD patients. These findings suggest that elevated aluminum, mercury, and cadmium in the circulation, especially in serum may play a role in the progression of AD.

%B J Alzheimers Dis %V 62 %P 361-372 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439342?dopt=Abstract %R 10.3233/JAD-170811 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Class-Specific Incidence of All-Cause Dementia and Alzheimer's Disease: A Latent Class Approach. %A Zammit, Andrea R %A Hall, Charles B %A Katz, Mindy J %A Muniz-Terrera, Graciela %A Ezzati, Ali %A Bennett, David A %A Lipton, Richard B %X

Identifying preclinical Alzheimer's disease (AD) is an important step toward developing approaches to early treatment and dementia prevention. We applied latent class analysis (LCA) to 10 baseline neuropsychological assessments for 1,345 participants from Einstein Aging Study. Time-to-event models for all-cause dementia and AD were run examining events in 4-year intervals. Five classes were identified: Mixed-Domain Impairment (n = 107), Memory-Specific Impairment (n = 457), Average (n = 539), Frontal Impairment (n = 118), and Superior Cognition (n = 124). Compared to the Average class, the Mixed-Domain Impairment and Memory-Specific Impairment classes were at higher risk of incident all-cause dementia and AD in the first 4 years from baseline, while the Frontal Impairment class was associated with higher risk between 4 and 8 years of follow-up. LCA identified classes which differ in cross-sectional cognitive patterns and in risk of dementia over specific follow-up intervals.

%B J Alzheimers Dis %V 66 %P 347-357 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282367?dopt=Abstract %R 10.3233/JAD-180604 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Clinical Evaluation of Amyloid-Related Imaging Abnormalities in Bapineuzumab Phase III Studies. %A Brashear, H Robert %A Ketter, Nzeera %A Bogert, Jennifer %A Di, Jianing %A Salloway, Stephen P %A Sperling, Reisa %X

BACKGROUND: Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) reported in patients with mild-to-moderate Alzheimer's disease in bapineuzumab phase III studies.

OBJECTIVES: Assess symptoms, clinical severity, and ARIA-E outcomes, and to evaluate effects on cognition and function.

METHODS: A centralized systematic sequential locked procedure and scoring system for assessment of magnetic resonance imaging scans in 1,331 APOE ɛ4 noncarriers and 1,121 carriers was conducted by experienced and trained pairs of neuroradiologists.

RESULTS: Treatment-emergent ARIA-E occurred in 15.8% of bapineuzumab and 0.8% placebo-treated patients. In all treated APOE ɛ4 noncarriers, the percentage of patients with ARIA-E was 5.6%, 13.4%, and 19.9% in the 0.5, 1.0, and 2.0 mg/kg groups respectively, and the incidence of symptomatic ARIA-E was 1.5%, 1.5%, and 7.8%, respectively. In carriers, ARIA-E occurred in 21.2% in the 0.5 mg/kg group, and symptomatic ARIA-E occurred in 2.4%. The clinical severity of ARIA-E in those patients in whom it was detected during the study was mild in 57.1%, 61.3%, and 50.0% of cases in 0.5, 1.0, and 2.0 mg/kg noncarriers respectively, and in 73.8% of cases in 0.5 mg/kg carriers. Vascular risk factors did not appear to increase susceptibility to ARIA-E. Rate of decline in cognition and function measured by changes in ADAS-Cog/11 and DAD total scores did not meaningfully differ in patients with ARIA-E versus those without ARIA-E. Extent of cognitive decline was similar over all visit intervals.

CONCLUSIONS: Overall, ARIA-E was mild and asymptomatic. ARIA-E did not demonstrate clinically meaningful acute or chronic impact on cognition or function.Registration: NCT00574132 (Bapineuzumab-301), NCT00575055 (Bapineuzumab-302).

%B J Alzheimers Dis %V 66 %P 1409-1424 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412493?dopt=Abstract %R 10.3233/JAD-180675 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Clinical Experience with Cerebrospinal Fluid Aβ42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia. %A Tariciotti, Leonardo %A Casadei, Matthew %A Honig, Lawrence S %A Teich, Andrew F %A McKhann Ii, Guy M %A Tosto, Giuseppe %A Mayeux, Richard %X

BACKGROUND: Elevated total tau (tTau), 181-phosphorylated phosphorylated tau (pTau), and low amyloid-β42 (Aβ42) in cerebrospinal fluid (CSF) represent a diagnostic biomarker for Alzheimer's disease (AD).

OBJECTIVE: The goal was to determine the overall accuracy of CSF Aβ42, tTau, pTau, and the Aβ42/total tau index (ATI) in a non-research, clinical setting for the diagnosis of AD.

METHODS: From medical records in 1,016 patients that had CSF studies for dementia over a 12-year period (2005 to 2017), we calculated the sensitivity and specificity of CSF Aβ42, tTau, and pTau and the ATI in relation to the final clinical diagnosis.

RESULTS: Compared with non-demented patients and patients with other dementias or mild cognitive impairment (MCI), the sensitivity and specificity of the recommended ATI and pTau cut-offs (ATI < 1.0 and pTau >61 pg/ml) for the diagnosis of AD were 0.88 and 0.72, respectively. Similar results were obtained comparing AD with non-demented patients only (0.88, 0.82) and AD with other types of dementia (0.81, 0.77). A subgroup of patients with presumed normal pressure hydrocephalus (n = 154) were biopsied at the time of shunt placement. Using the pathological manifestations of AD as the standard, the sensitivity was 0.83 while the specificity was 0.72.

CONCLUSIONS: In a non-research setting, CSF biomarkers for AD showed a high sensitivity in accordance with previous studies, but modest specificity differentiating AD from other types of dementia or MCI. This study of unselected patients provides a valid and realistic assessment of the diagnostic accuracy of these CSF biomarkers in clinical practice.

%B J Alzheimers Dis %V 65 %P 1417-1425 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149454?dopt=Abstract %R 10.3233/JAD-180548 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Clinical Subtypes of Dementia with Lewy Bodies Based on the Initial Clinical Presentation. %A Morenas-Rodriguez, Estrella %A Sala, Isabel %A Subirana, Andrea %A Pascual-Goñi, Elba %A Sánchez-Saudinós, Ma Belén %A Alcolea, Daniel %A Illán-Gala, Ignacio %A Carmona-Iragui, María %A Ribosa-Nogué, Roser %A Camacho, Valle %A Blesa, Rafael %A Fortea, Juan %A Lleo, Alberto %X

BACKGROUND: Dementia with Lewy bodies (DLB) is a heterogeneous disease in which clinical presentation, symptoms, and evolution widely varies between patients.

OBJECTIVE: To investigate the existence of clinical subtypes in DLB based on the initial clinical presentation.

METHODS: 81 patients with a clinical diagnosis of probable DLB were consecutively included. All patients underwent a neurological evaluation including a structured questionnaire about neuropsychiatric symptoms and sleep, an assessment of motor impairment (Unified Parkinson Disease Rating Scale subscale III), and a formal neuropsychological evaluation. Onset of core symptoms (hallucinations, parkinsonism, and fluctuations) and dementia were systematically reviewed from medical records. We applied a K-means clustering method based on the initial clinical presentation.

RESULTS: Cluster analysis yielded three different groups. Patients in cluster I (cognitive-predominant, n = 46) presented more frequently with cognitive symptoms (95.7%, n = 44, p < 0.001), and showed a longer duration from onset to DLB diagnosis (p < 0.001) than the other clusters. Patients in cluster II (neuropsychiatric-predominant, n = 22) were older at disease onset (78.1±5 versus 73.6±6.1 and 73.6±4.2 in clusters I and III, respectively, both p < 0.01), presented more frequently with psychotic symptoms (77.3%, n = 17), and had a shorter duration until the onset of hallucinations (p < 0.001). Patients in cluster III (parkinsonism-predominant, n = 13) showed a shorter time from onset to presence of parkinsonism (p < 0.001) and dementia (0.008).

CONCLUSIONS: Three clinical subtypes of DLB can be defined when considering the differential initial presentations. The proposed subtypes have distinct clinical profiles and progression patterns.

%B J Alzheimers Dis %V 64 %P 505-513 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889064?dopt=Abstract %R 10.3233/JAD-180167 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Clinical Trials for Disease-Modifying Therapies in Alzheimer's Disease: A Primer, Lessons Learned, and a Blueprint for the Future. %A Cummings, Jeffrey %A Ritter, Aaron %A Zhong, Kate %K Alzheimer Disease %K Animals %K Clinical Trials as Topic %K Humans %X

Alzheimer's disease (AD) has no currently approved disease-modifying therapies (DMTs), and treatments to prevent, delay the onset, or slow the progression are urgently needed. A delay of 5 years if available by 2025 would decrease the total number of patients with AD by 50% in 2050. To meet the definition of DMT, an agent must produce an enduring change in the course of AD; clinical trials of DMTs have the goal of demonstrating this effect. AD drug discovery entails target identification followed by high throughput screening and lead optimization of drug-like compounds. Once an optimized agent is available and has been assessed for efficacy and toxicity in animals, it progresses through Phase I testing with healthy volunteers, Phase II learning trials to establish proof-of-mechanism and dose, and Phase III confirmatory trials to demonstrate efficacy and safety in larger populations. Phase III is followed by Food and Drug Administration review and, if appropriate, market access. Trial populations include cognitively normal at-risk participants in prevention trials, mildly impaired participants with biomarker evidence of AD in prodromal AD trials, and subjects with cognitive and functional impairment in AD dementia trials. Biomarkers are critical in trials of DMTs, assisting in participant characterization and diagnosis, target engagement and proof-of-pharmacology, demonstration of disease-modification, and monitoring side effects. Clinical trial designs include randomized, parallel group; delayed start; staggered withdrawal; and adaptive. Lessons learned from completed trials inform future trials and increase the likelihood of success.

%B J Alzheimers Dis %V 64 %P S3-S22 %8 2018 Jun 12 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad179901?id=journal-of-alzheimers-disease%2Fjad179901 %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562511?dopt=Abstract %R 10.3233/JAD-179901 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Clinically-Translatable Machine Learning Algorithm for the Prediction of Alzheimer's Disease Conversion in Individuals with Mild and Premild Cognitive Impairment. %A Grassi, Massimiliano %A Perna, Giampaolo %A Caldirola, Daniela %A Schruers, Koen %A Duara, Ranjan %A Loewenstein, David A %K Aged %K Aged, 80 and over %K Algorithms %K Alzheimer Disease %K Area Under Curve %K Atrophy %K Brain %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Logistic Models %K Machine Learning %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Predictive Value of Tests %K Prognosis %K Regression Analysis %K Sensitivity and Specificity %K Support Vector Machine %X

BACKGROUND: Available therapies for Alzheimer's disease (AD) can only alleviate and delay the advance of symptoms, with the greatest impact eventually achieved when provided at an early stage. Thus, early identification of which subjects at high risk, e.g., with MCI, will later develop AD is of key importance. Currently available machine learning algorithms achieve only limited predictive accuracy or they are based on expensive and hard-to-collect information.

OBJECTIVE: The current study aims to develop an algorithm for a 3-year prediction of conversion to AD in MCI and PreMCI subjects based only on non-invasively and effectively collectable predictors.

METHODS: A dataset of 123 MCI/PreMCI subjects was used to train different machine learning techniques. Baseline information regarding sociodemographic characteristics, clinical and neuropsychological test scores, cardiovascular risk indexes, and a visual rating scale for brain atrophy was used to extract 36 predictors. Leave-pair-out-cross-validation was employed as validation strategy and a recursive feature elimination procedure was applied to identify a relevant subset of predictors.

RESULTS: 16 predictors were selected from all domains excluding sociodemographic information. The best model resulted a support vector machine with radial-basis function kernel (whole sample: AUC = 0.962, best balanced accuracy = 0.913; MCI sub-group alone: AUC = 0.914, best balanced accuracy = 0.874).

CONCLUSIONS: Our algorithm shows very high cross-validated performances that outperform the vast majority of the currently available algorithms, and all those which use only non-invasive and effectively assessable predictors. Further testing and optimization in independent samples will warrant its application in both clinical practice and clinical trials.

%B J Alzheimers Dis %V 61 %P 1555-1573 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29355115?dopt=Abstract %R 10.3233/JAD-170547 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Clinical-Neuropathological Correlations of Alzheimer's Disease and Related Dementias in Latino Volunteers. %A Soria, Jose A %A Huisa, Branko N %A Edland, Steven D %A Litvan, Irene %A Peavy, Guerry M %A Salmon, David P %A Hansen, Lawrence A %A Galasko, Douglas R %A Brewer, James B %A González, Hector M %A Rissman, Robert A %X

Clinical, neuropsychological, and neurological procedures used to diagnose Alzheimer's disease (AD) and related dementias were largely developed and validated in well-educated, non-Latino, English-speaking populations. Sociocultural and genetic differences in Latinos might influence the accuracy of clinical diagnosis of AD and other dementias. We aim to compare the accuracy of the clinical diagnosis of AD and related dementias in Latinos with the corresponding neuropathological diagnosis. From the UCSD Alzheimer's Disease Research Center longitudinal cohort, we selected all Latino participants who had autopsy neuropathological studies from 1991 to 2017. Participants underwent annual neurological clinical evaluations, standard neuropsychological tests, neuroimaging, and genotyping of Apolipoprotein E. We calculated the sensitivity and specificity of the clinical diagnosis of AD against the primary pathological diagnosis. Of the 34 participants with a primary neuropathological diagnosis of AD, 33 (97.1%) were correctly clinically diagnosed as having AD at the last clinical evaluation, and 1 was incorrectly diagnosed with dementia with Lewy bodies. Of the 19 participants without a primary neuropathological diagnosis of AD, 8 were incorrectly clinically diagnosed with probable AD at the last clinic evaluation. The clinical diagnosis of AD at the last clinical evaluation had 97.1% sensitivity and 57.9% specificity for autopsy-verified AD. In this Latino cohort, clinicians predicted AD pathological findings with high sensitivity but moderate specificity. Tangle-only dementia was the most common misdiagnosis. Our study suggests that current procedures and instruments to clinically determine AD in Latinos have high sensitivity compared with neuropathology, but specificity needs to be improved.

%B J Alzheimers Dis %V 66 %P 1539-1548 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412501?dopt=Abstract %R 10.3233/JAD-180789 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Clinic-Based Validation of Cerebrospinal Fluid Biomarkers with Florbetapir PET for Diagnosis of Dementia. %A Álvarez, Ignacio %A Aguilar, Miquel %A González, Jose Manuel %A Ysamat, Montse %A Lorenzo-Bosquet, Carles %A Alonso, Alvaro %A Tartari, Juan Pablo %A Romero, Silvia %A Diez-Fairen, Monica %A Carcel, Maria %A Pujalte, Francisco %A Pastor, Pau %K Aged %K Amyloid beta-Peptides %K Analysis of Variance %K Aniline Compounds %K Apolipoproteins E %K Biomarkers %K Cognition Disorders %K Dementia %K Ethylene Glycols %K Female %K Humans %K Male %K Middle Aged %K Peptide Fragments %K Positron-Emission Tomography %K tau Proteins %X

BACKGROUND: Cerebrospinal fluid (CSF) biomarker studies have shown variable accuracy for diagnosis of Alzheimer's disease (AD); therefore, internal validation is recommended.

OBJECTIVE: To investigate the correlation between CSF biomarkers and cerebral 18-Florbetapir positron emission tomography (Amyloid-PET) and calculate their sensitivity and specificity to obtain the optimal clinical cut-off points to diagnose the etiology of cognitive impairment.

METHODS: We performed Amyloid-PET scans and CSF biomarker levels analyses in 68 subjects (50 with mild cognitive impairment, 11 with AD dementia, and 7 with non-AD dementia). Visual examination of Amyloid-PET scans was performed. CSF analyses were performed using standard sandwich ELISA.

RESULTS: Amyloid-PET was positive in 36 subjects, negative in 26, and inconclusive in 6. Optimal clinical cut-off points for CSF markers were the following: amyloid-β 1-42 (Aβ42) = 629 pg/ml, total tau (t-tau) = 532 pg/ml, phosphorylated tau (p-tau) = 88 pg/ml, and t-tau/Aβ42 ratio = 0.58. T-tau/Aβ42 ratio showed the best sensitivity and specificity (92 and 84%, respectively). T-tau and p-tau CSF levels (r2 = 0.867) followed by the t-tau and t-tau/Aβ42 CSF ratio (r2 = 0.666) showed the strongest inter-marker correlation. Interestingly, subjects with inconclusive Amyloid-PET showed intermediate values for all CSF markers between negative and positive Amyloid-PET groups.

CONCLUSIONS: CSF t-tau/Aβ42 ratio appears to be the most accurate AD CSF marker. The presence of intermediate values for CSF markers among the subjects with inconclusive Amyloid-PET suggests the presence of other dementias associated with AD pathology or intermediate phenotypes.

%B J Alzheimers Dis %V 61 %P 135-143 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154286?dopt=Abstract %R 10.3233/JAD-170753 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology. %A Alosco, Michael L %A Sugarman, Michael A %A Besser, Lilah M %A Tripodis, Yorghos %A Martin, Brett %A Palmisano, Joseph N %A Kowall, Neil W %A Au, Rhoda %A Mez, Jesse %A DeCarli, Charles %A Stein, Thor D %A McKee, Ann C %A Killiany, Ronald J %A Stern, Robert A %X

BACKGROUND: White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been postulated to be a core feature of Alzheimer's disease. Clinicopathological studies are needed to elucidate and confirm this possibility.

OBJECTIVE: This study examined: 1) the association between antemortem WMH and autopsy-confirmed Alzheimer's disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH, and ADNP.

METHODS: The sample included 82 participants from the National Alzheimer's Coordinating Center's Data Sets who had quantitated volume of WMH from antemortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy.

RESULTS: 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p = 0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p = 0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts, and lacunes (ps < 0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP-participants (ps < 0.04).

CONCLUSIONS: This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer's disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.

%B J Alzheimers Dis %V 63 %P 1347-1360 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843242?dopt=Abstract %R 10.3233/JAD-180017 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Co-Expression of Glia Maturation Factor and Apolipoprotein E4 in Alzheimer's Disease Brain. %A Thangavel, Ramasamy %A Bhagavan, Sachin M %A Ramaswamy, Swathi Beladakere %A Surpur, Spurthi %A Govindarajan, Raghav %A Kempuraj, Duraisamy %A Zaheer, Smita %A Raikwar, Sudhanshu %A Ahmed, Mohammad E %A Selvakumar, Govindhasamy Pushpavathi %A Iyer, Shankar S %A Zaheer, Asgar %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Brain %K Case-Control Studies %K Fluorescent Antibody Technique %K Glia Maturation Factor %K Humans %K Neurofibrillary Tangles %K Plaque, Amyloid %X

Apolipoprotein E4 (ApoE4) is a major genetic risk factor for Alzheimer's disease (AD). The E4 allele of ApoE plays a crucial role in the inflammatory and neurodegenerative processes associated with AD. This is evident from the multiple effects of the ApoE isoforms in amyloid-β (Aβ) aggregation. Glia maturation factor (GMF) is a brain-specific neuroinflammatory protein that we have previously demonstrated to be significantly upregulated in various regions of AD brains compared to non-AD control brains and that it induces neurodegeneration. We have previously reported that GMF is predominantly expressed in the reactive astrocytes surrounding amyloid plaques (APs) in AD brain. In the present study, using immunohistochemical and dual immunofluorescence staining, we show the expression and colocalization of GMF and ApoE4 in AD brains. Our results show that ApoE4 is present within the APs of AD brain. Further, we found that GMF and ApoE4 were strongly expressed and co-associated in APs and in the reactive astrocytes surrounding APs in AD. An increased expression of GMF in APs and neurofibrillary tangles in the AD brain, and the co-localization of GMF and ApoE4 in APs suggest that GMF and ApoE4 together should be contributing to the neuropathological changes associated with AD.

%B J Alzheimers Dis %V 61 %P 553-560 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29172001?dopt=Abstract %R 10.3233/JAD-170777 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cognitive Decline in Preclinical Alzheimer's Disease: Amyloid-Beta versus Tauopathy. %A Huber, Colin M %A Yee, Connor %A May, Taylor %A Dhanala, Apoorva %A Mitchell, Cassie S %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Cognitive Dysfunction %K Disease Models, Animal %K Maze Learning %K Mice %K Reaction Time %K Recognition (Psychology) %K tau Proteins %X

 We perform a large-scale meta-analysis of 51 peer-reviewed 3xTg-AD mouse publications to compare Alzheimer's disease (AD) quantitative clinical outcome measures, including amyloid-β (Aβ), total tau, and phosphorylated tau (pTau), with cognitive performance in Morris water maze (MWM) and Novel Object Recognition (NOR). "High" levels of Aβ (Aβ40, Aβ42) showed significant but weak trends with cognitive decline (MWM: slope = 0.336, R2 = 0.149, n = 259, p < 0.001; NOR: slope = 0.156, R2 = 0.064, n = 116, p < 0.05); only soluble Aβ or directly measured Aβ meaningfully contribute. Tau expression in 3xTg-AD mice was within 10-20% of wild type and not associated with cognitive decline. In contrast, increased pTau is directly and significantly correlated with cognitive decline in MWM (slope = 0.408, R2 = 0.275, n = 371, p < < 0.01) and NOR (slope = 0.319, R2 = 0.176, n = 113, p < 0.05). While a variety of pTau epitopes (AT8, AT270, AT180, PHF-1) were examined, AT8 correlated most strongly with cognition (slope = 0.586, R2 = 0.521, n = 185, p < < 0.001). Multiple linear regression confirmed pTau is a stronger predictor of MWM performance than Aβ. Despite pTau's lower physical concentration than Aβ, pTau levels more directly and quantitatively correlate with 3xTg-AD cognitive decline. pTau's contribution to neurofibrillary tangles well after Aβ levels plateau makes pTau a viable treatment target even in late-stage clinical AD. Principal component analysis, which included hyperphosphorylation induced by kinases (pGSK3β, GSK3β, CDK5), identified phosphorylated ser9 GSK3β as the primary contributor to MWM variance. In summary, meta-analysis of cognitive decline in preclinical AD finds tauopathy more impactful than Aβ. Nonetheless, complex AD interactions dictate successful therapeutics harness synergy between Aβ and pTau, possibly through the GSK3 pathway.

%B J Alzheimers Dis %V 61 %P 265-281 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154274?dopt=Abstract %R 10.3233/JAD-170490 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cognitive Function in Individuals with Normal Weight Obesity: Results from the Third National Health and Nutrition Examination Survey (NHANES III). %A Malandrino, Noemi %A Capristo, Esmeralda %A Taveira, Tracey H %A Mingrone, Geltrude %A Wu, Wen-Chih %X

BACKGROUND/OBJECTIVE: Normal weight obesity (NWO) is associated with increased risk of metabolic syndrome, cardiovascular- and all-cause mortality. However, no data have been reported on the relationship between adiposity and cognitive performance in NWO. We therefore studied the association between cognitive function and body fat percentage (BF%) in NWO, using a representative sample of the United States population.

METHODS: A cross-sectional study was performed using the nationwide 1988 to 1994 data set from the Third National Health and Nutrition Examination Survey. Cognitive function was measured by three validated cognitive tests: simple reaction time test (SRTT), symbol digit substitution test (SDST), and serial digit learning test (SDLT). The association between BF% and cognitive performance was evaluated in 2,039 adults aged 20-59 years and with a body mass index ranging from 18.5 to 24.9 kg/m2. Linear regression modeling was used to adjust for potential confounders.

RESULTS: Increased BF% was significantly associated with poorer performance on SDLT in the entire study sample (coefficient [95% CI]: 0.15 [0.01, 0.29]) and with poorer performance on SDST in the age group 20-29 years (coefficient [95% CI]: 0.30 [0.10, 0.49]). Increased BF% did not significantly predict poorer performance on SRTT.

CONCLUSION: Higher BF% is significantly associated with poorer cognitive function in a nationally representative sample of US adults with NWO. The identification of possible complications associated with increased adipose tissue underlines the need to measure body fat content in NWO individuals, whose metabolic and cognitive dysfunction could go undetected for years due to their young age and normal body weight.

%B J Alzheimers Dis %V 65 %P 125-135 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010127?dopt=Abstract %R 10.3233/JAD-180264 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cognitive Impairment is Associated with Mortality in Hemodialysis Patients. %A Angermann, Susanne %A Schier, Johannes %A Baumann, Marcus %A Steubl, Dominik %A Hauser, Christine %A Lorenz, Georg %A Günthner, Roman %A Braunisch, Matthias C %A Kemmner, Stephan %A Satanovskij, Robin %A Haller, Bernhard %A Heemann, Uwe %A Lehnert, Thomas %A Bieber, Richard %A Pachmann, Martin %A Braun, Jürgen %A Scherf, Julia %A Schätzle, Gabriele %A Fischereder, Michael %A Grimmer, Timo %A Schmaderer, Christoph %X

BACKGROUND: The prevalence of cognitive impairment in hemodialysis patients is notably high. In previous studises performed in the general population, cognitive impairment has been associated with increased mortality.

OBJECTIVE: We evaluated the relationship between global cognitive function tested by a short screening instrument and mortality in hemodialysis patients.

METHODS: Cognitive testing was performed in 242 maintenance hemodialysis patients under standardized conditions at baseline using the Montreal Cognitive Assessment (MoCA).Cognitive impairment was defined as a MoCA test score ≤24 points, as published previously. All-cause mortality was monitored during a median follow-up of 3.54 years. Kaplan-Meier plot and Cox regression model adjusted for known risk factors for mortality in hemodialysis patients were used to examine a possible association between global cognitive function and all-cause mortality.

RESULTS: A MoCA test score ≤24 points resulted in a significant almost 3-fold higher hazard for all-cause mortality (unadjusted hazard ratio [HR]: 2.812; 95% confidence interval [95% CI]: 1.683-4.698; p < 0.001). After adjustment, this association was attenuated but remained significant (adjusted HR: 1.749; 95% CI: 1.007-3.038; p = 0.047).

CONCLUSION: Impairment of global cognitive function measured by a short screening instrument was identified for the first time as an independent predictor of all-cause mortality in hemodialysis patients. Thus, implementing the MoCA test in clinical routine could contribute to a better risk stratification of this patient population.

%B J Alzheimers Dis %V 66 %P 1529-1537 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412499?dopt=Abstract %R 10.3233/JAD-180767 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cognitive Training Improves Ratio Processing and Decision Making in Patients with Mild Cognitive Impairment. %A Burgio, Francesca %A Delazer, Margarete %A Meneghello, Francesca %A Pertl, Marie-Theres %A Semenza, Carlo %A Zamarian, Laura %X

BACKGROUND: Patients with mild cognitive impairment (MCI) show lower decision making and ratio processing abilities as compared to healthy peers.

OBJECTIVE: To evaluate whether cognitive training on number processing and/or executive functions improves performance on ratio processing and decision making under risk.

METHODS: In a controlled cross-over study, patients with MCI (n = 23; mean MMSE 26.48, SD 2.43) underwent a week of numerical training followed by a week of executive-functions training (subgroup A), or vice versa (subgroup B). Before training (T1), patients performed experimental tasks of decision making (Game of Dice Task, GDT; Probability-Associated Gambling task, PAG-60 task) and of ratio processing as well as a neuropsychological background assessment. Experimental tasks were also administered after the first (T2) and the second (T3) training week.

RESULTS: The numerical training and the training of executive functions had a differential effect on experimental tasks of ratio processing. Only the numerical training proved to be effective. The effects of the two training types on decision making under risk were less clear-cut. While no changes over time were observed in the GDT, performance on the PAG-60 task improved in both training subgroups. These improvements were apparent in one subgroup after a period of executive-functions training, in the other subgroup after both training weeks. That means, improvements are not attributable to one specific training type.

CONCLUSION: Patients with MCI can profit from a cognitive training on number processing and executive functions. Improvements are reflected in higher ratio processing abilities and more advantageous decisions after training. These results are consistent with assumptions of current cognitive models.

%B J Alzheimers Dis %V 64 %P 1213-1226 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010137?dopt=Abstract %R 10.3233/JAD-180461 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cognitive Variability Predicts Incident Alzheimer's Disease and Mild Cognitive Impairment Comparable to a Cerebrospinal Fluid Biomarker. %A Gleason, Carey E %A Norton, Derek %A Anderson, Eric D %A Wahoske, Michelle %A Washington, Danielle T %A Umucu, Emre %A Koscik, Rebecca L %A Dowling, N Maritza %A Johnson, Sterling C %A Carlsson, Cynthia M %A Asthana, Sanjay %K Aged %K Aged, 80 and over %K Algorithms %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Cross-Sectional Studies %K Female %K Humans %K Incidence %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Statistics, Nonparametric %K tau Proteins %X

BACKGROUND: Alzheimer's disease (AD) biomarkers are emerging as critically important for disease detection and monitoring. Most biomarkers are obtained through invasive, resource-intense procedures. A cognitive marker, intra-individual cognitive variability (IICV) may provide an alternative or adjunct marker of disease risk for individuals unable or disinclined to undergo lumbar puncture.

OBJECTIVE: To contrast risk of incident AD and mild cognitive impairment (MCI) associated with IICV to risk associated with well-established biomarkers: cerebrospinal fluid (CSF) phosphorylated tau protein (p-tau181) and amyloid-β 42 (Aβ42) peptide.

METHODS: Dispersion in cognitive performance, IICV, was estimated with a published algorithm, and included Trail Making Test A and B, Rey Auditory Verbal Learning Test (RAVLT), and the American National Adult Reading Test (ANART). CSF biomarkers were expressed as a ratio: p-tau181/Aβ42, wherein high values signified pathognomonic profiles. Logistic regression models included longitudinal data from 349 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who completed lumbar puncture. All subjects were cognitively healthy (n = 105) or diagnosed with MCI (n = 244) at baseline. We examined odds of conversion associated with baseline elevations in IICV and/or ratio of CSF p-tau181/Aβ42.

RESULTS: When included in models alone or in combination with CSF p-tau181/Aβ42, one standard IICV unit higher was associated with an estimated odds ratio for incident AD or MCI of 2.81 (95% CI: 1.83-4.33) in the most inclusive sample, and an odds ratio of 3.41 (95% CI: 2.03-5.73) when restricted to participants with MCI. Iterative analyses suggested that IICV independently improved model fit even when individual index components were included in comparative models.

CONCLUSIONS: These analyses provide preliminary support for IICV as a marker of incident AD and MCI. This easily-disseminated, non-invasive marker compared favorably to well-established CSF biomarkers.

%B J Alzheimers Dis %V 61 %P 79-89 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125485?dopt=Abstract %R 10.3233/JAD-170498 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Colocalization of Aluminum and Iron in Nuclei of Nerve Cells in Brains of Patients with Alzheimer's Disease. %A Yumoto, Sakae %A Kakimi, Shigeo %A Ishikawa, Akira %X

Increasing evidence indicates that metal-induced oxidative stress plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Recently, the presence of 8-hydroxydeoxyguanosine, a biomarker of oxidative DNA damage, was demonstrated in nuclear DNA (nDNA) in the AD brain. Iron (Fe) is a pro-oxidant metal capable of generating hydroxyl radicals that can oxidize DNA, and aluminum (Al) has been reported to facilitate Fe-mediated oxidation. In the present study, we examined the elements contained in the nuclei of nerve cells in AD brains using scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS). Our results demonstrated that Al and Fe were colocalized in the nuclei of nerve cells in the AD brain. Within the nuclei, the highest levels of both Al and Fe were measured in the nucleolus. The SEM-EDS analysis also revealed the colocalization of Al and Fe in the heterochromatin and euchromatin in neuronal nuclei in the AD brain. Notably, the levels of Al and Fe in the nucleus of nerve cells in the AD brain were markedly higher than those in age-matched control brains. We hypothesize that the colocalization of Al and Fe in the nucleus of nerve cells might induce oxidative damage to nDNA and concurrently inhibit the repair of oxidatively damaged nDNA. An imbalance caused by the increase in DNA damage and the decrease in DNA repair activities might lead to the accumulation of unrepaired damaged DNA, eventually causing neurodegeneration and the development of AD.

%B J Alzheimers Dis %V 65 %P 1267-1281 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149443?dopt=Abstract %R 10.3233/JAD-171108 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Combination Therapy of Serotonin Reuptake Inhibitors and Memantine for Obsessive- Compulsive Disorder: A Meta-Analysis of Double-Blind, Randomized, Placebo-Controlled Trials. %A Kishi, Taro %A Matsuda, Yuki %A Iwata, Nakao %X

We performed a meta-analysis to determine whether combination therapy with serotonin reuptake inhibitors (SRIs) and memantine (MEM) was beneficial for the treatment of obsessive- compulsive disorder. This study included three double-blind, randomized, placebo-controlled trials. MEM+SRI was superior to placebo+SRI with regard to response rate [primary outcome, n = 97; risk ratio = 0.22; 95% confidence intervals (CI) = 0.12-0.42; p < 0.00001; I2 = 0%; number needed to treat = 2], the Yale- Brown Obsessive- Compulsive Scale total [standardized mean difference (SMD) = - 4.56; 95% CI = - 8.50, - 0.62; p = 0.02], obsession subscale (SMD = - 4.39; 95% CI = - 5.94, - 2.85; p < 0.00001), and compulsion subscale score (SMD = - 4.60; 95% CI = - 7.64, - 1.55; p = 0.003). No significant differences in any safety outcome were found between the groups.

%B J Alzheimers Dis %V 64 %P 43-48 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865079?dopt=Abstract %R 10.3233/JAD-180237 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Combined Socio-Behavioral Evaluation Improves the Differential Diagnosis Between the Behavioral Variant of Frontotemporal Dementia and Alzheimer's Disease: In Search of Neuropsychological Markers. %A Dodich, Alessandra %A Cerami, Chiara %A Cappa, Stefano F %A Marcone, Alessandra %A Golzi, Valeria %A Zamboni, Michele %A Giusti, Maria Cristina %A Iannaccone, Sandro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Cognition %K Diagnosis, Differential %K Female %K Frontotemporal Dementia %K Humans %K Logistic Models %K Male %K Memory, Episodic %K Mental Recall %K Middle Aged %K Neuropsychological Tests %K Retrospective Studies %K Social Skills %X

BACKGROUND: Current diagnostic criteria for behavioral variant of frontotemporal dementia (bvFTD) and typical Alzheimer's disease (AD) include a differential pattern of neuropsychological impairments (episodic memory deficit in typical AD and dysexecutive syndrome in bvFTD). There is, however, large evidence of a frequent overlap in neuropsychological features, making the differential diagnosis extremely difficult.

OBJECTIVES: In this retrospective study, we evaluated the diagnostic value of different cognitive and neurobehavioral markers in bvFTD and AD patient groups.

METHODS: We included 95 dementia patients with a clinical and biomarker evidence of bvFTD (n = 48) or typical AD (n = 47) pathology. A clinical 2-year follow-up confirmed clinical classification. Performances at basic cognitive tasks (memory, executive functions, visuo-spatial, language) as well as social cognition skills and neurobehavioral profiles have been recorded. A stepwise logistic regression model compared the neuropsychological profiles between groups and assessed the accuracy of cognitive and neurobehavioral markers in discriminating bvFTD from AD.

RESULTS: Statistical comparison between patient groups proved social cognition and episodic memory impairments as main cognitive signatures of bvFTD and AD neuropsychological profiles, respectively. Only half of bvFTD patients showed attentive/executive deficits, questioning their role as cognitive marker of bvFTD. Notably, the large majority of bvFTD sample (i.e., 70%) poorly performed at delayed recall tasks. Logistic regression analysis identified social cognition performances, Frontal Behavioral Inventory and Mini-Mental State Examination scores as the best combination in distinguishing bvFTD from AD.

CONCLUSION: Social cognition tasks and socio-behavioral questionnaires are recommended in clinical settings to improve the accuracy of early diagnosis of bvFTD.

%B J Alzheimers Dis %V 61 %P 761-772 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254091?dopt=Abstract %R 10.3233/JAD-170650 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Combining Cognitive, Genetic, and Structural Neuroimaging Markers to Identify Individuals with Increased Dementia Risk. %A Payton, Nicola M %A Kalpouzos, Grégoria %A Rizzuto, Debora %A Fratiglioni, Laura %A Kivipelto, Miia %A Bäckman, Lars %A Laukka, Erika J %X

BACKGROUND: Cognitive and biological markers have shown varying degrees of success in identifying persons who will develop dementia.

OBJECTIVE: To evaluate different combinations of cognitive and biological markers and identify prediction models with the highest accuracy for identifying persons with increased dementia risk.

METHODS: Neuropsychological assessment, genetic testing (apolipoprotein E -APOE), and structural magnetic resonance imaging (MRI) were performed for 418 older individuals without dementia (60-97 years) from a population-based study (SNAC-K). Participants were followed for six years.

RESULTS: Cognitive, genetic, and MRI markers were systematically combined to create prediction models for dementia at six years. The most predictive individual markers were perceptual speed or carrying at least one APOEɛ4 allele (AUC = 0.875). The most predictive model (AUC = 0.924) included variables from all three modalities (category fluency, general knowledge, any ɛ4 allele, hippocampal volume, white matter-hyperintensity volume).

CONCLUSION: This study shows that combining markers within and between modalities leads to increased predictivity for future dementia. However, minor increases in predictive value should be weighed against the cost of additional tests in larger-scale screening.

%B J Alzheimers Dis %V 64 %P 533-542 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889068?dopt=Abstract %R 10.3233/JAD-180199 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Coming of Age of the Angiotensin Hypothesis in Alzheimer's Disease: Progress Toward Disease Prevention and Treatment? %A Kehoe, Patrick Gavin %X

There is wide recognition of a complex association between midlife hypertension and cardiovascular disease and later development of Alzheimer's disease (AD) and cognitive impairment. While significant progress has been made in reducing rates of mortality and morbidity due to cardiovascular disease over the last thirty years, progress towards effective treatments for AD has been slower. Despite the known association between hypertension and dementia, research into each disease has largely been undertaken in parallel and independently. Yet over the last decade and a half, the emergence of converging findings from pre-clinical and clinical research has shown how the renin angiotensin system (RAS), which is very important in blood pressure regulation and cardiovascular disease, warrants careful consideration in the pathogenesis of AD. Numerous components of the RAS have now been found to be altered in AD such that the multifunctional and potent vasoconstrictor angiotensin II, and similarly acting angiotensin III, are greatly altered at the expense of other RAS signaling peptides considered to contribute to neuronal and cognitive function. Collectively these changes may contribute to many of the neuropathological hallmarks of AD, as well as observed progressive deficiencies in cognitive function, while also linking elements of a number of the proposed hypotheses for the cause of AD. This review discusses the emergence of the RAS and its likely importance in AD, not only because of the multiple facets of its involvement, but also perhaps fortuitously because of the ready availability of numerous RAS-acting drugs, that could be repurposed as interventions in AD.

%B J Alzheimers Dis %V 62 %P 1443-1466 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562545?dopt=Abstract %R 10.3233/JAD-171119 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Common Variant in PLD3 Influencing Cerebrospinal Fluid Total Tau Levels and Hippocampal Volumes in Mild Cognitive Impairment Patients from the ADNI Cohort. %A Tan, Meng-Shan %A Wang, Ping %A Ma, Fang-Chen %A Li, Jie-Qiong %A Tan, Chen-Chen %A Yu, Jin-Tai %A Tan, Lan %X

Recent studies found the variants in Alzheimer's disease (AD) risk gene PLD3 were associated with cognitive function, but its detailed mechanism before typical AD onset was unknown. Our current study examined the impact of PLD3 common variant rs11667768 on cerebrospinal fluid (CSF) total-tau and phosphorylated-tau levels and structural MRI from the ADNI database. We found rs11667768 was significantly associated with CSF total-tau levels and hippocampal volumes at baseline and six-year follow-up in the total non-demented elderly group and the mild cognitive impairment subgroup, indicating a potential role of PLD3 common variants in influencing cognitive function through changing CSF total-tau levels and hippocampal volumes.

%B J Alzheimers Dis %V 65 %P 871-876 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103332?dopt=Abstract %R 10.3233/JAD-180431 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Comparing the Electronic and Standard Versions of the Montreal Cognitive Assessment in an Outpatient Memory Disorders Clinic: A Validation Study. %A Berg, Jody-Lynn %A Durant, January %A Léger, Gabriel C %A Cummings, Jeffrey L %A Nasreddine, Ziad %A Miller, Justin B %X

The Montreal Cognitive Assessment (MoCA) has become widely used as a brief test of cognitive function in patients with neurological disease. More convenient application of the MoCA might increase its use and enhance its utility. An electronic version of the MoCA has recently been developed. To establish validity of the electronic version (eMoCA), discrepancy scores, concordance correlation coefficients (CCC), and root mean squared differences (RMSD) were calculated between each administration method in a sample of 43 new adult patients presenting with primary memory complaints. The CCC was 0.84 and the RMSD was 2.27, with 76% of the sample having a difference score within 2 points. Overall, this study establishes adequate convergent validity between the MoCA and eMoCA among an adult population presenting with memory concerns.

%B J Alzheimers Dis %V 62 %P 93-97 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439349?dopt=Abstract %R 10.3233/JAD-170896 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Comparison between FCSRT and LASSI-L to Detect Early Stage Alzheimer's Disease. %A Matías-Guiu, Jordi A %A Cabrera-Martín, María Nieves %A Curiel, Rosie E %A Valles-Salgado, María %A Rognoni, Teresa %A Moreno-Ramos, Teresa %A Carreras, José Luis %A Loewenstein, David A %A Matías-Guiu, Jorge %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cues %K Female %K Fluorodeoxyglucose F18 %K Humans %K Male %K Memory Disorders %K Mental Recall %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %K Psychiatric Status Rating Scales %K ROC Curve %K Semantics %X

BACKGROUND: The Free and Cued Selective Reminding Test (FCSRT) is the most accurate test for the diagnosis of prodromal Alzheimer's disease (AD). Recently, a novel cognitive test, the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L), has been developed in order to provide an early diagnosis.

OBJECTIVE: To compare the diagnostic accuracy of the FCSRT and the LASSI-L for the diagnosis of AD in its preclinical and prodromal stages using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) as a reference.

METHODS: Fifty patients consulting for subjective memory complaints without functional impairment and at risk for AD were enrolled and evaluated using FCSRT, LASSI-L, and FDG-PET. Participants were evaluated using a comprehensive neurological and neuropsychological protocol and were assessed with the FCSRT and LASSI-L. FDG-PET was acquired concomitantly and used for classification of patients as AD or non-AD according to brain metabolism using both visual and semi-quantitative methods.

RESULTS: LASSI-L scores allowed a better classification of patients as AD/non-AD in comparison to FCSRT. Logistic regression analysis showed delayed recall and failure to recovery from proactive semantic interference from LASSI-L as independent statistically significant predictors, obtaining an area under the curve of 0.894. This area under the curve provided a better discrimination than the best FCSRT score (total delayed recall, area under the curve 0.708, p = 0.029).

CONCLUSIONS: The LASSI-L, a cognitive stress test, was superior to FCSRT in the prediction of AD features on FDG-PET. This emphasizes the possibility to advance toward an earlier diagnosis of AD from a clinical perspective.

%B J Alzheimers Dis %V 61 %P 103-111 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125488?dopt=Abstract %R 10.3233/JAD-170604 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Comparison of Different Hypotheses Regarding the Spread of Alzheimer's Disease Using Markov Random Fields and Multimodal Imaging. %A Dyrba, Martin %A Grothe, Michel J %A Mohammadi, Abdolreza %A Binder, Harald %A Kirste, Thomas %A Teipel, Stefan J %X

Alzheimer's disease (AD) is characterized by a cascade of pathological processes that can be assessed in vivo using different neuroimaging methods. Recent research suggests a systematic sequence of pathogenic events on a global biomarker level, but little is known about the associations and dependencies of distinct lesion patterns on a regional level. Markov random fields are a probabilistic graphical modeling approach that represent the interaction between individual random variables by an undirected graph. We propose the novel application of this approach to study the interregional associations and dependencies between multimodal imaging markers of AD pathology and to compare different hypotheses regarding the spread of the disease. We retrieved multimodal imaging data from 577 subjects enrolled in the Alzheimer's Disease Neuroimaging Initiative. Mean amyloid load (AV45-PET), glucose metabolism (FDG-PET), and gray matter volume (MRI) were calculated for the six principle nodes of the default mode network- a functional network of brain regions that appears to be preferentially targeted by AD. Multimodal Markov random field models were developed for three different hypotheses regarding the spread of the disease: the "intraregional evolution model", the "trans-neuronal spread" hypothesis, and the "wear-and-tear" hypothesis. The model likelihood to reflect the given data was evaluated using tenfold cross-validation with 1,000 repetitions. The most likely graph structure contained the posterior cingulate cortex as main hub region with edges to various other regions, in accordance with the "wear-and-tear" hypothesis of disease vulnerability. Probabilistic graphical models facilitate the analysis of interactions between several variables in a network model and therefore afford great potential to complement traditional multiple regression analyses in multimodal neuroimaging research.

%B J Alzheimers Dis %V 65 %P 731-746 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697557?dopt=Abstract %R 10.3233/JAD-161197 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Complexity and Selectivity of γ-Secretase Cleavage on Multiple Substrates: Consequences in Alzheimer's Disease and Cancer. %A Medoro, Alessandro %A Bartollino, Silvia %A Mignogna, Donatella %A Passarella, Daniela %A Porcile, Carola %A Pagano, Aldo %A Florio, Tullio %A Nizzari, Mario %A Guerra, Germano %A Di Marco, Roberto %A Intrieri, Mariano %A Raimo, Gennaro %A Russo, Claudio %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Humans %K Neoplasms %K Presenilin-1 %X

The processing of the amyloid-β protein precursor (AβPP) by β- and γ-secretases is a pivotal event in the genesis of Alzheimer's disease (AD). Besides familial mutations on the AβPP gene, or upon its overexpression, familial forms of AD are often caused by mutations or deletions in presenilin 1 (PSEN1) and 2 (PSEN2) genes: the catalytic components of the proteolytic enzyme γ-secretase (GS). The "amyloid hypothesis", modified over time, states that the aberrant processing of AβPP by GS induces the formation of specific neurotoxic soluble amyloid-β (Aβ) peptides which, in turn, cause neurodegeneration. This theory, however, has recently evidenced significant limitations and, in particular, the following issues are debated: 1) the concept and significance of presenilin's "gain of function" versus "loss of function"; and 2) the presence of several and various GS substrates, which interact with AβPP and may influence Aβ formation. The latter consideration is suggestive: despite the increasing number of GS substrates so far identified, their reciprocal interaction with AβPP itself, even in the AD field, is significantly unexplored. On the other hand, GS is also an important pharmacological target in the cancer field; inhibitors or GS activity are investigated in clinical trials for treating different tumors. Furthermore, the function of AβPP and PSENs in brain development and in neuronal migration is well known. In this review, we focused on a specific subset of GS substrates that directly interact with AβPP and are involved in its proteolysis and signaling, by evaluating their role in neurodegeneration and in cell motility or proliferation, as a possible connection between AD and cancer.

%B J Alzheimers Dis %V 61 %P 1-15 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103038?dopt=Abstract %R 10.3233/JAD-170628 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Comprehensive Characterization of the Pyroglutamate Amyloid-β Induced Motor Neurodegenerative Phenotype of TBA2.1 Mice. %A Dunkelmann, Tina %A Schemmert, Sarah %A Honold, Dominik %A Teichmann, Kerstin %A Butzküven, Elke %A Demuth, Hans-Ulrich %A Shah, Nadim Joni %A Langen, Karl-Josef %A Kutzsche, Janine %A Willbold, Dieter %A Willuweit, Antje %X

Alzheimer's disease (AD) is the most common neurodegenerative disorder and is being intensively investigated using a broad variety of animal models. Many of these models express mutant versions of human amyloid-β protein precursor (AβPP) that are associated with amyloid-β protein (Aβ)-induced early onset familial AD. Most of these models, however, do not develop bold neurodegenerative pathology and the respective phenotypes. Nevertheless, this may well be essential for their suitability to identify therapeutically active compounds that have the potential for a curative or at least disease-modifying therapy in humans. In this study, the new transgenic mouse model TBA2.1 was explored in detail to increase knowledge about the neurodegenerative process induced by the presence of pyroglutamate modified human Aβ3-42 (pEAβ3-42). Analysis of the sensorimotor phenotype, motor coordination, Aβ pathology, neurodegeneration, and gliosis revealed formation and progression of severe pathology and phenotypes including massive neuronal loss in homozygous TBA2.1 mice within a few months. In contrast, the start of a slight phenotype was observed only after 21 months in heterozygous mice. These data highlight the role of pEAβ3-42 in the disease development and progression of AD. Based on the findings of this study, homozygous TBA2.1 mice can be utilized to gain deeper understanding in the underlying mechanisms of pEAβ3-42 and might be suitable as an animal model for treatment studies targeting toxic Aβ species, complementary to the well described transgenic AβPP mouse models.

%B J Alzheimers Dis %V 63 %P 115-130 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578479?dopt=Abstract %R 10.3233/JAD-170775 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Is Computerized Working Memory Training Effective in Healthy Older Adults? Evidence from a Multi-Site, Randomized Controlled Trial. %A Simon, Sharon S %A Tusch, Erich S %A Feng, Nicole C %A Håkansson, Krister %A Mohammed, Abdul H %A Daffner, Kirk R %X

BACKGROUND: Developing effective interventions to attenuate age-related cognitive decline and prevent or delay the onset of dementia are major public health goals. Computerized cognitive training (CCT) has been marketed increasingly to older adults, but its efficacy remains unclear. Working memory (WM), a key determinant of higher order cognitive abilities, is susceptible to age-related decline and a relevant target for CCT in elders.

OBJECTIVE: To evaluate the efficacy of CCT focused on WM compared to an active control condition in healthy older adults.

METHODS: Eighty-two cognitively normal adults from two sites (USA and Sweden) were randomly assigned to Cogmed Adaptive or Non-Adaptive (active control) CCT groups. Training was performed in participants' homes, five days per week over five weeks. Changes in the performance of the Cogmed trained tasks, and in five neuropsychological tests (Trail Making Test Part A and Part B, Digit Symbol, Controlled Oral Word Association Test and Semantic Fluency) were used as outcome measures.

RESULTS: The groups were comparable at baseline. The Adaptive group showed robust gains in the trained tasks, and there was a time-by-group interaction for the Digit Symbol test, with significant improvement only after Adaptive training. In addition, the magnitude of the intervention effect was similar at both sites.

CONCLUSION: Home-based CCT Adaptive WM training appears more effective than Non-Adaptive training in older adults from different cultural backgrounds. We present evidence of improvement in trained tasks and on a demanding untrained task dependent upon WM and processing speed. The benefits over the active control group suggest that the Adaptive CCT gains were linked to providing a continuously challenging level of WM difficulty.

%B J Alzheimers Dis %V 65 %P 931-949 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103334?dopt=Abstract %R 10.3233/JAD-180455 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Concordance Between Cerebrospinal Fluid Biomarkers with Alzheimer's Disease Pathology Between Three Independent Assay Platforms. %A Doecke, James D %A Rembach, Alan %A Villemagne, Victor L %A Varghese, Shiji %A Rainey-Smith, Stephanie %A Sarros, Shannon %A Evered, Lisbeth A %A Fowler, Christopher J %A Pertile, Kelly K %A Rumble, Rebecca L %A Trounson, Brett %A Taddei, Kevin %A Laws, Simon M %A Macaulay, S Lance %A Bush, Ashley I %A Ellis, Kathryn A %A Martins, Ralph %A Ames, David %A Silbert, Brendan %A Vanderstichele, Hugo %A Masters, Colin L %A Darby, David G %A Li, Qiao-Xin %A Collins, Steven %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognition Disorders %K Female %K Humans %K Male %K Mental Status Schedule %K Peptide Fragments %K Positron-Emission Tomography %K ROC Curve %K tau Proteins %X

BACKGROUND: To enhance the accuracy of clinical diagnosis for Alzheimer's disease (AD), pre-mortem biomarkers have become increasingly important for diagnosis and for participant recruitment in disease-specific treatment trials. Cerebrospinal fluid (CSF) biomarkers provide a low-cost alternative to positron emission tomography (PET) imaging for in vivo quantification of different AD pathological hallmarks in the brains of affected subjects; however, consensus around the best platform, most informative biomarker and correlations across different methodologies are controversial.

OBJECTIVE: Assessing levels of Aβ-amyloid and tau species determined using three different versions of immunoassays, the current study explored the ability of CSF biomarkers to predict PET Aβ-amyloid (32 Aβ-amyloid-and 45 Aβ-amyloid+), as well as concordance between CSF biomarker levels and PET Aβ-amyloid imaging.

METHODS: Prediction and concordance analyses were performed using a sub-cohort of 77 individuals (48 healthy controls, 15 with mild cognitive impairment, and 14 with AD) from the Australian Imaging Biomarker and Lifestyle study of aging.

RESULTS: Across all three platforms, the T-tau/Aβ42 ratio biomarker had modestly higher correlation with SUVR/BeCKeT (ρ= 0.69-0.8) as compared with Aβ42 alone (ρ= 0.66-0.75). Differences in CSF biomarker levels between the PET Aβ-amyloid-and Aβ-amyloid+ groups were strongest for the Aβ42/Aβ40 and T-tau/Aβ42 ratios (p < 0.0001); however, comparison of predictive models for PET Aβ-amyloid showed no difference between Aβ42 alone and the T-tau/Aβ42 ratio.

CONCLUSION: This study confirms strong concordance between CSF biomarkers and PET Aβ-amyloid status is independent of immunoassay platform, supporting their utility as biomarkers in clinical practice for the diagnosis of AD and for participant enrichment in clinical trials.

%B J Alzheimers Dis %V 61 %P 169-183 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171991?dopt=Abstract %R 10.3233/JAD-170128 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Connected Speech Features from Picture Description in Alzheimer's Disease: A Systematic Review. %A Slegers, Antoine %A Filiou, Renée-Pier %A Montembeault, Maxime %A Brambati, Simona Maria %X

The language changes that occur over the course of Alzheimer's disease (AD) can impact communication abilities and have profound functional consequences. Picture description tasks can be used to approximate everyday communication abilities of AD patients. As various methods and variables have been studied over the years, current knowledge about the most affected features of AD discourse in the context of picture descriptions is difficult to summarize. This systematic review aims to provide researchers with an overview of the most common areas of impairment in AD discourse as they appear in picture description tasks. Based on the 44 articles fulfilling inclusion criteria, our findings reflect a multidimensional pattern of changes in the production (speech rate), syntactic (length of utterance), lexical (word-frequency and use of pronouns), fluency (repetitions and word-finding difficulties), semantic (information units), and discourse (efficiency) domains. We discuss our findings in the light of current research and point to potential scientific and clinical uses of picture description tasks in the context of AD.

%B J Alzheimers Dis %V 65 %P 519-542 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103314?dopt=Abstract %R 10.3233/JAD-170881 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Consent to Medical Procedures of Patients with Neurodegenerative Diseases: A Comparative Study of Legal Regulations in Selected European Countries and in the United States. %A Guzik-Makaruk, Ewa M %A Pływaczewski, Emil W %A Mroczko, Piotr %A Olesiuk-Okomska, Magda %A Kulczyńska-Przybik, Agnieszka %X

According to the projections of the statistical office of the European Union, Eurostat, nearly one third of EU citizens will be at least 65 in 2060. The U.S. population age 65 and older continues to increase and is projected to nearly double from 48 million to 88 million by 2050. Elderly people are especially exposed to neurodegenerative diseases (NDs). The most common ND is Alzheimer's disease (AD), a chronic and progressive disorder with a variety of pathological changes within neuronal tissue, which begin even 10-15 years before the onset of cognitive impairment symptoms. AD is perceived as a disease continuum and considered to include three basic phases: preclinical (asymptomatic) stage, mild cognitive impairment (MCI), and dementia due to AD. A very important issue, from medical and legal perspectives, is the NDs patient's consent to medical procedures, including diagnostic procedures, such as lumber puncture. NDs patients are not always able to express their consent and do not always understand the information provided by a physician. This applies to a group of patients in the final stages of NDs. This paper presents legal regulations of selected European countries and signalizes the U.S. legal solutions on the issue of NDs patients' informed consent to medical procedures.

%B J Alzheimers Dis %V 63 %P 53-67 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614670?dopt=Abstract %R 10.3233/JAD-171176 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Constructing a Local Potential Participant Registry to Improve Alzheimer's Disease Clinical Research Recruitment. %A Grill, Joshua D %A Hoang, Dan %A Gillen, Daniel L %A Cox, Chelsea G %A Gombosev, Adrijana %A Klein, Kirsten %A O'Leary, Steve %A Witbracht, Megan %A Pierce, Aimee %X

Potential participant registries are tools to address the challenge of slow recruitment to clinical research. In particular, registries may aid recruitment to secondary prevention clinical trials for Alzheimer's disease (AD), which enroll cognitively normal older individuals meeting specific genetic or biomarker criteria. Evidence of registry effectiveness is sparse, as is guidance on optimal designs or methods of conduct. We report our experiences of developing a novel local potential participant registry that implemented online enrollment and data collection. In the first year of operation, 957 individuals submitted email addresses to the registry, of whom 592 self-reported demographic, family history, and medical data. In addition, registrants provided information related to their interest and willingness to be contacted about studies. Local earned media and community education were the most effective methods of recruitment into the registry. Seventy-six (26%) of 298 registrants contacted about studies in the first year enrolled in those studies. One hundred twenty-nine registrants were invited to enroll in a preclinical AD trial, of whom 25 (18%) screened and 6 were randomized. These results indicate that registries can aid recruitment and provide needed guidance for investigators initiating new local registries.

%B J Alzheimers Dis %V 63 %P 1055-1063 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710723?dopt=Abstract %R 10.3233/JAD-180069 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Contribution of Bilingualism to Cognitive Reserve of an Italian Literature Professor at High Risk for Alzheimer's Disease. %A Lombardi, Gemma %A Polito, Cristina %A Berti, Valentina %A Bagnoli, Silvia %A Nacmias, Benedetta %A Pupi, Alberto %A Sorbi, Sandro %X

Bilingualism is an independent component of cognitive reserve that permits to delay dementia onset up to 5 years. We describe a case of a bilingual Italian man affected by mild cognitive impairment with high cognitive reserve that, despite the presence of multiple risk factors (ApoE ɛ4/ɛ4 genotype, older age, untreated Obstructive Sleep Apnea Syndrome, AD-like biomarker alterations) did not convert to Alzheimer's disease up to 5 years follow-up. The present case confirms the role of bilingualism as a strong protective factor for dementia, even in the occurrence of multiple risk factors.

%B J Alzheimers Dis %V 66 %P 1389-1395 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30475769?dopt=Abstract %R 10.3233/JAD-180736 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Conundrum of GSK3 Inhibitors: Is it the Dawn of a New Beginning? %A Bhat, Ratan V %A Andersson, Ulf %A Andersson, Shalini %A Knerr, Laurent %A Bauer, Udo %A Sundgren-Andersson, Anna K %X

Spanning over three decades of extensive drug discovery research, the efforts to develop a potent and selective GSK3 inhibitor as a therapeutic for the treatment of type 2 diabetes, Alzheimer's disease (AD), bipolar disorders and cancer have been futile. Since its initial discovery in 1980 and subsequent decades of research, one cannot underscore the importance of the target and the promise of a game changing disease modifier. Several pharmaceutical companies, biotech companies, and academic institutions raged in a quest to unravel the biology and discover potent and selective GSK3 inhibitors, some of which went through clinical trials. However, the conundrum of what happened to the fate of the AstraZeneca's GSK3 inhibitors and the undertaking to find a therapeutic that could control glycogen metabolism and aberrant tau hyperphosphorylation in the brain, and rescue synaptic dysfunction has largely been untold. AstraZeneca was in the forefront of GSK3 drug discovery research with six GSK3 drug candidates, one of which progressed up to Phase II clinical trials in the quest to untangle the tau hypothesis for AD. Analysis of key toxicity issues, serendipitous findings and efficacy, and biomarker considerations in relation to safety margins have limited the potential of small molecule therapeutics as a way forward. To guide future innovation of this important target, we reveal the roller coaster journey comprising of two decades of preclinical and clinical GSK3 drug discovery at AstraZeneca; the understanding of which could lead to improved GSK3 therapies for disease. These learnings in combination with advances in achieving kinase selectivity, different modes of action as well as the recent discovery of novel conjugated peptide technology targeting specific tissues have potentially provided a venue for scientific innovation and a new beginning for GSK3 drug discovery.

%B J Alzheimers Dis %V 64 %P S547-S554 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758944?dopt=Abstract %R 10.3233/JAD-179934 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Correlates of Subjective Cognitive Decline in Lesbian, Gay, Bisexual, and Transgender Older Adults. %A Flatt, Jason D %A Johnson, Julene K %A Karpiak, Stephen E %A Seidel, Liz %A Larson, Britta %A Brennan-Ing, Mark %X

BACKGROUND: Little is known about subjective cognitive decline (SCD) in lesbian, gay, bisexual, and transgender (LGBT) older adults.

OBJECTIVES: To examine SCD and its association with dementia risk factors, other physical and psychosocial health factors in LGBT older adults.

METHODS: A cross-sectional study of SCD was conducted with LGBT older adults, aged 50 and older (n = 210). SCD was categorized based on endorsement of memory problems and one other cognitive domain. Hierarchical logistic regression examined the associations between demographic factors, dementia risk factors, other health and psychosocial factors, and SCD.

RESULTS: Nearly 25% of LGBT older adults were classified as having SCD. LGBT older adults who were people of color (OR = 2.5; 95% CI = 1.1- 7.8), depressed (OR = 2.9; 95% CI = 1.3- 6.9), or reported having functional impairment (OR = 2.6; 95% CI = 1.1- 6.5) were significantly more likely to be classified as having SCD (Nagelkerke pseudo R2 = 0.27).

CONCLUSION: Depression and functional impairment should be considered when screening LGBT older adults for cognitive impairment and dementia. Future research on the cognitive impairment and dementia risk in LGBT older adults is needed.

%B J Alzheimers Dis %V 64 %P 91-102 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865050?dopt=Abstract %R 10.3233/JAD-171061 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Crosstalk between Peripheral Small Vessel Properties and Anxious-like Profiles: Sex, Genotype, and Interaction Effects in Mice with Normal Aging and 3×Tg-AD mice at Advanced Stages of Disease. %A Jiménez-Altayó, Francesc %A Sánchez-Ventura, Judith %A Vila, Elisabet %A Giménez-Llort, Lydia %X

Cardiovascular disease resulting from oxidative stress and inflammation can exacerbate Alzheimer's disease. This brief report provides the first evidence of compromised small peripheral mesenteric resistance artery (MRA) properties in 15-month-old 3xTg-AD mice. Females showed worse physiologically relevant MRA structural (increased passive external and internal diameters, cross sectional area) and functional (increased active internal diameters) alterations suggesting sex-dependent dysfunctions. At both physiological and high intraluminal pressures, vascular alterations correlated with the anxious-like behavioral profile, in a sex-dependent manner. Finally, the results unveil a crosstalk between peripheral small vessel properties and behavior in both 3xTg-AD mice and age-matched counterparts with normal aging.

%B J Alzheimers Dis %V 62 %P 1531-1538 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504535?dopt=Abstract %R 10.3233/JAD-171019 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cysteine-Rich Repeat Domains 2 and 4 are Amyloid-β Binding Domains of Neurotrophin Receptor p75NTR and Potential Targets to Block Amyloid-β Neurotoxicity. %A Wang, Ye-Ran %A Wang, Jun %A Liu, Yu-Hui %A Hu, Gong-Ling %A Gao, Chang-Yue %A Wang, Yan-Jiang %A Zhou, Xin-Fu %A Zeng, Fan %X

The p75 neurotrophin receptor (p75NTR) is an amyloid-β (Aβ) receptor that both mediates Aβ neurotoxicity and regulates Aβ production and deposition, thus playing an important role in the pathogenesis of Alzheimer's disease (AD). The extracellular domain of p75NTR (p75ECD), consisting of four cysteine-rich repeat domains (CRDs), was recently reported to be an endogenous anti-Aβ scavenger to block p75NTR-mediated neuronal death and neurite degeneration signaling of Aβ and pro-neurotrophins. Identification of the specific Aβ binding domains of p75NTR is crucial for illuminating their interactions and the etiology of AD. CRDs of p75ECD were obtained by expression of recombinant plasmids or direct synthesis. Aβ aggregation inhibiting test and immunoprecipitation assay were applied to locate the specific binding domains of Aβ to p75ECD. The Aβ neurotoxicity antagonistic effects of different CRDs were examined by cytotoxicity experiments including neurite outgrowth assay, propidium iodide (PI) staining, and MTT assay. In the Aβ aggregation inhibiting test, the fluorescence intensity in the CRD2 and CRD4 treatment groups was significantly lower than that in the CRD1 and CRD3 treatment groups. Immunoprecipitation assay and western blot confirmed that Aβ could bind to CRD2 and CRD4. Besides, CRD2 and CRD4 antagonized Aβ neurotoxicity suggested by longer neurite length, less PI labelled cells, and higher cell viability than the control group. Our results indicate that CRD2 and CRD4 are Aβ binding domains of p75NTR and capable of antagonizing Aβ neurotoxicity, and therefore are potential therapeutic targets to block the interaction of Aβ and p75NTR in the pathogenesis of AD.

%B J Alzheimers Dis %V 63 %P 139-147 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578485?dopt=Abstract %R 10.3233/JAD-171012 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dale Schenk One Year Anniversary: Fighting to Preserve the Memories. %A Overk, Cassia %A Masliah, Eliezer %X

It has been a year since we lost Dale Schenk on September 30, 2016. Dale's visionary work resulted in the remarkable discovery in 1999 that an experimental amyloid-β (Aβ) vaccine reduced the neurodegeneration in a transgenic model of Alzheimer's disease (AD). Following Dale's seminal work, several active and passive immunotherapies have since been developed and tested in the clinic for AD, Parkinson's disease (PD), and other neurodegenerative disorders. Here we provide a brief overview of the current state of development of immunotherapy for AD, PD, and other neurodegenerative disorders in the context of this anniversary. The next steps in the development of immunotherapies will require combinatorial approaches mixing antibodies against various targets (e.g., Aβ, α-syn, Tau, and TDP43) with small molecules that block toxicity, aggregation, inflammation, and promote cell survival.

%B J Alzheimers Dis %V 62 %P 1-13 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439357?dopt=Abstract %R 10.3233/JAD-171071 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Decade of Blood Biomarkers for Alzheimer's Disease Research: An Evolving Field, Improving Study Designs, and the Challenge of Replication. %A Shi, Liu %A Baird, Alison L %A Westwood, Sarah %A Hye, Abdul %A Dobson, Richard %A Thambisetty, Madhav %A Lovestone, Simon %X

Blood-based biomarkers represent a less invasive and potentially cheaper approach for aiding Alzheimer's disease (AD) detection compared with cerebrospinal fluid and some neuroimaging biomarkers. Acknowledging that many in the field have made great progress, here we review some of the work that our group has pursued to identify and validate blood-based proteomic biomarkers through both case control and AD pathology endophenotype-based approaches. Our focus is primarily to identify a minimally invasive and hopefully cost-effective blood-based biomarker to reduce screen failure in clinical trials where participants have prodromal or even pre-clinical disease. We summarize some of the key findings and approaches taken in these biomarker studies, while addressing the main challenges, including that of limited replication in the field, and discuss opportunities for biomarker development.

%B J Alzheimers Dis %V 62 %P 1181-1198 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562526?dopt=Abstract %R 10.3233/JAD-170531 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Decoupling of Local Metabolic Activity and Functional Connectivity Links to Amyloid in Alzheimer's Disease. %A Scherr, Martin %A Pasquini, Lorenzo %A Benson, Gloria %A Nuttall, Rachel %A Gruber, Martin %A Neitzel, Julia %A Brandl, Felix %A Sorg, Christian %X

BACKGROUND: Both ongoing local metabolic activity (LMA) and corresponding functional connectivity (FC) with remote brain regions are progressively impaired in Alzheimer's disease (AD), particularly in the posterior default mode network (pDMN); however, it is unknown how these impairments interact. It is well known that decreasing mean synaptic activity of a region, i.e., decreasing LMA, reduces the region's sensitivity to afferent input from other regions, i.e., FC.

OBJECTIVE: We hypothesized progressive decoupling between LMA and FC in AD, which is linked to amyloid-β pathology (Aβ).

METHODS: Healthy adults (n=20) and Aβ+patients without memory impairment (n=9), early MCI (n=21), late MCI (n=18) and AD (n=22) were assessed by resting-state fMRI, FDG-PET, and AV-45-PET to measure FC, LMA, and Aβ of the pDMN. Coupling between LMA and FC (rLA/FC) was estimated by voxelwise correlation.

RESULTS: RLMA/FC decreased with disease severity (F=20.09, p<0.001). This decrease was specifically associated with pDMN Aβ (r=-0.273, p=0.029) but not global Aβ (r=-0.112, p=0.378) and with the impact of Aβ on FC (i.e., rAβ/FC,r=-0.339; p=0.006). In multiple regression models rLMA/FC was also associated with memory impairment, reduced cognitive speed and flexibility, outperforming global Aβ, pDMN Aβ, pDMN LMA, and pDMN FC, respectively.

CONCLUSION: Results demonstrate increasing decoupling of LMA from its FC in AD. Data suggest that decoupling is driven by local Aβ and contributes to memory decline.

%B J Alzheimers Dis %V 64 %P 405-415 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843243?dopt=Abstract %R 10.3233/JAD-180022 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Decreased Event-Related Beta Synchronization During Memory Maintenance Marks Early Cognitive Decline in Mild Cognitive Impairment. %A Fodor, Zsuzsanna %A Sirály, Enikő %A Horváth, András %A Salacz, Pál %A Hidasi, Zoltán %A Csibri, Éva %A Szabó, Ádám %A Csukly, Gábor %X

Mild cognitive impairment (MCI) refers to a measurable deficit in cognition in the absence of dementia or impairment in activities of daily living. Working memory impairment is among the earliest signs of MCI. Oscillatory analysis of working memory might be a potential tool for identifying patients at increased risk of developing dementia. Our study aimed to assess the temporospatial pattern of spectral differences during working memory maintenance between MCI patients and healthy controls and to compare the sources of oscillatory activity between the two groups. Event-related spectral perturbation of 17 MCI patients and 21 healthy control participants was studied with 128-channel EEG during the Sternberg working memory task. Source localization was performed by using the eLORETA software. Among the participants, 13 MCI and 15 control participants underwent a structural brain MRI examination. Event-related synchronization (ERS) in the alpha and beta frequency band was significantly lower in MCI patients compared to healthy control participants during retention. Both study groups showed significant memory load-related enhancement in both frequency band. In the MCI group, source localization revealed significantly attenuated beta oscillatory activity in the inferior and middle temporal gyrus, in the fusiform gyrus, and in the cuneus. Beta ERS correlated significantly with the size of the hippocampus, entorhinal cortex, and parahippocampal gyrus. During the retention period, MCI is characterized by decreased alpha and beta ERS compared to controls indicating early impairment in neural networks serving working memory maintenance. The assessment of electrophysiological changes in the beta frequency range may provide a useful diagnostic tool for the early detection of cognitive impairment.

%B J Alzheimers Dis %V 63 %P 489-502 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29630552?dopt=Abstract %R 10.3233/JAD-171079 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Decreased Parietal Beta Power as a Sign of Disease Progression in Patients with Mild Cognitive Impairment. %A Musaeus, Christian Sandøe %A Nielsen, Malene Schjønning %A Østerbye, Natascha Nellum %A Høgh, Peter %X

BACKGROUND: Electroencephalography (EEG) power has previously been used to compare mild cognitive impairment (MCI) patients who progress to Alzheimer's disease (pMCI) with patients with MCI who remain stable (sMCI) by using beta power. However, the beta band is very broad and smaller frequency bands may improve accuracy.

OBJECTIVE: In the present study, we wanted to investigate whether it was possible to find any differences between pMCI and sMCI using relative power and whether these differences were correlated to cognitive function or neuropathology markers.

METHODS: 17 patients with AD, 27 patients with MCI, and 38 older healthy controls were recruited from two memory clinics and followed for three years. EEGs were recorded at baseline for all participants and relative power was calculated. All participants underwent adjusted batteries of standardized cognitive tests and lumbar puncture.

RESULTS: We found that pMCI showed decreased baseline relative power in the parietal electrodes in the beta1 band (13-17.99 Hz). At 2-year follow-up, we found changes in all baseline beta bands but most pronounced in the beta1 band. In addition, we found that qEEG parietal power was correlated with amyloid-β42 and anterograde memory.

CONCLUSION: These findings suggests that relative power in the parietal electrodes in the beta1 band may be a better way to discriminate between pMCI and sMCI at the time of diagnosis than the broad beta band. Similar findings have also been found with resting state fMRI. In addition, we found that anterograde memory was correlated to qEEG parietal beta1 power.

%B J Alzheimers Dis %V 65 %P 475-487 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056426?dopt=Abstract %R 10.3233/JAD-180384 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Decreased Prefrontal Activation during Matrix Reasoning in Predementia Progranulin Mutation Carriers. %A Alexander, Courtney %A Zeithamova, Dagmar %A Hsiung, Ging-Yuek R %A Mackenzie, Ian R %A Jacova, Claudia %K Adult %K Biomarkers %K Female %K Frontotemporal Dementia %K Functional Neuroimaging %K Heterozygote %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Mutation %K Prefrontal Cortex %K Progranulins %X

We tested the potential of task-based functional neuroimaging as a biomarker of emerging prefrontal brain changes in progranulin (GRN) mutations carriers. Five GRN mutation carriers free of frontotemporal dementia (FTD) and 11 non-carriers from families with FTD-GRN underwent functional MRI while solving matrix-reasoning problems. Mutation carriers displayed slower responses for more difficult problems and lower lateral prefrontal activation across all problems. Overall task-evoked posterior ventrolateral prefrontal activation predicted mutation status with 100% sensitivity and 91% specificity. Volumetric differences did not account for activation differences. Prefrontal activation may have utility as a biomarker in GRN mutation.

%B J Alzheimers Dis %V 62 %P 583-589 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480174?dopt=Abstract %R 10.3233/JAD-170716 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Deep Brain Stimulation of Frontal Lobe Networks to Treat Alzheimer's Disease. %A Scharre, Douglas W %A Weichart, Emily %A Nielson, Dylan %A Zhang, Jun %A Agrawal, Punit %A Sederberg, Per B %A Knopp, Michael V %A Rezai, Ali R %K Aged %K Alzheimer Disease %K Deep Brain Stimulation %K Female %K Frontal Lobe %K Humans %K Male %K Middle Aged %K Ohio %K Pilot Projects %K Positron-Emission Tomography %K Prospective Studies %X

The study objective was to evaluate the safety and efficacy of deep brain stimulation (DBS) at the ventral capsule/ventral striatum (VC/VS) region to specifically modulate frontal lobe behavioral and cognitive networks as a novel treatment approach for Alzheimer's disease (AD) patients. This is a non-randomized phase I prospective open label interventional trial of three subjects with matched comparison groups. AD participants given DBS for at least 18 months at the VC/VS target were compared on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), our primary outcome clinical measure, to matched groups without DBS from the AD Neuroimaging Initiative (ADNI) cohort. Serial 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) images of AD participants were also compared longitudinally over time. Three AD DBS participants were matched to subjects from the ADNI cohort. All participants tolerated DBS well without significant adverse events. All three AD DBS participants had less performance decline and two of them meaningfully less decline over time on our primary outcome measure, CDR-SB, relative to matched comparison groups from the ADNI using score trajectory slopes. Minimal changes or increased metabolism on FDG-PET were seen in frontal cortical regions after chronic DBS at the VC/VS target. The first use of DBS in AD at a frontal lobe behavior regulation target (VC/VS) was well-tolerated and revealed less performance decline in CDR-SB. Frontal network modulation to improve executive and behavioral deficits should be furthered studied in AD.

%B J Alzheimers Dis %V 62 %P 621-633 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29400666?dopt=Abstract %R 10.3233/JAD-170082 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Deep Brain Stimulation of the Memory Circuit: Improving Cognition in Alzheimer's Disease. %A Posporelis, Sotirios %A David, Anthony S %A Ashkan, Keyoumars %A Shotbolt, Paul %X

Deep brain stimulation (DBS) is an effective invasive treatment for a wide range of neurological and psychiatric disorders. Neurosurgically implanted electrodes deliver stimulation of pre-programmed amplitude, frequency, and pulse width within deep brain structures; those settings can be adjusted at a later stage according to individual needs for optimal response. This results in variable effects dependent on the targeted region. An established treatment for movement disorders, the effectiveness of DBS in dementia remains under investigation. Translational studies have uncovered a pro-cognitive effect mediated by changes on cellular as well as network level. Several groups have attempted to examine the benefits of DBS in Alzheimer's disease; differences in inclusion criteria and methodology make generalization of results difficult. This review aims to summarize all completed and ongoing human studies of DBS in Alzheimer's disease. The results are classified by targeted anatomical structure. Future directions, as well as economical and ethical arguments, are explored in the final section.

%B J Alzheimers Dis %8 2018 May 26 %G eng %R 10.3233/JAD-180212 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation. %A Leoutsakos, Jeannie-Marie S %A Yan, Haijuan %A Anderson, William S %A Asaad, Wael F %A Baltuch, Gordon %A Burke, Anna %A Chakravarty, M Mallar %A Drake, Kristen E %A Foote, Kelly D %A Fosdick, Lisa %A Giacobbe, Peter %A Mari, Zoltan %A McAndrews, Mary Pat %A Munro, Cynthia A %A Oh, Esther S %A Okun, Michael S %A Pendergrass, Jo Cara %A Ponce, Francisco A %A Rosenberg, Paul B %A Sabbagh, Marwan N %A Salloway, Stephen %A Tang-Wai, David F %A Targum, Steven D %A Wolk, David %A Lozano, Andres M %A Smith, Gwenn S %A Lyketsos, Constantine G %X

BACKGROUND: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years.

OBJECTIVE: To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years.

METHODS: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial.

RESULTS: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants.

CONCLUSION: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.

%B J Alzheimers Dis %V 64 %P 597-606 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914028?dopt=Abstract %R 10.3233/JAD-180121 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Default Mode Network Lateralization and Memory in Healthy Aging and Alzheimer's Disease. %A Banks, Sarah J %A Zhuang, Xiaowei %A Bayram, Ece %A Bird, Chris %A Cordes, Dietmar %A Caldwell, Jessica Z K %A Cummings, Jeffrey L %X

Lateralization of default mode network (DMN) functioning has been shown to change with age. Similarly, lateralization of frontal lobe function has been shown to decline in age. The impact of amyloid pathology and the progression of Alzheimer's disease (AD) on resting state lateralization has not been investigated. Due to the preferential involvement of the left hemisphere in verbal tasks, there may be a benefit to higher levels of left-lateralization in the performance of verbal memory tasks. Here we compared functional lateralization of the anterior and posterior DMN between four groups of participants: amyloid negative (Aβ-) and amyloid positive (Aβ+) groups with normal cognition (NC), and Aβ+ groups with mild cognitive impairment (Aβ+MCI) or dementia (Aβ+AD). Differences were evident between groups in posterior DMN; the Aβ-NC group was more left-lateralized than both cognitively impaired Aβ+ groups. There was no difference in anterior DMN. No differences in overall network connectivity between groups were observed, suggesting that the functional lateralization finding is not secondary to general changes in connectivity. Left-lateralization of both networks was associated with better verbal recall performance. Older subjects, overall, had less left functional lateralization of the anterior DMN.

%B J Alzheimers Dis %V 66 %P 1223-1234 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412488?dopt=Abstract %R 10.3233/JAD-180541 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Deficits in Regional Cerebral Blood Flow on Brain SPECT Predict Treatment Resistant Depression. %A Amen, Daniel G %A Taylor, Derek V %A Meysami, Somayeh %A Raji, Cyrus A %X

BACKGROUND: Depression remains an important risk factor for Alzheimer's disease, yet few neuroimaging biomarkers are available to identify treatment response in depression.

OBJECTIVE: To analyze and compare functional perfusion neuroimaging in persons with treatment resistant depression (TRD) compared to those experiencing full remission.

METHODS: A total of 951 subjects from a community psychiatry cohort were scanned with perfusion single photon emission computed tomography (SPECT) of the brain in both resting and task related settings. Of these, 78% experienced either full remission (n = 506) or partial remission (n = 237) and 11% were minimally responsive (n = 103) or non-responsive (11%. n = 106). Severity of depression symptoms were used to define these groups with changes in the Beck Depression Inventory prior to and following treatment. Voxel-based analyses of brain SPECT images from full remission compared to the worsening group was conducted with the statistical parametric mapping software, version 8 (SPM 8). Multiple comparisons were accounted for with a false discovery rate (p < 0.001).

RESULTS: Persons with depression that worsened following treatment had reduced cerebral perfusion compared to full remission in the multiple regions including the bilateral frontal lobes, right hippocampus, left precuneus, and cerebellar vermis. Such differences were observed on both resting and concentration SPECT scans.

CONCLUSION: Our findings identify imaging-based biomarkers in persons with depression related to treatment response. These findings have implications in understanding both depression to prognosis and its role as a risk factor for dementia.

%B J Alzheimers Dis %V 63 %P 529-538 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578481?dopt=Abstract %R 10.3233/JAD-170855 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Degenerative Amnesia for Past Public Events: An Attempt to Measure Storage and Retrieval. %A Lucchelli, Federica %A Saetti, Maria Cristina %A Spinnler, Hans %X

A still unsettled issue of amnesia concerns the differential contributions to recall impairment of the underlying retrieval and storage abilities. The aim of the present study was to disentangle and to measure such roles in the recall of past public events comparing patients with degenerative amnesia and healthy elderly. The experiment included 44 healthy elderly and two groups of participants with degenerative amnesia, namely 17 patients with amnestic mild cognitive impairment and 22 mild Alzheimer's disease patients. Recall of famous past public events was assessed by means of a 52-item questionnaire standardized for the Italian population. A latent-variable approach was adopted in order to infer the contributions of retrieval and storage to the recall performances. A stochastic model was adopted, which in a previous study of recall of recent and remote past public events in healthy elderly succeeded to prove reduced retrieval efficiency for more recent events. The results of the present study suggest that retrieval is more fragile than storage in all three experimental groups. A storage impairment turned out only in the Alzheimer's disease group, where it was limited to more recent memories. In view of the combined roles of the hippocampus and cortex in past memory processing, our results are consistent with the hypothesis that the degenerative process primarily impairs the strategic memory search. However, the sufficiency criterion of the adopted Markov model fell short of significance. Due to this statistical shortcoming, our conclusions, though consistent with the clinical predictions, are to be taken as provisional.

%B J Alzheimers Dis %V 66 %P 1083-1094 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400092?dopt=Abstract %R 10.3233/JAD-180436 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Delirium Severity Post-Surgery and its Relationship with Long-Term Cognitive Decline in a Cohort of Patients without Dementia. %A Vasunilashorn, Sarinnapha M %A Fong, Tamara G %A Albuquerque, Asha %A Marcantonio, Edward R %A Schmitt, Eva M %A Tommet, Douglas %A Gou, Yun %A Travison, Thomas G %A Jones, Richard N %A Inouye, Sharon K %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Cohort Studies %K Delirium %K Elective Surgical Procedures %K Female %K Humans %K Male %K Neuropsychological Tests %K Postoperative Complications %K Severity of Illness Index %X

BACKGROUND: Delirium has been associated with more rapid cognitive decline. However, it is unknown whether increased delirium severity is associated with a higher rate of long-term cognitive decline.

OBJECTIVE: To evaluate delirium severity and the presence and rate of cognitive decline over 36 months following surgery.

METHODS: We examined patients from the Successful Aging after Elective Surgery Study, who were age ≥70 years undergoing major elective surgery (N = 560). Delirium severity was determined by the peak Confusion Assessment Method-Severity (CAM-S) score for each patient's hospitalization and grouped based on the sample distribution: scores of 0-2, 3-7, and 8-19. A neuropsychological composite, General Cognitive Performance (GCP), and proxy-reported Informant Questionnaire for Cognitive Decline (IQCODE) were used to examine cognitive outcomes following surgery at 0, 1, and 2 months, and then every 6 months for up to 3 years.

RESULTS: No significant cognitive decline was observed for patients with peak CAM-S scores 0-2 (-0.17 GCP units/year, 95% confidence interval [CI] -0.35, 0.01). GCP scores decreased significantly in the group with peak CAM-S scores 3-7 (-0.30 GCP units/year, 95% CI -0.51, -0.09), and decreased almost three times faster in the highest delirium severity group (peak CAM-S scores 8-19; -0.82 GCP units/year, 95% CI -1.28, -0.37). A similar association was found for delirium severity and the proportion of patients who developed IQCODE impairment over time.

CONCLUSION: Patients with the highest delirium severity experienced the greatest rate of cognitive decline, which exceeds the rate previously observed for patients with dementia, on serial neuropsychological testing administered over 3 years, with a dose-response relationship between delirium severity and long-term cognitive decline.

%B J Alzheimers Dis %V 61 %P 347-358 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171992?dopt=Abstract %R 10.3233/JAD-170288 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dementia Care Competence Among Care Professionals and Reduced Challenging Behavior of Home-Dwelling Persons with Dementia: A Pre- and Post-Intervention Data Analysis. %A Nakanishi, Miharu %A Hirooka, Kayo %A Imai, Yasuaki %A Inoue, Shintaro %A Yukari, Yukio %A Katayama, Chie %A Miyamoto, Yuki %A Shindo, Yumi %A Ueno, Hideki %A Toya, Junichiro %A Takano, Yosuke %A Nishida, Atsushi %X

BACKGROUND: We developed a psychosocial dementia care program to help care managers and professional caregivers manage challenging behavior in home-dwelling persons with dementia in Japan. The program consists of a web-based tool for ongoing monitoring and assessment for challenging behavior, and multi-agency discussion meetings. Results of a cluster-randomized controlled trial indicate a reduction in challenging behavior through this program.

OBJECTIVES: The present study aimed to identify a key component of the developed program that is associated with a reduction in challenging behavior.

METHODS: We used consecutive data of the intervention and examined the association between challenging behavior in home-dwelling persons with dementia, professionals' competence, and the frequency of revision of action plans. Challenging behavior was assessed using the total score of the Neuropsychiatric Inventory. A baseline and follow-up questionnaire was completed by care professionals using a Japanese version of the Sense of Competence in Dementia Care Staff scale.

RESULTS: A total of 86 care professionals completed a 6-month intervention with 219 persons with dementia. The 86 care professionals significantly improved in their dementia care competence. Challenging behavior was significantly reduced among the 219 persons with dementia at follow-up regardless of the level of professionals' competence or the frequency of revision of action plans. Less pain was significantly related to the lower levels of challenging behavior.

CONCLUSION: The ongoing multi-agency discussion meetings, with a focus on challenging behavior, may have been the key component in the psychosocial dementia care program. Pain management should be emphasized in action plans for challenging behavior.

%B J Alzheimers Dis %V 64 %P 515-523 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914021?dopt=Abstract %R 10.3233/JAD-171077 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dementia Research: Populations, Progress, Problems, and Predictions. %A Hunter, Sally %A Smailagic, Nadja %A Brayne, Carol %X

Alzheimer's disease (AD) is a clinicopathologically defined syndrome leading to cognitive impairment. Following the recent failures of amyloid-based randomized controlled trials to change the course of AD, there are growing calls for a re-evaluation of basic AD research. Epidemiology offers one approach to integrating the available evidence. Here we examine relationships between evidence from population-based, clinicopathological studies of brain aging and a range of hypotheses from all areas of AD research. We identify various problems, including a lack of systematic approach to measurement of clinical and neuropathological factors associated with dementia in experimental and clinical settings, poor understanding of the strengths and weaknesses of different observational and experimental designs, a lack of clarity in relation to disease definitions from the clinical, neuropathological, and molecular perspectives, inadequate characterization of brain aging in the human population, difficulties in translation between laboratory-based and population-based evidence bases, and a lack of communication between different sections of the dementia research community. Population studies highlight complexity and predict that therapeutic approaches based on single disease features will not be successful. Better characterization of brain aging in the human population is urgently required to select biomarkers and therapeutic targets that are meaningful to human disease. The generation of detailed and reliable evidence must be addressed before progress toward therapeutic interventions can be made.

%B J Alzheimers Dis %V 64 %P S119-S143 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782317?dopt=Abstract %R 10.3233/JAD-179927 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Depression and Alzheimer's Disease Biomarkers Predict Driving Decline. %A Babulal, Ganesh M %A Chen, Suzie %A Williams, Monique M %A Trani, Jean-Francois %A Bakhshi, Parul %A Chao, Grace L %A Stout, Sarah H %A Fagan, Anne M %A Benzinger, Tammie L S %A Holtzman, David M %A Morris, John C %A Roe, Catherine M %X

BACKGROUND: Symptomatic Alzheimer's disease (AD) and depression independently increase crash risk. Additionally, depression is both a risk factor for and a consequence of AD.

OBJECTIVE: To examine whether a depression diagnosis, antidepressant use, and preclinical AD are associated with driving decline among cognitively normal older adults.

METHODS: Cognitively normal participants, age ≥65, were enrolled. Cox proportional hazards models evaluated whether a depression diagnosis, depressive symptoms (Geriatric Depression Scale), antidepressant use, cerebrospinal fluid (amyloid-β42 [Aβ42], tau, phosphorylated tau181 [ptau181]), and amyloid imaging biomarkers (Pittsburgh Compound B and Florbetapir) were associated with time to receiving a rating of marginal/fail on a road test. Age was adjusted for in all models.

RESULTS: Data were available from 131 participants with age ranging from 65.4 to 88.2 years and mean follow up of 2.4 years (SD = 1.0). A depression diagnosis was associated with a faster time to receiving a marginal/fail rating on a road test and antidepressant use (p = 0.024, HR = 2.62). Depression diagnosis and CSF and amyloid PET imaging biomarkers were associated with driving performance on the road test (p≤0.05, HR = 2.51-3.15). In the CSF ptau181 model, depression diagnosis (p = 0.031, HR = 2.51) and antidepressant use (p = 0.037, HR = 2.50) were statistically significant predictors. There were no interaction effects between depression diagnosis, antidepressant use, and biomarker groups. Depressive symptomology was not a statistically significant predictor of driving performance.

CONCLUSIONS: While, as previously shown, preclinical AD alone predicts a faster time to receiving a marginal/fail rating, these results suggest that also having a diagnosis of depression accelerates the onset of driving problems in cognitively normal older adults.

%B J Alzheimers Dis %V 66 %P 1213-1221 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400098?dopt=Abstract %R 10.3233/JAD-180564 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Depressive Symptoms Are Associated with Cognitive Function in the Elderly with Type 2 Diabetes. %A Guerrero-Berroa, Elizabeth %A Ravona-Springer, Ramit %A Schmeidler, James %A Heymann, Anthony %A Soleimani, Laili %A Sano, Mary %A Leroith, Derek %A Preiss, Rachel %A Zukran, Ruth %A Silverman, Jeremy M %A Beeri, Michal Schnaider %X

BACKGROUND: Type 2 diabetes (T2D) is a metabolic condition associated with poor clinical and cognitive outcomes including vascular disease, depressive symptoms, cognitive impairment, and dementia. In the general elderly population, depression has been consistently identified as a risk factor for cognitive impairment/decline. However, the association between depression and cognitive function in T2D has been understudied.

OBJECTIVE: We investigated the association between depression and cognitive function in a large sample of cognitively normal elderly with T2D.

METHODS: In this cross-sectional study, we examined 738 participants, aged 65-88 years old, enrolled in the Israel Diabetes and Cognitive Decline study. For each cognitive domain (Episodic Memory, Executive Function, Attention/Working Memory, Language/Semantic Categorization) and Overall Cognition, multiple linear regressions assessed its association with depression (score greater than 5 on the 15-item version of the Geriatric Depression Scale [GDS]), adjusting for age, sex, and education.

RESULTS: Depression (n = 66, 8.9%) was associated with worse performance on tasks of Executive Function (p = 0.004), Language/Semantic Categorization (p < 0.001), and Overall Cognition (p < 0.002), but not Episodic Memory (p = 0.643) or Attention/Working Memory (p = 0.488). Secondary analyses using GDS as a continuous variable did not substantially change the results. Adjusting also for a history of antidepressant medication use slightly weakened the findings.

CONCLUSION: Significant associations of depression with several cognitive domains and Overall Cognition even in cognitively normal elderly with T2D, suggest that depression may have a role in impaired cognitive function in T2D, which may be attenuated by antidepressants.

%B J Alzheimers Dis %V 65 %P 683-692 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103313?dopt=Abstract %R 10.3233/JAD-170778 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Designing an Internet-Based Multidomain Intervention for the Prevention of Cardiovascular Disease and Cognitive Impairment in Older Adults: The HATICE Trial. %A Barbera, Mariagnese %A Mangialasche, Francesca %A Jongstra, Susan %A Guillemont, Juliette %A Ngandu, Tiia %A Beishuizen, Cathrien %A Coley, Nicola %A Brayne, Carol %A Andrieu, Sandrine %A Richard, Edo %A Soininen, Hilkka %A Kivipelto, Miia %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cognitive Dysfunction %K Counseling %K Europe %K Exercise %K Female %K Healthy Aging %K Humans %K Internet %K Life Style %K Male %K Practice Guidelines as Topic %K Risk Factors %K Telemedicine %X

BACKGROUND: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet-based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults.

OBJECTIVE: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries.

METHODS: A comparative analysis of national and European guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention.

RESULTS: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country.

CONCLUSION: Despite differences in CVR management within the countries considered, it was possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally.

%B J Alzheimers Dis %V 62 %P 649-663 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480185?dopt=Abstract %R 10.3233/JAD-170858 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Detection of Dementia Cases in Two Swedish Health Registers: A Validation Study. %A Rizzuto, Debora %A Feldman, Adina L %A Karlsson, Ida K %A Dahl Aslan, Anna K %A Gatz, Margaret %A Pedersen, Nancy L %K Aged %K Aged, 80 and over %K Cause of Death %K Dementia %K Female %K Humans %K Incidence %K Longitudinal Studies %K Male %K Middle Aged %K Registries %K Sensitivity and Specificity %K Sweden %K Twin Studies as Topic %X

BACKGROUND: Population-based health registers are potential assets in epidemiological research; however, the quality of case ascertainment is crucial.

OBJECTIVE: To compare the case ascertainment of dementia, from the National Patient Register (NPR) and the Cause of Death Register (CDR) with dementia diagnoses from six Swedish population based studies.

METHODS: Sensitivity, specificity, and positive predictive value (PPV) of dementia identification in NPR and CDR were estimated by individual record linkage with six Swedish population based studies (n = 19,035). Time to detection in NPR was estimated using data on dementia incidence from longitudinal studies with more than two decades of follow-up.

RESULTS: Barely half of the dementia cases were ever detected by NPR or CDR. Using data from longitudinal studies we estimated that a record with a dementia diagnosis appears in the NPR on average 5.5 years after first diagnosis. Although the ability of the registers to detect dementia cases was moderate, the ability to detect non-dementia cases was almost perfect (99%). When registers indicate that there is a dementia diagnosis, there are very few instances in which the clinicians determined the person was not demented. Indeed, PPVs were close to 90%. However, misclassification between dementia subtype diagnoses is quite common, especially in NPR.

CONCLUSIONS: Although the overall sensitivity is low, the specificity and the positive predictive value are very high. This suggests that hospital and death registers can be used to identify dementia cases in the community, but at the cost of missing a large proportion of the cases.

%B J Alzheimers Dis %V 61 %P 1301-1310 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376854?dopt=Abstract %R 10.3233/JAD-170572 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Development of a High-Sensitivity Method for the Measurement of Human Nasal Aβ42, Tau, and Phosphorylated Tau. %A Liu, Ziyi %A Kameshima, Naoko %A Nanjo, Toshifumi %A Shiino, Akihiko %A Kato, Tomoko %A Shimizu, Shino %A Shimizu, Takeshi %A Tanaka, Sachiko %A Miura, Katsuyuki %A Tooyama, Ikuo %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Case-Control Studies %K Female %K Humans %K Male %K Middle Aged %K Nasal Mucosa %K Peptide Fragments %K Phosphorylation %K Reproducibility of Results %K ROC Curve %K tau Proteins %X

Cost-effective and feasible methods for early diagnosis of Alzheimer's disease (AD) are needed. We present two methods to measure AD-related biomarkers simultaneously from one nasal smear for the purpose of diagnosing AD. Japanese men and women aged 63-85 years old were recruited in 2015-2016 for this case-control study. A total of 25 AD cases and 25 controls (22 men and 28 women) participated in this research. Nasal smears were collected from the common nasal meatus, inferior concha, middle nasal meatus, and olfactory cleft, and the proteins in the samples were analyzed by two methods, which we named PGD (Pre-treatment with guanidine- n-Dodecyl-beta-D-maltoside solution) method 1 (PGD-I) and 2 (PGD-II). The PGD-I method measured total tau and amyloid-β (Aβ)42, but no differences in median levels of total tau and Aβ42 between AD cases and controls were found in any of the nasal locations. The PGD-II method measured Aβ42, total tau, and phosphorylated tau, but levels of Aβ40 in all nasal locations of both groups were near zero. Median levels of phosphorylated tau to total tau (p-tau/t-tau) ratios in the middle nasal meatus and in the olfactory cleft were significantly higher in AD cases than in controls, and could significantly predict AD. To assess diagnostic reliability, areas under the ROC curve were 0.74 (95% CL = 0.52-0.95, p = 0.030) for the middle nasal meatus and 0.72 (95% CL = 0.52-0.92, p = 0.029) for the olfactory cleft. Thus, PGD-I and PGD-II can detect AD-related biomarkers in nasal smears and PGD-II may be a useful tool for diagnosing AD.

%B J Alzheimers Dis %V 62 %P 737-744 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480194?dopt=Abstract %R 10.3233/JAD-170962 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Diagnosis of Mild Cognitive Impairment Due to Alzheimer's Disease with Transcranial Magnetic Stimulation. %A Padovani, Alessandro %A Benussi, Alberto %A Cantoni, Valentina %A Dell'Era, Valentina %A Cotelli, Maria Sofia %A Caratozzolo, Salvatore %A Turrone, Rosanna %A Rozzini, Luca %A Alberici, Antonella %A Altomare, Daniele %A Depari, Alessandro %A Flammini, Alessandra %A Frisoni, Giovanni B %A Borroni, Barbara %X

BACKGROUND: Considering the increasing evidence that disease-modifying treatments for Alzheimer's disease (AD) must be administered early in the disease course, the development of diagnostic tools capable of accurately identifying AD at early disease stages has become a crucial target. In this view, transcranial magnetic stimulation (TMS) has become an effective tool to discriminate between different forms of neurodegenerative dementia.

OBJECTIVE: To determine whether a TMS multi-paradigm approach can be used to correctly identify mild cognitive impairment (MCI) due to AD (AD MCI).

METHODS: A sample of 69 subjects with MCI were included and classified as AD MCI or MCI unlikely due to AD (non-AD MCI) based on 1) extensive neurological and neuropsychological evaluation, 2) MRI imaging, and 3) cerebrospinal fluid analysis or/and amyloid PET imaging. A paired-pulse TMS multi-paradigm approach assessing short interval intracortical inhibition-facilitation (SICI-ICF), dependent on GABAergic and glutamatergic intracortical circuits, respectively, and short latency afferent inhibition (SAI), dependent on cholinergic circuits, was performed.

RESULTS: We observed a significant impairment of SAI and unimpaired SICI and ICF in AD MCI as compared to non-AD MCI. According to ROC curve analysis, the SICI-ICF / SAI index differentiated AD MCI from non-AD MCI with a specificity of 87.9% and a sensitivity of 94.4%.

CONCLUSIONS: The assessment of intracortical connectivity with TMS could aid in the characterization of MCI subtypes, correctly identifying AD pathophysiology. TMS can be proposed as an adjunctive, non-invasive, inexpensive, and time-saving screening tool in MCI differential diagnosis.

%B J Alzheimers Dis %V 65 %P 221-230 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010131?dopt=Abstract %R 10.3233/JAD-180293 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Diagnostic and Prognostic Value of a Dual-Tasking Paradigm in a Memory Clinic. %A Nielsen, Malene Schjnning %A Simonsen, Anja Hviid %A Siersma, Volkert %A Hasselbalch, Steen Gregers %A Hoegh, Peter %K Aged %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Logistic Models %K Male %K Memory %K Middle Aged %K Neuropsychological Tests %K Prognosis %K Prospective Studies %K ROC Curve %X

BACKGROUND: Daily living requires the ability to perform dual-tasking. As cognitive skills decrease in dementia, performing a cognitive and motor task simultaneously become increasingly challenging and subtle gait abnormalities may even be present in pre-dementia stages. Therefore, a dual-tasking paradigm, such as the Timed Up and Go-Dual Task (TUG-DT), may be useful in the diagnostic assessment of mild cognitive impairment (MCI).

OBJECTIVE: To investigate the diagnostic and prognostic ability of a dual-tasking paradigm in patients with MCI or mild Alzheimer's disease (AD) and to evaluate the association between the dual-tasking paradigm and cerebrospinal fluid (CSF) AD biomarkers.

METHODS: The study is a prospective cohort study conducted in a clinical setting in two memory clinics. Eighty-six patients were included (28 MCI, 17 AD, 41 healthy controls (HC)). The ability to perform dual-tasking was evaluated by the TUG-DT. Patients underwent a standardized diagnostic assessment and were evaluated to determine progression yearly.

RESULTS: ROC curve analysis illustrated a high discriminative ability of the dual-tasking paradigm in separating MCI patients from HC (AUC: 0.78, AUC: 0.82) and a moderate discriminative ability in separating MCI from AD (AUC: 0.73, AUC: 0.55). Performance discriminated clearly between all groups (p < 0.01). Logistic regression analyses revealed a low prognostic value of the dual-tasking paradigm for progression and rate of cognitive decline. A moderately strong correlation between the dual-tasking paradigm and CSF AD biomarkers was observed.

CONCLUSION: In our study, we found that patients with MCI and mild AD have increasing difficulties in dual-tasking compared to healthy elderly. Hence, the dual-tasking paradigm may be a potential complement in the diagnostic assessment in a typical clinical setting.

%B J Alzheimers Dis %V 61 %P 1189-1199 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29278887?dopt=Abstract %R 10.3233/JAD-161310 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Diagnostic Value of Diffusion Tensor Imaging and Positron Emission Tomography in Early Stages of Frontotemporal Dementia. %A Krämer, Julia %A Lueg, Gero %A Schiffler, Patrick %A Vrachimis, Alexis %A Weckesser, Matthias %A Wenning, Christian %A Pawlowski, Matthias %A Johnen, Andreas %A Teuber, Anja %A Wersching, Heike %A Meuth, Sven G %A Duning, Thomas %X

BACKGROUND: Due to suboptimal sensitivity and specificity of structural and molecular neuroimaging tools, the diagnosis of behavioral variant frontotemporal dementia (bvFTD) remains challenging.

OBJECTIVE: Investigation of the sensitivity of diffusion tensor imaging (DTI) and fluorodeoxyglucose positron emission tomography (FDG-PET) to detect cerebral alterations in early stages of bvFTD despite inconspicuous conventional MRI.

METHODS: Thirty patients with early stages of bvFTD underwent a detailed neuropsychological examination, cerebral 3T MRI with DTI analysis, and FDG-PET. After 12 months of follow-up, all patients finally fulfilled the diagnosis of bvFTD. Individual FDG-PET data analyses showed that 20 patients exhibited a "typical" pattern for bvFTD with bifrontal and/or temporal hypometabolism (bvFTD/PET+), and that 10 patients showed a "non-typical"/normal pattern (bvFTD/PET-). DTI data were compared with 42 healthy controls in an individual and voxel-based group analysis. To examine the clinical relevance of the findings, associations between pathologically altered voxels of DTI or FDG-PET results and behavioral symptoms were estimated by linear regression analyses.

RESULTS: DTI voxel-based group analyses revealed microstructural degeneration in bifrontal and bitemporal areas in bvFTD/PET+ and bvFTD/PET- groups. However, when comparing the sensitivity of individual DTI data analysis with FDG-PET, DTI appeared to be less sensitive. Neuropsychological symptoms were considerably related to neurodegeneration within frontotemporal areas identified by DTI and FDG-PET.

CONCLUSION: DTI seems to be an interesting tool for detection of functionally relevant neurodegenerative alterations in early stages of bvFTD, even in bvFTD/PET- patients. However, at a single subject level, it seems to be less sensitive than FDG-PET. Thus, improvement of individual DTI analysis is necessary.

%B J Alzheimers Dis %V 63 %P 239-253 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614640?dopt=Abstract %R 10.3233/JAD-170224 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Diaphanous 1 (DIAPH1) is Highly Expressed in the Aged Human Medial Temporal Cortex and Upregulated in Myeloid Cells During Alzheimer's Disease. %A Derk, Julia %A Bermudez Hernandez, Keria %A Rodriguez, Moises %A He, Meilun %A Koh, Hyunwook %A Abedini, Andisheh %A Li, Huilin %A Fenyö, David %A Schmidt, Ann Marie %X

BACKGROUND: The receptor for advanced glycation end products (RAGE) is linked to cellular stress and inflammation during Alzheimer's disease (AD). RAGE signals through Diaphanous-1 (DIAPH1); however, the expression of DIAPH1 in the healthy and AD human brain has yet to be methodically addressed.

OBJECTIVE: To delineate the cell- and disease-state specific expression of DIAPH1 in the human medial temporal cortex during healthy aging and AD.

METHODS: We used semi-quantitative immunohistochemistry in the human medial temporal cortex paired with widefield and confocal microscopy and automated analyses to determine colocalization and relative expression of DIAPH1 with key cell markers and molecules in the brains of subjects with AD versus age-matched controls.

RESULTS: We report robust colocalization of DIAPH1 with myeloid cells and increased expression during AD, which strongly correlated to increased neutral lipids and morphology of inflamed myeloid cells. DIAPH1 moderately colocalized with markers of endothelial cells, astrocytes, neurons, and oligodendrocytes.

DISCUSSION: Our findings localize DIAPH1 particularly to myeloid cells in the CNS, especially in AD in the locations of lipid droplet accumulation, thereby implicating RAGE-DIAPH1 signaling in dysregulated lipid metabolism and morphological changes of inflamed myeloid cells in this disorder.

%B J Alzheimers Dis %V 64 %P 995-1007 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966194?dopt=Abstract %R 10.3233/JAD-180088 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Diazepam Toxicity Presenting as a Dementia Disorder. %A Kurlawala, Zimple %A Roberts, Jeffrey A %A McMillan, Joseph D %A Friedland, Robert P %X

The toxicity associated with long-standing benzodiazepine use in older persons is a critical issue. Several epidemiological reports have studied correlation between benzodiazepine use and risk of dementia development. In this manuscript, we used a case report to demonstrate how chronic diazepam use can cause cognitive deficits that resemble Alzheimer's disease and related conditions. Benzodiazepine use is common in the geriatric population and is often taken for long periods of time in improper doses. In combination with age-related cortical atrophy on the MRI, our patient risked being misdiagnosed with Alzheimer's disease or another dementing disorder if not for the systematic investigation to resolve his symptoms. With elimination of the offending dispensable drug (diazepam), the patient's cognition improved greatly.

%B J Alzheimers Dis %V 66 %P 935-938 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400100?dopt=Abstract %R 10.3233/JAD-180745 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Diet Supplementation with Hydroxytyrosol Ameliorates Brain Pathology and Restores Cognitive Functions in a Mouse Model of Amyloid-β Deposition. %A Nardiello, Pamela %A Pantano, Daniela %A Lapucci, Andrea %A Stefani, Massimo %A Casamenti, Fiorella %X

Alzheimer's disease is the most common form of dementia affecting a large proportion of aged people. Plant polyphenols have been reported to be potentially useful in the prevention of AD due to their multiple pharmacological activities. The aim of the present study was to assess whether the previously reported neuroprotective and anti-inflammatory effects resulting from oleuropein aglycone administration were reproduced by diet supplementation with similar amounts of its metabolite hydoxytyrosol (HT). Four-month-old TgCRND8 and wild type mice were treated for 8 weeks with a low-fat diet (5%) supplemented with HT (50 mg/kg of diet). We found that HT supplementation significantly improved cognitive functions of TgCRND8 mice and significantly reduced Aβ42 and pE3-Aβ plaque area and number in the cortex; in the hippocampal areas of HT-fed TgCRND8 mice, we found a significant reduction in the pE3-Aβ plaque number together with a tendency toward a reduction in Aβ42 load and pE3-Aβ plaque area, associated with a marked reduction of TNF-α expression and astrocyte reaction. Macroautophagy induction and modulation of MAPKs signaling were found to underlie the beneficial effects of HT. Our findings indicate that HT administration reproduces substantially the beneficial effects on behavioral performance and neuropathology previously reported in TgCRND8 mice fed with oleuropein aglycone, resulting in comparable neuroprotection.

%B J Alzheimers Dis %V 63 %P 1161-1172 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710709?dopt=Abstract %R 10.3233/JAD-171124 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Differences Between Women and Men in Incidence Rates of Dementia and Alzheimer's Disease. %A Beam, Christopher R %A Kaneshiro, Cody %A Jang, Jung Yun %A Reynolds, Chandra A %A Pedersen, Nancy L %A Gatz, Margaret %X

In the following brief report, we examined gender differences in incidence rates of any dementia, Alzheimer's disease (AD) alone, and non-Alzheimer's dementia alone in 16,926 women and men in the Swedish Twin Registry aged 65+. Dementia diagnoses were based on clinical workup and national health registry linkage. Incidence rates of any dementia and AD were greater in women than men, with any dementia rates diverging after age 85 and AD rates diverging around 80. This pattern is consistent with women's survival to older ages compared to men. These findings are similar to incidence rates reported in other Swedish samples.

%B J Alzheimers Dis %V 64 %P 1077-1083 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010124?dopt=Abstract %R 10.3233/JAD-180141 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Differences in Dementia Beliefs between Non-Demented Public Screeners and In-Home Screeners and Their Potential Impact on Future Dementia Screening Intention: The Nakajima Study. %A Yuki-Nozaki, Sohshi %A Noguchi-Shinohara, Moeko %A Domoto, Chiaki %A Ikeda, Yoshihisa %A Samuraki, Miharu %A Iwasa, Kazuo %A Yokogawa, Masami %A Asai, Kimiko %A Komai, Kiyonobu %A Nakamura, Hiroyuki %A Yamada, Masahito %X

In many cohort studies of dementia, while differences in sociodemographic characters between responders and non-responders of dementia screening have been reported, differences in dementia beliefs have been relatively less known. The aims of this study were to clarify dementia beliefs and to explore potential impacts on an intention to attend a future dementia screening in public screeners and in-home screeners, respectively. We performed a cross-sectional population-based study using a question about an intention to attend a future dementia screening and a questionnaire on dementia beliefs. Subjects were all residents aged 65 years or older in the north area of Nakajima, Japan (n = 385). All subjects were asked to attend a public dementia screening first. An in-home dementia screening was subsequently conducted in subjects with non-responders to a public screening. The questionnaire consisted of four dementia beliefs: "perceived susceptibility," "perceived severity," "perceived barriers," and "perceived benefits." Public screeners significantly expressed an intention to attend a future dementia screening more than in-home screeners (p = 0.002). In in-home screeners, low "perceived severity" were significantly associated with an intention to attend a future dementia screening [adjusted OR (95% CI) = 0.51 (0.32-0.80)]. In both public and in-home screeners, high "perceived benefits" were significantly associated with an intention to attend a future dementia screening [adjusted OR (95% CI) = 2.13 (1.46-3.10); adjusted OR (95% CI) = 2.56 (1.22-5.35), respectively]. It is necessary to reduce "perceived severity" among in-home screeners to increase dementia screening participants.

%B J Alzheimers Dis %V 62 %P 1651-1661 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614687?dopt=Abstract %R 10.3233/JAD-171177 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Differences in Synaptic Dysfunction Between rTg4510 and APP/PS1 Mouse Models of Alzheimer's Disease. %A Gelman, Simon %A Palma, Jonathan %A Tombaugh, Geoffrey %A Ghavami, Afshin %K Age Factors %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Analysis of Variance %K Animals %K Biophysics %K Disease Models, Animal %K Electric Stimulation %K Excitatory Postsynaptic Potentials %K Hippocampus %K Humans %K Mice %K Mice, Transgenic %K Mutation %K Presenilin-1 %K Synapses %K Synaptic Transmission %K tau Proteins %X

Genetically modified mice have provided insights into the progression and pathology of Alzheimer's disease (AD). Here, we have examined two mouse models of AD: the rTg4510 mouse, which overexpresses mutant human Tau gene, and the APP/PS1 mouse, which overexpresses mutant human genes for amyloid precursor protein and presenilin 1. Both models exhibit deficits in hippocampal function, but comparative analyses of these deficits are sparse. We used extracellular field potential recordings in hippocampal slices to study basal synaptic transmission (BST), paired-pulse facilitation (PPF), and long-term potentiation (LTP) at the Schaffer collateral-CA1 pyramidal cell synapses in both models. We found that 6-7, but not 2-3-month-old rTg4510 mice exhibited reduced pre-synaptic activation (fiber volley (FV) amplitude, ∼50%) and field excitatory post-synaptic potential (fEPSP) slope (∼40%) compared to wild-type controls. In contrast to previous reports, BST, when controlled for FV amplitude, was not altered in rTg4510. APP/PS1 mice (2-3 mo and 8-10 mo) had unchanged FV amplitude compared to wild-type controls, while fEPSP slope was reduced by ∼34% in older mice, indicating a deficit in BST. PPF was unchanged in 8-10-month-old APP/PS1 mice, but was reduced in 6-7-month-old rTg4510 mice. LTP was reduced only in older rTg4510 and APP/PS1 mice. Our data suggest that BST deficits appear earlier in APP/PS1 than in rTg4510, which exhibited no BST deficits at the ages tested. However, FV and synaptic plasticity deficits developed earlier in rTg4510. These findings highlight fundamental differences in the progression of synaptic pathology in two genetically distinct models of AD.

%B J Alzheimers Dis %V 61 %P 195-208 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154272?dopt=Abstract %R 10.3233/JAD-170457 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Different Abnormalities of Cortical Neural Synchronization Mechanisms in Patients with Mild Cognitive Impairment due to Alzheimer's and Chronic Kidney Diseases: An EEG Study. %A Lizio, Roberta %A Babiloni, Claudio %A Del Percio, Claudio %A Losurdo, Antonia %A Vernò, Lucia %A De Tommaso, Marina %A Montemurno, Anna %A Dalfino, Giuseppe %A Cirillo, Pietro %A Soricelli, Andrea %A Ferri, Raffaele %A Noce, Giuseppe %A Pascarelli, Maria Teresa %A Catania, Valentina %A Nobili, Flavio %A Famá, Francesco %A Orzi, Francesco %A Giubilei, Franco %A Buttinelli, Carla %A Triggiani, A Ivano %A Frisoni, Giovanni B %A Scisci, Anna Maria %A Mastrofilippo, Nicola %A Procaccini, Deni Aldo %A Gesualdo, Loreto %X

This study tested whether resting state alpha rhythms (8-13 Hz) may characterize mild cognitive impairment due to Alzheimer's disease (ADMCI) compared with MCI due to chronic kidney disease (CKDMCI). Clinical and resting state eyes-closed electroencephalographic (rsEEG) rhythms from 40 ADMCI, 29 CKDMCI, and 45 cognitively normal elderly (Nold) subjects were available in a national archive. Age, gender, and education were matched in the three groups, and Mini-Mental State Evaluation (MMSE) score was paired in the ADMCI and CKDMCI groups. Delta (<4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz) cortical sources were estimated by eLORETA freeware and classified across individuals by area under the receiver operating characteristic curve (AUROCC). Compared with Nold group, posterior alpha 1 source activities were more reduced in ADMCI than CKDMCI group. In contrast, widespread delta source activities were greater in CKDMCI than ADMCI group. These source activities correlated with the MMSE score and correctly classified between Nold and all MCI individuals (AUROCC = 0.8-0.85) and between ADMCI and CKDMCI subjects (AUROCC = 0.75). These results suggest that early AD affects cortical neural synchronization at alpha frequencies underpinning brain arousal and low vigilance in the quiet wakefulness. In contrast, CKD may principally affect cortical neural synchronization at the delta frequencies. Future prospective cross-validation studies will have to test these candidate rsEEG markers for clinical applications and drug discovery.

%B J Alzheimers Dis %V 65 %P 897-915 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103322?dopt=Abstract %R 10.3233/JAD-180245 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Different Cognitive Frailty Models and Health- and Cognitive-related Outcomes in Older Age: From Epidemiology to Prevention. %A Panza, Francesco %A Lozupone, Madia %A Solfrizzi, Vincenzo %A Sardone, Rodolfo %A Dibello, Vittorio %A Di Lena, Luca %A D'Urso, Francesca %A Stallone, Roberta %A Petruzzi, Massimo %A Giannelli, Gianluigi %A Quaranta, Nicola %A Bellomo, Antonello %A Greco, Antonio %A Daniele, Antonio %A Seripa, Davide %A Logroscino, Giancarlo %X

Frailty, a critical intermediate status of the aging process that is at increased risk for negative health-related events, includes physical, cognitive, and psychosocial domains or phenotypes. Cognitive frailty is a condition recently defined by operationalized criteria describing coexisting physical frailty and mild cognitive impairment (MCI), with two proposed subtypes: potentially reversible cognitive frailty (physical frailty/MCI) and reversible cognitive frailty (physical frailty/pre-MCI subjective cognitive decline). In the present article, we reviewed the framework for the definition, different models, and the current epidemiology of cognitive frailty, also describing neurobiological mechanisms, and exploring the possible prevention of the cognitive frailty progression. Several studies suggested a relevant heterogeneity with prevalence estimates ranging 1.0-22.0% (10.7-22.0% in clinical-based settings and 1.0-4.4% in population-based settings). Cross-sectional and longitudinal population-based studies showed that different cognitive frailty models may be associated with increased risk of functional disability, worsened quality of life, hospitalization, mortality, incidence of dementia, vascular dementia, and neurocognitive disorders. The operationalization of clinical constructs based on cognitive impairment related to physical causes (physical frailty, motor function decline, or other physical factors) appears to be interesting for dementia secondary prevention given the increased risk for progression to dementia of these clinical entities. Multidomain interventions have the potential to be effective in preventing cognitive frailty. In the near future, we need to establish more reliable clinical and research criteria, using different operational definitions for frailty and cognitive impairment, and useful clinical, biological, and imaging markers to implement intervention programs targeted to improve frailty, so preventing also late-life cognitive disorders.

%B J Alzheimers Dis %V 62 %P 993-1012 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562543?dopt=Abstract %R 10.3233/JAD-170963 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Differential Effect of APOE ɛ4 Status and Elevated Pulse Pressure on Functional Decline in Cognitively Normal Older Adults. %A Werhane, Madeleine L %A Thomas, Kelsey R %A Edmonds, Emily C %A Bangen, Katherine J %A Tran, My %A Clark, Alexandra L %A Nation, Daniel A %A Gilbert, Paul E %A Bondi, Mark W %A Delano-Wood, Lisa %X

BACKGROUND/OBJECTIVE: The APOE ɛ4 allele and increased vascular risk have both been independently linked to cognitive impairment and dementia. Since few studies have characterized how these risk factors affect everyday functioning, we investigated the relationship between APOE ɛ4 genotype and elevated pulse pressure (PP) on functional change in cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

METHODS: 738 normally aging participants underwent APOE genotyping, and baseline PP was calculated from blood pressure indices. The Functional Activities Questionnaire (FAQ) was completed by participants' informant at baseline and 6, 12, 24, 36, and 48-month follow-up visits. Multiple linear regression and multilevel modeling were used to examine the effects of PP and APOE ɛ4 genotype on cross-sectional and longitudinal FAQ scores, respectively.

RESULTS: Adjusting for demographic and clinical covariates, results showed that both APOE ɛ4 status and elevated PP predicted greater functional difficulty trajectories across four years of follow-up. Interestingly, however, elevated PP was associated with greater functional decline over time in ɛ4 non-carriers versus carriers.

CONCLUSION: Results show that, although APOE ɛ4 status is the prominent predictor of functional difficulty for ɛ4 carriers, an effect of arterial stiffening on functional difficulty was observed in non-carriers. Future studies are needed in order to clarify the etiology of the association between PP and different brain aging processes, and further explore its utility as a marker of dementia risk. The present study underscores the importance of targeting modifiable risk factors such as elevated PP to prevent or slow functional decline and pathological brain aging.

%B J Alzheimers Dis %V 62 %P 1567-1578 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562507?dopt=Abstract %R 10.3233/JAD-170918 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Differential Pattern of Phospholipid Profile in the Temporal Cortex from E280A-Familiar and Sporadic Alzheimer's Disease Brains. %A Villamil-Ortiz, Javier Gustavo %A Barrera-Ocampo, Alvaro %A Arias-Londoño, Julián David %A Villegas, Andrés %A Lopera, Francisco %A Cardona-Gómez, Gloria Patricia %K Adult %K Aged %K Aged, 80 and over %K Alanine %K Alzheimer Disease %K Analysis of Variance %K Fatty Acids %K Female %K Gene Expression Regulation %K Glutamic Acid %K Humans %K Lysophosphatidylcholines %K Male %K Mass Spectrometry %K Middle Aged %K Mutation %K Phosphatidylethanolamines %K Phospholipids %K Presenilin-1 %K Temporal Lobe %X

Lipids are considered important factors in the pathogenesis of Alzheimer's disease (AD). In this study, we realized a comparative analysis of the phospholipid profile and phospholipid composition of the temporal cortex from E280A-familiar AD (FAD), sporadic AD (SAD), and healthy human brains. Findings showed a significant decrease of lysophosphatidylcholine and phosphatidylethanolamine formed by low levels of polyunsaturated fatty acids (20 : 4, 22 : 6) in AD brains. However, phosphatidylethanolamine-ceramide and phosphoglycerol were significantly increased in SAD, conformed by high levels of (18 : 0/18 : 1) and (30/32/36 : 0/1/2), respectively. Together, the findings suggest a deficiency in lysophosphacholine and phosphatidylethanolamine, and alteration in the balance between poly- and unsaturated fatty acids in both types of AD, and a differential pattern of phospholipid profile and fatty acid composition between E280A FAD and SAD human brains.

%B J Alzheimers Dis %V 61 %P 209-219 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125487?dopt=Abstract %R 10.3233/JAD-170554 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Differentiating between Alzheimer's Disease and Vascular Cognitive Impairment: Is the "Memory Versus Executive Function" Contrast Still Relevant? %A Andriuta, Daniela %A Roussel, Martine %A Barbay, Mélanie %A Despretz-Wannepain, Sandrine %A Godefroy, Olivier %X

BACKGROUND: The contrast between memory versus executive function impairments is commonly used to differentiate between neurocognitive disorders (NCDs) due to Alzheimer's disease (AD) and vascular cognitive impairment (VCI). We reconsidered this question because of the current use of AD biomarkers and the recent revision of the criteria for AD, VCI, and dysexecutive syndrome.

OBJECTIVE: To establish and compare the neuropsychological profiles in AD (i.e., with positive CSF biomarkers) and in VCI.

METHODS: We included 62 patients with mild or major NCDs due to pure AD (with positive CSF biomarker assays), and 174 patients (from the GRECogVASC cohort) with pure VCI. The neuropsychological profiles were compared after stratification for disease severity (mild or major NCD). We defined a memory-executive function index (the mean z score for the third free recall and the delayed free recall in the Free and Cued Selective Reminding Test minus the mean z score for category fluency and the completion time in the Trail Making Test part B) and determined its diagnostic accuracy.

RESULTS: Compared with VCI patients, patients with AD had significantly greater memory impairments (p = 0.001). Executive function was impaired to a similar extent in the two groups (p = 0.11). Behavioral executive disorders were more prominent in the AD group (p = 0.001). Although the two groups differed significant with regard to the memory-executive function index (p < 0.001), the latter's diagnostic accuracy was only moderate (sensitivity: 63%, specificity: 87%).

CONCLUSION: Although the contrast between memory and executive function impairments was supported at the group level it does not reliably discriminate between AD and VCI at the individual level.

%B J Alzheimers Dis %V 63 %P 625-633 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689726?dopt=Abstract %R 10.3233/JAD-171097 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Diffuse Amyloid-β Plaques, Neurofibrillary Tangles, and the Impact of APOE in Elderly Persons' Brains Lacking Neuritic Amyloid Plaques. %A Abner, Erin L %A Neltner, Janna H %A Jicha, Gregory A %A Patel, Ela %A Anderson, Sonya L %A Wilcock, Donna M %A Van Eldik, Linda J %A Nelson, Peter T %X

Data from a large autopsy series were analyzed to address questions pertinent to primary age-related tauopathy (PART) and Alzheimer's disease (AD): what factors are associated with increased severity of neurofibrillary degeneration in brains that lack neuritic amyloid plaques?; is there an association between Apolipoprotein E (APOE) alleles and PART pathologic severity independent of amyloid-β (Aβ) deposits?; and, how do the stains used to detect plaques and tangles impact the experimental results? Neuropathologic data were evaluated from elderly research volunteers whose brain autopsies were performed at University of Kentucky Alzheimer's Disease Center (UK-ADC; N = 145 subjects). All of the included subjects' brains lacked neuritic amyloid plaques according to the CERAD diagnostic criteria and the average final MMSE score before death was 26.8±4.6 stdev. The study incorporated evaluation of tissue with both silver histochemical stains and immunohistochemical stains to compare results; the immunohistochemical stains (Aβ and phospho-tau) were scanned and quantified using digital pathologic methods. Immunohistochemical stains provided important advantages over histochemical stains due to sensitivity and detectability via digital methods. When AD-type pathology was in its presumed earliest phases, neocortical parenchymal Aβ deposits were associated with increased medial temporal lobe neurofibrillary tangles. The observation supports the NIA-AA consensus recommendation for neuropathologic diagnoses, because even these "diffuse" Aβ deposits signal that AD pathobiologic mechanisms are occurring. Further, the data were most compatible with the hypothesis that the APOEɛ4 allele exerts its effect(s) via driving Aβ deposition, i.e., an "upstream" influence, rather than being associated directly with Aβ- independent PART pathology.

%B J Alzheimers Dis %V 64 %P 1307-1324 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040735?dopt=Abstract %R 10.3233/JAD-180514 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dilated Perivascular Spaces in the Centrum Semiovale Begin to Develop in Middle Age. %A Ishikawa, Masatsune %A Yamada, Shigeki %A Yamamoto, Kazuo %K Adult %K Aged %K Aged, 80 and over %K Aging %K Cerebral Amyloid Angiopathy %K Corpus Callosum %K Cross-Sectional Studies %K Female %K Humans %K Japan %K Logistic Models %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Multivariate Analysis %K Prospective Studies %K Young Adult %X

BACKGROUND: Dilated perivascular spaces in the centrum semiovale (CSO-PVS) are closely related to small vessel disease. However, recent studies have revealed that cerebral amyloid angiopathy can cause dilation of the CSO-PVS and obstruction of interstitial fluid flow along the intramural periarterial drainage.

OBJECTIVE: To examine the severity and age-related prevalence of CSO-PVS through magnetic resonance imaging (MRI) and investigate their clinically relevant factors.

METHODS: This study included 1,060 subjects who participated in our brain program. The subjects ranged from 23 to 83 years in age and were active in society. The frequencies of the MRI abnormalities of small vessel diseases, including CSO-PVS, were examined. The CSO-PVS severity was classified into three grades: G0, G1, G2, according to the visual rating. The subjects were divided into five age groups and their age-related frequencies were also studied. Using the clinico-laboratory data of 712 subjects, the clinically relevant factors of CSO-PVS were investigated using logistic regression analysis.

RESULTS: The frequencies of all G0 ("normal") MRI abnormalities significantly decreased with age. A high prevalence of G2 CSO-PVS was observed (24%) in the youngest group aged≤39 years, whereas other MRI abnormalities in this group were not or rarely observed. In multivariable logistic regression analyses, G2 CSO-PVS was found to be closely associated with age, hypertension, and the estimated glomerular filtration ratio.

CONCLUSIONS: This study reveals that CSO-PVS begin to develop in subjects aged less than 39 years. Age-related changes are involved. Further studies are necessary to elucidate the pathophysiological role of the CSO-PVS.

%B J Alzheimers Dis %V 61 %P 1619-1626 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376866?dopt=Abstract %R 10.3233/JAD-170755 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Diosgenin Attenuates Lipopolysaccharide-Induced Parkinson's Disease by Inhibiting the TLR/NF-κB Pathway. %A Li, Bingyu %A Xu, Pengli %A Wu, Shuyan %A Jiang, Zhixian %A Huang, Zhijian %A Li, Qian %A Chen, Danhong %X

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Diosgenin is a natural steroid saponin which was shown to play a beneficial role in Alzheimer's disease.

OBJECTIVE: This study sought to investigate the potential effect of diosgenin on a rat model of PD.

METHODS: Sprague Dawley rats were subjected to intra-striatal injection of lipopolysaccharide (LPS) and treated with diosgenin. Stepping, Whisker, and Cylinder tests were carried out to determine the motor function, and the expression of tyrosine hydroxylase was detected by immunohistochemistry. The levels of multiple proinflammatory cytokines, oxidative stress related factors and proteins involved in Toll-like receptor (TLR)/nuclear factor kappa B (NF-κB) pathway were measured. The synergistic effect of environment enrichment on diosgenin was also investigated.

RESULTS: Intra-striatal injection of LPS caused motor deficits in rats, induced inflammatory response and oxidative stress response, and activated the TLR/NF-κB pathway both in vivo and in vitro. Diosgenin could attenuate the LPS-induced alterations. Enriched environment enhanced the effect of diosgenin to ameliorate the LPS-induced motor deficits in rats and decreased the protein levels of TLR2, TLR4, and nuclear NF-κB in diosgenin treated PD rats.

CONCLUSION: Diosgenin had a beneficial effect in LPS-induced rat PD models, by suppressing the TLR/NF-κB signaling pathway. Environmental enrichment could play a synergistic effect with diosgenin, by enhancing the inhibitory effect of diosgenin on the TLR/ NF-κB signaling pathway.

%B J Alzheimers Dis %V 64 %P 943-955 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966203?dopt=Abstract %R 10.3233/JAD-180330 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dipeptidyl-Peptidase Activity of Meprin β Links N-truncation of Aβ with Glutaminyl Cyclase-Catalyzed pGlu-Aβ Formation. %A Schlenzig, Dagmar %A Cynis, Holger %A Hartlage-Rübsamen, Maike %A Zeitschel, Ulrike %A Menge, Katja %A Fothe, Anja %A Ramsbeck, Daniel %A Spahn, Claudia %A Wermann, Michael %A Roßner, Steffen %A Buchholz, Mirko %A Schilling, Stephan %A Demuth, Hans-Ulrich %X

The formation of amyloid-β (Aβ) peptides is causally involved in the development of Alzheimer's disease (AD). A significant proportion of deposited Aβ is N-terminally truncated and modified at the N-terminus by a pGlu-residue (pGlu-Aβ). These forms show enhanced neurotoxicity compared to full-length Aβ. Although the truncation may occur by aminopeptidases after formation of Aβ, recently discovered processing pathways of amyloid-β protein precursor (AβPP) by proteases such as meprin β may also be involved. Here, we assessed a role of meprin β in forming Aβ3-40/42, which is the precursor of pGlu-Aβ3-40/42 generated by glutaminyl cyclase (QC). Similar to QC, meprin β mRNA is significantly upregulated in postmortem brain from AD patients. A histochemical analysis supports the presence of meprin β in neurons and astrocytes in the vicinity of pGlu-Aβ containing deposits. Cleavage of AβPP-derived peptides by meprin β in vitro results in peptides Aβ1-x, Aβ2-x, and Aβ3-x. The formation of N-truncated Aβ by meprin β was also corroborated in cell culture. A subset of the generated peptides was converted into pGlu-Aβ3-40 by an addition of glutaminyl cyclase, supporting the preceding formation of Aβ3-40. Further analysis of the meprin β cleavage revealed a yet unknown dipeptidyl-peptidase-like activity specific for the N-terminus of Aβ1-x. Thus, our data suggest that meprin β contributes to the formation of N-truncated Aβ by endopeptidase and exopeptidase activity to generate the substrate for QC-catalyzed pGlu-Aβ formation.

%B J Alzheimers Dis %V 66 %P 359-375 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320570?dopt=Abstract %R 10.3233/JAD-171183 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Disease Course Varies According to Age and Symptom Length in Alzheimer's Disease. %A Barnes, Josephine %A Bartlett, Jonathan W %A Wolk, David A %A van der Flier, Wiesje M %A Frost, Chris %X

Health-care professionals, patients, and families seek as much information as possible about prognosis for patients with Alzheimer's disease (AD); however, we do not yet have a robust understanding of how demographic factors predict prognosis. We evaluated associations between age at presentation, age of onset, and symptom length with cognitive decline as measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating sum-of-boxes (CDR-SOB) in a large dataset of AD patients. Age at presentation was associated with post-presentation decline in MMSE (p < 0.001), with younger patients showing faster decline. There was little evidence of an association with change in CDR-SOB. Symptom length, rather than age, was the strongest predictor of MMSE and CDR-SOB at presentation, with increasing symptom length associated with worse outcomes. The evidence that younger AD patients have a more aggressive disease course implies that early diagnosis is essential.

%B J Alzheimers Dis %V 64 %P 631-642 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914016?dopt=Abstract %R 10.3233/JAD-170841 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dissecting the Role of 5-Lipoxygenase in the Homocysteine-Induced Alzheimer's Disease Pathology. %A Di Meco, Antonio %A Li, Jian-Guo %A Praticò, Domenico %X

Alzheimer's disease (AD) affects over 40 million patients around the world and poses a huge economic burden on society since no effective therapy is available yet. While the cause(s) for the most common sporadic form of the disease are still obscure, lifestyle and different environmental factors have emerged as modulators of AD susceptibility. Hyperhomocysteinemia (HHCY), a condition of high circulating levels of homocysteine, is an independent but modifiable risk factor for AD. Studies in AD mouse models have linked HHCY with memory impairment, amyloidosis, tau pathology, synaptic dysfunction, and neuroinflammation. However, the exact mechanism by which HHCY affects AD pathogenesis is unclear. The 5-lipoxygenase (5LO) is a protein upregulated in postmortem AD brains and plays a functional role in AD pathogenesis. Recently, in vitro and in vivo studies showed that HHCY effects on amyloid-β and tau pathology, synapse and memory impairments are dependent on the activation of the 5LO enzymatic pathway, since its genetic absence or pharmacological inhibition prevents them. HHCY induces 5LO gene upregulation by lowering the methylation of its promoter, which results in increased translation and transcription of its mRNA. Based on these findings, we propose that epigenetic modification of 5LO represents the missing biological link between HHCY and AD pathogenesis, and for this reason it represents a viable therapeutic target to prevent AD development in individuals bearing this risk factor.

%B J Alzheimers Dis %V 62 %P 1337-1344 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254095?dopt=Abstract %R 10.3233/JAD-170700 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Distinct Cognitive and Brain Morphological Features in Healthy Subjects Unaware of Informant-Reported Cognitive Decline. %A Sánchez-Benavides, Gonzalo %A Grau-Rivera, Oriol %A Cacciaglia, Raffaele %A Suárez-Calvet, Marc %A Falcon, Carles %A Minguillon, Carolina %A Gramunt, Nina %A Sala-Vila, Aleix %A Gispert, Juan Domingo %A Molinuevo, José Luis %X

BACKGROUND: Subtle cognitive decline preceding cognitive impairment can be self-perceived, referred to as subjective cognitive decline (SCD), or go unrecognized.

OBJECTIVE: To study the clinical, cognitive, and structural neuroimaging characteristics of psychometrically normal subjects without self-awareness of cognitive decline (unaware decliners, UD) and to compare them with SCD participants and controls.

METHODS: 2,640 participants from the ALFA cohort, 1,899 controls, 173 UD (decline reported by the informant only), and 568 SCD underwent clinical and cognitive explorations. A subset of 530 underwent structural MRI (379 Controls; 43 UD; 108 SCD). Linear models adjusting for confounders (age, sex, education, and mood state) were used to assess group differences on cognition and voxel-wise grey matter (GM) volumes.

RESULTS: 6.6% were UD while 21.5% SCD. No differences in anxiety and depression were observed between controls and UD, while SCD did (p < 0.01). UD showed lower performance in the Memory Binding Test free recall (p < 0.005) than controls, but no differences compared to SCD. Right medial frontal and insular increments of GM volumes were observed in UD with respect to controls. Informant report of decline in UD and SCD was associated with lower left hippocampal GM volume but related to memory performance only in UD (rho = 0.46, p = 0.002).

CONCLUSIONS: UD had worse memory performance than controls which correlated with hippocampal GM volume and presented brain volume increments in self-appraisal areas (medial frontal and insula). Individuals unaware of cognitive decline may represent a distinct group at risk for cognitive impairment and support the usefulness of informant-reported cognitive decline.

%B J Alzheimers Dis %V 65 %P 181-191 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010134?dopt=Abstract %R 10.3233/JAD-180378 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Distinct Neuroanatomical Correlates of Neuropsychiatric Symptoms in the Three Main Forms of Genetic Frontotemporal Dementia in the GENFI Cohort. %A Sellami, Leila %A Bocchetta, Martina %A Masellis, Mario %A Cash, David M %A Dick, Katrina M %A van Swieten, John %A Borroni, Barbara %A Galimberti, Daniela %A Tartaglia, Maria Carmela %A Rowe, James B %A Graff, Caroline %A Tagliavini, Fabrizio %A Frisoni, Giovanni %A Finger, Elizabeth %A de Mendonça, Alexandre %A Sorbi, Sandro %A Warren, Jason D %A Rohrer, Jonathan D %A Laforce, Robert %X

BACKGROUND: The overlap between frontotemporal dementia (FTD) and primary psychiatric disorders has been brought to light by reports of prominent neuropsychiatric symptoms (NPS) in FTD-related genetic mutations, particularly among C9orf72 and GRN carriers. It has been recently demonstrated that early neuroanatomical changes in genetic FTD may be different across the major disease-causing mutations.

OBJECTIVE: We aimed to identify whether NPS could be driven by distinct structural correlates.

METHODS: One hundred and sixty-seven mutation carriers (75 GRN, 60 C9orf72, and 32 MAPT) were included from the Genetic FTD Initiative (GENFI) study, a large international cohort of genetic FTD. Neuropsychiatric symptoms including delusions, hallucinations (visual, auditory, and tactile), depression, and anxiety were investigated using a structured interview. Voxel-based morphometry was performed to identify neuroanatomical correlates of NPS.

RESULTS: Psychotic symptoms correlated mainly with grey matter (GM) atrophy in the anterior insula, left thalamus, cerebellum, and cortical regions including frontal, parietal, and occipital lobes in GRN mutations carriers. GM atrophy in posterior structures of the default-mode network was associated with anxiety in the GRN group. Delusions in C9orf72 expansion carriers were mainly associated with left frontal cortical atrophy. Cerebellar atrophy was found to be correlated only with anxiety in C9orf72 carriers. NPS in the MAPT group were mainly associated with volume loss in the temporal lobe.

CONCLUSION: Neuroanatomical correlates of NPS appear to be distinct across the main forms of genetic FTD. Overall, our findings support overlapping brain structural changes between FTD and primary psychiatric disorders.

%B J Alzheimers Dis %V 65 %P 147-163 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010122?dopt=Abstract %R 10.3233/JAD-180053 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Distinct Patterns of Rich Club Organization in Alzheimer's Disease and Subcortical Vascular Dementia: A White Matter Network Study. %A Lee, Wha Jin %A Han, Cheol E %A Aganj, Iman %A Seo, Sang Won %A Seong, Joon-Kyung %X

Recent advances in neuroimaging technology have shown that rich club organization in human brain networks plays a crucial role in global communication and cognitive functionality. In this study, we investigated rich club organization within white matter structural brain networks in two common types of dementia, Alzheimer's disease (AD) and subcortical vascular dementia (SVaD). We recruited 30 AD patients ([11C] Pittsburgh compound-B (PiB) PET positive), 39 SVaD patients (PiB negative), and 72 age-, gender-, and education-matched cognitively normal (CN) subjects. Rich club organization was significantly disrupted in both dementia patient groups, which exhibited higher rich club coefficients than the CN group. Rich club organization in the patient groups was primarily disrupted over the left frontal and left middle temporal areas when compared to the CN group. The number of rich club nodes was significantly reduced in the dementia groups, which was more severe in SVaD (p = 0.0107, permutation-based t-test). Although rich club organization was disrupted both in the patient groups, its disruption pattern is different between them. The rich-club connections normalized by degree-and-strength preserved random networks were significantly increased in the dementia groups with SVaD more severely, and feeder connections were reduced more significantly than in AD. Furthermore, SVaD patients exhibited more sporadic disruption in white matter connectivity than AD patients, with local connections showing a more significant degree of deterioration. Combined with the distinct disruption in rich club nodes, these findings may imply a differing role for rich club organization in AD and SVaD, due to different pathological mechanisms.

%B J Alzheimers Dis %V 63 %P 977-987 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710719?dopt=Abstract %R 10.3233/JAD-180027 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Distinct White Matter Changes Associated with Cerebrospinal Fluid Amyloid-β1-42 and Hypertension. %A Al-Janabi, Omar M %A Brown, Christopher A %A Bahrani, Ahmed A %A Abner, Erin L %A Barber, Justin M %A Gold, Brian T %A Goldstein, Larry B %A Murphy, Ronan R %A Nelson, Peter T %A Johnson, Nathan F %A Shaw, Leslie M %A Smith, Charles D %A Trojanowski, John Q %A Wilcock, Donna M %A Jicha, Gregory A %X

BACKGROUND: Alzheimer's disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults.

OBJECTIVE: To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations.

METHODS: Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer's Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans. CSF Aβ1-42 levels were measured as a marker of AD, and fluid-attenuated inversion recovery imaging and diffusion tensor imaging were obtained to assess WM macro- and microstructural properties. Linear regression analyses were used to assess the relationships among WM alterations, cerebrovascular disease risk, and AD pathology. Voxelwise analyses were performed to examine spatial patterns of WM alteration associated with each pathology.

RESULTS: HTN and CSF Aβ1-42 levels were each associated with white matter hyperintensities (WMH). Also, CSF Aβ1-42 levels were associated with alterations in normal appearing white matter fractional anisotropy (NAWM-FA), whereas HTN was marginally associated with alterations in NAWM-FA. Linear regression analyses demonstrated significant main effects of HTN and CSF Aβ1-42 on WMH volume, but no significant HTN×CSF Aβ1-42 interaction. Furthermore, voxelwise analyses showed unique patterns of WM alteration associated with hypertension and CSF Aβ1-42.

CONCLUSION: Associations of HTN and lower CSF Aβ1-42 with WM alteration were statistically and spatially distinct, suggesting independent rather than synergistic effects. Considering such spatial distributions may improve diagnostic accuracy to address each underlying pathology.

%B J Alzheimers Dis %V 66 %P 1095-1104 %8 2018 Nov 23 %G eng %N 3 %R 10.3233/JAD-180663 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Distribution of Cerebrospinal Fluid Biomarker Profiles in Patients Explored for Cognitive Disorders. %A Paquet, Claire %A Bouaziz-Amar, Elodie %A Cognat, Emmanuel %A Volpe-Gillot, Lisette %A Haddad, Victor %A Mahieux, Florence %A Dekimeche, Siham %A Defontaines, Benedicte %A Chabriat, Hugues %A Belin, Catherine %A Texeira, Antonio %A Goutagny, Stephane %A Questel, Frank %A Azuar, Julien %A Sellier, Pierre-Olivier %A Laplanche, Jean-Louis %A Hugon, Jacques %A Dumurgier, Julien %X

BACKGROUND: CSF Alzheimer's disease (AD) biomarkers allow classifying individuals based on their levels of amyloid and neurodegeneration pathologies.

OBJECTIVE: To investigate the distribution of AD biomarker profiles from patients suffering from cognitive disorders.

METHODS: We analyzed 3001 patients with cognitive disorders and referred by 18 French memory clinics located in and around Paris. Patients were classified as normal, amyloidosis (A+/N-), amyloidosis and neurodegeneration (A+/N+) or suspected non-AD pathophysiology (SNAP), according to their CSF levels of biomarkers. Analysis were performed for the overall population and stratified by gender, age quintiles, and Mini-Mental State Examination (MMSE) score quintiles. Results were compared to previous findings in cohorts of healthy elderly adults.

RESULTS: 37% of the sample were classified as A+/N+, 22% were classified A+/N-, and 15% as SNAP. The A+/N+ profile was associated with female gender, advanced age, and lower MMSE score, while the A+/N-profile was observed more frequently in men and the distribution was stable across age and MMSE. The SNAP profile showed no association with gender or age, was less frequent in patients with lower MMSE, and had a lower repartition than the one previously reported in asymptomatic populations.

CONCLUSIONS: While A+/N+ patients had the clinical characteristics typically observed in AD, A+/N-patients had a different epidemiological pattern (higher frequency in men, no association with advanced age or lower MMSE). The SNAP profile was less frequent than previously reported in the general elderly population, suggesting that this profile is not a frequent cause of memory impairment in this population.

%B J Alzheimers Dis %V 64 %P 889-897 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966201?dopt=Abstract %R 10.3233/JAD-180240 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Distribution of Urinary Alzheimer-Associated Neuronal Thread Protein and Its Association with Common Chronic Diseases in the General Population. %A Jin, He %A Guan, Shaochen %A Wang, Rong %A Fang, Xianghua %A Liu, Hongjun %A Wu, Yanchuan %A Zhang, Yanlei %A Liu, Chunxiao %X

BACKGROUND: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been found to be a biomarker for Alzheimer's disease (AD).

OBJECTIVE: The aim of the present study was to investigate the distribution of Alzheimer-associated neuronal thread protein and its relationship to common chronic diseases in the general population.

METHODS: Urine samples of 1,805 participants were collected from four districts (Xi Cheng, Fang Shan, Tong Zhou, and Yan Qing) in Beijing. The assessment in this study included a questionnaire that captured participants' demographic information, use of medication and histories of disease, neurological examinations, psychometric evaluations, physical and clinical examinations, and laboratory tests.

RESULTS: Urine AD7c-NTP level was increased among the population over 60 years old and females exhibited higher levels than males. These results controlled for other demographic factors such as education levels, employment status, body mass index and current residence. The urine AD7c-NTP levels exhibited no association with non-neurological diseases (0.3346±0.4482 ng/ml), such as hypertension (0.3445±0.4187), stroke (0.3652±0.4010), diabetes (0.3319±0.4371), dyslipidemia (0.3440±0.4314), renal insufficiency (0.3223±0.3909), cancer (0.5055±1.0006), chronic lung disease (0.2911±0.2852), chronic liver disease (0.5579±0.6726), severe depression symptoms (0.5186±0.7040), and mild depression symptoms (0.3669±0.3811).

CONCLUSIONS: Cut-off values for urine AD7c-NTP levels for different age groups and genders should be established. AD7c-NTP levels proved relatively stable in the body and were not impacted by demographic factors or common chronic diseases.

%B J Alzheimers Dis %V 65 %P 433-442 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040733?dopt=Abstract %R 10.3233/JAD-180441 %0 Journal Article %J J Alzheimers Dis %D 2018 %T DJ-1 Suppresses Cytoplasmic TDP-43 Aggregation in Oxidative Stress-Induced Cell Injury. %A Lei, Yang %A Zhang, Zhi-Feng %A Lei, Rui-Xue %A Wang, Shu %A Zhuang, Yang %A Liu, An-Chun %A Wu, Yan %A Chen, Juan %A Tang, Jun-Chun %A Pan, Meng-Xian %A Liu, Rui %A Liao, Wei-Jing %A Feng, Yu-Gong %A Wan, Qi %A Zheng, Mei %X

DJ-1 (also called PARK7) is a multifunctional redox-sensitive protein that is protective against oxidative stress-induced cell death. TAR DNA-binding protein 43 (TDP-43) is a major protein component of pathological inclusions in amyotrophic lateral sclerosis and frontotemporal dementia. Reducing aberrant aggregation of TDP-43 is a potential approach to prevent cell death. To investigate whether DJ-1 might inhibit TDP-43 aggregation to exert a protective effect in oxidative stress-induced injury, we tested the protein level and subcellular localization of TDP-43 and DJ-1 in SH-SY5Y cells transfected with wild-type DJ-1, DJ-1 mutant (L166P) cDNA, or DJ-1 siRNA. We show that oxidative stress induced by paraquat leads to the formation of cytosolic TDP-43 aggregation in SH-SY5Y cells. DJ-1 overexpression decreases paraquat-induced cytoplasmic accumulation of TDP-43 in SH-SY5Y cells and protects against paraquat-induced cell death. Transfection of DJ-1 L166P mutant or DJ-1 siRNA leads to increased cytosolic aggregation of TDP-43 in paraquat-treated SH-SY5Y cells and promotes cell death. These data suggest that DJ-1 may protect against oxidative stress-induced cell death through the suppression of cytoplasmic TDP-43 aggregation.

%B J Alzheimers Dis %V 66 %P 1001-1014 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30372676?dopt=Abstract %R 10.3233/JAD-180460 %0 Journal Article %J J Alzheimers Dis %D 2018 %T DNA Hypomethylation in Blood Links B3GALT4 and ZADH2 to Alzheimer's Disease. %A Madrid, Andy %A Hogan, Kirk J %A Papale, Ligia A %A Clark, Lindsay R %A Asthana, Sanjay %A Johnson, Sterling C %A Alisch, Reid S %X

Differentially methylated positions (DMPs) between persons with and without late-onset Alzheimer's disease (LOAD) were observed at 477 of 769,190 loci in a plurality of genes. Of these, 17 were shared with DMPs identified using clinical LOAD markers analyzed independently as continuous variables comprising Rey Auditory Verbal Learning Test scores, cerebrospinal fluid total tau (t-tau) and phosphorylated tau 181 (p-tau181) levels, and t-tau/Aβ1-42 (Aβ42), p-tau181/Aβ42, and Aβ42/Aβ1-40 (Aβ40) ratios. In patients with LOAD, 12 of the shared 17 DMPs were hypomethylated in B3GALT4 (Beta-1,3-galatcosyltransferase 4) (EC 2.4.1.62), and 5 were hypomethylated in ZADH2 (Prostaglandin reductase 3) (EC 1.3.1.48).

%B J Alzheimers Dis %V 66 %P 927-934 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30372681?dopt=Abstract %R 10.3233/JAD-180592 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Do Cardiometabolic Risk Factors Influence Amyloid, Tau, and Neuronal Function in APOE4 Carriers and Non-Carriers in Alzheimer's Disease Trajectory? %A Femminella, Grazia Daniela %A Taylor-Davies, Genevieve %A Scott, James %A Edison, Paul %X

Cardiovascular risk could be calculated using Qrisk2. It is suggested that cardiovascular risk factors influence the progression of Alzheimer's disease (AD). However, studies have not specifically evaluated the influence of cardiovascular risk using Qrisk2 on neuropathological progression and AD biomarkers. The aim of the study was to evaluate the influence of cardiovascular risk factors using Qrisk2 on CSF amyloid-β (Aβ) and tau, 18F-AV45-PET, 18F-FDG-PET, MRI, and cognitive measures in APOE4 negative cognitively normal and mild cognitive impairment (MCI) subjects. 614 cognitively normal, early, and late MCI subjects were selected from the ADNI cohort with a 2-year follow-up. CSF Aβ and tau, 18F-AV45-PET, 18F-FDG-PET, MRI, and cognitive measures along with modified Qrisk2 were evaluated. APOE4 non-carrier, high cardiovascular risk sub-group of early and late MCI and cognitively normal subjects, demonstrated worse biomarker and cognitive profile at baseline and during follow up compared to low cardiovascular risk group. Additionally, similar pattern was also observed in APOE4 carriers. We demonstrated that Qrisk2 and APOE4 were independent predictors of biomarker and clinical progression in AD trajectory. High cardiovascular risk is associated with biomarker changes in APOE4 non-carriers in prodromal AD, which may suggest that treatment of cardiovascular risk is an effective prevention strategy even in APOE4 negative subjects and may influence disease progression independent of amyloid pathology. Demonstration of accelerated neuropathological changes in both APOE4 carriers and non-carriers suggest that focusing on modifiable cardiovascular risk factors is an effective preventative strategy while we eagerly waiting for new treatments.

%B J Alzheimers Dis %V 64 %P 981-993 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966204?dopt=Abstract %R 10.3233/JAD-180365 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Does Fatty Acid Composition in Subcutaneous Adipose Tissue Differ between Patients with Alzheimer's Disease and Cohabiting Proxies? %A Faxen-Irving, Gerd %A Falahati, Farshad %A Basun, Hans %A Eriksdotter, Maria %A Vedin, Inger %A Wahlund, Lars-Olof %A Schultzberg, Marianne %A Hjorth, Erik %A Palmblad, Jan %A Cederholm, Tommy %A Freund-Levi, Yvonne %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Dietary Supplements %K Fatty Acids, Omega-3 %K Female %K Humans %K Male %K Regression Analysis %K Subcutaneous Fat %X

Low tissue levels of the major marine ω3 fatty acids (FAs) DHA and EPA are found in Alzheimer's disease (AD). We investigated if healthy proxies to AD patients have higher levels of these ω3 FAs. We observed lower levels of EPA and DHA in subcutaneous adipose tissue biopsies from 64 AD patients compared with 16 cognitively healthy proxies. No significant difference was observed when pairwise comparisons were made between a subset of 16 AD patients and their co-habiting proxies. Larger studies are needed to replicate these findings and to determine if they could depend on FA intake or differences in metabolism.

%B J Alzheimers Dis %V 61 %P 515-519 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154271?dopt=Abstract %R 10.3233/JAD-170359 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Does the Genetic Feature of the Chinese Tree Shrew (Tupaia belangeri chinensis) Support Its Potential as a Viable Model for Alzheimer's Disease Research? %A Fan, Yu %A Luo, Rongcan %A Su, Ling-Yan %A Xiang, Qun %A Yu, Dandan %A Xu, Ling %A Chen, Jia-Qi %A Bi, Rui %A Wu, Dong-Dong %A Zheng, Ping %A Yao, Yong-Gang %K Alzheimer Disease %K Amino Acid Sequence %K Animals %K Biomedical Research %K Disease Models, Animal %K Gene Expression Profiling %K Humans %K Male %K Mice %K Tupaia %X

Alzheimer's disease (AD) is a neurodegenerative disease with increasing incidence across the world and no cure at the present time. An ideal animal model would facilitate the understanding of the pathogenesis of AD and discovery of potential therapeutic targets. The Chinese tree shrew (Tupaia belangeri chinensis) has a closer genetic affinity to primates relative to rodents, and can attain ages of 8 years or older, which represents another advantage for the study of neurodegenerative diseases such as AD compared to primates. Here, we analyzed 131 AD-related genes in the Chinese tree shrew brain tissues based on protein sequence identity, positive selection, mRNA, and protein expression by comparing with those of human, rhesus monkey, and mouse. In particular, we focused on the Aβ and neurofibrillary tangles formation pathways, which are crucial to AD pathogenesis. The Chinese tree shrew had a generally higher sequence identity with human than that of mouse versus human for the AD pathway genes. There was no apparent selection on the tree shrew lineage for the AD-related genes. Moreover, expression pattern of the Aβ and neurofibrillary tangle formation pathway genes in tree shrew brain tissues resembled that of human brain tissues, with a similar aging-dependent effect. Our results provided an essential genetic basis for future AD research using the tree shrew as a viable model.

%B J Alzheimers Dis %V 61 %P 1015-1028 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332044?dopt=Abstract %R 10.3233/JAD-170594 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Does Treating Vascular Risk Factors Prevent Dementia and Alzheimer's Disease? A Systematic Review and Meta-Analysis. %A Larsson, Susanna C %A Markus, Hugh S %X

BACKGROUND: Epidemiological evidence has associated Alzheimer's disease (AD) with vascular risk factors (VRFs), but whether treatment of VRFs reduces the incidence of dementia and AD is uncertain.

OBJECTIVE: To conduct a systematic review and meta-analysis to summarize available data on the impact of treatment of VRFs on dementia and AD incidence.

METHODS: Pertinent studies published until 1 January 2018 were identified from PubMed. Both randomized controlled trials (RCT) and prospective studies that investigated the impact of treatment of VRFs on dementia or AD incidence were included.

RESULTS: Eight RCTs and 52 prospective studies were identified. Antihypertensive treatment was associated with a non-significant reduced risk of dementia in RCTs (n = 5; relative risk [RR], 0.84; 95% confidence interval [CI], 0.69-1.02) and prospective studies (n = 3; RR, 0.77; 95% CI, 0.58-1.01) and with reduced AD risk in prospective studies (n = 5; RR = 0.78; 95% CI, 0.66-0.91). In prospective studies, treatment of hyperlipidemia with statins, but not nonstatin lipid-lowering agents, was associated with reduced risk of dementia (n = 17; RR, 0.77; 95% CI, 0.63-0.95) and AD (n = 13; RR, 0.86; 95% CI, 0.80-0.92). The single RCT on statins and dementia incidence showed no association. Data from one RCT and six prospective studies did not support a beneficial impact of antidiabetic drugs or insulin therapy on dementia risk.

CONCLUSION: Current evidence indicates that antihypertensives and statins might reduce the incidence of dementia and AD. Further trials to determine the effect of VRF on AD are needed.

%B J Alzheimers Dis %V 64 %P 657-668 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914039?dopt=Abstract %R 10.3233/JAD-180288 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Down-Expression of ACE and IDE Exacerbates Exogenous Amyloid-β Neurotoxicity in CB2R-/- Mice. %A Wang, Lin %A Shi, Fang-Xiao %A Xu, Wei-Qi %A Cao, Yun %A Li, Na %A Li, Man %A Wang, Qun %A Wang, Jian-Zhi %A Tian, Qing %A Yu, Li-Kai %A Zhou, Xin-Wen %X

Alzheimer's disease (AD) is characterized by neuritic plaques and neurofibrillary tangles. It is reported that enzymatic degradation of amyloid-β (Aβ) plays a pivotal role in Aβ accumulation and type-2 cannabinoid receptor (CB2R) participates in Aβ processing in the brain; however, the underlying mechanisms remain unclear. We determined that Aβ degradation-related proteins are significantly different between CB2R-/- mice and wild-type (WT) mice via proteomic analysis. Moreover, the data demonstrated that the angiotensin converting enzyme (ACE) and insulin-degrading enzyme (IDE) levels are substantially attenuated, and the Aβ level is significantly enhanced in CB2R-/--Aβ1 - 42 mice compared with that of WT-Aβ1 - 42 mice. Furthermore, Aβ-mediated synaptic dysfunction, the loss of memory associated proteins, and the suppression of glutamatergic transmission are more severe in CB2R-/--Aβ1 - 42 mice than that in WT-Aβ1 - 42 mice. CB2R activation could decrease Aβ1 - 40 and Aβ1 - 42 levels and enhance ACE and IDE levels with its selective agonist JWH133; however, AM630 (CB2R antagonist) abrogates all changes induced by JWH133 in N2a cells with AβPP overexpression. Taken together, our study demonstrated that the deletion of CB2R reduces exogenous Aβ degradation and aggravates the toxicity of Aβ via the reduction of ACE and IDE, which suggests that CB2R is involved in the onset of AD and a potential therapeutic target for AD.

%B J Alzheimers Dis %V 64 %P 957-971 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29991137?dopt=Abstract %R 10.3233/JAD-180142 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Drugs for Dementia and Excess of Hospitalization: A Longitudinal French Study. %A François, Mathilde %A Sicsic, Jonathan %A Pelletier Fleury, Nathalie %K Aged %K Aged, 80 and over %K Cholinesterase Inhibitors %K Dementia %K Female %K France %K Health Expenditures %K Hospitalization %K Humans %K Longitudinal Studies %K Male %K Rivastigmine %X

BACKGROUND: The impact of adverse effects of drugs for dementia on the risk of hospitalization has not been much studied despite the impact of hospitalizations on cognitive decline.

OBJECTIVE: To determine if the main adverse effects of cholinesterase inhibitors and memantine may be associated with excess of hospitalization and to quantify the subsequent impact on healthcare expenditures.

METHODS: A representative sample of the French national health insurance beneficiaries aged 65 and older and suffering from dementia were included and followed from 2007 to 2014. Binary logit models for longitudinal data (GEE estimation technique) were used to estimate the excess of hospitalization events related to the adverse effects of anti-dementia drugs and then to derive the additional costs of hospitalizations for the public health insurance fund.

RESULTS: In total, 7,668 patients were followed, generating 111,133 individual observations over the 8-year period. Treated patients were hospitalized significantly more than non-treated patients (adjusted Odd Ratio (OR) = 1.08, 95% confidence interval (95% CI) = [1.02 to 1.13], p = 0.004), mainly with cholinesterase inhibitors for cardiac (OR = 1.21, 95% CI = [1.01 to 1.46], p = 0.034) and gastrointestinal events (OR = 1.43, 95% CI = [1.01-2.05], p = 0.045), especially with rivastigmine. When extrapolated to the entire population, this corresponded to an annual additional cost of € 55,000.

CONCLUSION: Prescription of antidementia drugs, more specifically rivastigmine, increases the risk of hospitalizations via their cardiac and gastrointestinal adverse effects and lead to additional health care expenditures. Even though these results must be confirmed, they may encourage cautious consideration of the balance between benefits and harms before a prescription is given.

%B J Alzheimers Dis %V 61 %P 1627-1637 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376848?dopt=Abstract %R 10.3233/JAD-170371 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dual Time-Point [18F]Florbetaben PET Delivers Dual Biomarker Information in Mild Cognitive Impairment and Alzheimer's Disease. %A Florek, Lisa %A Tiepolt, Solveig %A Schroeter, Matthias L %A Berrouschot, Jörg %A Saur, Dorothee %A Hesse, Swen %A Jochimsen, Thies %A Luthardt, Julia %A Sattler, Bernhard %A Patt, Marianne %A Hoffmann, Karl-Titus %A Villringer, Arno %A Classen, Joseph %A Gertz, Hermann-Josef %A Sabri, Osama %A Barthel, Henryk %X

BACKGROUND: Current research diagnostic criteria for Alzheimer's disease (AD) and mild cognitive impairment (MCI) due to AD include biomarkers to supplement clinical testing. Recently, we demonstrated that dual time-point [18F]FBB PET is able to deliver both blood flow and amyloid-β (Aβ) load surrogates.

OBJECTIVE: The aim of this study was to investigate whether these surrogates can be utilized as AD biomarkers.

METHODS: 112 subjects (41 with MCI, 50 with probable/possible AD, 21 with other dementias) underwent dual time-point [18F]FBB PET. Data were visually and relative quantitatively (Herholz scores for the early and composite SUVRs for the late PET data) analyzed.

RESULTS: In the early images AD-typical patterns were present in 42% /27% /33% of probable/possible AD/MCI/other dementia cases. In late [18F]FBB PET, 42% /29% /38% of probable/possible AD/ MCI/other dementia cases were Aβ-positive. 17% of the MCIs were categorized as "MCI due to AD-high likelihood", 44% of the probable ADs as "probable AD with high evidence of AD pathophysiological process" and 28% of the possible ADs as "possible AD with evidence of AD pathophysiological process". 27% of all subjects showed a positive diagnostic and progression biomarker. Herholz scores were lower (0.85±0.05 versus 0.88±0.04, p = 0.015) for probable/possible AD versus MCI. Composite late phase SUVRs were significantly higher (1.65±0.23 versus 1.15±0.17, p < 0.005) in Aβ-positive versus Aβ-negative patients. Herholz and MMSE scores were positively correlated (R = 0.30 p = 0.006).

CONCLUSION: Dual time-point [18F]FBB PET provides dual biomarker information which enables to categorize MCI and AD dementia patients according to established diagnostic criteria. Thus, dual time-point [18F]FBB PET has great potential to supplement diagnostic dementia workups.

%B J Alzheimers Dis %V 66 %P 1105-1116 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400095?dopt=Abstract %R 10.3233/JAD-180522 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dual-Task Gait and Alzheimer's Disease Genetic Risk in Cognitively Normal Adults: A Pilot Study. %A Whitson, Heather E %A Potter, Guy G %A Feld, Jody A %A Plassman, Brenda L %A Reynolds, Kelly %A Sloane, Richard %A Welsh-Bohmer, Kathleen A %X

BACKGROUND: Dual-task paradigms, in which an individual performs tasks separately and then concurrently, often demonstrate that people with neurodegenerative disorders experience more dual-task interference, defined as worse performance in the dual-task condition compared to the single-task condition.

OBJECTIVE: To examine how gait-cognition dual-task performance differs between cognitively normal older adults with and without an APOE ɛ4 allele.

METHODS: Twenty-nine individuals ages 60 to 72 with normal cognition completed a dual-task protocol in which walking and cognitive tasks (executive function, memory) were performed separately and concurrently. Fourteen participants carried APOE ɛ4 alleles (ɛ3/ɛ4 or ɛ2/ɛ4); fifteen had APOE genotypes (ɛ2/ɛ2, ɛ2/ɛ3, or ɛ3/ɛ3) associated with lower risk of Alzheimer's disease (AD).

RESULTS: The two risk groups did not differ by age, sex, race, education, or gait or cognitive measures under single-task conditions. Compared to low risk participants, APOE ɛ4 carriers tended to exhibit greater dual-task interference. Both the memory and executive function tasks resulted in dual-task interference on gait, but effect sizes for a group difference were larger when the cognitive task was executive function. In the dual-task protocol that combined walking and the executive function task, effect sizes for group difference in gait interference were larger (0.62- 0.70) than for cognitive interference (0.45- 0.47).

DISCUSSION: Dual-task paradigms may reveal subtle changes in brain function in asymptomatic individuals at heightened risk of AD.

%B J Alzheimers Dis %V 64 %P 1137-1148 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010120?dopt=Abstract %R 10.3233/JAD-180016 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dynamic Causal Modeling of Preclinical Autosomal-Dominant Alzheimer's Disease. %A Penny, Will %A Iglesias-Fuster, Jorge %A Quiroz, Yakeel T %A Lopera, Francisco Javier %A Bobes, Maria A %X

Dynamic causal modeling (DCM) is a framework for making inferences about changes in brain connectivity using neuroimaging data. We fitted DCMs to high-density EEG data from subjects performing a semantic picture matching task. The subjects are carriers of the PSEN1 mutation, which leads to early onset Alzheimer's disease, but at the time of EEG acquisition in 1999, these subjects were cognitively unimpaired. We asked 1) what is the optimal model architecture for explaining the event-related potentials in this population, 2) which connections are different between this Presymptomatic Carrier (PreC) group and a Non-Carrier (NonC) group performing the same task, and 3) which network connections are predictive of subsequent Mini-Mental State Exam (MMSE) trajectories. We found 1) a model with hierarchical rather than lateral connections between hemispheres to be optimal, 2) that a pathway from right inferotemporal cortex (IT) to left medial temporal lobe (MTL) was preferentially activated by incongruent items for subjects in the PreC group but not the NonC group, and 3) that increased effective connectivity among left MTL, right IT, and right MTL was predictive of subsequent MMSE scores.

%B J Alzheimers Dis %8 2018 Mar 16 %G eng %R 10.3233/JAD-170405 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dysregulation and Dislocation of SFPQ Disturbed DNA Organization in Alzheimer's Disease and Frontotemporal Dementia. %A Lu, Jing %A Shu, Runzhe %A Zhu, Yan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Animals %K Brain %K Cell Line, Tumor %K DNA Damage %K Female %K Frontotemporal Dementia %K Gene Expression Regulation %K Humans %K Male %K Mice %K PTB-Associated Splicing Factor %K tau Proteins %K Translocation, Genetic %X

SFPQ (Splicing factor proline- and glutamine-rich) is a DNA and RNA binding protein involved in transcription, pre-mRNA splicing, and DNA damage repair. SFPQ was found dysregulated in a few tauopathies such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). In addition, knock-down of SFPQ induced FTD-like behavior in mouse. To confirm the role of SFPQ in AD and FTD, we analyzed the brain sections from the AD and FTD brain samples with SFPQ upregulation and dislocation. Specifically, we observed SFPQ dislocated to the cytoplasm and nuclear envelopes, and DNA structures and organizations were associated with these dislocation phenotypes in AD and FTD brains. Consistently, we also found decreased DAPI intensities and smaller chromocenters associated with SFPQ dislocation in nerural-2a (N2a) cells. As the upregulation and hyperphosphorylation of tau protein is a hallmark of AD and FTD, our study sought to investigate potential interactions between tau and SFPQ by co-transfection and co-immunoprecipitation assays in N2a cells. SFPQ dislocation was found enhanced with tau co-transfection and tau co-transfection further resulted in extended DNA disorganization in N2a cells. Overall, our results indicate that dysregulation and dislocation of SFPQ and subsequent DNA disorganization might be a novel pathway in the progression of AD and FTD.

%B J Alzheimers Dis %V 61 %P 1311-1321 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376859?dopt=Abstract %R 10.3233/JAD-170659 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early and Persistent O-GlcNAc Protein Modification in the Streptozotocin Model of Alzheimer's Disease. %A Dos Santos, João Paulo Almeida %A Vizuete, Adriana %A Hansen, Fernanda %A Biasibetti, Regina %A Gonçalves, Carlos-Alberto %K Alzheimer Disease %K Analysis of Variance %K Animals %K Antibiotics, Antineoplastic %K Brain %K Disease Models, Animal %K Glial Fibrillary Acidic Protein %K Glucose %K Glutathione %K Insulin Receptor Substrate Proteins %K Lactoylglutathione Lyase %K Male %K Maze Learning %K N-Acetylglucosaminyltransferases %K Rats %K Rats, Wistar %K S100 Calcium Binding Protein beta Subunit %K Streptozocin %K Time Factors %X

 O-GlcNAc transferase (OGT), an enzyme highly expressed in brain tissue, catalyzes the addition of N-acetyl-glucosamine (GlcNAc) to hydroxyl residues of serine and threonine of proteins. Brain protein O-GlcNAcylation is diminished in Alzheimer's disease (AD), and OGT targets include proteins of the insulin-signaling pathway (e.g., insulin receptor susbtrate-1, IRS-1). We hypothesized that ICV streptozotocin (STZ) also affects O-GlcNAc protein modification. We investigated hippocampal metabolic changes in Wistar rats, particularly OGT levels and insulin resistance, as well as related astroglial activities, immediately after ICV STZ administration (first week) and later on (fourth week). We found an early (at one week) and persistent (at fourth week) decrease in OGT in the ICV STZ model of AD, characterized by a spatial cognitive deficit. Consistent with this observation, we observed a decrease in protein O-GlnNAc modification at both times. Increased phosphorylation at serine-307 of IRS-1, which is related to insulin resistance, was observed on the fourth week. The decrease in OGT and consequent protein O-GlnNAc modifications appear to precede the decrease in glucose uptake and increment of the glyoxalase system observed in the hippocampus. Changes in glial fibrillary acidic protein and S100B in the hippocampus, as well as the alterations in cerebrospinal fluid S100B, confirm the astrogliosis. Moreover, decreases in glutamine synthetase and glutathione content suggest astroglial dysfunction, which are likely implicated in the neurodegenerative cascade triggered in this model. Together, these data contribute to the understanding of neurochemical changes in the ICV STZ model of sporadic AD, and may explain the decreases in protein O-GlcNAc levels and insulin resistance observed in AD.

%B J Alzheimers Dis %V 61 %P 237-249 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154269?dopt=Abstract %R 10.3233/JAD-170211 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early and Selective Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models. %A Lanzillotta, Chiara %A Tramutola, Antonella %A Meier, Shelby %A Schmitt, Frederick %A Barone, Eugenio %A Perluigi, Marzia %A Di Domenico, Fabio %A Abisambra, Jose F %X

Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. DS individuals have an increased risk of developing Alzheimer's disease (AD)-like pathology and dementia by the age of 40 due to the triplication of several genes involved in the formation of amyloid plaques and tau tangles. Further, DS and AD are characterized by the aberrant accumulation of unfolded/misfolded proteins resulting from over-burdened protein quality control systems. The accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR). Long-term activation of the UPR mediates neuronal dysfunction in AD. We hypothesized that the UPR is impacted in a mouse model of DS. To test this, we performed gene and protein expression analysis of ER stress markers in the Ts65Dn mouse model of DS at 3, 9, and 18 months. We identified activation of the PERK pathway in Ts65Dn DS mice at 3 months of age compared to euploid controls. We also determined that the early and overt UPR activation decreased with age, the UPR signal was significantly reduced by 18 months. Our data suggest that UPR activation in DS mouse models occurs early before consistent brain neurodegeneration and might be an essential contributor to dys-proteostasis.

%B J Alzheimers Dis %V 62 %P 347-359 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439332?dopt=Abstract %R 10.3233/JAD-170617 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early Candidate Urine Biomarkers for Detecting Alzheimer's Disease Before Amyloid-β Plaque Deposition in an APP (swe)/PSEN1dE9 Transgenic Mouse Model. %A Zhang, Fanshuang %A Wei, Jing %A Li, Xundou %A Ma, Chao %A Gao, Youhe %X

Alzheimer's disease (AD) is an incurable age-associated neurodegenerative disorder that is characterized by irreversible progressive cognitive deficits and extensive brain damage. The identification of candidate biomarkers before amyloid-β plaque deposition occurs is therefore of great importance for the early intervention of AD. Urine, which is not regulated by homeostatic mechanisms, theoretically accumulates changes associated with AD earlier than cerebrospinal fluid and blood. In this study, an APP (swe)/PSEN1dE9 transgenic mouse model was used to identify candidate biomarkers for early AD. Urine samples were collected from 4-, 6-, and 8-month-old transgenic mouse models, and the urinary proteomes were profiled using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The levels of 29 proteins differed significantly between wild type and 4-month-old mice, which had not started to accumulate amyloid-β plaques. Among these proteins, 13 have been associated with the mechanisms of AD, while 9 have been suggested as AD biomarkers. Our results indicated that urine proteins enable detection of AD before amyloid-β plaque deposition, which may present an opportunity for intervention.

%B J Alzheimers Dis %V 66 %P 613-637 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320578?dopt=Abstract %R 10.3233/JAD-180412 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early Detection of Alzheimer's Disease Based on the Patient's Creative Drawing Process: First Results with a Novel Neuropsychological Testing Method. %A Heymann, Petra %A Gienger, Regine %A Hett, Andreas %A Müller, Stephan %A Laske, Christoph %A Robens, Sibylle %A Ostermann, Thomas %A Elbing, Ulrich %X

Based on the knowledge of art therapy, we developed a new neuropsychological drawing test in order to identify individuals with mild cognitive impairment (MCI) as well as dementia patients and healthy controls (HC). By observing a variety of drawing characteristics of 92 participants with a mean age of 67.7, art therapy and dementia experts discriminate HC from MCI, early dementia of the Alzheimer-type (eDAT), and moderate dementia of the Alzheimer-type (mDAT) by the process analysis of tree drawings on a digitizing tablet. The art therapist's average categorical rating of healthy and MCI or demented individuals matched the clinical diagnosis by 88%. In a first small study, we analyzed interrater reliability, sensitivity, specificity, negative and positive predicted values of our tree drawing test (TDT) in comparison with the clock drawing test (CDT). Similar values of moderate interrater reliability were found for the TDT (0.56) as well as for the CDT (0.54). A significant high sensitivity of 0.9 within this binary impairment scale (HC versus impaired or demented) can be demonstrated. Substantial values for the specificity (0.67) could be obtained that however remain under a perfect value of the CDT (1.0). Considering 31 individuals that received the clinical diagnosis "impaired or demented" the TDT shows a higher recognition rate for the MCI group than the CDT. Furthermore in 8 of 12 borderline cases of clinical diagnosis, the outcome of the TDT diagnosis was consistent with the final clinical result.

%B J Alzheimers Dis %V 63 %P 675-687 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689720?dopt=Abstract %R 10.3233/JAD-170946 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early Emotional Attention is Impacted in Alzheimer's Disease: An Eye-Tracking Study. %A Bourgin, Jessica %A Guyader, Nathalie %A Chauvin, Alan %A Juphard, Alexandra %A Sauvée, Mathilde %A Moreaud, Olivier %A Silvert, Laetitia %A Hot, Pascal %X

Emotional deficits have been repetitively reported in Alzheimer's disease (AD) without clearly identifying how emotional processing is impaired in this pathology. This paper describes an investigation of early emotional processing, as measured by the effects of emotional visual stimuli on a saccadic task involving both pro (PS) and anti (AS) saccades. Sixteen patients with AD and 25 age-matched healthy controls were eye-tracked while they had to quickly move their gaze toward a positive, negative, or neutral image presented on a computer screen (in the PS condition) or away from the image (in the AS condition). The age-matched controls made more AS mistakes for negative stimuli than for other stimuli, and triggered PSs toward negative stimuli more quickly than toward other stimuli. In contrast, patients with AD showed no difference with regard to the emotional category in any of the tasks. The present study is the first to highlight a lack of early emotional attention in patients with AD. These results should be taken into account in the care provided to patients with AD, since this early impairment might seriously degrade their overall emotional functioning.

%B J Alzheimers Dis %V 63 %P 1445-1458 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782325?dopt=Abstract %R 10.3233/JAD-180170 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early Impairments of Hippocampal Neurogenesis in 5xFAD Mouse Model of Alzheimer's Disease Are Associated with Altered Expression of SOXB Transcription Factors. %A Zaletel, Ivan %A Schwirtlich, Marija %A Perović, Milka %A Jovanović, Mirna %A Stevanović, Milena %A Kanazir, Selma %A Puškaš, Nela %X

Dysregulation of neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus has been related to cognitive deficits and memory loss in neurodegenerative diseases, such as Alzheimer's disease (AD). Members of the B group of SOX transcription factors play critical roles in regulating neurogenesis in the embryonic and adult nervous system, including maintaining the multipotency, renewal, and cell fate decision of neural stem/progenitor cells. The aim of the present study was to evaluate the expression patterns of selected SOXB proteins in the SGZ, of 8-week-old male and female 5xFAD mice, which represent a transgenic model of AD with a severe and very early development of amyloid pathology. Immunohistochemical analysis showed a significant decrease in the number of cells expressing SOX1, SOX2, and SOX21 transcription factors within the SGZ of 5xFAD mice in comparison to their non-transgenic counterparts which coincidences with reduced number of doublecortin immunoreactive immature neurons found in Tg males. Despite observed changes in expressional pattern of examined SOXB proteins, the proliferative capacity evaluated by the number of Ki-67 immunoreactive cells remained unaffected in transgenic mice of both genders. Based on our results, we suggest that SOXB proteins might be considered as new biomarkers for the detection of early impairments in adult neurogenesis in different animal models or/and new targets in human regenerative medicine.

%B J Alzheimers Dis %V 65 %P 963-976 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103323?dopt=Abstract %R 10.3233/JAD-180277 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early Intervention with a Multi-Ingredient Dietary Supplement Improves Mood and Spatial Memory in a Triple Transgenic Mouse Model of Alzheimer's Disease. %A Hutton, Craig P %A Lemon, Jennifer A %A Sakic, Boris %A Rollo, C David %A Boreham, Douglas R %A Fahnestock, Margaret %A Wojtowicz, J Martin %A Becker, Suzanna %X

The increasing global burden of Alzheimer's disease (AD) and failure of conventional treatments to stop neurodegeneration necessitates an alternative approach. Evidence of inflammation, mitochondrial dysfunction, and oxidative stress prior to the accumulation of amyloid-β in the prodromal stage of AD (mild cognitive impairment; MCI) suggests that early interventions which counteract these features, such as dietary supplements, may ameliorate the onset of MCI-like behavioral symptoms. We administered a polyphenol-containing multiple ingredient dietary supplement (MDS), or vehicle, to both sexes of triple transgenic (3xTg-AD) mice and wildtype mice for 2 months from 2-4 months of age. We hypothesized that the MDS would preserve spatial learning, which is known to be impaired in untreated 3xTg-AD mice by 4 months of age. Behavioral phenotyping of animals was done at 1-2 and 3-4 months of age using a comprehensive battery of tests. As previously reported in males, both sexes of 3xTg-AD mice exhibited increased anxiety-like behavior at 1-2 months of age, prior to deficits in learning and memory, which did not appear until 3-4 months of age. The MDS did not reduce this anxiety or prevent impairments in novel object recognition (both sexes) or on the water maze probe trial (females only). Strikingly, the MDS specifically prevented 3xTg-AD mice (both sexes) from developing impairments (exhibited by untreated 3xTg-AD controls) in working memory and spatial learning. The MDS also increased sucrose preference, an indicator of hedonic tone. These data show that the MDS can prevent some, but not all, psychopathology in an AD model.

%B J Alzheimers Dis %V 64 %P 835-857 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914019?dopt=Abstract %R 10.3233/JAD-170921 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early Stage Alterations in CA1 Extracellular Region Proteins Indicate Dysregulation of IL6 and Iron Homeostasis in the 5XFAD Alzheimer's Disease Mouse Model. %A Gurel, Busra %A Cansev, Mehmet %A Sevinc, Cansu %A Kelestemur, Seda %A Ocalan, Busra %A Cakir, Aysen %A Aydin, Sami %A Kahveci, Nevzat %A Ozansoy, Mehmet %A Taskapilioglu, Ozlem %A Ulus, Ismail Hakki %A Başar, Merve Karayel %A Sahin, Betul %A Tuzuner, Mete Bora %A Baykal, Ahmet Tarik %K Alzheimer Disease %K Animals %K CA1 Region, Hippocampal %K Chromatography, Liquid %K Disease Models, Animal %K Female %K Homeostasis %K Interleukin-6 %K Iron %K Mice %K Mice, Transgenic %K Proteomics %K Tandem Mass Spectrometry %X

In recent years, an increasing number of research papers revealed that the compositional and volumetric alterations in the extracellular matrix are the consequences of aging and may be related to Alzheimer's disease (AD). In this study, we aimed to demonstrate the alterations in hippocampal extracellular fluid proteins in vivo using the 5XFAD mouse model. Samples were obtained from hippocampi of 5XFAD mice (n = 6) and their non-transgenic littermates by intracerebral push-pull perfusion technique at 3 months of age, representing the pre-pathological stage of the AD. Proteins in the hippocampal perfusates were analyzed by Ultra Performance Liquid Chromatography-Electrospray Ionization Quadrupole Time-of-Flight Mass Spectrometry (UPLC-ESI-qTOF-MS/MS). 178 proteins were identified and 19 proteins of them were found to be statistically significantly altered (p≤0.05, fold change ≥40%, unique peptide count ≥3) in the hippocampal CA1 extracellular fluid of the 5XFAD mouse model. Ingenuity pathway analysis of the protein expression results identified IL6 as an upstream regulator. The upregulation of IL6 was validated by immunohistochemical staining of the hippocampus and cortex of the 5XFAD mice prior to Aβ plaque formation. Furthermore, the iron level in the hippocampus was measured by inductively coupled plasma-mass spectrometry as IL6 is mentioned in several studies to take part in iron homeostasis and inflammation and found to be increased in 5XFAD mice hippocampus. Alterations in extracellular matrix proteins in addition to increasing amount of hippocampal IL6 and iron in the early stages of AD may reveal inflammation-mediated iron dyshomeostasis in the early stages of neurodegeneration.

%B J Alzheimers Dis %V 61 %P 1399-1410 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376847?dopt=Abstract %R 10.3233/JAD-170329 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early Tau Burden Correlates with Higher Rate of Atrophy in Transentorhinal Cortex. %A Xie, Long %A Das, Sandhitsu R %A Wisse, Laura E M %A Ittyerah, Ranjit %A Yushkevich, Paul A %A Wolk, David A %X

Neurofibrillary tangle (NFT) pathology is linked to neurodegeneration in the medial temporal lobe (MTL). Using a tailored pipeline, we correlated atrophy rate, as measured from retrospective longitudinal MRI, with NFT burden, measured from 18F-AV-1451 PET, within MTL regions of earliest NFT pathology. In amyloid-β positive but not amyloid-β negative individuals, we found significant correlation between 18F-AV-1451 uptake and atrophy rate that was strongest in the transentorhinal cortex, the first region with NFT pathology. This supports the role of NFTs in driving neurodegeneration and the utility of 18F-AV-1451 PET and structural measurement of transentorhinal cortex in tracking early tau-mediated disease progression.

%B J Alzheimers Dis %V 62 %P 85-92 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439350?dopt=Abstract %R 10.3233/JAD-170945 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Economic Burden, Mortality, and Institutionalization in Patients Newly Diagnosed with Alzheimer's Disease. %A Black, Christopher M %A Fillit, Howard %A Xie, Lin %A Hu, Xiaohan %A Kariburyo, M Furaha %A Ambegaonkar, Baishali M %A Baser, Onur %A Yuce, Huseyin %A Khandker, Rezaul K %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cohort Studies %K Comorbidity %K Cost of Illness %K Female %K Humans %K Institutionalization %K Male %K Neuropsychological Tests %X

BACKGROUND: Current information is scarce regarding comorbid conditions, treatment, survival, institutionalization, and health care utilization for Alzheimer's disease (AD) patients.

OBJECTIVES: Compare all-cause mortality, rate of institutionalization, and economic burden between treated and untreated newly-diagnosed AD patients.

METHODS: Patients aged 65-100 years with ≥1 primary or ≥2 secondary AD diagnoses (ICD-9-CM:331.0] with continuous medical and pharmacy benefits for ≥12 months pre-index and ≥6 months post-index date (first AD diagnosis date) were identified from Medicare fee-for-service claims 01JAN2011-30JUN2014. Patients with AD treatment claims or AD/AD-related dementia diagnosis during the pre-index period were excluded. Patients were assigned to treated and untreated cohorts based on AD treatment received post-index date. Total 8,995 newly-diagnosed AD patients were identified; 4,037 (44.8%) were assigned to the treated cohort. Time-to-death and institutionalization were assessed using Cox regression. To compare health care costs and utilizations, 1 : 1 propensity score matching (PSM) was used.

RESULTS: Untreated patients were older (83.85 versus 81.44 years; p < 0.0001), with more severe comorbidities (mean Charlson comorbidity index: 3.54 versus 3.22; p < 0.0001). After covariate adjustment, treated patients were less likely to die (hazard ratio[HR] = 0.69; p < 0.0001) and were associated with 20% lower risk of institutionalization (HR = 0.801; p = 0.0003). After PSM, treated AD patients were less likely to have hospice visits (3.25% versus 9.45%; p < 0.0001), and incurred lower annual all-cause costs ($25,828 versus $30,110; p = 0.0162).

CONCLUSION: After controlling for comorbidities, treated AD patients have better survival, lower institutionalization, and sometimes fewer resource utilizations, suggesting that treatment and improved care management could be beneficial for newly-diagnosed AD patients from economic and clinical perspectives.

%B J Alzheimers Dis %V 61 %P 185-193 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103033?dopt=Abstract %R 10.3233/JAD-170518 %0 Journal Article %J J Alzheimers Dis %D 2018 %T EEG Theta Power Is an Early Marker of Cognitive Decline in Dementia due to Alzheimer's Disease. %A Musaeus, Christian Sandøe %A Engedal, Knut %A Høgh, Peter %A Jelic, Vesna %A Mørup, Morten %A Naik, Mala %A Oeksengaard, Anne-Rita %A Snaedal, Jon %A Wahlund, Lars-Olof %A Waldemar, Gunhild %A Andersen, Birgitte Bo %X

BACKGROUND: Quantitative EEG (qEEG) power could potentially be used as a diagnostic tool for Alzheimer's disease (AD) and may further our understanding of the pathophysiology. However, the early qEEG power changes of AD are not well understood.

OBJECTIVE: To investigate the early changes in qEEG power and the possible correlation with memory function and cerebrospinal fluid biomarkers. In addition, whether qEEG power could discriminate between AD, mild cognitive impairment (MCI), and older healthy controls (HC) at the individual level.

METHODS: Standard EEGs from 138 HC, 117 MCI, and 117 AD patients were included from six Nordic memory clinics. All EEGs were recorded consecutively before the diagnosis and were not used for the consensus diagnosis. Absolute and relative power was calculated for both eyes closed and open condition.

RESULTS: At group level using relative power, we found significant increases globally in the theta band and decreases in high frequency power in the temporal regions for eyes closed for AD and, to a lesser extent, for MCI compared to HC. Relative theta power was significantly correlated with multiple neuropsychological measures and had the largest correlation coefficient with total tau. At the individual level, the classification rate for AD and HC was 72.9% for relative power with eyes closed.

CONCLUSION: Our findings suggest that the increase in relative theta power may be the first change in patients with dementia due to AD. At the individual level, we found a moderate classification rate for AD and HC when using EEGs alone.

%B J Alzheimers Dis %V 64 %P 1359-1371 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29991135?dopt=Abstract %R 10.3233/JAD-180300 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Effect of Chronic Cerebral Hypoperfusion on Amyloid-β Metabolism in a Transgenic Mouse Model of Alzheimer's Disease (PS1V97L). %A Yang, Heyun %A Hou, Tingting %A Wang, Wei %A Luo, Yumin %A Yan, Feng %A Jia, Jianping %X

Alzheimer's disease (AD) and cerebrovascular disease often coexist. However, it is difficult to determine how chronic cerebral hypoperfusion affects the metabolism of amyloid-β peptides (Aβ) in a living patient with AD. Thus, we developed an animal model of this condition, using transgenic mice (PS1V97L) and right common carotid artery ligation to create chronic cerebral hypoperfusion. The metabolic processes associated with amyloid-β peptide (Aβ) were observed and evaluated in this PS1V97L plus hypoperfusion model. Compared with control mice, the model revealed significantly upregulated expression of Aβ (including Aβ oligomers), with decreased α-secretase activity and expression and increased β-secretase activity and expression. Furthermore, the model revealed increased mRNA and protein expression of the receptor for advanced glycation end products (RAGE) and decreased mRNA and protein expression of low-density lipoprotein receptor-related protein 1 (LRP-1); both these are Aβ transporters. Moreover, the model revealed decreased activity and expression of neprilysin, which is a peripheral Aβ degrading enzyme. These findings suggest that hypoperfusion may magnify the effect of AD on Aβ metabolism by aggravating its abnormal production, transport, and clearance.

%B J Alzheimers Dis %V 62 %P 1609-1621 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614686?dopt=Abstract %R 10.3233/JAD-171094 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effect of Cilostazol on Incident Dementia in Elderly Men and Women with Ischemic Heart Disease. %A Kim, Mi-Young %A Noh, Yoojin %A Son, Sang Joon %A Shin, Sooyoung %A Paik, Hee-Young %A Lee, Sukhyang %A Jung, Yi-Sook %X

BACKGROUND: Ischemic heart disease (IHD) is associated with cognitive decline and may contribute to an increased risk of dementia.

OBJECTIVE: The goal of the present study was to investigate whether cilostazol use is associated with a lower risk of incident dementia in Asian patients with IHD, and whether these effects differed based on sex.

METHODS: This retrospective cohort study was performed using the Korean National Insurance Claim Data of the Health Insurance Review and Assessment Service; the duration of the study was from January 1, 2007 to December 31, 2015. The study group comprised 66,225 patients with IHD, aged >65 years, who had received cilostazol. Age- and sex-matched IHD patients without cilostazol exposure were selected as the control group. The risk of dementia was compared between the cilostazol and control groups.

RESULTS: Compared to the control group, total cilostazol users had a marginally significant lower risk of incident dementia. After stratification by sex, the reducing effect of cilostazol on incident dementia was significant in female participants, but not in male participants. Female patients who had cilostazol for over 2 years showed a clinically meaningful preventive effect (HR, 0.85; 95% CI, 0.82-0.88).

CONCLUSIONS: This study suggested that cilostazol treatment may reduce the risk of incident dementia in Korean patients with IHD. Its beneficial effect was remarkably significant in female patients who received cilostazol for over a 2-year period.

%B J Alzheimers Dis %V 63 %P 635-644 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660935?dopt=Abstract %R 10.3233/JAD-170895 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effect of Education on Alzheimer's Disease-Related Neuroimaging Biomarkers in Healthy Controls, and Participants with Mild Cognitive Impairment and Alzheimer's Disease: A Cross-Sectional Study. %A Wada, Masataka %A Noda, Yoshihiro %A Shinagawa, Shunichiro %A Chung, Jun Ku %A Sawada, Kyosuke %A Ogyu, Kamiyu %A Tarumi, Ryosuke %A Tsugawa, Sakiko %A Miyazaki, Takahiro %A Yamagata, Bun %A Graff-Guerrero, Ariel %A Mimura, Masaru %A Nakajima, Shinichiro %X

BACKGROUND: Cognitive reserve is the acquired capacity reflecting a functional brain adaptability/flexibility in the context of aging. Educational attainment is thought to be among the most important factors that contribute to cognitive reserve.

OBJECTIVE: The aim of this study is to investigate the relationships among duration of education and Alzheimer's disease (AD) related neuroimaging biomarkers such as amyloid-β deposition, glucose metabolism, and brain volumes in each stage of AD.

METHODS: We reanalyzed a part of the datasets of the Alzheimer's Disease Neuroimaging Initiative. Participants were between 55 and 90 years of age and diagnosed as one of the following: healthy controls (HC), mild cognitive impairment (MCI), or AD. Multiple regression analyses were conducted to examine the relationships among duration of education and amyloid-β deposition (n = 825), brain metabolism (n = 1,304), and brain volumes (n = 1,606) among three groups using data for 18F-Florbetapir (AV-45) imaging, fludeoxyglucose (FDG) positron emission tomography, and T1-weighted magnetic resonance imaging.

RESULTS: Duration of education had no correlations with amyloid-β deposition or brain metabolism in any groups. However, duration of education was positively associated with the total brain volume only in participants with MCI.

CONCLUSIONS: Our findings suggest that education may exert a protective effect on total brain volume in the MCI stage but not in HC or AD. Thus, education may play an important role in preventing the onset of dementia through brain reserve in MCI.

%B J Alzheimers Dis %V 63 %P 861-869 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689728?dopt=Abstract %R 10.3233/JAD-171168 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effect of Fluvoxamine on Amyloid-β Peptide Generation and Memory. %A Kim, Woojin Scott %A Fu, YuHong %A Dobson-Stone, Carol %A Hsiao, Jen-Hsiang T %A Shang, Kani %A Hallupp, Marianne %A Schofield, Peter R %A Garner, Brett %A Karl, Tim %A Kwok, John B J %X

Alzheimer's disease is characterized by abnormal amyloid-β (Aβ) peptide accumulation beginning decades before symptom onset. An effective prophylactic treatment aimed at arresting the amyloidogenic pathway would therefore need to be initiated prior to the occurrence of Aβ pathology. The SIGMAR1 gene encodes a molecular chaperone that modulates processing of the amyloid-β protein precursor (AβPP). Fluvoxamine is a selective serotonin reuptake inhibitor and a potent SIGMAR1 agonist. We therefore hypothesized that fluvoxamine treatment would reduce Aβ production and improve cognition. We firstly investigated the impact of SIGMAR1 on AβPP processing, and found that overexpression and knockdown of SIGMAR1 significantly affected γ-secretase activity in SK-N-MC neuronal cells. We then tested the impact of fluvoxamine on Aβ production in an amyloidogenic cell model, and found that fluvoxamine significantly reduced Aβ production by inhibiting γ-secretase activity. Finally, we assessed the efficacy of long-term treatment (i.e., ∼8 months) of 10 mg/kg/day fluvoxamine in the J20 amyloidogenic mouse model; the treatment was initiated prior to the occurrence of predicted Aβ pathology. Physical examination of the animals revealed no overt pathology or change in weight. We conducted a series of behavioral tests to assess learning and memory, and found that the fluvoxamine treatment significantly improved memory function as measured by novel object recognition task. Two other tests revealed no significant change in memory function. In conclusion, fluvoxamine has a clear impact on γ-secretase activity and AβPP processing to generate Aβ, and may have a protective effect on cognition in the J20 mice.

%B J Alzheimers Dis %V 62 %P 1777-1787 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614681?dopt=Abstract %R 10.3233/JAD-171001 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effect of Physical Activity on the Progression of Alzheimer's Disease: The Clinical Research Center for Dementia of South Korea Study. %A Minn, Yang-Ki %A Choi, Seong Hye %A Suh, Young Ju %A Jeong, Jee Hyang %A Kim, Eun-Joo %A Kim, Jong Hun %A Park, Kyung Won %A Park, Moon Ho %A Youn, Young Chul %A Yoon, Bora %A Choi, Seok-Jin %A Oh, Youn Kyung %A Yoon, Soo Jin %X

BACKGROUND: There is a lack of research on the effects of physical activity (PA) on the progression of Alzheimer's disease (AD).

OBJECTIVES: We investigated whether PA is associated with progression of dementia and mortality in AD.

METHODS: In the present study, 934 patients with mild-to-moderate AD were included. PA was evaluated using a questionnaire written by the caregiver. The outcome measures were the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Seoul-Instrumental Activities of Daily Living (S-IADL), Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI), a global composite score of neuropsychological subtests, and mortality. They were evaluated annually and received a maximum of three follow-up examinations.

RESULTS: Between-group differences compared with the no PA group in the change of CDR-SB scores were -0.431 (95% CI = -0.824∼-0.039; p = 0.031) for the moderate PA group (150-750 minutes per week of moderate intensity PA), and -1.148 (-1.656∼-0.639; p < 0.001) for the high PA group (>750 minutes per week). As PA increased, there was a significant trend to slow the rate of increase in the CDR-SB, S-IADL, and CGA-NPI scores. The patients with ≥150 minutes per week for each of non-recreational and recreational PAs had a lower risk of mortality compared to those with <150 minutes per week for each of the PAs (hazard ratio 0.22, 95% CI = 0.05∼0.88; p = 0.033).

CONCLUSION: More PA is associated with slower progression of dementia severity, functional decline, and abnormal behavior, and with a lower risk of mortality in AD.

%B J Alzheimers Dis %V 66 %P 249-261 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282355?dopt=Abstract %R 10.3233/JAD-180333 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effectiveness of a Personalized Brain-Computer Interface System for Cognitive Training in Healthy Elderly: A Randomized Controlled Trial. %A Yeo, Si Ning %A Lee, Tih Shih %A Sng, Wei Theng %A Heo, Min Quan %A Bautista, Dianne %A Cheung, Yin Bun %A Zhang, Hai Hong %A Wang, Chuanchu %A Chin, Zheng Yang %A Feng, Lei %A Zhou, Juan %A Chong, Mei Sian %A Ng, Tze Pin %A Krishnan, K Ranga %A Guan, Cuntai %X

BACKGROUND: Cognitive training has been demonstrated to improve cognitive performance in older adults. To date, no study has explored personalized training that targets the brain activity of each individual.

OBJECTIVE: This is the first large-scale trial that examines the usefulness of personalized neurofeedback cognitive training.

METHODS: We conducted a randomized-controlled trial with participants who were 60-80 years old, with Clinical Dementia Rating (CDR) score of 0-0.5, Mini-Mental State Examination (MMSE) score of 24 and above, and with no neuropsychiatric diagnosis. Participants were randomly assigned to the Intervention or Waitlist-Control group. The training system, BRAINMEM, has attention, working memory, and delayed recall game components. The intervention schedule comprised 24 sessions over eight weeks and three monthly booster sessions. The primary outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score after the 24-session training.

RESULTS: There were no significant between-subjects differences in overall cognitive performance post-intervention. However, a sex moderation effect (p = 0.014) was present. Men in the intervention group performed better than those in the waitlist group (mean difference, +4.03 (95% CI 0.1 to 8.0), p = 0.046. Among females, however, both waitlist-control and intervention participants improved from baseline, although the between-group difference in improvement did not reach significance. BRAINMEM also received positive appraisal and intervention adherence from the participants.

CONCLUSION: A personalized neurofeedback intervention is potentially feasible for use in cognitive training for older males. The sex moderation effect warrants further investigation and highlights the importance of taking sex into account during cognitive training.

%B J Alzheimers Dis %V 66 %P 127-138 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30248056?dopt=Abstract %R 10.3233/JAD-180450 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effectiveness of Anti-Dementia Drugs in Extremely Severe Alzheimer's Disease: A 12-Week, Multicenter, Randomized, Single-Blind Study. %A Hong, Yun Jeong %A Choi, Seong Hye %A Jeong, Jee Hyang %A Park, Kyung Won %A Na, Hae Ri %X

BACKGROUND/OBJECTIVE: There is insufficient evidence to guide decisions concerning how long anti-dementia drug (ADD) regimens should be maintained in severe Alzheimer's disease (AD). We investigated whether patients with extremely severe AD who were already receiving donepezil or memantine benefited from continuing treatment.

METHODS: In this randomized and rater-blinded trial, 65 AD patients with a Mini-Mental State Examination score from 0 to 5 and a score of 6c or worse on Functional Assessment Staging were randomly assigned to an ADD-continuation group (N = 30) or an ADD-discontinuation group (N = 35). The current use of donepezil or memantine was maintained for 12 weeks in the ADD-continuation group and was discontinued after baseline in the ADD-discontinuation group. Efficacy measures were obtained at baseline and 12 weeks. The primary efficacy variable was the change from baseline to the end of the study in Baylor Profound Mental State Examination (BPMSE) scores.

RESULTS: The change in the BPMSE from baseline to the end of the study in the ADD-continuation group (a 0.4-point improvement) was not equivalent to that in the ADD-discontinuation group (a 0.5-point decline), as determined by two one-sided tests of equivalence. Study withdrawals due to adverse events (11.4% versus 6.7%) were more frequent in the ADD-discontinuation group than in the ADD-continuation group.

CONCLUSION: Continued treatment with donepezil or memantine seems unequal and might be superior to withdrawal of the drugs in terms of the effects on global cognition in patients with extremely severe AD. Current Controlled Trials number: KCT0000874 (CRIS).

%B J Alzheimers Dis %V 63 %P 1035-1044 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710726?dopt=Abstract %R 10.3233/JAD-180159 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Effectiveness of Psychosocial and Behavioral Interventions for Informal Dementia Caregivers: Meta-Analyses and Meta-Regressions. %A Jütten, Linda Helena %A Mark, Ruth Elaine %A Wicherts, Jelte Michiel %A Sitskoorn, Margriet Maria %X

BACKGROUND: Many psychosocial and behavioral interventions have been developed for informal dementia caregivers. Because existing meta-analyses only focused on a limited number of interventions and outcomes, how effective these interventions are overall and which interventions components are associated with larger effects has yet to be explored.

OBJECTIVE: To provide a comprehensive meta-analysis of the effectiveness of psychosocial and behavioral interventions on burden, depression, anxiety, quality of life, stress, and sense of competence in informal dementia caregivers. In addition, we examined if interventions which utilized more sessions and/or were delivered personally (face-to-face) had larger effect sizes. In exploratory meta-regressions, we examined seven additional moderators.

METHODS: The protocol was registered with PROSPERO, number CRD42017062555. We systematically searched the literature to identify controlled trials assessing the effect of psychosocial and behavioral interventions on the six outcome measures, for informal dementia caregivers. We performed six random effects meta-analyses, to assess the pooled effect sizes of the interventions. In addition, we performed separate meta-regressions, for each outcome, for each moderator.

RESULTS: The sample consisted of 60 studies. For all outcomes except anxiety, the pooled effects were small and in favor of the intervention group. No moderator was found to systematically predict these effects. There were no indications for publication bias or selection bias based on significance.

CONCLUSION: Overall, the interventions yield significant (small) effects, independent of intervention characteristics. Future research should explore options to enhance the effectiveness of interventions aimed at assisting informal caregivers.

%B J Alzheimers Dis %V 66 %P 149-172 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30248057?dopt=Abstract %R 10.3233/JAD-180508 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Effects and Meanings of Receiving a Diagnosis of Mild Cognitive Impairment or Alzheimer's Disease When One Lives Alone. %A Portacolone, Elena %A Johnson, Julene K %A Covinsky, Kenneth E %A Halpern, Jodi %A Rubinstein, Robert L %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Emotions %K Female %K Health Services %K Humans %K Interviews as Topic %K Male %K Residence Characteristics %K Single Person %X

BACKGROUND: One third of older adults with cognitive impairment live alone and are at high risk for poor health outcomes. Little is known about how older adults who live alone experience the process of receiving a diagnosis of mild cognitive impairment (MCI) or Alzheimer's disease (AD).

OBJECTIVE: The aim of this study was to understand the effects and meanings of receiving a diagnosis of MCI or AD on the lived experience of older adults living alone.

METHODS: This is a qualitative study of adults age 65 and over living alone with cognitive impairment. Participants' lived experiences were elicited through ethnographic interviews and participant observation in their homes. Using a qualitative content analysis approach, interview transcripts and fieldnotes were analyzed to identify codes and themes.

RESULTS: Twenty-nine older adults and 6 members of their social circles completed 114 ethnographic interviews. Core themes included: relief, distress, ambiguous recollections, and not knowing what to do. Participants sometimes felt uplifted and relieved by the diagnostic process. Some participants did not mention having received a diagnosis or had only partial recollections about it. Participants reported that, as time passed, they did not know what to do with regard to the treatment of their condition. Sometimes they also did not know how to prepare for a likely worsening of their condition, which they would experience while living alone.

CONCLUSION: Findings suggest the need for more tailored care and follow-up as soon as MCI or AD is diagnosed in persons living alone.

%B J Alzheimers Dis %V 61 %P 1517-1529 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376864?dopt=Abstract %R 10.3233/JAD-170723 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effects of a 3-Year Multi-Domain Intervention with or without Omega-3 Supplementation on Cognitive Functions in Older Subjects with Increased CAIDE Dementia Scores. %A Chhetri, Jagadish K %A de Souto Barreto, Philipe %A Cantet, Christelle %A Pothier, Kristell %A Cesari, Matteo %A Andrieu, Sandrine %A Coley, Nicola %A Vellas, Bruno %X

Findings from recent Alzheimer's disease prevention trials have shown subjects with increased dementia score based upon mid-life cardiovascular risk factors, to benefit from multi-domain intervention strategies to some extent. The effects of such interventions on cognitive functions remains yet to be well-established. This study is a secondary analysis of the MAPT study, 1,293 older subjects (mean age 75 years) with high CAIDE score (i.e., ≥6) were classified according to the four intervention groups: 1) multi-domain intervention plus placebo, 2) isolated supplementation with Omega-3 polyunsaturated fatty acid (n-3 PUFA), 3) combination of the two interventions, and 4) placebo alone. Linear mixed-model repeated-measures analyses were used to assess the cognitive changes according to various neuropsychological test scores between intervention groups compared to the placebo at 36 months from baseline. Compared to the placebo, group with multi-domain intervention in combination withn-3PUFA was found to show significant improvement in the delayed total recall test of the free and cued selective reminding test (FCSRT) (mean±standard error(SE) = 0.20±0.10) and MMSE orientation test (mean±SE = 0.15±0.06) at 36 months. Isolated multi-domain intervention group showed significant less decline in the MMSE orientation test (mean±SE = 0.12±0.06) compared to the placebo. There was significant less improvement (mean±SE = - 1.01±0.46) in the FCSRT free recall test in the n-3 PUFA intervention group compared to the placebo at 36 months. Our findings show high-risk subjects for dementia screened with CAIDE dementia score might benefit from multi-domain intervention strategies as in the MAPT study, particularly in the orientation and delayed recall domain.

%B J Alzheimers Dis %V 64 %P 71-78 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865075?dopt=Abstract %R 10.3233/JAD-180209 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effects of Composite Supplement Containing Astaxanthin and Sesamin on Cognitive Functions in People with Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled Trial. %A Ito, Naoki %A Saito, Hitomi %A Seki, Shinobu %A Ueda, Fumitaka %A Asada, Takashi %X

BACKGROUND: Dementia and its first or transitional stage, mild cognitive impairment (MCI), is a major concern for the aging Japanese society. Thus, the use of dietary supplements to improve or maintain cognitive function has become a topic of public interest.

OBJECTIVE: In this study, we evaluated the effects of a composite supplement containing food-derived antioxidants, specifically astaxanthin and sesamin (AS), on cognitive function in people with MCI.

METHOD: Twenty-one healthy participants with MCI were recruited in our double-blind placebo-controlled pilot study. They were assigned to either an AS group, who received ingestible capsules containing AS, or a placebo group, who received identical placebo capsules. To assess cognitive functions, we performed the Japanese version of the Central Nervous System Vital Signs (CNSVS) test and the Alzheimer's Disease Assessment Scale-Cog test at baseline, after 6 weeks, and after 12 weeks of dietary supplementation.

RESULTS: The CNSVS test revealed significant improvements in psychomotor speed and processing speed in the AS group compared with the placebo group, suggesting that the daily supplementation of AS improved cognitive functions related to the ability to comprehend, and perform complex tasks quickly and accurately.

CONCLUSION: Our results provide support for the use of AS as a dietary supplementation for improving cognitive functions.

%B J Alzheimers Dis %V 62 %P 1767-1775 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614679?dopt=Abstract %R 10.3233/JAD-170969 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effects of Exergaming in People with Dementia: Results of a Systematic Literature Review. %A van Santen, Joeke %A Dröes, Rose-Marie %A Holstege, Marije %A Henkemans, Olivier Blanson %A van Rijn, Annelies %A de Vries, Ralph %A van Straten, Annemieke %A Meiland, Franka %X

BACKGROUND: Physical exercise benefits functioning, health, and well-being. However, people living with dementia in particular hardly engage in exercise. Exergaming (exercise and gaming) is an innovative, fun, and relatively safe way of exercising in a virtual reality or gaming environment. It may help people living with dementia overcome barriers they can experience regarding regular exercise activities.

OBJECTIVE: This systematic literature review aims to provide an overview of the cost-effectiveness of exergaming and its effects on physical, cognitive, emotional, and social functioning, as well as the quality of life in people living with dementia.

METHODS: PubMed, Embase, Cinahl, PsycINFO, the Cochrane Library, and the Web of Science Core Collection were searched. Selection of studies was carried out by at least two independent researchers.

RESULTS: Three studies were found to be eligible and were included in this review. Two of these showed some statistically significant effects of exergaming on physical, cognitive, and emotional functioning in people living with dementia, although based on a very small sample. No articles were found about the cost-effectiveness of exergaming.

CONCLUSIONS: Only a few controlled studies have been conducted into the effectiveness of exergaming, and these show very little significant benefits. More well-designed studies are necessary to examine the effects of exergaming.

%B J Alzheimers Dis %V 63 %P 741-760 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689716?dopt=Abstract %R 10.3233/JAD-170667 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effects of Gender and Other Confounding Factors on Leptin Concentrations in Alzheimer's Disease: Evidence from the Combined Analysis of 27 Case-Control Studies. %A Zhou, Futao %A Chen, Shuangrong %X

Leptin, as a link between fat mass and the brain, has been reported to be associated with gender. The gender differences in leptin levels between Alzheimer's disease (AD) and healthy elderly controls are inconclusive so far. To quantitatively summarize the leptin data available from female and male patients with AD, we searched PubMed and EMBASE for articles published from inception to July 20, 2017. Data were extracted from 27 studies, consisting of 3,014 participants. The pooled results showed that the overall leptin levels were lower in AD (Hedges' g = -0.481; p = 0.002) than in controls, and the leptin levels in whole blood and serum were decreased with moderate and large effect sizes (g = -0.677, -0.839; respectively; both of p-values <0.001) in AD compared with controls. In blood, there were significantly lower concentrations of leptin in female AD than in female controls (g = -0.590; p = 0.014), but not in male case-control group (g = -0.666; p = 0.067). Meta-regression analysis demonstrated that the decreased extent of leptin levels in AD paralleled the degree of the severity of dementia symptoms, as well as the alterations of body mass index (p-values ≤0.002). The findings provide strong evidence that 1) the blood concentrations of leptin are lower in female AD patients than in female controls; and 2) the greater the severity of dementia symptoms, the greater the decreases in the blood leptin levels. But more future investigations on the blood leptin levels in male AD patients is warranted.

%B J Alzheimers Dis %V 62 %P 477-486 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439354?dopt=Abstract %R 10.3233/JAD-170983 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effects of Meditation and Music-Listening on Blood Biomarkers of Cellular Aging and Alzheimer's Disease in Adults with Subjective Cognitive Decline: An Exploratory Randomized Clinical Trial. %A Innes, Kim E %A Selfe, Terry Kit %A Brundage, Kathleen %A Montgomery, Caitlin %A Wen, Sijin %A Kandati, Sahiti %A Bowles, Hannah %A Khalsa, Dharma Singh %A Huysmans, Zenzi %X

BACKGROUND: Telomere length (TL), telomerase activity (TA), and plasma amyloid-β (Aβ) levels have emerged as possible predictors of cognitive decline and dementia.

OBJECTIVE: To assess the: 1) effects of two 12-week relaxation programs on TL, TA, and Aβ levels in adults with subjective cognitive decline; and 2) relationship of biomarker changes to those in cognitive function, psychosocial status, and quality of life (QOL).

METHODS: Participants were randomized to a 12-week Kirtan Kriya meditation (KK) or music listening (ML) program and asked to practice 12 minutes/day. Plasma Aβ(38/40/42) and peripheral blood mononuclear cell TL and TA were measured at baseline and 3 months. Cognition, stress, sleep, mood, and QOL were assessed at baseline, 3 months, and 6 months.

RESULTS: Baseline blood samples were available for 53 participants (25 KK, 28 ML). The KK group showed significantly greater increases in Aβ40 than the ML group. TA rose in both groups, although increases were significant only among those with higher practice adherence and lower baseline TA. Changes in both TL and TA varied by their baseline values, with greater increases among participants with values ≤50th percentile (ps-interaction <0.006). Both groups improved in cognitive and psychosocial status (ps ≤0.05), with improvements in stress, mood, and QOL greater in the KK group. Rising Aβ levels were correlated with gains in cognitive function, mood, sleep, and QOL at both 3 and 6 months, associations that were particularly pronounced in the KK group. Increases in TL and TA were also correlated with improvements in certain cognitive and psychosocial measures.

CONCLUSION: Practice of simple mind-body therapies may alter plasma Aβ levels, TL, and TA. Biomarker increases were associated with improvements in cognitive function, sleep, mood, and QOL, suggesting potential functional relationships.

%B J Alzheimers Dis %V 66 %P 947-970 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320574?dopt=Abstract %R 10.3233/JAD-180164 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Effects of Music Therapy on Cognition, Psychiatric Symptoms, and Activities of Daily Living in Patients with Alzheimer's Disease. %A Lyu, Jihui %A Zhang, Jingnan %A Mu, Haiyan %A Li, Wenjie %A Champ, Mei %A Xiong, Qian %A Gao, Tian %A Xie, Lijuan %A Jin, Weiye %A Yang, Wan %A Cui, Mengnan %A Gao, Maolong %A Li, Mo %X

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, affecting millions of older people worldwide. However, pharmacological therapies have not achieved desirable clinical efficacy in the past decades. Non-pharmacological therapies have been receiving increased attention to treat dementia in recent years.

OBJECTIVE: This study explores the effects of music therapy on cognitive function and mental wellbeing of patients with AD.

METHODS: A total number of 298 AD patients with mild, moderate, or severe dementia participated in the study. The participants with each grade of severity were randomly divided into three groups, which were a singing group, a lyric reading group, and a control group. These three groups received different interventions for three months. All participants underwent a series of tests on cognitive functions, neuropsychological symptoms, and activities of daily living at baseline, three months, and six months.

RESULTS: The analysis shows that music therapy is more effective for improving verbal fluency and for alleviating the psychiatric symptoms and caregiver distress than lyrics reading in patients with AD. Stratified analysis shows that music therapy is effective for enhancing memory and language ability in patients with mild AD and reducing the psychiatric symptoms and caregiver distress in patients with moderate or severe AD. However, no significant effect was found for activities of daily living in patients with mild, moderate, or severe AD.

CONCLUSION: This study suggests that music therapy is effective in enhancing cognitive function and mental wellbeing and can be recommended as an alternative approach to manage AD associated symptoms.

%B J Alzheimers Dis %V 64 %P 1347-1358 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29991131?dopt=Abstract %R 10.3233/JAD-180183 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effects of Physical Exercise on Alzheimer's Disease Biomarkers: A Systematic Review of Intervention Studies. %A Frederiksen, Kristian Steen %A Gjerum, Le %A Waldemar, Gunhild %A Hasselbalch, Steen Gregers %K Alzheimer Disease %K Biomarkers %K Exercise %K Hippocampus %K Humans %K Outcome Assessment (Health Care) %K Physical Therapy Modalities %X

Physical exercise may be an important adjunct to pharmacological treatment of Alzheimer's disease (AD). Animal studies indicate that exercise may be disease modifying through several mechanisms including reduction of AD pathology. We carried out a systematic review of intervention studies of physical exercise with hippocampal volume (on MRI), amyloid-β, total tau, phosphorylated tau in cerebrospinal fluid (CSF), 18F-FDG-PET or amyloid PET as outcome measures in healthy subjects, patients with subjective memory complaints, mild cognitive impairment, or AD. We identified a total of 8 studies of which 6 investigated the effects of exercise on hippocampal volume in healthy subjects and 1 on CSF biomarkers and 1 on hippocampal volume in AD, and none investigating the remaining outcome measures or patient groups. Methodological quality of identified studies was generally low. One study found a detrimental effect on hippocampal volume and one found a positive effect, whereas the remaining studies did not find an effect of exercise on outcome measures. The present systematic study identified a relatively small number of studies, which did not support an effect of exercise on hippocampal volume. Methodological issues such small to moderate sample sizes and inadequate ramdomization procedures further limits conclusions. Our findings highlight the difficulties in conducting high quality studies of exercise and further studies are needed before definite conclusions may be reached.

%B J Alzheimers Dis %V 61 %P 359-372 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154278?dopt=Abstract %R 10.3233/JAD-170567 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Efficacy, Acceptability, and Safety of Intravenous Immunoglobulin Administration for Mild-To-Moderate Alzheimer's Disease: A Systematic Review and Meta-Analysis. %A Okuya, Makoto %A Matsunaga, Shinji %A Ikuta, Toshikazu %A Kishi, Taro %A Iwata, Nakao %X

A systematic review and meta-analysis of the efficacy/safety of intravenous immunoglobulin (IVIG) administration in mild-to-moderate Alzheimer's disease (AD) patients was performed. Six randomized double-blind, placebo-controlled trials (n = 801) were included in this study. No significant difference in cognitive function was observed between the groups. Moreover, IVIG was inferior to placebo in behavioral disturbances (mean difference = 2.19). Further, IVIG administration was associated with a higher incidence of rash than placebo. Our results do not support IVIG administration for mild-to-moderate AD, suggesting that IVIG is not effective to treat mild-to-moderate AD and that it deteriorates behavioral and psychological symptoms of dementia in mild-to-moderate AD.

%B J Alzheimers Dis %V 66 %P 1379-1387 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30452419?dopt=Abstract %R 10.3233/JAD-180888 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Elevation of Plasma Amyloid-β Level is More Significant in Early Stage of Cognitive Impairment: A Population-Based Cross-Sectional Study. %A Wang, Jin %A Qiao, Fan %A Shang, Suhang %A Li, Pei %A Chen, Chen %A Dang, Liangjun %A Jiang, Yu %A Huo, Kang %A Deng, Meiying %A Wang, Jingyi %A Qu, Qiumin %X

BACKGROUND: Aggregation and deposition of amyloid-β (Aβ) in the brain is the main pathological change of Alzheimer's disease (AD). Decreased Aβ42 in the cerebrospinal fluid has been confirmed as a biomarker of AD; however, the relationship between plasma Aβ and cognitive impairment is currently unclear.

OBJECTIVE: The aim was to explore the relationship between plasma Aβ and cognitive impairment in a cross-sectional study.

METHODS: A total of 1,314 subjects (age above 40) from a village in the suburbs of Xi'an, China were enrolled between October 8, 2014 and March 30, 2015. A validated Chinese version of the Mini-Mental State Examination and neuropsychological battery were used to assess cognition. Levels of plasma Aβ42 and Aβ40 were tested using commercial enzyme-linked immunosorbent assay. Relationship of plasma Aβ and cognitive impairment was analyzed using logistic regression analysis.

RESULTS: Of the enrolled subjects, 1,180 (89.80%) had normal cognition, 85 (6.47%) had possible cognitive impairment and 49 (3.73%) had probable cognitive impairment. Logistic regression analysis showed that the Aβ42/Aβ40 ratio (OR = 4.042, 95% CI: 1.248-11.098, p = 0.012) and plasma Aβ42 (OR = 1.036, 95% CI: 1.003-1.071, p = 0.031) was higher in the possible cognitive impairment than that in the normal cognition group. Furthermore, the plasma Aβ42/Aβ40 ratio was higher in the possible cognitive impairment group than that in the probable cognitive impairment group (OR = 0.029, 95% CI: 0.002-0.450, p = 0.011).

CONCLUSIONS: Levels of plasma Aβ42 and Aβ42/Aβ40 ratio were elevated in patients with possible cognitive impairment, indicating that plasma Aβ42 and Aβ42/Aβ40 ratio increases may be more pronounced in early stage of cognitive impairment.

%B J Alzheimers Dis %V 64 %P 61-69 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865072?dopt=Abstract %R 10.3233/JAD-180140 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Emergence of a New Conceptual Framework for Alzheimer's Disease. %A Dubois, Bruno %X

The New Criteria for the diagnosis of Alzheimer's disease (AD), published by a group of experts in 2007, have resulted in a revolution in the comprehension of the disease. Before 2007, the diagnosis of AD dementia was done through a process of exclusion: it was considered in the case of patients with a dementia syndrome without identified etiologies. This traditional algorithm had three major limitations that penalize the disease: 1) a low accuracy of the performance which may share responsibility for negative results in clinical trials; 2) a late identification of the patients only when they reach the threshold of dementia which may delay the activation of optimal care; and last but not least, 3) an absence of clear recognition of AD as a disease because of the lack of specific arguments for its identification. Since 2007, the disease has gained a clear definition based on positive evidence: a specific clinical phenotype (the amnestic syndrome of the hippocampal type) and the presence of biomarkers, considered as a biological signature of the disease. Thanks to these positive arguments, AD is a clinically and biologically well-delineated disease, no longer defined as "probable". It is now possible to certify that a given patient has or does not have the disease. Like diabetes, cancer, hyperthyroidism or any other disorder, AD has now a clear definition with well-defined borders. The disease has entered the world of medicine with identified diseases with a biological fingerprint. This is the story of this adventure that we will present now.

%B J Alzheimers Dis %V 62 %P 1059-1066 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036825?dopt=Abstract %R 10.3233/JAD-170536 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The End of the Beginning of the Alzheimer's Disease Nightmare: A Devil's Advocate's View. %A Wimo, Anders %X

Although there have been so many failures in Alzheimer's disease (AD) modifying trials, there are still many compounds in the pipeline and the hope still remains that the entrance of disease-modifying treatment (DMT) for AD will positively and dramatically change the whole situation of AD treatment. However, if DMT does enter the market, it will be the beginning of a great number of challenges and problems. The current infrastructure for diagnostics of early (pre-dementia) AD does not have the capacity to meet the demands and expectations of the population. Neither is there capacity for treatment monitoring and follow-ups. If screening is considered, there will be a great risk for false positive cases and a great number of people who will have to undergo diagnostics. There will be high costs for diagnostics and treatment initially, while potential benefits will occur much later in other sectors than where the payers for treatment are. Although there are great hopes that prevention of cardiovascular risk factors and changes in lifestyle might impact the risk for dementia, there is still no consensus that this is the case. Finally, the relevance of different AD paradigms such as amyloid and tau is still a matter of discussion, particularly regarding the oldest old.

%B J Alzheimers Dis %8 2018 Apr 25 %G eng %R 10.3233/JAD-179905 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Endocannabinoid and Muscarinic Signaling Crosstalk in the 3xTg-AD Mouse Model of Alzheimer's Disease. %A Llorente-Ovejero, Alberto %A Manuel, Iván %A Lombardero, Laura %A Giralt, Maria Teresa %A Ledent, Catherine %A Giménez-Llort, Lydia %A Rodríguez-Puertas, Rafael %X

The endocannabinoid system, which modulates emotional learning and memory through CB1 receptors, has been found to be deregulated in Alzheimer's disease (AD). AD is characterized by a progressive decline in memory associated with selective impairment of cholinergic neurotransmission. The functional interplay of endocannabinoid and muscarinic signaling was analyzed in seven-month-old 3xTg-AD mice following the evaluation of learning and memory of an aversive stimulus. Neurochemical correlates were simultaneously studied with both receptor and functional autoradiography for CB1 and muscarinic receptors, and regulations at the cellular level were depicted by immunofluorescence. 3xTg-AD mice exhibited increased acquisition latencies and impaired memory retention compared to age-matched non-transgenic mice. Neurochemical analyses showed changes in CB1 receptor density and functional coupling of CB1 and muscarinic receptors to Gi/o proteins in several brain areas, highlighting that observed in the basolateral amygdala. The subchronic (seven days) stimulation of the endocannabinoid system following repeated WIN55,212-2 (1 mg/kg) or JZL184 (8 mg/kg) administration induced a CB1 receptor downregulation and CB1-mediated signaling desensitization, normalizing acquisition latencies to control levels. However, the observed modulation of cholinergic neurotransmission in limbic areas did not modify learning and memory outcomes. A CB1 receptor-mediated decrease of GABAergic tone in the basolateral amygdala may be controlling the limbic component of learning and memory in 3xTg-AD mice. CB1 receptor desensitization may be a plausible strategy to improve behavior alterations associated with genetic risk factors for developing AD.

%B J Alzheimers Dis %V 64 %P 117-136 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865071?dopt=Abstract %R 10.3233/JAD-180137 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Endocytosis and Transcytosis of Amyloid-β Peptides by Astrocytes: A Possible Mechanism for Amyloid-β Clearance in Alzheimer's Disease. %A Domínguez-Prieto, Marta %A Velasco, Ana %A Tabernero, Arantxa %A Medina, José M %X

Amyloid-β (Aβ) peptides, Aβ40, Aβ42, and recently Aβ25 - 35, have been directly implicated in the pathogenesis of Alzheimer's disease (AD). We have previously shown that all three peptides decrease neuronal viability, but Aβ40 also promotes synaptic disassembling. In this work, we have studied the effects of these peptides on astrocytes in primary culture and found that the three Aβ peptides were internalized by astrocytes and significantly decreased astrocyte viability, while increasing ROS production. Aβ peptide internalization is temperature-dependent, a fact that supports the idea that Aβ peptides are actively endocytosed by astrocytes. However, inhibiting caveolae formation by methyl-beta-cyclodextrin or by silencing caveolin-1 with RNA interference did not prevent Aβ endocytosis, which suggests that Aβ peptides do not use caveolae to enter astrocytes. Conversely, inhibition of clathrin-coated vesicle formation by chlorpromazine or by silencing clathrin with RNA interference significantly decreased Aβ internalization and partially reverted the decrease of astrocyte viability caused by the presence of Aβ. These results suggest that Aβ is endocytosed by clathrin-coated vesicles in astrocytes. Aβ-loaded astrocytes, when co-incubated with non-treated astrocytes in separate wells but with the same incubation medium, promoted cell death in non-treated astrocytes; a fact that was associated with the presence of Aβ inside previously unloaded astrocytes. This phenomenon was inhibited by the presence of chlorpromazine in the co-incubation medium. These results suggest that astrocyte may perform Aβ transcytosis, a process that could play a role in the clearance of Aβ peptides from the brain to cerebrospinal fluid.

%B J Alzheimers Dis %V 65 %P 1109-1124 %8 2018 Sep 25 %G eng %N 4 %& 1109 %R 10.3233/JAD-180332 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Endogenous Murine Amyloid-β Peptide Assembles into Aggregates in the Aged C57BL/6J Mouse Suggesting These Animals as a Model to Study Pathogenesis of Amyloid-β Plaque Formation. %A Ahlemeyer, Barbara %A Halupczok, Sascha %A Rodenberg-Frank, Elke %A Valerius, Klaus-Peter %A Baumgart-Vogt, Eveline %K Age Factors %K Aged %K Aged, 80 and over %K alpha-Synuclein %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Disease Models, Animal %K Female %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Neurofibrillary Tangles %K Neurons %K Plaque, Amyloid %K tau Proteins %X

Amyloid-β peptide (Aβ), paired helical filament-tau (PHF-tau), and α-synuclein are in the focus of neuroscience research because they aggregate in brains of patients with Alzheimer's and Parkinson's diseases. For this purpose, transgenic mouse models were used containing the human genes for AβPP/presenilin/tau or α-synuclein with the most frequent mutations. This is not ideal because most patients develop sporadic forms of the diseases with no causative single gene defect and furthermore the aggregation of human proteins in man is not necessarily the same in rodents. We hypothesized that for such cases the aged mouse could be an alternative model and analyzed the distribution of endogenous Aβ, PHF-tau, and α-synuclein in mouse brains at different ages. Whereas Aβ was below detectable levels at birth, it was present at high levels in the 15-month-old mouse. Aβ was found in the cytosol and lysosomes of neurons of the temporal cortex, cingulate area, pons, and cerebellum as well as extracellularly in the periventricular zone. Contrary to Aβ, mouse brain was devoid of PHF-tau-positive neurofibrillary tangles. α-Synuclein was detectable in the newborn mouse with highest levels in the marginal zone of the lateral cortex and average levels in the hippocampus, pons, and cerebellum. Brain-area specific differences in the α-synuclein level persisted up to 15 months of age, but increased 3-fold in all areas over time. α-Synuclein resided in the neuropil, but not in intracellular aggregates even in the aged mouse. We suggest the aged mouse as a model to study Aβ plaque formation.

%B J Alzheimers Dis %V 61 %P 1425-1450 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376876?dopt=Abstract %R 10.3233/JAD-170923 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Epigenetic Drug Repositioning for Alzheimer's Disease Based on Epigenetic Targets in Human Interactome. %A Chatterjee, Paulami %A Roy, Debjani %A Rathi, Nitin %K Alzheimer Disease %K Antipsychotic Agents %K Computational Biology %K Drug Repositioning %K Epigenesis, Genetic %K Epigenomics %K Humans %K MicroRNAs %K Protein Interaction Maps %K PubMed %X

BACKGROUND: Epigenetics has emerged as an important field in drug discovery. Alzheimer's disease (AD), the leading neurodegenerative disorder throughout the world, is shown to have an epigenetic basis. Currently, there are very few effective epigenetic drugs available for AD.

OBJECTIVE: In this work, for the first time we have proposed 14 AD repositioning epigenetic drugs and identified their targets from extensive human interactome.

METHODS: Interacting partners of the AD epigenetic proteins were identified from the extensive human interactome to construct Epigenetic Protein-Protein Interaction Network (EP-PPIN). Epigenetic Drug-Target Network (EP-DTN) was constructed with the drugs associated with the proteins of EP-PPIN. Regulation of non-coding RNAs associated with the target proteins of these drugs was also studied. AD related target proteins, epigenetic targets, enriched pathways, and functional categories of the proposed repositioning drugs were also studied.

RESULTS: The proposed 14 AD epigenetic repositioning drugs have overlapping targets and miRs with known AD epigenetic targets and miRs. Furthermore, several shared functional categories and enriched pathways were obtained for these drugs with FDA approved epigenetic drugs and known AD drugs.

CONCLUSIONS: The findings of our work might provide insight into future AD epigenetic-therapeutics.

%B J Alzheimers Dis %V 61 %P 53-65 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29199645?dopt=Abstract %R 10.3233/JAD-161104 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Episodic Memory and Learning Dysfunction Over an 18-Month Period in Preclinical and Prodromal Alzheimer's Disease. %A Baker, Jenalle E %A Lim, Yen Ying %A Jaeger, Judith %A Ames, David %A Lautenschlager, Nicola T %A Robertson, Joanne %A Pietrzak, Robert H %A Snyder, Peter J %A Villemagne, Victor L %A Rowe, Christopher C %A Masters, Colin L %A Maruff, Paul %X

Recent meta-analyses suggest that episodic memory impairment associated with preclinical Alzheimer's disease (AD) equates to 0.15-0.24 standard deviations below that of cognitively healthy older adults. The current study aimed to characterize impairments in verbal acquisition and recall detectable at a single assessment, and investigate how verbal learning and episodic memory deteriorates in preclinical AD. A verbal list-learning task, the International Shopping List Test (ISLT), was administered multiple times over an 18-month period, to three groups of participants: amyloid-beta negative healthy older adults (Aβ- CN; n = 50); Aβ+ positive healthy older adults (preclinical AD; n = 25); and Aβ+ positive individuals diagnosed with mild cognitive impairment (prodromal AD; n = 22). At baseline, there was no significant difference between the preclinical AD and control groups rate of acquisition, or total and delayed recall, however all indices were impaired in prodromal AD. Performance on ISLT total score improved in the control group over the 18-month period, but showed a moderate magnitude decline in the preclinical AD group (Cohen's d = - 0.63, [- 1.12, - 0.14]) and the prodromal AD group (Cohen's d = - 0.36, [- 0.94, 0.22]). No significant impairment in acquisition associated with preclinical AD was seen at baseline. Individuals with preclinical AD showed a significantly different performance on the ISLT total score over an 18-month period, compared to those without abnormal Aβ. Individuals with prodromal AD showed substantial impairment on the ISLT at baseline and declined to a greater extent over time.

%B J Alzheimers Dis %V 65 %P 977-988 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103330?dopt=Abstract %R 10.3233/JAD-180344 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Epitomic Characterization of the Specificity of the Anti-Amyloid Aβ Monoclonal Antibodies 6E10 and 4G8. %A Baghallab, Ibtisam %A Reyes-Ruiz, Jorge Mauricio %A Abulnaja, Khalid %A Huwait, Etimad %A Glabe, Charles %X

The monoclonal antibodies 6E10 and 4G8 are among the first anti-amyloid monoclonal antibodies against Aβ and the most widely used antibodies in Alzheimer's disease research. Although the epitopes for 6E10 and 4G8 have been reported to correspond to residues 1-16 and 17-24, a more recent high-resolution mapping approach indicates that 6E10 maps to residues 4-10 while 4G8 maps to residues 18-23. To characterize the binding specificity of both antibodies in greater detail, we used immunoselection of random sequences from phage display library followed by deep sequencing and analysis of resulting patterns from thousands of immunoselected sequences. We found that the minimum sequence required for 6E10 binding is R-x-D with over half (53%) of the immunoselected sequences conforming to this pattern. The vast majority of these sequences contain an H at position x (R-H-D), corresponding to residues 5-7 of the Aβ target sequences, but Y is also permitted at this position in a minority of sequences. For 4G8 we found that the most frequent pattern is F-x-A contained in approximately 30% of the sequences, followed by F-A, L-x(3)-A, L-x-F, and F-F each accounting for approximately 18% of the sequences. The F-x-A motif also occurs in islet amyloid poly peptide which may explain why 4G8 also recognizes amyloid fibrils of this peptide. Immunoselection of random sequences and deep sequencing may also be a facile and efficient means of determining residues critical for antibody binding and validating the specificity of monoclonal antibodies and polyclonal antisera.

%B J Alzheimers Dis %V 66 %P 1235-1244 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412489?dopt=Abstract %R 10.3233/JAD-180582 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Erythromyeloid-Derived TREM2: A Major Determinant of Alzheimer's Disease Pathology in Down Syndrome. %A Raha-Chowdhury, Ruma %A Henderson, James W %A Raha, Animesh Alexander %A Stott, Simon R W %A Vuono, Romina %A Foscarin, Simona %A Wilson, Liam %A Annus, Tiina %A Fincham, Robert %A Allinson, Kieren %A Devalia, Vinod %A Friedland, Robert P %A Holland, Anthony %A Zaman, Shahid H %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Cell Line %K Disease Progression %K Down Syndrome %K Exosomes %K Female %K Humans %K Immunity, Innate %K Macrophages %K Male %K Membrane Glycoproteins %K Microglia %K Middle Aged %K Phagocytosis %K Polymorphism, Single Nucleotide %K Receptors, Immunologic %X

BACKGROUND: Down syndrome (DS; trisomy 21) individuals have a spectrum of hematopoietic and neuronal dysfunctions and by the time they reach the age of 40 years, almost all develop Alzheimer's disease (AD) neuropathology which includes senile plaques and neurofibrillary tangles. Inflammation and innate immunity are key players in AD and DS. Triggering receptor expressed in myeloid cells-2 (TREM2) variants have been identified as risk factors for AD and other neurodegenerative diseases.

OBJECTIVE: To investigate the effects of TREM2 and the AD-associated R47H mutation on brain pathology and hematopoietic state in AD and DS.

METHODS: We analyzed peripheral blood, bone marrow, and brain tissue from DS, AD, and age-matched control subjects by immunohistochemistry and western blotting. TREM2-related phagocytosis was investigated using a human myeloid cell line.

RESULTS: TREM2 protein levels in brain and sera declined with age and disease progression in DS. We observed soluble TREM2 in brain parenchyma that may be carried by a subset of microglia, macrophages, or exosomes. Two DS cases had the AD-associated TREM2-R47H mutation, which manifested a morphologically extreme phenotype of megakaryocytes and erythrocytes in addition to impaired trafficking of TREM2 to the erythroid membrane. TREM2 was shown to be involved in phagocytosis of red blood cells. TREM2 was seen in early and late endosomes. Silencing TREM2 using siRNA in THP1 cells resulted in significant cell death.

CONCLUSION: We provide evidence that peripheral TREM2 originating from erythromyeloid cells significantly determines AD neuropathology in DS subjects. Understanding the molecular signaling pathways mediated by TREM2 may reveal novel therapeutic targets.

%B J Alzheimers Dis %V 61 %P 1143-1162 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29278889?dopt=Abstract %R 10.3233/JAD-170814 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Establishing a New Screening System for Mild Cognitive Impairment and Alzheimer's Disease with Mental Rotation Tasks that Evaluate Visuospatial Function. %A Suzuki, Ayuko %A Shinozaki, Jun %A Yazawa, Shogo %A Ueki, Yoshino %A Matsukawa, Noriyuki %A Shimohama, Shun %A Nagamine, Takashi %K Aged %K Aged, 80 and over %K Agnosia %K Alzheimer Disease %K Case-Control Studies %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Early Diagnosis %K Eye Movements %K Female %K Humans %K Male %K Mental Status Schedule %K Reaction Time %K ROC Curve %X

BACKGROUND: The mental rotation task is well-known for the assessment of visuospatial function; however, it has not been used for screening of dementia patients.

OBJECTIVE: The aim of this study was to create a simple screening test for patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) by focusing on non-amnestic symptoms.

METHODS: Age-matched healthy controls (age 75.3±6.8), patients with MCI (76.5±5.5), and AD (78.2±5.0) participated in this study. They carried out mental rotation tasks targeting geometric graphics or alphabetical characters with three rotating angles (0°, 90°, and 180°) and indicated the correct answer. Response accuracy and reaction time were recorded along with their eye movements using an eye tracker. To quantify their visual processing strategy, the run count ratio (RC ratio) was calculated by dividing the mean number of fixations in incorrect answers by that in correct answers.

RESULTS: AD patients showed lower accuracy and longer reaction time than controls. They also showed a significantly greater number of fixation and smaller saccade amplitude than controls, while fixation duration did not differ significantly. The RC ratio was higher for AD, followed by MCI and control groups. By setting the cut-off value to 0.47 in the 180° rotating angle task, we could differentiate MCI patients from controls with a probability of 80.0%.

CONCLUSIONS: We established a new screening system for dementia patients by evaluating visuospatial function. The RC ratio during a mental rotation task is useful for discriminating MCI patients from controls.

%B J Alzheimers Dis %V 61 %P 1653-1665 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376869?dopt=Abstract %R 10.3233/JAD-170801 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Ethical Arguments Concerning the Use of Alzheimer's Disease Biomarkers in Individuals with No or Mild Cognitive Impairment: A Systematic Review and Framework for Discussion. %A Smedinga, Marthe %A Tromp, Krista %A Schermer, Maartje H N %A Richard, Edo %X

BACKGROUND: The shift to defining Alzheimer's disease (AD) as a biological continuum, which is characterized by the presence of biomarkers instead of clinical symptoms, has sparked a widespread debate. Insight into the given arguments and their underlying moral values is crucial to ensure well-considered and appropriate AD biomarker testing in the future.

OBJECTIVE: To critically review the arguments in favor of or against AD biomarker testing in people with no or mild cognitive impairment and to explicate their underlying moral values.

METHODS: Seven databases were systematically searched for publications mentioning arguments of interest. Arguments are identified using qualitative data-analysis and evaluated within an ethical framework.

RESULTS: Our search yielded 3,657 articles of which 34 met the inclusion criteria. We discuss the clusters of arguments separate from their evaluation and the assessment of the debate as a whole. The right to know, which derives from the moral value of respect for autonomy, is a central argument in favor of biomarker testing. On the other hand, fear of the disease and lack of a disease-modifying treatment may result in a negative balance of good over inflicted harms, which argues against its use.

CONCLUSION: Critical evaluation and weighing of the given arguments in a specific context, within an ethical framework, demonstrates the necessity to differentiate between what we hope or expect from research and where we currently stand. While AD biomarkers may have an indispensable value for research, the current advantage for clinical practice appears limited.

%B J Alzheimers Dis %V 66 %P 1309-1322 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30507575?dopt=Abstract %R 10.3233/JAD-180638 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Ethyl Acetate Extract of Leaves of Ugni molinae Turcz. Improves Neuropathological Hallmarks of Alzheimer's Disease in Female APPswe/PS1dE9 Mice Fed with a High Fat Diet. %A Jara-Moreno, Daniela %A Castro-Torres, Rubn D %A Ettcheto, Miren %A Auladell, Carme %A Kogan, Marcelo J %A Folch, Jaume %A Verdaguer, Ester %A Cano, Amanda %A Busquets, Oriol %A Delporte, Carla %A Camins, Antoni %X

The most common type of dementia is Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by impairment in cognitive performance in aged individuals. Currently, there is no effective pharmacological treatment that cures the disease due to the lack of knowledge on the actual mechanisms involved in its pathogenesis. In the last decades, the amyloidogenic hypothesis has been the most studied theory trying to explain the origin of AD, yet it does not address all the concerns relating to its development. In the present study, a possible new preclinical treatment of AD was evaluated using the ethyl acetate extract (EAE) of leaves of Ugni molinae Turcz. (synonym Myrtus ugni Molina Family Myrtacea). The effects were assessed on female transgenic mice from a preclinical model of familial AD (APPswe/PS1dE9) combined with a high fat diet. This preclinical model was selected due to the already available experimental and observational data proving the relationship between obesity, gender, metabolic stress, and cognitive dysfunction; related to characteristics of sporadic AD. According to chemical analyses, EAE would contain polyphenols such as tannins, flavonoid derivatives, and phenolic acids, as well as pentacyclic triterpenoids that exhibit neuroprotective, anti-inflammatory, and antioxidant effects. In addition, the treatment evidenced its capacity to prevent deterioration of memory capacity and reduction of progression speed of AD neuropathology.

%B J Alzheimers Dis %V 66 %P 1175-1191 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400089?dopt=Abstract %R 10.3233/JAD-180174 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Evaluating Peripersonal Space through the Functional Transcranial Doppler: Are We Paving the Way for Early Detecting Mild Cognitive Impairment to Dementia Conversion? %A Marra, Angela %A Naro, Antonino %A Chillura, Antonino %A Bramanti, Alessia %A Maresca, Giuseppa %A De Luca, Rosaria %A Manuli, Alfredo %A Bramanti, Placido %A Calabrò, Rocco Salvatore %X

BACKGROUND: Identifying the patients with mild cognitive impairment (MCI) who may develop dementia (MDC) is challenging. The study of peripersonal space (PPS) by using functional transcranial Doppler (fTCD) could be used for this purpose.

OBJECTIVE: To identify changes in cerebral blood flow (CBF) during motor tasks targeting PPS, which can predict MDC.

METHODS: We evaluated the changes in CBF in 22 patients with MCI and 23 with dementia [Alzheimer's disease (AD) and vascular dementia (VaD)] during a motor task (passive mobilization, motor imagery, and movement observation) in which the hand of the subject moved forward and backward the face.

RESULTS: CBF increased when the hand approached the face and decreased when the hand moved from the face in the healthy controls (HCs). CBF changed were detectable only in patients with MCI but not in those with the AD and those who were MDC after 8-month follow-up. On the other hand, the patients with VaD presented a paradoxical response to the motor task (i.e., a decrease of CBF rather than an increase, as observed in HCs and MCI). Therefore, we found a modulation of PPS-related CBF only in HCs and patients with stable MCI (at the 8-month follow-up).

CONCLUSIONS: fTCD may allow preliminarily differentiating and following-up the patients with MCI and MDC, thus allowing the physician to plan beforehand more individualized cognitive rehabilitative training.

%B J Alzheimers Dis %V 62 %P 133-143 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439353?dopt=Abstract %R 10.3233/JAD-170973 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Evaluation of Matrix Metalloproteinase-2 (MMP-2) and -9 (MMP-9) and Their Tissue Inhibitors (TIMP-1 and TIMP-2) in Plasma from Patients with Neurodegenerative Dementia. %A Tuna, Gamze %A Yener, Görsev Gülmen %A Oktay, Gülgün %A İşlekel, Gül Hüray %A Kİrkalİ, Fatoş Güldal %X

Matrix metalloproteinases (MMPs) are substantial regulators of learning and memory and might be involved in neurodegeneration. It is known that MMPs are involved in pathogenesis of Alzheimer's disease (AD) and are particularly involved in the amyloid-β processing pathway. However, information on circulating levels of these proteins and their tissue inhibitors (TIMPs) in AD and other neurodegenerative dementia (ND) diseases such as dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) is not clear. Therefore, this study was directed toward finding out how plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 vary in AD, DLB, and FTD; and investigating the correlation of the levels of MMPs and their inhibitors with clinical parameters of the patients. MMP-2, MMP-9, TIMP-1, and TIMP-2 levels were measured by enzyme linked immunosorbent assay (ELISA). Plasma MMP-2 levels were significantly lower in all the patient groups than in the age-matched healthy controls (HCs) (p < 0.05). MMP-9 levels were significantly lower in the FTD patients than in the HCs (p < 0.05). Also, TIMP-1 levels were lower in the AD and FTD patients than in the HCs (p < 0.05). TIMP-2 levels were similar in all the groups. These findings highlight the importance of circulating MMPs in ND and suggest that MMPs and their inhibitors might play a role in impaired amyloid-β peptide metabolism which is responsible for the genesis and progression of ND. Furthermore, measurement of MMP-2 and MMP-9 and their inhibitors may be of great importance for large scale basic research and clinical studies of ND.

%B J Alzheimers Dis %V 66 %P 1265-1273 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412498?dopt=Abstract %R 10.3233/JAD-180752 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Evaluation of Ocular Perfusion in Alzheimer's Disease Using Optical Coherence Tomography Angiography. %A Lahme, Larissa %A Esser, Eliane Luisa %A Mihailovic, Natasa %A Schubert, Friederike %A Lauermann, Jost %A Johnen, Andreas %A Eter, Nicole %A Duning, Thomas %A Alnawaiseh, Maged %X

BACKGROUND: There is increasing evidence for the involvement of cerebrovascular factors in Alzheimer's disease (AD).

OBJECTIVE: To evaluate retinal and optic nerve head perfusion in patients with AD using optical coherence tomography angiography (OCTA), and to analyze the correlations of quantitative OCTA metrics with AD pathology and vascular cerebral lesions in AD patients.

METHODS: 36 eyes of 36 patients with AD (study group) and 38 eyes of 38 healthy subjects (control group) were prospectively included in this study. OCTA was performed using RTVue XR Avanti with AngioVue. In addition, patients underwent a detailed ophthalmological and neurological examination including Mini-Mental State Examination, cerebral magnetic resonance imaging, and amyloid-β (Aβ) and tau levels in the cerebrospinal fluid (CSF).

RESULTS: The flow density in the superficial retinal OCT angiogram of the macula in the study group was significantly lower compared to the control group (p = 0.001). There was a significant correlation between the flow density in the superficial retinal OCT angiogram of the macula, as measured using OCTA, and the Fazekas scale (Spearman's correlation coefficient = -0.520; p = 0.003). There was no significant correlation between the Aβ or tau levels in the CSF and the flow density data.

CONCLUSION: Patients with AD showed a reduced flow density in the radial peripapillary capillaries layer and in the superficial retinal OCT angiogram when compared with healthy controls. The reduced retinal flow density measured using OCTA is not specifically associated with AD pathology but is associated with the vascular cerebral lesions in AD.

%B J Alzheimers Dis %V 66 %P 1745-1752 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30507577?dopt=Abstract %R 10.3233/JAD-180738 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Evolvability of Amyloidogenic Proteins in Human Brain. %A Hashimoto, Makoto %A Ho, Gilbert %A Sugama, Shuei %A Takamatsu, Yoshiki %A Shimizu, Yuka %A Takenouchi, Takato %A Waragai, Masaaki %A Masliah, Eliezer %X

 Currently, the physiological roles of amyloidogenic proteins (APs) in human brain, such as amyloid-β and α-synuclein, are elusive. Given that many APs arose by gene duplication and have been resistant against the pressures of natural selection, APs may be associated with some functions that are advantageous for survival of offspring. Nonetheless, evolvability is the sole physiological quality of APs that has been characterized in microorganisms such as yeast. Since yeast and human brain may share similar strategies in coping with diverse range of critical environmental stresses, the objective of this paper was to discuss the potential role of evolvability of APs in aging-associated neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Given the heterogeneity of APs in terms of structure and cytotoxicity, it is argued that APs might be involved in preconditioning against diverse stresses in human brain. It is further speculated that these stress-related APs, most likely protofibrillar forms, might be transmitted to offspring via the germline, conferring preconditioning against forthcoming stresses. Thus, APs might represent a vehicle for the inheritance of the acquired characteristics against environmental stresses. Curiously, such a characteristic of APs is reminiscent of Charles Darwin's 'gemmules', imagined molecules of heritability described in his pangenesis theory. We propose that evolvability might be a physiological function of APs during the reproductive stage and neurodegenerative diseases could be a by-product effect manifested later in aging. Collectively, our evolvability hypothesis may play a complementary role in the pathophysiology of APs with the conventional amyloid cascade hypothesis.

%B J Alzheimers Dis %V 62 %P 73-83 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439348?dopt=Abstract %R 10.3233/JAD-170894 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Examining the Relationship between Trace Lithium in Drinking Water and the Rising Rates of Age-Adjusted Alzheimer's Disease Mortality in Texas. %A Fajardo, Val Andrew %A Fajardo, Val Andrei %A LeBlanc, Paul J %A MacPherson, Rebecca E K %K Adult %K Age Factors %K Alzheimer Disease %K Drinking Water %K Female %K Humans %K Lithium %K Longitudinal Studies %K Male %K Obesity %K Prevalence %K Risk Factors %K Statistics as Topic %K Texas %K Young Adult %X

BACKGROUND: Alzheimer's disease (AD) mortality rates have steadily increased over time. Lithium, the current gold standard treatment for bipolar disorder, can exert neuroprotective effects against AD.

OBJECTIVE: We examined the relationship between trace levels of lithium in drinking water and changes in AD mortality across several Texas counties.

METHODS: 6,180 water samples from public wells since 2007 were obtained and averaged for 234 of 254 Texas counties. Changes in AD mortality rates were calculated by subtracting aggregated age-adjusted mortality rates obtained between 2000-2006 from those obtained between 2009-2015. Using aggregated rates maximized the number of counties with reliable mortality data. Correlational analyses between average lithium concentrations and changes in AD mortality were performed while also adjusting for gender, race, education, rural living, air pollution, physical inactivity, obesity, and type 2 diabetes.

RESULTS: Age-adjusted AD mortality rate was significantly increased over time (+27%, p < 0.001). Changes in AD mortality were negatively correlated with trace lithium levels (p = 0.01, r = -0.20), and statistical significance was maintained after controlling for most risk factors except for physical inactivity, obesity, and type 2 diabetes. Furthermore, the prevalence of obesity and type 2 diabetes positively correlated with changes in AD mortality (p = 0.01 and 0.03, respectively), but also negatively correlated with trace lithium in drinking water (p = 0.05 and <0.0001, respectively).

CONCLUSION: Trace lithium in water is negatively linked with changes in AD mortality, as well as obesity and type 2 diabetes, which are important risk factors for AD.

%B J Alzheimers Dis %V 61 %P 425-434 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103043?dopt=Abstract %R 10.3233/JAD-170744 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Executive and Language Subjective Cognitive Decline Complaints Discriminate Preclinical Alzheimer's Disease from Normal Aging. %A Valech, Natalia %A Tort-Merino, Adrià %A Coll-Padrós, Nina %A Olives, Jaume %A León, María %A Rami, Lorena %A Molinuevo, José Luis %K Aged %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Executive Function %K Factor Analysis, Statistical %K Female %K Humans %K Language %K Male %K Middle Aged %K Neuropsychological Tests %K Self Report %X

BACKGROUND: There is a need to specify the profile of subjective cognitive decline in preclinical Alzheimer's disease (preAD).

OBJECTIVES: To explore specific items of the Subjective Cognitive Decline Questionnaire (SCD-Q) that discriminate preAD from normal aging.

METHODS: 68 cognitively normal older adults were classified as controls (n = 52) or preAD (n = 16) according to amyloid-β (Aβ) levels. An exploratory factor analysis and item analysis of the SCD-Q were performed. Informant reports of the SCD-Q were used to corroborate the findings of self-reports. One-year neuropsychological follow-up was available.

RESULTS: Four SCD-Q factors were extracted: EM-factor (episodic memory), A-factor (attention), O-factor (organization), and L-factor (language). PreAD reported a significantly higher decline in L-factor (F(1) = 6.49; p = 0.014) and A-factor (F(1) = 4.04; p = 0.049) compared to controls, and showed a higher frequency of perceived decline in SCD-Q items related with language and executive tasks (Sig-items.) Significant discriminative powers for Aβ-positivity were found for L-factor (AUC = 0.75; p = 0.003) and A-factor (AUC = 0.74; p = 0.004). Informants in the preAD group confirmed significantly higher scores in L-factor and Sig-items. A significant time×group interaction was found in the Semantic Fluency and Stroop tests, with the preAD group showing a decrease in performance at one-year.

CONCLUSIONS: Our results suggest that SCD-Q items related with language and executive decline may help in prediction algorithms to detect preAD. Validation in an independent population is needed.

%B J Alzheimers Dis %V 61 %P 689-703 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254090?dopt=Abstract %R 10.3233/JAD-170627 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Executive Dysfunction Detected with the Frontal Assessment Battery in Alzheimer's Disease Versus Vascular Dementia. %A D'Onofrio, Grazia %A Panza, Francesco %A Sancarlo, Daniele %A Addante, Filomena %A Solfrizzi, Vincenzo %A Cantarini, Chiara %A Mangiacotti, Antonio %A Lauriola, Michele %A Cascavilla, Leandro %A Paris, Francesco %A Lozupone, Madia %A Daniele, Antonio %A Greco, Antonio %A Seripa, Davide %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Comorbidity %K Dementia, Vascular %K Executive Function %K Female %K Frontal Lobe %K Geriatric Assessment %K Humans %K Logistic Models %K Male %K Polypharmacy %K Severity of Illness Index %X

Alzheimer's disease (AD) and vascular dementia (VaD) lead to progressive decline in executive function. We estimated the prevalence of executive dysfunction in AD and VaD patients, investigating cognitive, functional, and clinical correlates and also using a multidimensional approach based on a standardized comprehensive geriatric assessment (CGA). We included 215 patients (115 AD patients and 100 VaD patients) consecutively evaluated with a complete cognitive and affective assessment, a CGA, and the Frontal Assessment Battery (FAB) with six subtests investigating conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. The prevalence of dysexecutive syndrome screened with a FAB score <12 points was high in both AD (97 patients) and VaD (77 patients) (84.3% versus 77.0%, p = 0.171). AD patients were significantly younger, with higher grade of cognitive impairment and less severe comorbidity and polypharmacy than VaD patients. AD patients showed a significantly higher impairment in FAB total score and five FAB subtests (conceptualization, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy) than VaD patients. These findings were largely confirmed in a sub-analysis conducted subdividing the sample in mild and moderate-to-severe demented patients and suggesting that in moderate-to-severe AD there was higher impairment in FAB total score and four FAB subtests (conceptualization, sensitivity to interference, inhibitory control, and environmental autonomy). Executive dysfunction could be greater in AD patients with moderate-to-severe dementia compared to VaD patients, although our groups were also not matched for age, comorbidity or polypharmacy, which could also exert an effect.

%B J Alzheimers Dis %V 62 %P 699-711 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480171?dopt=Abstract %R 10.3233/JAD-170365 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Exercise Training on Locomotion in Patients with Alzheimer's Disease: A Feasibility Study. %A Pedrinolla, Anna %A Venturelli, Massimo %A Fonte, Cristina %A Munari, Daniele %A Benetti, Maria Vittoria %A Rudi, Doriana %A Tamburin, Stefano %A Muti, Ettore %A Zanolla, Luisa %A Smania, Nicola %A Schena, Federico %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomechanical Phenomena %K Exercise Test %K Exercise Therapy %K Feasibility Studies %K Female %K Gait %K Humans %K Italy %K Male %K Single-Blind Method %X

BACKGROUND: Although current literature has shown that patients with Alzheimer's disease (AD) have worse locomotion compared with healthy counterparts, no studies have focused on the efficacy of exercise training in improving gait abnormalities including biomechanics and metabolic aspects, in this population.

OBJECTIVE: To verify the effectiveness of exercise training (ET) on gait parameters (i.e., speed, step and stride length, single and double support, and energy cost of walking (Cw)) in patients with AD with respect to a standard cognitive treatment (CT).

METHODS: In this study, we included a small portion of data belonging to a larger study (ClinicalTrials.gov number, NCT03034746). Patients with AD (Mini-Mental State Examination 22±5) were included in the study. Gait parameters and Cw were assessed at baseline and after 6 months (72 treatment sessions) of treatment. ET included 90 min of aerobic and strength training. CT included 90 min of cognitive stimuli.

RESULTS: The 16 patients assigned to ET exhibited significant improvement of Cw (-0.9±0.1 J/kg·m-1), while differences in gait parameters were negligible. The effect on gait parameters were undetectable in the 18 patients assigned to CT (-0.2±0.5 J/kg·m-1).

CONCLUSIONS: Data from this study showed that ET program seems effective in improving Cw in patients with AD. Interestingly, the positive effect of ET on Cw was not coupled with ameliorations of patient's gait parameters, suggesting that the gain of metabolic aspects of locomotion were the main factors responsible for this positive result.

%B J Alzheimers Dis %V 61 %P 1599-1609 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376858?dopt=Abstract %R 10.3233/JAD-170625 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Exploring the Profile of Incidental Memory in Patients with Amnestic Mild Cognitive Impairment and Mild Alzheimer's Disease. %A Kontaxopoulou, Dionysia %A Beratis, Ion N %A Fragkiadaki, Stella %A Pavlou, Dimosthenis %A Andronas, Nikos %A Yannis, George %A Economou, Alexandra %A Papanicolaou, Andrew C %A Papageorgiou, Sokratis G %X

Incidental memory can be defined as the ability to acquire information unintentionally. The present study investigated incidental memory performance in amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD) patients; additionally, hippocampal atrophy between groupswas examined. Twenty-nine aMCI patients (14 with hippocampal atrophy, measured by the Medial Temporal Lobe Atrophy scale), 15 mild AD patients, and 20 cognitively intact individuals underwent a detailed medical and neuropsychological assessment examining intentional memory, using the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test. Participants first took part in a driving simulator experiment, followed by an unexpected incidental memory questionnaire referring to elements related to the driving simulation. The mild AD group performed worse than the aMCI group and the control group both in incidental and intentional memory tasks, whereas the aMCI group differed significantly from the control group only in the intentional memory tasks. The incidental recognition memory task was the only measure that differed between aMCI patients with and without hippocampal atrophy. Moreover, incidental memory tasks were the only measures that correlated significantly with both left and right hippocampal atrophy. The current findings indicate that incidental memory testing may provide potentially useful information for detecting aMCI patients with greater hippocampal atrophy, who may be considered at higher risk of developing dementia due to AD.

%B J Alzheimers Dis %V 65 %P 617-627 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056423?dopt=Abstract %R 10.3233/JAD-180328 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Exploring the Role of Cognitive Factors in a New Instrument for Elders' Financial Capacity Assessment. %A Giannouli, Vaitsa %A Stamovlasis, Dimitrios %A Tsolaki, Magda %X

BACKGROUND: The influence of cognitive factors on financial capacity across the dementia spectrum of cognitive aging, Alzheimer's disease (AD), and mild cognitive impairment (MCI) has been little investigated, while it has not been investigated at all in other types of dementia as well as in extended samples of elders in Greece.

OBJECTIVE: The aim of this study is to investigate financial capacity, to develop a tool, test its psychometric properties, validate, and then test the tool in groups of healthy controls compared to elders with dementia, while examining other facets of their cognitive performance.

METHODS: 719 elders from Greece including healthy participants and patients with different types of dementia were examined with Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS) and a battery of neuropsychological tests concerning various cognitive functions.

RESULTS: Significantly different profiles in the scores and subscores of LCPLTAS for all the groups of dementia patients were found, with a general incapacity finding for all the dementia groups including the MCI patients. Logistic regression showed that Mini-Mental State Examination (MMSE), Geriatric Depression Scale, and Trail Making Part B predicted competence on LCPLTAS for the dementia patients. Persons with MCI and dementia had lower financial knowledge scores than those without cognitive impairment, with MMSE scores below 27 suggestive as an indication of financial incapacity.

CONCLUSION: The LCPLTAS provides information for a strong positive correlation with MMSE, while the use both of MMSE and LCPLTAS as adequate measures of financial (in)capacity is discussed for the Greek legal procedures regarding elder guardianship cases.

%B J Alzheimers Dis %V 62 %P 1579-1594 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504530?dopt=Abstract %R 10.3233/JAD-170812 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Exposure to General Anesthesia and Risk of Dementia: A Nationwide Population-Based Cohort Study. %A Kim, Clara Tammy %A Myung, Woojae %A Lewis, Matthew %A Lee, Hyewon %A Kim, Satbyul Estella %A Lee, Kyungsang %A Lee, Chunsoo %A Choi, Junbae %A Kim, Ho %A Carroll, Bernard J %A Kim, Doh Kwan %X

BACKGROUND: There is a growing concern that general anesthesia could increase the risk of dementia. However, the relationship between anesthesia and subsequent dementia is still undetermined.

OBJECTIVE: To determine whether the risk of dementia increases after exposure to general anesthesia.

METHODS: A population-based prospective cohort study analyzing the Korean National Health Insurance Service-National Sample Cohort database was conducted of all persons aged over 50 years (n = 219,423) from 1 January 2003 and 31 December 2013.

RESULTS: 44,956 in the general anesthesia group and 174,469 in the control group were followed for 12 years. The risk of dementia associated with previous exposure to general anesthesia was increased after adjusting for all covariates such as gender, age, health care visit frequency, and co-morbidities (Hazard ratio = 1.285, 95% confidence interval = 1.262-1.384, time-varying Cox hazard model). In addition, the number of anesthetic agents administered, the number of exposures to general anesthesia, the cumulative exposure time, and the organ category involved in surgery were associated with risk of dementia.

CONCLUSION: In light of the increasing societal burden of dementia, careful surveillance for dementia and prevention guidelines for patients after general anesthesia are needed.

%B J Alzheimers Dis %V 63 %P 395-405 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614656?dopt=Abstract %R 10.3233/JAD-170951 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Exposure to Strong Anticholinergic Medications and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort. %A Gray, Shelly L %A Anderson, Melissa L %A Hanlon, Joseph T %A Dublin, Sascha %A Walker, Rod L %A Hubbard, Rebecca A %A Yu, Onchee %A Montine, Thomas J %A Crane, Paul K %A Sonnen, Josh A %A Keene, C Dirk %A Larson, Eric B %X

BACKGROUND: Anticholinergic medication exposure has been associated with increased risk for dementia. No study has examined the association between anticholinergic medication use and neuropathologic lesions in a community-based sample.

OBJECTIVE: To examine the relationship between anticholinergic exposure and dementia-related neuropathologic changes.

METHODS: Within a community-based autopsy cohort (N = 420), we ascertained use of anticholinergic medications over a 10-year period from automated pharmacy data and calculated total standardized daily doses (TSDD). We used modified Poisson regression to calculate adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the association between anticholinergic exposure and dementia-associated neuropathology. Inverse probability weighting was used to account for selection into the autopsy cohort.

RESULTS: Heavy anticholinergic exposure (≥1,096 TSDD) was not associated with greater neuropathologic changes of Alzheimer's disease; the adjusted RRs for heavy use of anticholinergics (≥1,096 TSDD) compared to no use were 1.22 (95% CI 0.81-1.88) for neuritic plaque scores and 0.89 (0.47-1.66) for extent of neurofibrillary degeneration. Moderate (91-1,095 TSDD) and heavy use of anticholinergics was associated with a significantly lower cerebral microinfarct burden compared with no use with adjusted RRs of 0.44 (0.21-0.89) and 0.24 (0.09-0.62), respectively. Anticholinergic exposure was not associated with macroscopic infarcts or atherosclerosis.

CONCLUSIONS: Use of anticholinergic medications is not associated with Alzheimer's disease-related neuropathologic changes but is associated with lower cerebral microinfarct burden. Further research into biological mechanisms underlying the anticholinergic-dementia link is warranteds.

%B J Alzheimers Dis %V 65 %P 607-616 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056417?dopt=Abstract %R 10.3233/JAD-171174 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Expression Profiling of Cytokine, Cholinergic Markers, and Amyloid-β Deposition in the APPSWE/PS1dE9 Mouse Model of Alzheimer's Disease Pathology. %A Reale, Marcella %A D'Angelo, Chiara %A Costantini, Erica %A Di Nicola, Marta %A Yarla, Nagnedra Sastry %A Kamal, Mohammad Amjad %A Salvador, Nieves %A Perry, George %X

BACKGROUND: Alzheimer's disease (AD), a neurodegenerative disease, is associated with dysfunction of the olfactory and the entorhinal cortex of the brain that control memory and cognitive functions and other daily activities. Pro-inflammatory cytokines, amyloid-β (Aβ), and the cholinergic system play vital roles in the pathophysiology of AD. However, the role of changes in cholinergic system components, Aβ accumulation, and cytokines in both the olfactory and entorhinal cortex is not known clearly.

OBJECTIVE: The present study is aimed to evaluate the changes of cholinergic system components, Aβ accumulation, and cytokines in both the olfactory bulb (OB) and entorhinal cortex (EC) of young and aged APPSWE/PS1dE9 transgenic (Tg) mice.

METHODS: We have explored the changes of cholinergic system components, Aβ accumulation, and expression profiling of cytokines in the OB and EC of aged APPswe transgenic mice and age-matched wild type mice using quantitative Real-Time PCR assays and immunohistochemistry techniques.

RESULTS: In aged Tg mice, a significant increase of expression of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and chemokine MCP1 (p < 0.001, p < 0.001, and p = 0.001, respectively) and a significant reduction of nAChRα4 (p = 0.048) and AChE (p = 0.023) was observed when compared with age-matched wild type mice. Higher levels of AChE and BuChE are expressed in OB and EC of the APPSWE/PS1dE9 of Tg mice. Aβ accumulation was observed in OB and EC of the APPSWE/PS1dE9 of Tg mice.

CONCLUSION: The study demonstrates the expression profiling of pro-inflammatory cytokines and cholinergic markers as well as Aβ accumulation in OB and EC of the APPSWE/PS1dE9 Tg mice. Moreover, the study also demonstrated that the APPSWE/PS1dE9 Tg mice can be useful as a mouse model to understand the role of pro-inflammatory cytokines and cholinergic markers in pathophysiology of AD.

%B J Alzheimers Dis %V 62 %P 467-476 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439355?dopt=Abstract %R 10.3233/JAD-170999 %0 Journal Article %J J Alzheimers Dis %D 2018 %T FDDNP-PET Tau Brain Protein Binding Patterns in Military Personnel with Suspected Chronic Traumatic Encephalopathy1. %A Chen, Stephen T %A Siddarth, Prabha %A Merrill, David A %A Martinez, Jacqueline %A D Emerson, Natacha %A Liu, Jie %A Wong, Koon-Pong %A Satyamurthy, Nagichettiar %A Giza, Christopher C %A Huang, Sung-Cheng %A Fitzsimmons, Robert P %A Bailes, Julian %A Omalu, Bennet %A Barrio, Jorge R %A Small, Gary W %X

BACKGROUND: Our group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired professional football players with suspected chronic traumatic encephalopathy differ from those of tau and amyloid aggregate binding observed in Alzheimer's disease (AD) patients and cognitively-intact controls.

OBJECTIVE: To compare these findings with those from military personnel with histories of mild traumatic brain injury(mTBI).

METHODS: FDDNP-PET brain scans were compared among 7 military personnel and 15 retired players with mTBI histories and cognitive and/or mood symptoms, 24 AD patients, and 28 cognitively-intact controls. Nonparametric ANCOVAs with Tukey-Kramer adjusted post-hoc comparisons were used to test for significant differences in regional FDDNP binding among subject groups.

RESULTS: FDDNP brain binding was higher in military personnel compared to controls in the amygdala, midbrain, medial thalamus, pons, frontal and anterior and posterior cingulate regions (p < 0.01-0.0001). Binding patterns in the military personnel were similar to those of the players except for the amygdala and striatum (binding higher in players; p = 0.02-0.003). Compared with the AD group, the military personnel showed higher binding in the midbrain (p = 0.0008) and pons (p = 0.002) and lower binding in the medial temporal, lateral temporal, and parietal regions (all p = 0.02).

CONCLUSION: This first study of in vivo tau and amyloid brain signals in military personnel with histories of mTBI shows binding patterns similar to those of retired football players and distinct from the binding patterns in AD and normal aging, suggesting the potential value of FDDNP-PET for early detection and treatment monitoring in varied at-risk populations.

%B J Alzheimers Dis %8 2018 Jul 17 %G eng %R 10.3233/JAD-171152 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Findings from the Swedish Study on Familial Alzheimer's Disease Including the APP Swedish Double Mutation. %A Thordardottir, Steinunn %A Graff, Caroline %X

This is a brief summary of the findings from the Swedish study on familial Alzheimer's disease (FAD). Similar to other FAD studies, it includes prospective assessments of cognitive function, tissue sampling, and technical analyses such as MRI and PET. This 24-year-old study involves 69 individuals with a 50% risk of inheriting a disease-causing mutation in presenilin 1 (PSEN1 H163Y or I143T), or amyloid precursor protein (the Swedish APP or the arctic APP mutation) who have made a total of 169 visits. Our results show the extraordinary power in this study design to unravel the earliest changes in preclinical AD. The Swedish FAD study will continue and future research will focus on disentangling the order of pathological change using longitudinal data as well as modeling the changes in patient derived cell systems.

%B J Alzheimers Dis %V 64 %P S491-S496 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614673?dopt=Abstract %R 10.3233/JAD-179922 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The First Historically Reported Italian Family with FTD/ALS Teaches a Lesson on C9orf72 RE: Clinical Heterogeneity and Oligogenic Inheritance. %A Giannoccaro, Maria Pia %A Bartoletti-Stella, Anna %A Piras, Silvia %A Casalena, Alfonsina %A Oppi, Federico %A Ambrosetto, Giovanni %A Montagna, Pasquale %A Liguori, Rocco %A Parchi, Piero %A Capellari, Sabina %K Adult %K Amyotrophic Lateral Sclerosis %K C9orf72 Protein %K Cerebral Cortex %K DNA Repeat Expansion %K Female %K Frontotemporal Dementia %K Genetic Testing %K Humans %K Male %K Membrane Glycoproteins %K Middle Aged %K Multifactorial Inheritance %K Mutation %K Pedigree %X

BACKGROUND: In 1969, Dazzi and Finizio reported the second observation of frontotemporal dementia (FTD) - amyotrophic lateral sclerosis (ALS) association in a large Italian kindred affected by an autosomal dominant form of ALS with high penetrance, frequent bulbar onset, and frequent cognitive decline.

OBJECTIVE: To expand the original characterization of this family and report the link with the C9orf72 repeat expansion (RE).

METHODS: We followed or reviewed the medical records of thirteen patients belonging to the original family and performed genetic analyses in four individuals.

RESULTS: Eight patients presented with ALS, four with FTD, and one with schizophrenia. The C9orf72 RE was found in three patients but not in the healthy survivor. Additionally, we found a novel possible pathogenic variant in the ITM2B gene in one patient with a complex phenotype, associating movement disorders, psychiatric and cognitive features, deafness, and optic atrophy. The neuropathological examination of this patient did not show the classical features of ITM2B mutation related dementias suggesting that the putative pathogenic mechanism does not involve cellular mislocalization of the protein or the formation of amyloid plaques.

CONCLUSION: We showed that the original Italian pedigree described with FTD/ALS carries the C9orf72 RE. Moreover, the finding of an additional mutation in another dementia causing gene in a patient with a more complex phenotype suggests a possible role of genetic modifiers in the disease. Together with other reports showing the coexistence of mutations in multiple ALS/FTD causative genes in the same family, our study supports an oligogenic etiology of ALS/FTD.

%B J Alzheimers Dis %V 62 %P 687-697 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480190?dopt=Abstract %R 10.3233/JAD-170913 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Forgetting Rate on the Recency Portion of a Word List Differentiates Mild to Moderate Alzheimer's Disease from Other Forms of Dementi. %A Turchetta, Chiara Stella %A Perri, Roberta %A Fadda, Lucia %A Caruso, Giulia %A De Simone, Maria Stefania %A Caltagirone, Carlo %A Carlesimo, Giovanni Augusto %X

Patients with Alzheimer's disease (AD) demonstrate a disproportionately larger forgetting rate in episodic memory tasks. Previous studies documented that, in comparison with healthy controls, the increased forgetting manifested by AD patients in word list recall tasks is confined to the recency portion of the list with normal forgetting rates on the primacy and mid-list portions. In this study we compared the primacy, mid-list, and recency ratios, obtained by dividing the immediate and delayed recall of words in position 1-4, 5-11, and 12-15 of a 15-word list, in different groups of demented patients, i.e., AD, frontal variant of frontotemporal dementia (fvFTD), Lewy body disease (LBD), subcortical ischemic vascular dementia (SIVD), and a group of normal controls (NC). The aim was to investigate whether the above reported forgetting pattern would differentiate AD performance from that of other dementia groups. Results of the statistical analysis showed that only the recency ratio differentiated AD from patients in the other dementia groups. Consistently, hierarchical logistic regression analyses demonstrated that the recency ratio discriminated between AD patients and individuals affected by other forms of dementia. In particular, the discrimination power was high in differentiating AD from fvFTD patients but was less accurate in differentiating AD from LBD and SIVD patients. We assume that the increased forgetting in AD patients is due to a deficit in memory consolidation mechanisms (specific to AD) that prevent the terminal items in a list from being transferred from a temporary short-term memory store to a stable long-term memory store.

%B J Alzheimers Dis %V 66 %P 461-470 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320591?dopt=Abstract %R 10.3233/JAD-180690 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Fragmentation of the Golgi Apparatus in Neuroblastoma Cells Is Associated with Tau-Induced Ring-Shaped Microtubule Bundles. %A Rodríguez-Cruz, Fanny %A Torres-Cruz, Francisco Miguel %A Monroy-Ramírez, Hugo Christian %A Escobar-Herrera, Jaime %A Basurto-Islas, Gustavo %A Avila, Jesús %A Garcia-Sierra, Francisco %X

Abnormal fibrillary aggregation of tau protein is a pathological condition observed in Alzheimer's disease and other tauopathies; however, the presence and pathological significance of early non-fibrillary aggregates of tau remain under investigation. In cell and animal models expressing normal or modified tau, toxic effects altering the structure and function of several membranous organelles have also been reported in the absence of fibrillary structures; however, how these abnormalities are produced is an issue yet to be addressed. In order to obtain more insights into the mechanisms by which tau may disturb intracellular membranous elements, we transiently overexpressed human full-length tau and several truncated tau variants in cultured neuroblastoma cells. After 48 h of transfection, either full-length or truncated tau forms produced significant fragmentation of the Golgi apparatus (GA) with no changes in cell viability. Noteworthy is that in the majority of cells exhibiting dispersion of the GA, a ring-shaped array of cortical or perinuclear microtubule (Mt) bundles was also generated under the expression of either variant of tau. In contrast, Taxol treatment of non-transfected cells increased the amount of Mt bundles but not sufficiently to produce fragmentation of the GA. Tau-induced ring-shaped Mt bundles appeared to be well-organized and stable structures because they were resistant to Nocodazole post-treatment and displayed a high level of tubulin acetylation. These results further indicate that a mechanical force generated by tau-induced Mt-bundling may be responsible for Golgi fragmentation and that the repeated domain region of tau may be the main promoter of this effect.

%B J Alzheimers Dis %8 2018 Aug 14 %G eng %R 10.3233/JAD-180547 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A 'Framingham-like' Algorithm for Predicting 4-Year Risk of Progression to Amnestic Mild Cognitive Impairment or Alzheimer's Disease Using Multidomain Information. %A Steenland, Kyle %A Zhao, Liping %A John, Samantha E %A Goldstein, Felicia C %A Levey, Allan %A Alvaro, Alonso %X

BACKGROUND: There are no agreed-upon variables for predicting progression from unimpaired cognition to amnestic mild cognitive impairment (aMCI), or from aMCI to Alzheimer's disease (AD).

OBJECTIVE: Use ADNI data to develop a 'Framingham-like' prediction model for a 4-year period.

METHODS: We developed models using the strongest baseline predictors from six domains (demographics, neuroimaging, CSF biomarkers, genetics, cognitive tests, and functional ability). We chose the best predictor from each domain, which was dichotomized into more versus less harmful.

RESULTS: There were 224 unimpaired individuals and 424 aMCI subjects with baseline data on all predictors, of whom 37 (17% ) and 150 (35% ) converted to aMCI and AD, respectively, during 4 years of follow-up. For the unimpaired, CSF tau/Aβ ratio, hippocampal volume, and a memory score predicted progression. For those aMCI at baseline, the same predictors plus APOE4 status and functional ability predicted progression. Demographics and family history were not important predictors for progression for either group. The fit statistic was good for the unimpaired-aMCI model (C-statistic 0.80) and very good for the aMCI-AD model (C-statistic 0.91). Among the unimpaired, those with no harmful risk factors had a 4-year predicted 2% risk of progression, while those with the most harmful risk factors had a predicted 35% risk. The aMCI subjects with no harmful risk factors had a predicted 1% risk of progression those with all six harmful risk factors had a predicted 90% risk.

CONCLUSION: Our parsimonious model accurately predicted progression from unimpaired to aMCI with three variables, and from aMCI to AD with five variables.

%B J Alzheimers Dis %V 63 %P 1383-1393 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843232?dopt=Abstract %R 10.3233/JAD-170769 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Free Heme and Amyloid-β: A Fatal Liaison in Alzheimer's Disease. %A Chiziane, Elisabeth %A Telemann, Henriette %A Krueger, Martin %A Adler, Juliane %A Arnhold, Jürgen %A Alia, A %A Flemmig, Jörg %K Alzheimer Disease %K Amino Acid Sequence %K Amyloid %K Amyloid beta-Peptides %K Animals %K Brain %K Disease Models, Animal %K Heme %K Humans %K Hydrogen Peroxide %K Mice %K Mice, Transgenic %K Oxidation-Reduction %K Peptide Fragments %K Peroxidases %X

While the etiology of Alzheimer's disease (AD) is still unknown, an increased formation of amyloid-β (Aβ) peptide and oxidative processes are major pathological mechanism of the disease. The interaction of Aβ with free heme leads to the formation of peroxidase-active Aβ-heme complexes. However, enzyme-kinetic data and systematic mutational studies are still missing. These aspects were addressed in this study to evaluate the role of Aβ-heme complexes in AD. The enzyme-kinetic measurements showed peroxidase-specific pH- and H2O2-dependencies. In addition, the enzymatic activity of Aβ-heme complexes constantly increased at higher peptide excess. Moreover, the role of the Aβ sequence for the named enzymatic activity was tested, depicting human-specific R5, Y10, and H13 as essential amino acids. Also by studying Y10 as an endogenous peroxidase substrate for Aβ-heme complexes, ratio-specific effects were observed, showing an optimal dityrosine formation at an about 40-fold peptide excess. As dityrosine formation promotes Aβ fibrillation while free heme disturbs protein aggregation, we also investigated the effect of Aβ-heme complex-derived peroxidase activity on the formation of Aβ fibrils. The fluorescence measurements showed a different fibrillation behavior at strong peroxidase activity, leading also to altered fibril morphologies. The latter was detected by electron microscopy. As illustrated by selected in vivo measurements on a mouse model of AD, the disease is also characterized by Aβ-derived microvessel destructions and hemolytic processes. Thus, thrombo-hemorrhagic events are discussed as a source for free heme in brain tissue. In summary, we suggest the formation and enzymatic activity of Aβ-heme complexes as pathological key features of AD.

%B J Alzheimers Dis %V 61 %P 963-984 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332049?dopt=Abstract %R 10.3233/JAD-170711 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Free Radical-Generating System Regulates Amyloid Oligomers: Involvement of Cathepsin B. %A Llorente, Patricia %A Kristen, Henrike %A Sastre, Isabel %A Toledano-Zaragoza, Ana %A Aldudo, Jesús %A Recuero, María %A Bullido, Maria J %X

Amyloid-β (Aβ), a major component of senile plaques, is generated via the proteolysis of amyloid-β protein precursor (AβPP). This cleavage also produces AβPP fragment-derived oligomers which can be highly neurotoxic. AβPP metabolism/processing is affected by many factors, one of which is oxidative stress (OS). Associated with aging, OS is an important risk factor for Alzheimer's disease. In addition, the protein degradation systems, especially those involving cathepsins, are impaired in aging brains. Moreover, cathepsin B (CTSB) is a cysteine protease with potentially specific roles in AβPP proteolysis (β-secretase activity) and Aβ clearance (Aβ degradative activity). The present work examines the effect of OS and the involvement of CTSB in amyloid oligomer formation. The xanthine/xanthine oxidase (X-XOD) free radical generating system induced the partial inhibition of CTSB activity, which was accompanied by an increase in large amyloid oligomers. These were located throughout the cytosol and in endo-lysosomal vesicles. Cells treated with the CTSB inhibitor CA-074Me also showed increased amyloid oligomer levels, whereas those subjected to OS in the presence of the inhibitor showed no such increase. However, CTSB inhibition clearly modulated the AβPP metabolism/processing induced by X-XOD, as revealed by the increase in intracellular AβPP and secreted α-secretase-cleaved soluble AβPP. The present results suggest that CTSB participates in the changes of amyloid oligomer induced by mild OS.

%B J Alzheimers Dis %V 66 %P 1397-1408 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400084?dopt=Abstract %R 10.3233/JAD-170159 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Frequency and Correlates of Subjective Memory Complaints in Parkinson's Disease with and without Mild Cognitive Impairment: Data from the Parkinson's Disease Cognitive Impairment Study. %A Baschi, Roberta %A Nicoletti, Alessandra %A Restivo, Vincenzo %A Recca, Deborah %A Zappia, Mario %A Monastero, Roberto %X

Subjective memory complaints (SMC) may represent the preclinical phase of mild cognitive impairment (MCI) due to Alzheimer's disease. Dementia/MCI have been described with a high prevalence in Parkinson's disease (PD), but whether SMC may predict the development of cognitive impairment has been barely explored. To evaluate the frequency and clinical correlates of isolated SMC (PD-SMC) or within the construct of MCI in subjects with PD, 147 PD patients from the PArkinson's disease COgnitive impairment Study (PACOS) were consecutively recruited for the study. This is a multicenter study involving two Movement Disorder Centers in south Italy. All subjects underwent comprehensive neuropsychological evaluation and PD-MCI was diagnosed according to Litvan's criteria. The Memory Assessment Clinics Questionnaire was used to assess SMC. Logistic regression analysis, adjusted for demographics and significant covariates, was used to evaluate clinical differences between groups. Forty-two (28.6%) individuals presented with PD without SMC and/or MCI (PDw), 40 (27,2%) with PD-SMC, 48 (32,6%) PD-SMC-MCI, and 17 (11,6%) PD-MCI without SMC (PD-MCI). When compared to PDw, PD-SMC was significantly associated with anxiety (OR = 3.93, 95% CI = 1.18-13.03), while PD-SMC-MCI related to motor progression (OR = 5.29, 95% CI = 1.12-24.86), and instrumental disability (OR = 6.98, 95% CI = 2.08-23.38). About 60% of patients showed SMC, in isolation or within the MCI frame. The role of SMC in PD seems to have a different etiology depending on the presence/absence of MCI. In particular, PD-SMC would represent a subjective reaction to the disease, while PD-SMC-MCI would depict motor progression and disability.

%B J Alzheimers Dis %V 63 %P 1015-1024 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710711?dopt=Abstract %R 10.3233/JAD-171172 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Frequency of Cardiovascular Genetic Risk Factors in a Calabrian Population and Their Effects on Dementia. %A Maletta, Raffaele %A Smirne, Nicoletta %A Bernardi, Livia %A Anfossi, Maria %A Gallo, Maura %A Conidi, Maria Elena %A Colao, Rosanna %A Puccio, Gianfranco %A Curcio, Sabrina A M %A Laganà, Valentina %A Frangipane, Francesca %A Cupidi, Chiara %A Mirabelli, Maria %A Vasso, Franca %A Torchia, Giusi %A Muraca, Maria G %A Di Lorenzo, Raffaele %A Rose, Giuseppina %A Montesanto, Alberto %A Passarino, Giuseppe %A Bruni, Amalia C %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Case-Control Studies %K Cholesterol Ester Transfer Proteins %K Cohort Studies %K Dementia, Vascular %K Female %K Frontotemporal Dementia %K Gene Frequency %K Humans %K Italy %K Male %K Middle Aged %K Polymorphism, Genetic %K Risk Factors %X

BACKGROUND: Several genetic variants playing a key role in cholesterol levels, blood pressure, and vascular dysfunction influence the risk of Alzheimer's disease (AD) and vascular dementia (VaD). The many meta-analysis studies carried out on large numbers of samples in different populations have not provided clear results to date, because a trans-ethnic shift of risk genotypes in different populations is often observed.

OBJECTIVES: To determine genotypes allele frequencies of the polymorphisms most frequently identified to be correlated with cardio-cerebrovascular disease and AD in a Southern Italy population and to investigate their possible association with dementia.

METHODS: The genotype and allele frequencies of 13 cardio-cerebrovascular risk polymorphisms were assessed and their possible association with dementia was investigated in a case-control study, including 221 consecutive unrelated subjects diagnosed with dementia (120 subjects affected by AD, 55 by frontotemporal dementia, and 33 by vascular dementia) and 218 matched controls of Calabrian origin.

RESULTS: Carriers of at least one APOEɛ4 allele resulted to be at higher risk of AD [OR(95% CI) = 2.721(1.477-5.011)] and VaD [OR(95% CI) = 6.205(2.356-16.342)] compared to non-carriers. Individuals with the IV genotype of the CETP polymorphism were more likely to have AD [OR(95% CI) = 2.427(1.364-4.319)] and VaD [OR(95% CI) = 3.649(1.455-9.152)] compared to subjects with the II-VV genotypes.

CONCLUSION: CETP I405V polymorphism is likely a risk factor for AD and VaD in our cohort, independent of APOEɛ4 status. Unmodifiable genetic risk factors should be taken into account to promote a healthy lifestyle to prevent dementia.

%B J Alzheimers Dis %V 61 %P 1179-1187 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332048?dopt=Abstract %R 10.3233/JAD-170687 %0 Journal Article %J J Alzheimers Dis %D 2018 %T From Cerebrospinal Fluid to Blood: The Third Wave of Fluid Biomarkers for Alzheimer's Disease. %A Zetterberg, Henrik %A Blennow, Kaj %X

The past five years have seen an enormous development in the field of fluid biomarkers for Alzheimer's disease (AD) and related disorders. The proteins that constitute the foundation for the cerebrospinal fluid (CSF) tests for the classical AD pathologies are now being explored as potential blood-based biomarkers, thanks to the recent implementation of ultrasensitive measurement technologies in academic and clinical laboratories worldwide. The current blood-derived data are still less clear than those obtained using CSF as the sample type, but independent research suggests that there are biomarker signals in blood that relate to plaque and tangle pathologies in AD, which are relevant to explore further. Additionally, neurofilament light has emerged as the first robust blood-based biomarker for neurodegeneration in a broad range of central nervous system disorders, as well as for acute brain injuries. Here, we briefly recapitulate the first and second waves of fluid biomarker analysis in AD, i.e., the development and validation of established and novel CSF biomarkers for the disorder, followed by a focused discussion on blood-based biomarkers for AD, which we describe as the third wave of fluid biomarker analysis that hopefully will gain further momentum during the coming five years.

%B J Alzheimers Dis %V 64 %P S271-S279 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758941?dopt=Abstract %R 10.3233/JAD-179926 %0 Journal Article %J J Alzheimers Dis %D 2018 %T From Subjective Cognitive Decline to Alzheimer's Disease: The Predictive Role of Neuropsychological Assessment, Personality Traits, and Cognitive Reserve. A 7-Year Follow-Up Study. %A Bessi, Valentina %A Mazzeo, Salvatore %A Padiglioni, Sonia %A Piccini, Carolina %A Nacmias, Benedetta %A Sorbi, Sandro %A Bracco, Laura %X

The aim of this study was to evaluate the accuracy of neuropsychological assessment in predicting conversion from subjective cognitive decline (SCD) and mild cognitive impairment (MCI) to Alzheimer's disease (AD) and the effect of personality traits and cognitive reserve in progression from SCD to MCI. As part of a longitudinal, clinical-neuropsychological-genetic survey on SCD and MCI, 284 patients referred to our hospital between 1990 and 2017 were included. All patients underwent clinical-extensive neuropsychological evaluation and Apolipoprotein E genotyping; personality traits were assessed in a subgroup. Each patient underwent clinical-neuropsychological follow-up. Subjects with a follow-up shorter than two years were excluded. A total of 212 subjects were, after exclusions, considered: 26 out of 109 SCD subjects progressed to MCI (SCD-p), 15 converted to AD (SCD-c), and 68 remained stable (SCD-s). Of 103 MCI subjects, 39 converted to AD (MCI-c) and 64 remained stable (MCI-s). At baseline, SCD-c performed significantly worse than SCD-s in tests assessing long-term verbal memory. MCI-c showed worse performance on neuropsychological tests for short- and long-term verbal memory and for ecological evaluation of memory (RBMT). These tests provided good accuracy in distinguishing MCI-c and MCI-s. Emotional stability was significantly lower in SCD-s than in SCD-p while higher intellectual activities were associated with a lower risk of conversion to MCI. Our results suggest that memory neuropsychological tests may represent a reliable tool to estimate the risk of progression to AD. Personality and lifestyle factors could provide useful information to identify SCD subjects who may develop an objective cognitive impairment.

%B J Alzheimers Dis %V 63 %P 1523-1535 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782316?dopt=Abstract %R 10.3233/JAD-171180 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Frontal Cortex Epigenetic Dysregulation During the Progression of Alzheimer's Disease. %A Mahady, Laura %A Nadeem, Muhammad %A Malek-Ahmadi, Michael %A Chen, Kewei %A Perez, Sylvia E %A Mufson, Elliott J %X

Although the frontal cortex plays an important role in cognitive function and undergoes neuronal dysfunction in Alzheimer's disease (AD), the factors driving these cellular alterations remain unknown. Recent studies suggest that alterations in epigenetic regulation play a pivotal role in this process in AD. We evaluated frontal cortex histone deacetylase (HDAC) and sirtuin (SIRT) levels in tissue obtained from subjects with a premortem diagnosis of no-cognitive impairment (NCI), mild cognitive impairment (MCI), mild to moderate AD (mAD), and severe AD (sAD) using quantitative western blotting. Immunoblots revealed significant increases in HDAC1 and HDAC3 in MCI and mAD, followed by a decrease in sAD compared to NCI. HDAC2 levels remained stable across clinical groups. HDAC4 was significantly increased in MCI and mAD, but not in sAD compared to NCI. HDAC6 significantly increased during disease progression, while SIRT1 decreased in MCI, mAD, and sAD compared to NCI. HDAC1 levels negatively correlated with perceptual speed, while SIRT1 positively correlated with perceptual speed, episodic memory, global cognitive score, and Mini-Mental State Examination. HDAC1 positively, while SIRT1 negatively correlated with cortical neurofibrillary tangle counts. These findings suggest that dysregulation of epigenetic proteins contribute to neuronal dysfunction and cognitive decline in the early stage of AD.

%B J Alzheimers Dis %V 62 %P 115-131 %8 2018 Feb 6 %G eng %N 1 %R 10.3233/JAD-171032 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Frontotemporal Dementia and Chorea Associated with a Compound Heterozygous TREM2 Mutation. %A Redaelli, Veronica %A Salsano, Ettore %A Colleoni, Lara %A Corbetta, Paola %A Tringali, Giovanni %A Del Sole, Angelo %A Giaccone, Giorgio %A Rossi, Giacomina %X

Frontotemporal dementia (FTD) is clinically characterized by behavioral changes, language impairment, and executive dysfunction. FTD usually belongs to the frontotemporal lobar degeneration (FTLD) disease group, and its familial forms are dominantly inherited and linked to a group of genes relevant to frontal and temporal brain pathology, such as MAPT, GRN, C9ORF72, TARDBP, CHMP2B, VCP, and FUS. However, FTD can also be associated with different clinical or pathological phenotypes caused by mutations in other genes, whose heredity can be dominant or recessive. In this work we report on a familial case of FTD characterized by behavioral changes and aphasia, very early onset and very long duration, choreic movements, and white matter lesions at magnetic resonance imaging. We performed a wide-range genetic analysis, using a next generation sequencing approach, to evaluate a number of genes involved in neurodegeneration. We found a previously unreported compound heterozygous mutation in TREM2, that is commonly associated with the recessively inherited Nasu-Hakola disease. We discuss the differential diagnosis to be taken into account in cases of FTD presenting with atypical features.

%B J Alzheimers Dis %V 63 %P 195-201 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578490?dopt=Abstract %R 10.3233/JAD-180018 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Frontotemporal Dementia Misdiagnosed for Post-Treatment Lyme Disease Syndrome or vice versa? A Treviso Dementia (TREDEM) Registry Case Report. %A Di Battista, Maria Elena %A Dell'Acqua, Carola %A Baroni, Luciana %A Fenoglio, Chiara %A Galimberti, Daniela %A Gallucci, Maurizio %X

We describe the case of a 61-year-old woman diagnosed with Borreliosis at the age of 57. Subsequently, the patient developed depression, anxiety, and behavioral disturbances. A lumbar puncture excluded the condition of Neuroborreliosis. The diagnostic workup included: an MRI scan, a 18F-FDG PET, a 123I-ioflupane-SPECT, an amyloid-β PET, a specific genetic analysis, and a neuropsychological evaluation. Based on our investigation, the patient was diagnosed with probable behavioral-frontotemporal dementia (bvFTD), whereas in the previous years, the patient had been considered firstly as a case of Post-Treatment-Lyme Disease and, secondly, a psychiatric patient. We believe that, in the present case, such initial symptoms of Borrelia infection may have superimposed on those of bvFTD rather than playing as a contributory cause.

%B J Alzheimers Dis %V 66 %P 445-451 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282363?dopt=Abstract %R 10.3233/JAD-180524 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Gait in Mild Alzheimer's Disease: Feasibility of Multi-Center Measurement in the Clinic and Home with Body-Worn Sensors: A Pilot Study. %A Mc Ardle, Ríona %A Morris, Rosie %A Hickey, Aodhán %A Del Din, Silvia %A Koychev, Ivan %A Gunn, Roger N %A Lawson, Jennifer %A Zamboni, Giovanna %A Ridha, Basil %A Sahakian, Barbara J %A Rowe, James B %A Thomas, Alan %A Zetterberg, Henrik %A MacKay, Clare %A Lovestone, Simon %A Rochesteron, Lynn %X

Gait is emerging as a potential diagnostic tool for cognitive decline. The 'Deep and Frequent Phenotyping for Experimental Medicine in Dementia Study' (D&FP) is a multicenter feasibility study embedded in the United Kingdom Dementia Platform designed to determine participant acceptability and feasibility of extensive and repeated phenotyping to determine the optimal combination of biomarkers to detect disease progression and identify early risk of Alzheimer's disease (AD). Gait is included as a clinical biomarker. The tools to quantify gait in the clinic and home, and suitability for multi-center application have not been examined. Six centers from the National Institute for Health Research Translational Research Collaboration in Dementia initiative recruited 20 individuals with early onset AD. Participants wore a single wearable (tri-axial accelerometer) and completed both clinic-based and free-living gait assessment. A series of macro (behavioral) and micro (spatiotemporal) characteristics were derived from the resultant data using previously validated algorithms. Results indicate good participant acceptability, and potential for use of body-worn sensors in both the clinic and the home. Recommendations for future studies have been provided. Gait has been demonstrated to be a feasible and suitable measure, and future research should examine its suitability as a biomarker in AD.

%B J Alzheimers Dis %V 63 %P 331-341 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614664?dopt=Abstract %R 10.3233/JAD-171116 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Gamma Band Neural Stimulation in Humans and the Promise of a New Modality to Prevent and Treat Alzheimer's Disease. %A McDermott, Barry %A Porter, Emily %A Hughes, Diarmaid %A McGinley, Brian %A Lang, Mark %A O'Halloran, Martin %A Jones, Marggie %X

Existing treatments for Alzheimer's disease (AD) have questionable efficacy with a need for research into new and more effective therapies to both treat and possibly prevent the condition. This review examines a novel therapeutic modality that shows promise for treating AD based on modulating neuronal activity in the gamma frequency band through external brain stimulation. The gamma frequency band is roughly defined as being between 30 Hz-100 Hz, with the 40 Hz point being of particular significance. The epidemiology, diagnostics, existing pathological models, and related current treatment targets are initially briefly reviewed. Next, the concept of external simulation triggering brain activity in the gamma band with potential demonstration of benefit in AD is introduced with reference to a recent important study using a mouse model of the disease. The review then presents a selection of relevant studies that describe the neurophysiology involved in brain stimulation by external sources, followed by studies involving application of the modality to clinical scenarios. A table summarizing the results of clinical studies applied to AD patients is also reported and may aid future development of the modality. The use of a therapy based on modulation of gamma neuronal activity represents a novel non-invasive, non-pharmacological approach to AD. Although use in clinical scenarios is still a relatively recent area of research, the technique shows good signs of efficacy and may represent an important option for treating AD in the future.

%B J Alzheimers Dis %V 65 %P 363-392 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040729?dopt=Abstract %R 10.3233/JAD-180391 %0 Journal Article %J J Alzheimers Dis %D 2018 %T GDF11 Rejuvenates Cerebrovascular Structure and Function in an Animal Model of Alzheimer's Disease. %A Zhang, Wei %A Guo, Yi %A Li, Bo %A Zhang, Qi %A Liu, Jian-Hui %A Gu, Guo-Jun %A Wang, Jin-Hong %A Bao, Rui-Kang %A Chen, Yu-Jie %A Xu, Jian-Rong %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Behavior, Animal %K Cerebral Amyloid Angiopathy %K Disease Models, Animal %K Growth Differentiation Factors %K Maze Learning %K Mice %K Mice, Transgenic %K Prefrontal Cortex %K Presenilin-1 %X

Cerebral amyloid angiopathy (CAA) is present in up to 90% of patients with Alzheimer's disease (AD), and may interact with classical neuropathology to exacerbate cognitive decline. Since growth differentiation factor 11 (GDF11) can activate vascular remodeling, we tested its effects on cognitive function and neuroinflammatory changes of AD model mice. We intravenously administered GDF11 or vehicle daily to 12-month-old transgenic mice overexpressing the amyloid-β protein precursor (AβPP)/PS1). Cognitive function was monitored using the Morris water maze, and after conclusion of the treatment, we assessed the morphology and presence of inflammatory markers in the cerebral vasculature. Subchronic treatment of adult AβPP/PS1 mice with GDF11 rescued cognitive function and ameliorated cerebrovascular function. In particular, the de novo genesis of small blood vessels and the expression of vascular-related proteins were significantly higher than in the vehicle-treated AβPP/PS1 mice, whereas the expressions of the inflammatory markers Iba-1 and GFAP significantly decreased in proportion to the lower ratio of two forms of amyloid-β (Aβ40/42). Daily intravenous treatment with GDF11-injection can rejuvenate respects of cognition and cerebrovascular changes in AD mice.

%B J Alzheimers Dis %V 62 %P 807-819 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480172?dopt=Abstract %R 10.3233/JAD-170474 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Gene Transfer Induced Hypercholesterolemia in Amyloid Mice. %A Grames, Mychal S %A Dayton, Robert D %A Lu, Xiaohong %A Schilke, Robert M %A Alexander, J Steven %A Orr, A Wayne %A Barmada, Sami J %A Woolard, Matthew D %A Klein, Ronald L %X

A risk factor for cardiovascular disease (CVD), mutant PCSK9, was expressed in APP/PS1 mice to study the CVD-Alzheimer's disease inter-relationship. Cholesterol levels were elevated by 5-6-fold from 3 to 13 weeks after PCSK9 gene transfer. We tested whether hypercholesterolemia would increase amyloid-β plaques at a relatively early stage of plaque deposition. Plaque burden was increased in the hippocampus of PCSK9 treated mice though the increase was modest compared to the large elevation in cholesterol. Elevating cholesterol via gene transfer could be valuable in a variety of disease models compared to making crosses with germ-line transgenic mouse models of CVD.

%B J Alzheimers Dis %V 65 %P 1079-1086 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30124449?dopt=Abstract %R 10.3233/JAD-180494 %0 Journal Article %J J Alzheimers Dis %D 2018 %T General Practice Clinical Data Help Identify Dementia Hotspots: A Novel Geospatial Analysis Approach. %A Bagheri, Nasser %A Wangdi, Kinley %A Cherbuin, Nicolas %A Anstey, Kaarin J %K Age Factors %K Aged %K Aged, 80 and over %K Australia %K Dementia %K Demography %K Epidemiological Monitoring %K Female %K General Practice %K Humans %K Male %K Retrospective Studies %K Sex Factors %K Topography, Medical %X

We have a poor understanding of whether dementia clusters geographically, how this occurs, and how dementia may relate to socio-demographic factors. To shed light on these important questions, this study aimed to compute a dementia risk score for individuals to assess spatial variation of dementia risk, identify significant clusters (hotspots), and explore their association with socioeconomic status. We used clinical records from 16 general practices (468 Statistical Area level 1 s, N = 14,746) from the city of west Adelaide, Australia for the duration of 1 January 2012 to 31 December 2014. Dementia risk was estimated using The Australian National University-Alzheimer's Disease Risk Index. Hotspot analyses were applied to examine potential clusters in dementia risk at small area level. Significant hotspots were observed in eastern and southern areas while coldspots were observed in the western area within the study perimeter. Additionally, significant hotspots were observed in low socio-economic communities. We found dementia risk scores increased with age, sex (female), high cholesterol, no physical activity, living alone (widow, divorced, separated, or never married), and co-morbidities such as diabetes and depression. Similarly, smoking was associated with a lower dementia risk score. The identification of dementia risk clusters may provide insight into possible geographical variations in risk factors for dementia and quantify these risks at the community level. As such, this research may enable policy makers to tailor early prevention strategies to the correct individuals within their precise locations.

%B J Alzheimers Dis %V 61 %P 125-134 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125484?dopt=Abstract %R 10.3233/JAD-170079 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Generation and Partial Characterization of Rabbit Monoclonal Antibody to Pyroglutamate Amyloid-β3-42 (pE3-Aβ). %A Mehta, Pankaj D %A Patrick, Bruce A %A Barshatzky, Marc %A Mehta, Sangita P %A Frackowiak, Janusz %A Mazur-Kolecka, Bozena %A Wegiel, Jerzy %A Wisniewski, Thomas %A Miller, David L %X

N-terminally truncated pyroglutamate amyloid-β (Aβ) peptide starting at position 3 represents a significant fraction of Aβ peptides (pE3-Aβ) in amyloid plaques of postmortem brains from patients with Alzheimer's disease (AD) and older persons with Down syndrome (DS). Studies in transgenic mouse models of AD also showed that pE3-Aβ is a major component of plaques, and mouse monoclonal antibody to pE3-Aβ appears to be a desirable therapeutic agent for AD. Since small peptides do not typically elicit a good immune response in mice, but do so favorably in rabbits, our aims were to generate and partially characterize a rabbit monoclonal antibody (RabmAb) to pE3-Aβ. The generated RabmAb was found to be specific for pE3-Aβ, since it showed no reactivity with Aβ16, Aβ40, Aβ42, Aβ3-11, and pE11-17 Aβ peptides in an enzyme linked immunosorbent assay (ELISA). The isotype of the antibody was found to be IgG class. The antibody possesses high affinity to pE3-Aβ with dissociation constant (KD) for the antibody of 1 nM. The epitope of the antibody lies within the sequence of pE3-FRHD. In dot blotting, the optimal detection of pE3-Aβ was at an antibody concentration of 0.5 μg/ml. The threshold of pE3-Aβ detection was 2 fmol. The antibody was sensitive enough to detect 10 pg/ml of pE3-Aβ in sandwich ELISA. pE3-Aβ was detected in AD and DS brain extracts in ELISA and immunoblotting. Immunohistological studies showed immunolabeling of plaques and blood vessels in brains from patients with AD, and DS showing AD pathology. Thus, the antibody can be widely applied in AD and DS research, and therapeutic applications.

%B J Alzheimers Dis %V 62 %P 1635-1649 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504532?dopt=Abstract %R 10.3233/JAD-170898 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Generation of a New Tau Knockout (tauΔex1) Line Using CRISPR/Cas9 Genome Editing in Mice. %A Tan, Daniel C S %A Yao, Sherilyn %A Ittner, Arne %A Bertz, Josefine %A Ke, Yazi D %A Ittner, Lars M %A Delerue, Fabien %X

Alzheimer's disease and other dementias present with tau pathology. Several mouse lines with knockout of the tau-encoding Mapt gene have been reported, yet findings often differed between lines and sites. Here, we report a new tau knockout strain (tauΔex1), generated by CRISPR/Cas9-mediated genome editing of intron -1/exon 1 of Mapt in C57Bl/6J mice. TauΔex1 mice had no overt phenotype, but, in line with previous models, they showed a significantly reduced susceptibility to excitotoxic seizures, with normal memory formation in young mice. This new in vivo resource will be made freely available to the research community.

%B J Alzheimers Dis %V 62 %P 571-578 %8 2018 %G eng %N 2 %R 10.3233/JAD-171058 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Genetic Heterogeneity of Alzheimer's Disease: Embracing Research Partnerships. %A Nacmias, Benedetta %A Bagnoli, Silvia %A Piaceri, Irene %A Sorbi, Sandro %X

Studies on the genetics of Alzheimer's disease (AD) have revealed the complexity and heterogeneity of the disease. All our studies have supported this evidence and contribute to the current understanding of the genetic architecture of AD. This report reviews the success of our investigations, focusing on the implications and importance of the genetics of AD, and demonstrates the relevance of research strategies embracing partnerships.

%B J Alzheimers Dis %V 62 %P 903-911 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103034?dopt=Abstract %R 10.3233/JAD-170570 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Genetic Interaction with Plasma Lipids on Alzheimer's Disease in the Framingham Heart Study. %A Peloso, Gina M %A Beiser, Alexa S %A DeStefano, Anita L %A Seshadri, Sudha %X

Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer's disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40-60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p = 0.006), but no interaction of the GRS with HDL-C (p = 0.458) or LDL-C (p = 0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p-value < 0.05 (rs11218343 and APOEɛ4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings.

%B J Alzheimers Dis %V 66 %P 1275-1282 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412497?dopt=Abstract %R 10.3233/JAD-180751 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Genetic Risk for Age-Related Cognitive Impairment Does Not Predict Cognitive Performance in Middle Age. %A Korthauer, Laura E %A Awe, Elizabeth %A Frahmand, Marijam %A Driscoll, Ira %X

Alzheimer's disease (AD) is characterized by memory loss and executive dysfunction, which correspond to structural changes to the medial temporal lobes (MTL) and prefrontal cortex (PFC), respectively. Given the overlap in cognitive deficits between healthy aging and the earliest stages of AD, early detection of AD remains a challenge. The goal of the present study was to study MTL- and PFC-dependent cognitive functioning in middle-aged individuals at genetic risk for AD or cognitive impairment who do not currently manifest any clinical symptoms. Participants (N = 150; aged 40-60 years) underwent genotyping of 47 single nucleotide polymorphisms (SNPs) in six genes previously associated with memory or executive functioning: APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT. They completed two MTL-dependent tasks, the virtual Morris Water Task (vMWT) and transverse patterning discriminations task (TPDT), and the PFC-dependent reversal learning task. Although age was associated with poorer performance on the vMWT and TPDT within this middle-aged sample, there were no genotype-associated differences in cognitive performance. Although the vMWT and TPDT may be sensitive to age-related changes in cognition, carriers of APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT risk alleles do not exhibit alteration in MTL- and PFC-dependent functioning in middle age compared to non-carriers.

%B J Alzheimers Dis %V 64 %P 459-471 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865048?dopt=Abstract %R 10.3233/JAD-171043 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Genetically Determined Serum Uric Acid and Alzheimer's Disease Risk. %A Yuan, Hongjuan %A Yang, Wenjie %X

To evaluate whether genetically increased serum uric acid levels influence the risk of Alzheimer's disease (AD), we used genome-wide significant single nucleotide polymorphisms for uric acid as the instrumental variables, and undertook a Mendelian randomization (MR) study to estimate the effect of uric acid on the risk of AD. The MR method prevents bias due to reverse causation (e.g., uric acid changes because of AD) and minimizes bias due to confounding of both measured and unmeasured confounders. We used the summary statistics from The International Genomics of Alzheimer's Project Consortium that is the largest AD genome-wide association study of 74,046 individuals of European ethnicity including 25,580 AD cases. We further performed sensitivity analyses to evaluate the assumptions of the MR method. The MR analyses did not support a causal role of genetically elevated serum uric acid on AD risk (odds ratio: 1.02, 95% confidence interval: 0.93-1.12, p = 0.65). Sensitivity analyses, including MR-Egger regression, suggested no strong evidence of bias due to pleiotropy. In conclusion, lifelong genetically increased serum uric acid levels have no protective effect on the risk of AD.

%B J Alzheimers Dis %V 65 %P 1259-1265 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149453?dopt=Abstract %R 10.3233/JAD-180538 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Genotyping of the Alzheimer's Disease Genome-Wide Association Study Index Single Nucleotide Polymorphisms in the Brains for Dementia Research Cohort. %A Brookes, Keeley J %A McConnell, George %A Williams, Kirsty %A Chaudhury, Sultan %A Madhan, Gaganjit %A Patel, Tulsi %A Turley, Christopher %A Guetta-Baranes, Tamar %A Bras, Jose %A Guerreiro, Rita %A Hardy, John %A Francis, Paul T %A Morgan, Kevin %X

The Brains for Dementia Research project is a recently established longitudinal cohort which aims to provide brain tissue for research purposes from neuropathologically defined samples. Here we present the findings from our analysis on the 19 established GWAS index SNPs for Alzheimer's disease, in order to demonstrate if the BDR sample also displays association to these variants. A highly significant association of the APOEɛ4 allele was identified (p = 3.99×10-12). Association tests for the 19 GWAS SNPs found that although no SNPs survive multiple testing, nominal significant findings were detected and concordance with the Lambert et al. GWAS meta-analysis was observed.

%B J Alzheimers Dis %V 64 %P 355-362 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914034?dopt=Abstract %R 10.3233/JAD-180191 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Geographical Distribution and Diversity of Gut Microbial NADH:Ubiquinone Oxidoreductase Sequence Associated with Alzheimer's Disease. %A Paley, Elena L %A Merkulova-Rainon, Tatiana %A Faynboym, Aleksandr %A Shestopalov, Valery I %A Aksenoff, Igor %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Anti-Bacterial Agents %K Biological Transport %K DNA Primers %K Electron Transport Complex I %K Feces %K Female %K Gastrointestinal Microbiome %K Geography %K Host-Pathogen Interactions %K Humans %K Male %K Middle Aged %K Sequence Analysis, DNA %K Young Adult %X

Earlier we reported induction of neurotoxicity and neurodegeneration by tryptophan metabolites that link the metabolic alterations to Alzheimer's disease (AD). Tryptophan is a product of Shikimate pathway (SP). Human cells lack SP, which is found in human gut bacteria exclusively using SP to produce aromatic amino acids (AAA). This study is a first attempt toward gene-targeted analysis of human gut microbiota in AD fecal samples. The oligonucleotide primers newly-designed for this work target SP-AAA in environmental bacteria associated with human activity. Using polymerase chain reaction (PCR), we found unique gut bacterial sequence in most AD patients (18 of 20), albeit rarely in controls (1 of 13). Cloning and sequencing AD-associated PCR products (ADPP) enables identification of Na(+)-transporting NADH: Ubiquinone reductase (NQR) in Clostridium sp. The ADPP of unrelated AD patients possess near identical sequences. NQR substrate, ubiquinone is a SP product and human neuroprotectant. A deficit in ubiquinone has been determined in a number of neuromuscular and neurodegenerative disorders. Antibacterial therapy prompted an ADPP reduction in an ADPP-positive control person who was later diagnosed with AD-dementia. We explored the gut microbiome databases and uncovered a sequence similarity (up to 97%) between ADPP and some healthy individuals from different geographical locations. Importantly, our main finding of the significant difference in the gut microbial genotypes between the AD and control human populations is a breakthrough.

%B J Alzheimers Dis %V 61 %P 1531-1540 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376868?dopt=Abstract %R 10.3233/JAD-170764 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Ginkgo biloba Extract EGb 761 and Its Specific Components Elicit Protective Protein Clearance Through the Autophagy-Lysosomal Pathway in Tau-Transgenic Mice and Cultured Neurons. %A Qin, Yiren %A Zhang, Yu %A Tomic, Inge %A Hao, Wenlin %A Menger, Michael D %A Liu, Chunfeng %A Fassbender, Klaus %A Liu, Yang %X

Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by extracellular amyloid-β (Aβ) deposits and intracellular neurofibrillary tangles (NFT) in many brain regions. NFT are primarily composed of hyperphosphorylated tau protein (p-Tau). Aβ and p-Tau are two major pathogenic molecules with tau acting downstream to Aβ to induce neuronal degeneration. In this study, we investigated whether Ginkgo biloba extract EGb 761 reduces cerebral p-Tau level and prevents AD pathogenesis. Human P301S tau mutant-transgenic mice were fed with EGb 761, added to the regular diet for 2 or 5 months. We observed that treatment with EGb 761 for 5 months significantly improved the cognitive function of mice, attenuated the loss of synaptophysin and recovered the phosphorylation of CREB in the mouse brain. Treatment with EGb 761 for 5 but not 2 months also decreased p-Tau protein amount and shifted microglial pro-inflammatory to anti-inflammatory activation in the brain. As potential therapeutic mechanisms, we demonstrated that treatment with EGb 761, especially the components of ginkgolide A, bilobalide, and flavonoids, but not with purified ginkgolide B or C, increased autophagic activity and degradation of p-Tau in lysosomes of neurons. Inhibiting ATG5 function or treating cells with Bafilomycin B1 abolished EGb 761-enhanced degradation of p-Tau in cultured neurons. Additionally, we observed that 5- instead of 2-month-treatment with EGb 761 inhibited the activity of p38-MAPK and GSK-3β. Therefore, long-term treatment with Ginkgo biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology through mechanisms against multiple AD pathogenic processes.

%B J Alzheimers Dis %V 65 %P 243-263 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010136?dopt=Abstract %R 10.3233/JAD-180426 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Glia Maturation Factor and Mast Cell-Dependent Expression of Inflammatory Mediators and Proteinase Activated Receptor-2 in Neuroinflammation. %A Kempuraj, Duraisamy %A Selvakumar, Govindhasamy Pushpavathi %A Thangavel, Ramasamy %A Ahmed, Mohammad Ejaz %A Zaheer, Smita %A Kumar, Keerthana Kuppamma %A Yelam, Anudeep %A Kaur, Harleen %A Dubova, Iuliia %A Raikwar, Sudhanshu P %A Iyer, Shankar S %A Zaheer, Asgar %X

Parkinson's disease (PD) is characterized by the presence of inflammation-mediated dopaminergic neurodegeneration in the substantia nigra. Inflammatory mediators from activated microglia, astrocytes, neurons, T-cells and mast cells mediate neuroinflammation and neurodegeneration. Administration of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induces PD like motor deficits in rodents. 1-methyl-4-phenylpyridinium (MPP+), a toxic metabolite of MPTP activates glial cells, neurons and mast cells to release neuroinflammatory mediators. Glia maturation factor (GMF), mast cells and proteinase activated receptor-2 (PAR-2) are implicated in neuroinflammation. Alpha-synuclein which induces neurodegeneration increases PAR-2 expression in the brain. However, the exact mechanisms are not yet understood. In this study, we quantified inflammatory mediators in the brains of MPTP-administered wild type (Wt), GMF-knockout (GMF-KO), and mast cell knockout (MC-KO) mice. Additionally, we analyzed the effect of MPP+, GMF, and mast cell proteases on PAR-2 expression in astrocytes and neurons in vitro. Results show that the levels of interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and the chemokine (C-C motif) ligand 2 (CCL2) were lesser in the brains of GMF-KO mice and MC-KO mice when compared to Wt mice brain after MPTP administration. Incubation of astrocytes and neurons with MPP+, GMF, and mouse mast cell protease-6 (MMCP-6) and MMCP-7 increased the expression of PAR-2. Our studies show that the absence of mast cells and GMF reduce the expression of neuroinflammatory mediators in the brain. We conclude that GMF along with mast cell interactions with glial cells and neurons during neuroinflammation can be explored as a new therapeutic target for PD and other neuroinflammatory disorders.

%B J Alzheimers Dis %V 66 %P 1117-1129 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30372685?dopt=Abstract %R 10.3233/JAD-180786 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Glucagon-Like Peptide-2 Receptor is Involved in Spatial Cognitive Dysfunction in Rats After Chronic Cerebral Hypoperfusion. %A Xie, Yan-Chun %A Yao, Zhao-Hui %A Yao, Xiao-Li %A Pan, Jian-Zhen %A Zhang, Shao-Feng %A Zhang, Yong %A Hu, Ji-Chang %X

Chronic cerebral hypoperfusion (CCH) affects the aging population and especially patients with neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. CCH is closely related to the cognitive dysfunction in these diseases. Glucagon-like peptide-2 receptor (GLP2R) mRNA and protein are highly expressed in the gut and in hippocampal neurons. This receptor is involved in the regulation of food intake and the control of energy balance and glucose homeostasis. The present study employed behavioral techniques, electrophysiology, western blotting, immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and Golgi staining to investigate whether the expression of GLP2R changes after CCH and whether GLP2R is involved in cognitive impairment caused by CCH. Our findings show that CCH significantly decreased hippocampal GLP2R mRNA and protein levels. GLP2R upregulation could prevent CCH-induced cognitive impairment. It also improved the CCH-induced impairment of long-term potentiation and long-term depression. Additionally, GLP2R modulated after CCH the AKT-mTOR-p70S6K pathway in the hippocampus. Moreover, an upregulation of the GLP2R increased the neurogenesis in the dentate gyrus, neuronal activity, and density of dendritic spines and mushroom spines in hippocampal neurons. Our findings reveal the involvement of GLP2R via a modulation of the AKT-mTOR-p70S6K pathway in the mechanisms underlying CCH-induced impairments of spatial learning and memory. We suggest that the GLP2R and the AKT-mTOR-p70S6K pathway in the hippocampus are promising targets to treat cognition deficits in CCH.

%B J Alzheimers Dis %V 66 %P 1559-1576 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30452417?dopt=Abstract %R 10.3233/JAD-180782 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Gradual Cerebral Hypoperfusion Impairs Fear Conditioning and Object Recognition Learning and Memory in Mice: Potential Roles of Neurodegeneration and Cholinergic Dysfunction. %A Mehla, Jogender %A Lacoursiere, Sean %A Stuart, Emily %A McDonald, Robert J %A Mohajerani, Majid H %K Animals %K Brain %K Carotid Stenosis %K Cerebrovascular Circulation %K Choline O-Acetyltransferase %K Conditioning (Psychology) %K Disease Models, Animal %K Fear %K Fluoresceins %K Learning Disorders %K Male %K Mice %K Mice, Inbred C57BL %K Phosphopyruvate Hydratase %K Postural Balance %K Recognition (Psychology) %X

In the present study, male C57BL/6J mice were subjected to gradual cerebral hypoperfusion by implanting an ameroid constrictor (AC) on the left common carotid artery (CCA) and a stenosis on the right CCA. In the sham group, all surgical procedures were kept the same except no AC was implanted and stenosis was not performed. One month following the surgical procedures, fear conditioning and object recognition tests were conducted to evaluate learning and memory functions and motor functions were assessed using a balance beam test. At the experimental endpoint, mice were perfused and brains were collected for immunostaining and histology. Learning and memory as well as motor functions were significantly impaired in the hypoperfusion group. The immunoreactivity to choline acetyltransferase was decreased in dorsal striatum and basal forebrain of the hypoperfusion group indicating that cholinergic tone in these brain regions was compromised. In addition, an increased number of Fluoro-Jade positive neurons was also found in cerebral cortex, dorsal striatum and hippocampus indicating neurodegeneration in these brain regions. Based on this pattern of data, we argued that this mouse model would be a useful tool to investigate the therapeutic interventions for the treatment of vascular dementia. Additionally, this model could be employed to exploit the effect of microvascular occlusions on cognitive impairment in the absence and presence of Alzheimer's disease pathology.

%B J Alzheimers Dis %V 61 %P 283-293 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154281?dopt=Abstract %R 10.3233/JAD-170635 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Growth Hormone-Releasing Hormone Modulation of Neuronal Exosome Biomarkers in Mild Cognitive Impairment. %A Winston, Charisse N %A Goetzl, Edward J %A Baker, Laura D %A Vitiello, Michael V %A Rissman, Robert A %X

Age-related changes in cognition are linked to decreased expression of somatotropins, GHRH and IGF-1. Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are heterogeneous conditions. The loss of GHRH signaling in the brain may be mechanistically involved in AD pathogenesis. The consequent need to identify AD at an early and perhaps more treatable stage has fueled research into blood-based, exosome biomarkers. Plasma exosomes from participants enrolled in a randomized, double-blind, placebo-controlled 20-week trial of GHRH administration, were isolated, precipitated, and enriched by immuno-absorption with anti-L1CAM antibody (neural adhesion protein) from adults with MCI and age-matched, cognitively normal controls (CNC). Extracted protein cargo from neuronally-derived exosomes (NDEs) were assessed by ELISAs for protein levels implicated in AD neuropathology and for synaptic proteins altered by AD. Plasma NDE concentrations of Aβ1-42 were significantly increased while plasma NDE concentrations of NRGN, synaptophysin, synaptotagmin, and synaptopodin were significantly decreased in patients with MCI, independent of GHRH treatment. Plasma NDE concentrations of ptau-S396 and GAP43 were not affected by cognitive status (CNC versus MCI) or by GHRH treatment. Aβ1-42, neurogranin (NRGN), synaptophysin, synaptotagmin, and synaptopodin demonstrated the highest diagnostic accuracy for distinguishing between CNC and MCI patients, while synaptophysin and synaptotagmin demonstrated moderate accuracy in distinguishing between placebo-treated and GHRH-treated, MCI patients.

%B J Alzheimers Dis %V 66 %P 971-981 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30372675?dopt=Abstract %R 10.3233/JAD-180302 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Gut Microbiome is Altered in Patients with Alzheimer's Disease. %A Zhuang, Zhen-Qian %A Shen, Lin-Lin %A Li, Wei-Wei %A Fu, Xue %A Zeng, Fan %A Gui, Li %A Lü, Yang %A Cai, Min %A Zhu, Chi %A Tan, Yin-Ling %A Zheng, Peng %A Li, Hui-Yun %A Zhu, Jie %A Zhou, Hua-Dong %A Bu, Xian-Le %A Wang, Yan-Jiang %X

Previous studies suggest that gut microbiota is associated with neuropsychiatric disorders, such as Parkinson's disease, amyotrophic lateral sclerosis, and depression. However, whether the composition and diversity of gut microbiota is altered in patients with Alzheimer's disease (AD) remain largely unknown. In the present study, we collected fecal samples from 43 AD patients and 43 age- and gender-matched cognitively normal controls. 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. The composition of gut microbiota was different between the two groups. Several bacteria taxa in AD patients were different from those in controls at taxonomic levels, such as Bacteroides, Actinobacteria, Ruminococcus, Lachnospiraceae, and Selenomonadales. Our findings suggest that gut microbiota is altered in AD patients and may be involved in the pathogenesis of AD.

%B J Alzheimers Dis %V 63 %P 1337-1346 %8 2018 May 30 %G eng %N 4 %& 1337 %R 10.3233/JAD-180176 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The GWAS Risk Genes for Depression May Be Actively Involved in Alzheimer's Disease. %A Ni, Hua %A Xu, Min %A Zhan, Gui-Lai %A Fan, Yu %A Zhou, Hejiang %A Jiang, Hong-Yan %A Lu, Wei-Hong %A Tan, Liwen %A Zhang, Deng-Feng %A Yao, Yong-Gang %A Zhang, Chen %X

Depression is one of the most frequent psychiatric symptoms observed in people during the development of Alzheimer's disease (AD). We hypothesized that genetic factors conferring risk of depression might affect AD development. In this study, we screened 31 genes, which were located in 19 risk loci for major depressive disorder (MDD) identified by two recent large genome-wide association studies (GWAS), in AD patients at the genomic and transcriptomic levels. Association analysis of common variants was performed by using summary statistics of the International Genomics of Alzheimer's Project (IGAP), and association analysis of rare variants was conducted by sequencing the entire coding region of the 31 MDD risk genes in 107 Han Chinese patients with early-onset and/or familial AD. We also quantified the mRNA expression alterations of these MDD risk genes in brain tissues of AD patients and AD mouse models, followed by protein-protein interaction network prediction to show their potential effects in AD pathways. We found that common and rare variants of L3MBTL2 were significantly associated with AD. mRNA expression levels of 18 MDD risk genes, in particular SORCS3 and OAT, were differentially expressed in AD brain tissues. 13 MDD risk genes were predicted to physically interact with core AD genes. The involvement of HACE1, NEGR1, and SLC6A15 in AD was supported by convergent lines of evidence. Taken together, our results showed that MDD risk genes might play an active role in AD pathology and supported the notion that depression might be the "common cold" of psychiatry.

%B J Alzheimers Dis %V 64 %P 1149-1161 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010129?dopt=Abstract %R 10.3233/JAD-180276 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Harpagoside Rescues the Memory Impairments in Chronic Cerebral Hypoperfusion Rats by Inhibiting PTEN Activity. %A Chen, Chen %A Zhang, Haifeng %A Xu, Hongliang %A Xue, Rui %A Zheng, Yake %A Wu, Tianwen %A Lian, Yajun %X

Vascular dementia (VaD) is the second most common dementia worldwide. Unlike Alzheimer's disease, VaD does not yet have effective therapeutic drugs. Harpagoside is the most important component extracted from Harpagophytum procumbens, a traditional Chinese medicine that has been widely used. The neuroprotective effects of harpagoside have been studied in Aβ- and MPTP-induced neurotoxicity. However, whether harpagoside is protective against VaD is not clear. In this study, with the use of chronic cerebral hypoperfusion rats, a well-known VaD model, we demonstrated that chronic administration (two months) of harpagoside was able to restore both the spatial learning/memory and fear memory impairments. Importantly, the protective effects of harpagoside were not due to alterations in the physiological conditions, metabolic parameters, or locomotor abilities of the rats. Meanwhile, we found that harpagoside suppressed the overactivation of PTEN induced by CCH by enhancing PTEN phosphorylation. Furthermore, harpagoside elevated the activity of Akt and inhibited the activity of GSK-3β, downstream effectors of PTEN. Overall, our study suggested that harpagoside treatment might be a potential therapeutic drug targeting the cognitive impairments of VaD.

%B J Alzheimers Dis %V 63 %P 445-455 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614669?dopt=Abstract %R 10.3233/JAD-171170 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Healthy versus Entorhinal Cortical Atrophy Identification in Asymptomatic APOE4 Carriers at Risk for Alzheimer's Disease. %A Konishi, Kyoko %A Joober, Ridha %A Poirier, Judes %A MacDonald, Kathleen %A Chakravarty, Mallar %A Patel, Raihaan %A Breitner, John %A Bohbot, Véronique D %K Aged %K Alleles %K Alzheimer Disease %K Apolipoprotein E4 %K Atrophy %K Case-Control Studies %K Entorhinal Cortex %K Female %K Heterozygote %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Risk Factors %K Spatial Memory %X

Early detection of Alzheimer's disease (AD) has been challenging as current biomarkers are invasive and costly. Strong predictors of future AD diagnosis include lower volume of the hippocampus and entorhinal cortex, as well as the ɛ4 allele of the Apolipoprotein E gene (APOE) gene. Therefore, studying functions that are critically mediated by the hippocampus and entorhinal cortex, such as spatial memory, in APOE ɛ4 allele carriers, may be key to the identification of individuals at risk of AD, prior to the manifestation of cognitive impairments. Using a virtual navigation task developed in-house, specifically designed to assess spatial versus non-spatial strategies, the current study is the first to differentiate functional and structural differences within APOE ɛ4 allele carriers. APOE ɛ4 allele carriers that predominantly use non-spatial strategies have decreased fMRI activity in the hippocampus and increased atrophy in the hippocampus, entorhinal cortex, and fimbria compared to APOE ɛ4 allele carriers who use spatial strategies. In contrast, APOE ɛ4 allele carriers who use spatial strategies have grey matter levels comparable to non-APOE ɛ4 allele carriers. Furthermore, in a leave-one-out analysis, grey matter in the entorhinal cortex could predict navigational strategy with 92% accuracy.

%B J Alzheimers Dis %V 61 %P 1493-1507 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29278888?dopt=Abstract %R 10.3233/JAD-170540 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Hedonic Assessment of Odors: A Comparison of Two Sensory Scales for Use with Alzheimer's Disease Patients and Elderly Individuals. %A Atanasova, Boriana %A Mondon, Karl %A Dreyfuss, Lise %A Beaufils, Emilie %A Desmidt, Thomas %A Hommet, Caroline %A El-Hage, Wissam %A Belzung, Catherine %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Humans %K Linear Models %K Male %K Olfaction Disorders %K Olfactory Perception %K Severity of Illness Index %K Smell %X

BACKGROUND: Several clinical studies concerning the olfactory function of patients with cognitive impairment have used sensory scales to investigate hedonic perception. However, no study has focused on the choice of the most appropriate sensory hedonic scale for the individuals with neurodegenerative disorders or other psychiatric diseases involving cognitive deficits.

OBJECTIVE: The aim of this study was to investigate the ability of patients with Alzheimer's disease (AD) to use two hedonic scales (category scale and linear scale) and compare their discriminatory capacity, repeatability, and ease of use. This should allow us to identify the most appropriate hedonic scale for patients with AD.

METHODS: We recruited 18 patients with mild to moderate AD, and 20 healthy volunteers matched for gender, age, smoking status, and educational level. The participants underwent a clinical assessment and hedonic evaluation of three odorants (pleasant, unpleasant, and neutral), using a five-point category scale and a 10-cm linear scale with a marked mid-point.

RESULTS: AD patients were able to use hedonic scales as well as paired healthy elderly subjects. The linear scale performed slightly better in terms of ease of use for both patients and healthy controls and discriminatory capacity for AD patients. The results for AD patients and controls with both scales were repeatable.

CONCLUSION: The linear scale may be more appropriate for AD patients pending further studies involving a larger population of patients, using several odorants.

%B J Alzheimers Dis %V 61 %P 929-938 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254084?dopt=Abstract %R 10.3233/JAD-170433 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Heme Oxygenase 1 Induces Tau Oligomer Formation and Synapse Aberrations in Hippocampal Neurons. %A Si, Zizhen %A Wang, Xidi %A Zhang, Zhujun %A Wang, Jinxin %A Li, Jihong %A Li, Jing %A Li, Ling %A Li, Yuanxin %A Peng, Yahui %A Sun, Chongran %A Hui, Yang %A Gao, Xu %X

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by behavioral changes and cognitive decline. Recent evidence suggests that it is the soluble forms of tau oligomers (Tau-O) and Aβ oligomers (oAβ) rather than the well-studied insoluble protein aggregates that possess the neurotoxicity, infectivity, and amplification underlying disease progression. Heme oxygenase 1 (HO-1), an inducible enzyme upregulated in the cortex and hippocampus of AD brains, was reported to damage neural structures and disrupt brain function, suggesting possible contributions to Tau-O-mediated neurodegeneration. In this study, we focused on the effects of HO-1 on Tau-O formation. In hippocampus of HO-1-overexpressing transgenic mice and neural 2a (N2a) cells, Tau-O was co-localized with HO-1 as visualized by immunofluorescence staining. Furthermore, primary cultured hippocampal neurons from HO-1 transgenic mice showed elevated Tau-O and concomitant reductions in spine density and length as well as dendritic length, diameter, and arborization. Blocking Tau-O formation by isoprenaline reversed these HO-1-induced morphological changes. These results indicated that HO-1 contributes to Tau-O formation and ensuing synaptic damage. Thus, HO-1 is a promising target for AD drug development.

%B J Alzheimers Dis %8 2018 Jul 19 %G eng %R 10.3233/JAD-180451 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Heparin Modulates the Kinetics of Zinc-Induced Aggregation of Amyloid-β Peptides. %A Radko, Sergey P %A Khmeleva, Svetlana A %A Mantsyzov, Alexey B %A Kiseleva, Yana Y %A Mitkevich, Vladimir A %A Kozin, Sergey A %A Makarov, Alexander A %X

Zinc-induced aggregation of amyloid-β peptides (Aβ) is considered to contribute to the pathogenesis of Alzheimer's disease. While glycosaminoglycans (GAGs) that are commonly present in interneuronal space are known to enhance Aβ self-aggregation in vitro, the impact of GAGs on the formation of zinc-induced amorphous Aβ aggregates has not yet been thoroughly studied. Here, employing dynamic light scattering, bis-ANS fluorimetry, and sedimentation assays, we demonstrate that heparin serving as a representative GAG modulates the kinetics of zinc-induced Aβ42 aggregation in vitro by slowing the rate of aggregate formation and aggregate size growth. By using synthetic Aβ16 peptides to model the Aβ metal-binding domain (MBD), heparin was found to effectively interact with MBDs in complex with zinc ions. We suggest that heparin adsorbs to the surface of growing zinc-induced Aβ42 aggregates via electrostatic interactions, thus creating a steric hindrance that inhibits further inclusion of monomeric and/or oligomeric zinc-Aβ42 complexes. Furthermore, the adsorbed heparin can interfere with the zinc-bridging mechanism of Aβ42 aggregation, requiring the formation of two zinc-mediated interaction interfaces in the MBD. As revealed by computer simulations of the zinc-Aβ16 homodimer complexed with a heparin chain, heparin can interact with the MBD via polar contacts with residues Arg-5 and Tyr-10, resulting in a conformational rearrangement that hampers the formation of the second zinc-mediated interaction in the MBD interface. The findings of this study suggest that GAGs, which are common in the in vivo macromolecular environment, may have a substantial impact on the time course of zinc-induced Aβ aggregation.

%B J Alzheimers Dis %V 63 %P 539-550 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29630553?dopt=Abstract %R 10.3233/JAD-171120 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Heritability of Frontotemporal Lobar Degeneration: Validation of Pedigree Classification Criteria in a Northern Italy Cohort. %A Fostinelli, Silvia %A Ciani, Miriam %A Zanardini, Roberta %A Zanetti, Orazio %A Binetti, Giuliano %A Ghidoni, Roberta %A Benussi, Luisa %K Age of Onset %K Aged %K C9orf72 Protein %K Cohort Studies %K Female %K Frontotemporal Lobar Degeneration %K Genetic Counseling %K Genetic Testing %K Humans %K Italy %K Male %K Middle Aged %K Mutation %K Pedigree %K Progranulins %K tau Proteins %X

A large portion of frontotemporal lobar degeneration (FTLD) patients has a family history of disease and the presence of a pathogenic mutation confirms the clinical diagnosis. Recently, standardized criteria to evaluate FTLD pedigree, based on first- and second-degree affected relatives, their age at onset, and clinical phenotype, were proposed and validated in an American cohort. Herein we applied these criteria to 402 Italian FTLD pedigrees and assessed mutation frequencies in GRN, C9orf72, and MAPT genes with the aim of validating these criteria. Moreover, we evaluated whether genetic counseling requests reflect the estimated family risk. 12.4% of pedigrees had high family history, 6.5% medium, 15.4% low; 39% were apparent sporadic cases and 26.6% had family history of unknown significance. Mutations frequencies were in line with the categorization proposed: the highest rate was found in the most at-risk families (74%) and decreased in other categories (medium: 15.4%; low: 9.7%; sporadic: 1.3%). Mutation carriers with unknown family history (5.6%) were mostly early-onset patients. Detected mutation frequency was comparable with the US-cohort (13.7%), but mutations distribution among genes was different, with higher frequency of GRN mutations (9.4%) in our cohort. An elevated proportion of FTLD patients belonging to "high risk" pedigrees asked for genetic counseling (42%); requests decreased according to the estimated family risk (medium: 26.9%; low: 17.7%; sporadic: 5.1%). In conclusion, the proposed pedigree classification criteria, herein further validated, should be incorporated in the FTLD diagnostic work-up. Moreover, our data suggest to extend genetic screening to early-onset patients with unknown family history.

%B J Alzheimers Dis %V 61 %P 753-760 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226869?dopt=Abstract %R 10.3233/JAD-170661 %0 Journal Article %J J Alzheimers Dis %D 2018 %T High Caregiver Burden in Young Onset Dementia: What Factors Need Attention? %A Lim, Linda %A Zhang, Angeline %A Lim, Levinia %A Choong, Tanya-Marie %A Silva, Eveline %A Ng, Adeline %A Kandiah, Nagaendran %K Adaptation, Psychological %K Age of Onset %K Aged %K Aged, 80 and over %K Behavioral Symptoms %K Caregivers %K Cost of Illness %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Stress, Psychological %K Surveys and Questionnaires %X

BACKGROUND: There is an increase in prevalence of young onset dementia (YOD). The specific problems among YOD patients and levels of caregiver burden (CB) in this group warrants further evaluation.

OBJECTIVE: To evaluate and compare level of CB in YOD and late onset dementia (LOD). Also, we sought to understand the specific factors, such as neuropsychiatric symptoms, that may affect the levels of caregiver burden in the YOD group.

METHODS: Patient-caregiver dyads with YOD and LOD were recruited from a tertiary neurology center. Levels of CB between YOD and LOD were compared among 183 patient-caregiver dyads. CB was quantified using the Zarit Burden Inventory (ZBI). Neuropsychological evaluations as well as the Neuropsychiatric Inventory were performed. Factors that influenced level of CB in YOD group was investigated with regression analyses.

RESULTS: There were 57 YOD and 126 LOD dyads. Caregivers of YOD subjects reported significantly higher levels of burden compared to caregivers of LOD subjects (ZBI: 17.3 versus 13.94; p = 0.015). 52.6% of YOD caregivers reported a high caregiver burden. When compared to caregivers of LOD, the odds of a caregiver of YOD reporting high caregiver burden was 2.34 (95% CI: 1.22-4.49: p = 0.010). YOD dyads with a high caregiver burden had significantly higher neuropsychiatric inventory scores. Risk factors for high caregiver burden in YOD included family history of dementia and behavioral symptoms including disinhibited behavior, delusions, and apathy.

CONCLUSION: Targeted support for caregivers of patients with YOD is needed to address the higher CB in this group.

%B J Alzheimers Dis %V 61 %P 537-543 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171995?dopt=Abstract %R 10.3233/JAD-170409 %0 Journal Article %J J Alzheimers Dis %D 2018 %T High-Density Lipoprotein Subclasses and Mild Cognitive Impairment: Study of Outcome and aPolipoproteins in Dementia (STOP-Dementia)1. %A Ohtani, Ryo %A Nirengi, Shinsuke %A Nakamura, Michikazu %A Murase, Nagako %A Sainouchi, Makoto %A Kuwata, Yasuhiro %A Takata, Masaki %A Masuda, Yuuichi %A Kotani, Kazuhiko %A Sakane, Naoki %X

BACKGROUND: High-density lipoprotein (HDL) containing apolipoprotein A-I is associated with the pathogenesis of Alzheimer's disease (AD). HDL particle size is modified in the presence of pathological conditions, while the significance of the HDL particle size remains controversial.

OBJECTIVE: The aim of this study was to investigate the HDL lipoprotein subclasses in mild cognitive impairment (MCI) and AD.

METHODS: This cross-sectional study included 20 AD patients, 17 MCI patients, and 17 age-matched controls without cognitive impairment, selected from the database of the Study of Outcome and aPolipoproteins in Dementia (STOP-Dementia) registry. The diagnoses of AD and MCI were performed by expert neurologists according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition criteria. Serum HDL subclasses were measured by electrophoretic separation of lipoproteins using the Lipoprint System. The neutrophil-lymphocyte ratio (NLR), a marker of inflammation, was calculated by dividing the neutrophil count by the lymphocyte count.

RESULTS: Small-sized HDL particle levels in the MCI group were significantly higher than in the control group, although there was no difference in serum HDL-cholesterol levels between MCI and control groups. NLR in the MCI group was higher than in the control group, but this difference was non-significant (p = 0.09). There was no difference in HDL subclasses or NLR between the AD and control groups.

CONCLUSION: These findings suggest that HDL subclasses might be associated with the development of MCI.

%B J Alzheimers Dis %V 66 %P 289-296 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30248050?dopt=Abstract %R 10.3233/JAD-180135 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Higher Blood Vitamin C Levels are Associated with Reduction of Apolipoprotein E E4-related Risks of Cognitive Decline in Women: The Nakajima Study. %A Noguchi-Shinohara, Moeko %A Abe, Chiemi %A Yuki-Nozaki, Sohshi %A Dohmoto, Chiaki %A Mori, Ayaka %A Hayashi, Koji %A Shibata, Syutaro %A Ikeda, Yoshihisa %A Sakai, Kenji %A Iwasa, Kazuo %A Yokogawa, Masami %A Ishimiya, Mai %A Nakamura, Hiroyuki %A Yokoji, Hidehiro %A Komai, Kiyonobu %A Nakamura, Hiroyuki %A Yamada, Masahito %X

BACKGROUND: Antioxidants like vitamins C and E may minimize the risk for Alzheimer's disease.

OBJECTIVE: We examined whether vitamins C and E modify the apolipoprotein E (APOE) E4-related risks for developing cognitive decline.

METHODS: We conducted a population-based prospective study including Japanese residents aged 65 years from Nakajima, Japan. The participants received an evaluation of cognitive function and underwent blood tests including tests for vitamins C and E levels and APOE phenotypes. The APOE E4-by-gender-by-vitamin C or E interactions on developing cognitive decline were analyzed.

RESULTS: Of 606 participants with normal cognitive function determined using a baseline survey (2007-2008), 349 completed the follow up survey between 2014 and 2016. In women with APOE E4, significantly reduced risk for cognitive decline was observed for the highest blood vitamin C concentration tertile [multivariate OR 0.10 (95% CI 0.01-0.93)] compared with the lowest tertile. In men without APOE E4, significantly reduced risk for cognitive decline was observed for the highest blood vitamin E concentration tertile [multivariate OR 0.19 (0.05-0.74)] as compared with the lowest tertile.

CONCLUSION: Our results demonstrate significant beneficial effects of vitamins C and E in reducing the risk of cognitive decline in women with APOE E4 and men without APOE E4, respectively.

%B J Alzheimers Dis %V 63 %P 1289-1297 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758939?dopt=Abstract %R 10.3233/JAD-170971 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Hippocampal Sclerosis in the Oldest Old: A Finnish Population-Based Study. %A Kero, Mia %A Raunio, Anna %A Polvikoski, Tuomo %A Tienari, Pentti J %A Paetau, Anders %A Myllykangas, Liisa %X

BACKGROUND: There are only few population-based studies that have systemically investigated the prevalence of hippocampal sclerosis (HS) in the very old. The frequency of unilateral versus bilateral HS has been rarely studied.

OBJECTIVE: We investigated the prevalence and laterality of HS and its association with other neurodegenerative and vascular pathologies in a population-based sample of very elderly. Furthermore, the concomitant presence of immunoreactivity for TDP-43, p62, and HPtau was studied.

METHODS: The population-based Vantaa 85+ study includes all inhabitants of the city of Vantaa, who were >85 years in 1991 (n = 601). Neuropathological assessment was possible in 302 subjects. Severity of neuronal loss of CA sectors and subiculum was determined bilaterally by HE- staining. Immunohistochemistry performed using antibodies for TDP-43, p62, and HPtau.

RESULTS: Neuronal loss and pathological changes in the hippocampus sector CA1 and subiculum were observed in 47 of the 302 individuals (16%), and 51% of these changes were bilateral. HS without comorbid neurodegenerative pathology was found in 1/47 subjects with HS (2%). Dementia (p < 0.001) and TDP-43 immunopositivity of the granular cell layer of the dentate fascia (p < 0.001) were strongly associated with HS. The CERAD score, immunopositivity for HPtau and p62 in the granular cell layer of the fascia dentate were also associated.

CONCLUSION: HS is prevalent (16%) in the oldest old population, but HS without any comorbid neurodegenerative pathology is rare. The high frequency of unilateral HS (49%) implied that bilateral sampling of hippocampi should be routine practice in neuropathological examination.

%B J Alzheimers Dis %V 63 %P 263-272 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614661?dopt=Abstract %R 10.3233/JAD-171068 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Hippocampal Stratum Radiatum, Lacunosum, and Moleculare Sparing in Mild Cognitive Impairment. %A Su, Li %A Hayes, Lawrence %A Soteriades, Soteris %A Williams, Guy %A Brain, Susannah A E %A Firbank, Michael J %A Longoni, Giulia %A Arnold, Robert J %A Rowe, James B %A O'Brien, John T %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Atrophy %K Cognitive Dysfunction %K Disease Progression %K Entorhinal Cortex %K Female %K Hippocampus %K Humans %K Imaging, Three-Dimensional %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Reproducibility of Results %X

BACKGROUND: Alzheimer's disease (AD) is associated with atrophy in entorhinal cortex (ERC), the hippocampus, and its subfields Cornu Ammonis 1 (CA1) and subiculum, which predict conversion from mild cognitive impairment (MCI) to clinical AD. The stratum radiatum, lacunosum, and moleculare (SRLM) are also important gateways involving ERC and CA1, which are affected by early AD pathology.

OBJECTIVE: To assess whether the SRLM is affected in MCI and AD.

METHODS: In this proof-of-concept study, 27 controls, 13 subjects with AD, and 22 with MCI underwent 3T MRI. T1 maps were used for whole-hippocampal volumetry, T2 maps were segmented for hippocampal subfield areas, entorhinal cortex and subiculum thickness, and evaluated for SRLM integrity.

RESULTS: Significant CA1 atrophy and subiculum thinning were found in both AD and MCI compared to similarly aged controls. However, SRLM integrity was only significantly reduced in AD but not in MCI compared to controls. There were no significant differences in other hippocampal subfields (CA2, CA3/dentate gyrus) or ERC thickness between the groups. Finally, CA1 and CA3/DG areas and SRLM clarity were correlated with clinical and cognitive measurements of disease severity.

CONCLUSION: Although this study was cross sectional, it suggests a progression of specific subfield changes from MCI to established AD that is associated with the reduced integrity of SRLM, which may reflect more widespread hippocampal involvement as the disease progresses and the relative preservation of SRLM in MCI. These results provide new MRI biomarkers for disease staging and understanding of the neurobiology in AD.

%B J Alzheimers Dis %V 61 %P 415-424 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171994?dopt=Abstract %R 10.3233/JAD-170344 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Hippocampal Subfield Volumetry: Differential Pattern of Atrophy in Different Forms of Genetic Frontotemporal Dementia. %A Bocchetta, Martina %A Iglesias, Juan Eugenio %A Scelsi, Marzia A %A Cash, David M %A Cardoso, M Jorge %A Modat, Marc %A Altmann, Andre %A Ourselin, Sebastien %A Warren, Jason D %A Rohrer, Jonathan D %X

BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder, with a strong genetic component. Previous research has shown that medial temporal lobe atrophy is a common feature of FTD. However, no study has so far investigated the differential vulnerability of the hippocampal subfields in FTD.

OBJECTIVES: We aimed to investigate hippocampal subfield volumes in genetic FTD.

METHODS: We in6/2/2018vestigated hippocampal subfield volumes in a cohort of 75 patients with genetic FTD (age: mean (standard deviation) 59.3 (7.7) years; disease duration: 5.1 (3.4) years; 29 with MAPT, 28 with C9orf72, and 18 with GRN mutations) compared with 97 age-matched controls (age: 62.1 (11.1) years). We performed a segmentation of their volumetric T1-weighted MRI scans to extract hippocampal subfields volumes. Left and right volumes were summed and corrected for total intracranial volumes.

RESULTS: All three groups had smaller hippocampi than controls. The MAPT group had the most atrophic hippocampi, with the subfields showing the largest difference from controls being CA1-4 (24-27%, p < 0.0005). For C9orf72, the CA4, CA1, and dentate gyrus regions (8-11%, p < 0.0005), and for GRN the presubiculum and subiculum (10-14%, p < 0.0005) showed the largest differences from controls.

CONCLUSIONS: The hippocampus was affected in all mutation types but a different pattern of subfield involvement was found in the three genetic groups, consistent with differential cortical-subcortical network vulnerability.

%B J Alzheimers Dis %V 64 %P 497-504 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889066?dopt=Abstract %R 10.3233/JAD-180195 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Histological and Behavioral Phenotypes of a Novel Mutated APP Knock-In Mouse. %A Plucińska, Kaja %A Crouch, Barry %A Yeap, Jie M %A Stoppelkamp, Sandra %A Riedel, Gernot %A Platt, Bettina %X

Gene mutations within amyloid precursor protein (APP or AβPP) and/or presenilin 1 (PS1) genes are determinants of familial Alzheimer's disease (fAD) and remain fundamental for experimental models. Here, we generated a neuronal knock-in mouse (PLB2APP) with mutated human APPSwe/Lon and investigated histopathology and behavioral phenotypes. Additionally, PLB2APP mice were cross-bred with a presenilin (PS1A246E) line to assess the impact of this gene combination. Immunohistochemistry determined amyloid-β (Aβ) pathology, astrogliosis (via GFAP labelling), and neuronal densities in hippocampal and cortical brain regions. One-year old PLB2APP mice showed higher levels of intracellular Aβ in CA1, dentate gyrus, and cortical regions compared to PLBWT controls. Co-expression of PS1 reduced hippocampal but elevated cortical Aβ build-up. Amyloid plaques were sparse in aged PLB2APP mice, and co-expression of PS1 promoted plaque formation. Heightened GFAP expression followed the region-specific pattern of Aβ in PLB2APP and PLB2APP/PS1 mice. Behaviorally, habituation to a novel environment was delayed in 6-month-old PLB2APP mice, and overall home-cage activity was reduced in both lines at 6 and 12 months, particularly during the dark phase. Spatial learning in the water maze was impaired in PLB2APP mice independent of PS1 expression and associated with reduced spatial navigation strategies. Memory retrieval was compromised in PLB2APP mice only. Our data demonstrate that low expression of APP is sufficient to drive histopathological and cognitive changes in mice without overexpression or excessive plaque deposition. AD-like phenotypes were altered by co-expression of PS1, including a shift from hippocampal to cortical Aβ pathology, alongside reduced deficits in spatial learning.

%B J Alzheimers Dis %V 65 %P 165-180 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040726?dopt=Abstract %R 10.3233/JAD-180336 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Homocysteine and Cerebral Atrophy: The Epidemiology of Dementia in Singapore Study. %A Tan, Bryce %A Venketasubramanian, Narayanaswamy %A Vrooman, Henri %A Cheng, Ching-Yu %A Wong, Tien Yin %A Ikram, Mohammad Kamran %A Chen, Christopher %A Hilal, Saima %K Aged %K Atrophy %K Biomarkers %K Dementia %K Female %K Homocysteine %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Organ Size %K Risk Factors %K Singapore %K White Matter %X

BACKGROUND: Plasma homocysteine levels are increasingly studied as a potential risk factor for dementia. Elevated homocysteine levels have been linked with gray and white matter volume reduction among individuals with mild cognitive impairment and Alzheimer's disease. However, the effects of homocysteine on brain changes in preclinical stages of dementia remain unexplored.

OBJECTIVE: To examine the association of elevated homocysteine levels with markers of neurodegeneration, i.e., white and gray matter volume in an elderly population.

METHODS: The study included 768 participants (mean age: 69.6±6.5 years, 51.3% women) from the Epidemiology of Dementia In Singapore study. Participants underwent a brain MRI scan and blood tests. Serum homocysteine was measured using competitive immunoassay. Cortical thickness and subcortical structural volume were quantified using FreeSurfer whereas white matter volume was quantified using a previous validated method.

RESULTS: Higher homocysteine levels were significantly associated with decreased global white matter volume [mean difference (β) in volume (ml) per micromole per liter (μmol/l) increase in homocysteine levels: - 0.555, 95% Confidence Interval (CI): - 0.873; - 0.237], decreased parietal cortical thickness [β in thickness (μm) per μmol/l increase in homocysteine levels:- 1.429, 95% CI: - 2.781; - 0.077], and smaller volumes of the thalamus [β: - 0.017, 95% CI: - 0.026; - 0.008], brainstem [β: - 0.037, 95% CI: - 0.058; - 0.016], and accumbens [β: - 0.004, 95% CI: - 0.006; - 0.002].

CONCLUSION: Higher homocysteine levels were associated with cerebral atrophy. Further studies are required to assess whether lowering plasma homocysteine levels may prevent neurodegenerative changes or delay progression of clinical symptoms before the development of dementia.

%B J Alzheimers Dis %V 62 %P 877-885 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480177?dopt=Abstract %R 10.3233/JAD-170796 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Homocysteine and Dementia: An International Consensus Statement. %A Smith, A David %A Refsum, Helga %A Bottiglieri, Teodoro %A Fenech, Michael %A Hooshmand, Babak %A McCaddon, Andrew %A Miller, Joshua W %A Rosenberg, Irwin H %A Obeid, Rima %K Cognition %K Cognitive Dysfunction %K Consensus %K Dementia %K Dietary Supplements %K Homocysteine %K Humans %K Meta-Analysis as Topic %K Review Literature as Topic %K Risk Factors %K Vitamin B Complex %X

Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer's disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 μmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia.

%B J Alzheimers Dis %V 62 %P 561-570 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad171042?id=journal-of-alzheimers-disease%2Fjad171042 %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480200?dopt=Abstract %R 10.3233/JAD-171042 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Honokiol Alleviates Cognitive Deficits of Alzheimer's Disease (PS1V97L) Transgenic Mice by Activating Mitochondrial SIRT3. %A Li, Haitao %A Jia, Jianping %A Wang, Wei %A Hou, Tingting %A Tian, Yuanruhua %A Wu, Qiaoqi %A Xu, Lingzhi %A Wei, Yiping %A Wang, Xiu %X

Accumulating evidence has demonstrated that mitochondrial dysfunction is a prominent early event in the progression of Alzheimer's disease (AD). Whether protecting mitochondrial function can reduce amyloid-β oligomer (AβO)-induced neurotoxicity in PS1V97L transgenic mice remains unknown. In this study, we examined the possible protective effects of honokiol (HKL) on mitochondrial dysfunction induced by AβOs in neurons, and cognitive function in AD PS1V97Ltransgenic mice. We determined that HKL increased mitochondrial sirtuin 3 (SIRT3) expression levels and activity, which in turn markedly improved ATP production and weakened mitochondrial reactive oxygen species production. We demonstrated that the enhanced energy metabolism and attenuated oxidative stress of HKL restores AβO-mediated mitochondrial dysfunction in vitro and in vivo. Consequently, memory deficits in the PS1V97L transgenic mice were rescued by HKL in the early stages. These results suggest that HKL has therapeutic potential for delaying the onset of AD symptoms by alleviating mitochondrial impairment and increasing hyperactivation of SIRT3 in the pathogenesis of preclinical AD.

%B J Alzheimers Dis %V 64 %P 291-302 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865070?dopt=Abstract %R 10.3233/JAD-180126 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Hospitalization after Oral Antibiotic Initiation in Finnish Community Dwellers with and without Alzheimer's Disease: Retrospective Register-Based Cohort Study. %A Järvinen, Heli %A Taipale, Heidi %A Koponen, Marjaana %A Tanskanen, Antti %A Tiihonen, Jari %A Tolppanen, Anna-Maija %A Hartikainen, Sirpa %X

BACKGROUND: Persons with Alzheimer's disease (AD) are frequently hospitalized from infection-related causes. There are no previous studies investigating hospitalization associated with antibiotic initiation in persons with AD.

OBJECTIVE: To investigate the frequency and risk of hospitalization associated with oral antibiotic initiation among community dwellers with and without AD.

METHODS: We performed a retrospective register-based study utilizing register-based Medication Use and Alzheimer's disease (MEDALZ) cohort. It includes all community dwellers diagnosed with AD during 2005-2011 in Finland and their matched comparison persons without AD. Antibiotic use was initiated by 34,785 persons with and 36,428 without AD. Drug use data were collected from Prescription Register and comorbidities from Special Reimbursement and Hospital Care Registers. Infection diagnoses were collected from the Hospital Care Register. Factors associated with hospitalization were estimated utilizing logistic regression models.

RESULTS: Risk of hospitalization following antibiotic initiation was higher among antibiotic initiators with AD than without AD (adjusted odds ratio, aOR, 1.37, 95% Cl 1.28-1.46).Strongest association with hospitalization was found for oral glucocorticoid use, aOR 1.41 (1.25-1.59); epilepsy, aOR 1.33 (1.10-1.63); and active cancer, aOR 1.30 (1.14-1.49). Among initiators of cephalexin, pivmecillinam, amoxicillin/amoxicillin, and enzyme inhibitor and doxycycline, persons with AD were more frequently hospitalized than persons without AD. A quarter of hospitalized antibiotic initiators had infection diagnosis in their hospital care records.

CONCLUSIONS: Persons with AD initiating an antibiotic had a higher risk for hospitalization than antibiotic initiators without AD. Further research is needed to determine whether infection-related hospitalization could be reduced.

%B J Alzheimers Dis %V 64 %P 437-445 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914029?dopt=Abstract %R 10.3233/JAD-180125 %0 Journal Article %J J Alzheimers Dis %D 2018 %T How Does Utilization of Health Care Services Change in People with Dementia Served by Dementia Care Networks? Results of the Longitudinal, Observational DemNet-D-Study. %A Thyrian, Jochen René %A Michalowsky, Bernhard %A Hertel, Johannes %A Wübbeler, Markus %A Gräske, Johannes %A Holle, Bernhard %A Schäfer-Walkmann, Susanne %A Wolf-Ostermann, Karin %A Hoffmann, Wolfgang %X

BACKGROUND: There is no common definition for the Dementia Care Network (DCN). They are heterogeneous and there is no general, longitudinal evidence for the effects of DCN.

OBJECTIVE: We describe changes in utilization of health services by people served by dementia care networks in Germany and factors associated with those changes over time.

METHODS: Primary data was assessed in 560 people with dementia (PwD) and their caregivers supported by DCN in Germany; sociodemographic and clinical variables, utilization of services; DCN were characterized according to governance. The design: observational study with face-to-face interviews at two time points over a period of one year. Data was assessed via semi-structured interviews at the participants' homes.

RESULTS: Utilization of health services in this study is consistently higher than reported for the general population and does not significantly change over time. The strongest predictor of utilization of any service after one year was the use of this service at baseline (OR from 3.23 to 44.16). Higher activities of daily functioning increased the chances to utilize specialist physicians (OR = 1.32; 95% -CI: 1.08-1.63) or occupational therapy (OR = 1.24; 95% -CI: 1.02-1.50) significantly. Being a female decreased chances to utilize specialist physicians (OR = 0.57; 95% -CI: 0.37-0.87) and increased the chances to utilize no services (OR = 2.08; 95% -CI: 1.29-3.33).

CONCLUSION: While health care acknowledges the importance and benefits of dementia care networks (i.e., in Germany, the results were considered in new German legislation (SGB XI)), further research is needed to define this kind of service delivery to facilitate comparison as well as promote evidence-based implementation.

%B J Alzheimers Dis %V 66 %P 1609-1617 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30507578?dopt=Abstract %R 10.3233/JAD-180758 %0 Journal Article %J J Alzheimers Dis %D 2018 %T HSV-1-Specific IgG Subclasses Distribution and Serum Neutralizing Activity in Alzheimer's Disease and in Mild Cognitive Impairment. %A Agostini, Simone %A Mancuso, Roberta %A Hernis, Ambra %A Costa, Andrea Saul %A Nemni, Raffaello %A Clerici, Mario %X

Human Herpes Simplex Virus type 1 (HSV-1) infection is suggested to play a role in the development of Alzheimer's disease (AD). Immunoglobulin G (IgG) neutralize HSV-1 activity, but the virus can evade IgG-mediated immune responses by expressing receptor that efficiently binds the Fc portion of all IgG subclasses with the exception of IgG3. We analyzed HSV-1-specific IgG subclasses and IgG-mediated serum neutralization activity against HSV-1 in individuals with a diagnosis of either AD or mild cognitive impairment (MCI), comparing the results with those obtained in age-matched healthy controls (HC). 186 individuals were enrolled in the study: 67 AD, 58 MCI, and 61 HC. HSV-1 IgG titers and subclasses, neutralizing antibody (NAb) titers, and complement C3 concentration-critical component of antibody-mediated effector activity-were measured in sera by ELISA; IgG neutralizing activity was performed on HSV-1 infected Vero cells. Results showed that, whereas HSV-1-specific IgG1, IgG2, and IgG4 titers as well as complement C3 serum concentration were comparable in all groups of individuals, IgG3 were more frequently detected in MCI (89%) compared to AD (75%; p < 0.05) and HC (68%; p = 0.003), whereas the titer is similar among the three groups (AD: 0.66±0.21 OD; MCI: 0.68±0.24 OD; HC: 0.72±0.28 OD). Notably, HSV-1 specific neutralizing ability of AD sera was reduced even in the presence of high quantity of IgG3. As IgG3 plays a key role in counteracting the ability of HSV-1 to evade immune responses, these data reinforce the hypothesis of a pathogenetic role of HSV-1 in AD.

%B J Alzheimers Dis %V 63 %P 131-138 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578484?dopt=Abstract %R 10.3233/JAD-170966 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Human Gut Microbiota in Health and Alzheimer's Disease. %A Szablewski, Leszek %K Alzheimer Disease %K Diet, High-Fat %K Dysbiosis %K Gastrointestinal Microbiome %K Gastrointestinal Tract %K Humans %K Risk Factors %X

Gut microbiota plays a crucial role in human health and disease. The alterations in the composition of gut microbiota may cause the onset of certain human pathologies. One of these is Alzheimer's disease (AD). High-fat diets, administration of antibiotics, lack of probiotics and/or prebiotics in diet increase the risk of AD. On the other hand, modulation of the composition of gut microbiota may decrease the risk of AD and be able to slow down the progression of AD.

%B J Alzheimers Dis %V 62 %P 549-560 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480188?dopt=Abstract %R 10.3233/JAD-170908 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Humanin Exerts Neuroprotection During Cardiac Ischemia-Reperfusion Injury. %A Kumfu, Sirinart %A Charununtakorn, Savitree T %A Jaiwongkam, Thidarat %A Chattipakorn, Nipon %A Chattipakorn, Siriporn C %K Animals %K Apoptosis %K Blood-Brain Barrier %K Brain %K Intracellular Signaling Peptides and Proteins %K Male %K Microscopy, Electron %K Mitochondria %K Myocardial Reperfusion Injury %K Neurons %K Neuroprotection %K Neuroprotective Agents %K Oxidative Stress %K Rats %K Rats, Wistar %K Signal Transduction %X

Cardiac ischemia-reperfusion (I/R) injury has been shown to impair brain function. Humanin analogue (HNG) given prior to cardiac ischemia has been shown to attenuate both heart and brain mitochondrial dysfunction caused by cardiac I/R injury. In a clinical setting, patients received medical treatment for acute myocardial infarction either during or after the onset of myocardial ischemia; thus, in this study, we tested the hypothesis that the administration of HNG during cardiac I/R injury has therapeutic potential for brain protection. Thirty-six male Wistar rats were divided into two groups: a cardiac I/R group (n = 30), and a sham group (n = 6). The I/R rats were then divided into five subgroups to receive: 1) vehicle; 2) HNG (84 μg/kg); 3) HNG (168 μg/kg); 4) HNG (252 μg/kg) intravenously administered during the cardiac-ischemia; and 5) HNG at 252 μg/kg given at the onset of reperfusion. At the end of treatment, brains were removed for determination of blood-brain barrier (BBB) breakdown, oxidative stress, brain mitochondrial function, brain mitochondrial dynamics, p-tau, amyloid-β (Aβ) and apoptosis. HNG at a dose of 168 and 252 μg/kg administered during ischemia, and 252 μg/kg given at the onset of reperfusion effectively attenuated the brain mitochondrial dysfunction, tau hyperphosphorylation and Aβ accumulation, and apoptosis, without reducing BBB breakdown, brain oxidative stress, or mitochondrial dynamic, caused by cardiac I/R injury. In conclusion, humanin exerted neuroprotection during induced cardiac I/R injury via improvement in brain mitochondrial function, and the reduction of Alzheimer's disease pathology and apoptosis.

%B J Alzheimers Dis %V 61 %P 1343-1353 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376862?dopt=Abstract %R 10.3233/JAD-170708 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Hypercapnic and Hypoxic Respiratory Response During Wakefulness and Sleep in a Streptozotocin Model of Alzheimer's Disease in Rats. %A Vicente, Mariane C %A Almeida, Maria C %A Bícego, Kênia C %A Carrettiero, Daniel C %A Gargaglioni, Luciane H %X

Besides the typical cognitive decline, patients with Alzheimer's disease (AD) develop disorders of the respiratory system, such as sleep apnea, shortness of breath, and arrhythmias. These symptoms are aggravated with the progression of the disease. However, the cause and nature of these disturbances are not well understood. Here, we treated animals with intracerebroventricular streptozotocin (STZ, 2 mg/kg), a drug that has been described to cause Alzheimer-like behavioral and histopathological impairments. We measured ventilation (V̇E), electroencephalography, and electromyography during normocapnia, hypercapnia, and hypoxia in Wistar rats. In addition, we performed western blot analyses for phosphorylated tau, total tau, and amyloid-β (Aβ) peptide in the locus coeruleus (LC), retrotrapezoid nucleus, medullary raphe, pre-Bötzinger/Bötzinger complex, and hippocampus, and evaluated memory and learning acquisition using the Barnes maze. STZ treatment promoted memory and learning deficits and increased the percentage of total wakefulness during normocapnia and hypercapnia due to a reduction in the length of episodes of wakefulness. CO2-drive to breathe during wakefulness was increased by 26% in STZ-treated rats due to an enhanced tidal volume, but no changes in V̇E were observed in room air or hypoxic conditions. The STZ group also showed a 70% increase of Aβ in the LC and no change in tau protein phosphorylation. In addition, no alteration in body temperature was observed. Our findings suggest that AD animals present an increased sensitivity to CO2 during wakefulness, enhanced Aβ in the LC, and sleep disruption.

%B J Alzheimers Dis %V 65 %P 1159-1174 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30124447?dopt=Abstract %R 10.3233/JAD-180397 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Hypoxia-Induced Signaling Activation in Neurodegenerative Diseases: Targets for New Therapeutic Strategies. %A Jha, Niraj Kumar %A Jha, Saurabh Kumar %A Sharma, Renu %A Kumar, Dhiraj %A Ambasta, Rashmi K %A Kumar, Pravir %X

For the maintenance of cellular homeostasis and energy metabolism, an uninterrupted supply of oxygen (O2) is routinely required in the brain. However, under the impaired level of O2 (hypoxia) or reduced blood flow (ischemia), the tissues are not sufficiently oxygenated, which triggers disruption of cellular homeostasis in the brain. Hypoxia is known to have a notable effect on controlling the expression of proteins involved in a broad range of biological processes varying from energy metabolism, erythropoiesis, angiogenesis, neurogenesis to mitochondrial trafficking and autophagy, thus facilitating neuronal cells to endure in deprived O2. On the contrary, hypoxia to the brain is a major source of morbidity and mortality in humans culminating in cognitive impairment, gradual muscle weakness, loss of motor activity, speech deficit, and paralysis as well as other pathological consequences. Further, hypoxia resulting in reduced O2 deliveries to brain tissues is supposed to cause neurodegeneration in both in vivo and in vitro models. Similarly, chronic exposure to hypoxia has also been reportedly involved in defective vessel formation. Such vascular abnormalities lead to altered blood flow, reduced nutrient delivery, and entry of otherwise restricted infiltrates, thereby limiting O2 availability to the brain and causing neurological disabilities. Moreover, the precise mechanistic role played by hypoxia in mediating key processes of the brain and alternatively, in triggering pathological signals associated with neurodegeneration remains mysterious. Therefore, this review elucidates the intricate role played by hypoxia in modulating crucial processes of the brain and their severity in neuronal damage. Additionally, the involvement of numerous pharmacological approaches to compensate hypoxia-induced neuronal damage has also been addressed, which may be considered as a potential therapeutic approach in hypoxia-mediated neurodegeneration.

%B J Alzheimers Dis %V 62 %P 15-38 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439330?dopt=Abstract %R 10.3233/JAD-170589 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Imaging Biomarkers of Neurodegeneration in Alzheimer's Disease: Distinct Contributions of Cortical MRI Atrophy and FDG-PET Hypometabolism. %A Benvenutto, Agnès %A Giusiano, Bernard %A Koric, Lejla %A Gueriot, Claude %A Didic, Mira %A Felician, Olivier %A Guye, Maxime %A Guedj, Eric %A Ceccaldi, Mathieu %X

BACKGROUND: Neurodegeneration biomarkers are routinely used in the diagnosis of Alzheimer's disease (AD).

OBJECTIVE: To evaluate the respective contributions of two neuroimaging biomarkers, structural MRI and 18FDG-PET, in the assessment of neurodegeneration in AD dementia.

METHODS: Patients with mild AD dementia diagnosed based on clinical and cerebrospinal fluid criteria and cognitively healthy subjects, from the Marseille cohort ADAge with cognitive, structural MRI and 18FDG-PET assessments, were included. Extent of atrophy on MRI and of hypometabolism on 18FDG-PET were individually evaluated in each patient using a voxel-based analysis on whole-brain approach and compared to healthy subjects. Patients were divided in distinct groups according to their atrophy extent on the one hand and to their hypometabolism extent on the other, then, to their imaging profile combining the extent of the two biomarkers.

RESULTS: Fifty-two patients were included. The MMSE score was significantly lower in the "Extensive hypometabolism" group than in the "Limited hypometabolism" group (respectively 19.5/30 versus 23/30). A lower Innotest Amyloid Tau Index was associated with an extensive hypometabolism (p = 0.04). There were more patients with low educational level in the "Extensive atrophy" group, while a higher educational level was more found in the "Limited atrophy" group (p = 0.005).

CONCLUSION: 18FDG-PET hypometabolism extent is associated with the pathological processes and clinical severity of AD, while MRI atrophy seems to be influenced by the cognitive reserve. In the context of mild AD dementia, these two biomarkers of neurodegeneration are thus not interchangeable and require to be considered in combination rather than in isolation.

%B J Alzheimers Dis %V 65 %P 1147-1157 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30124446?dopt=Abstract %R 10.3233/JAD-180292 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Immunohistochemical Analysis of Activin Receptor-Like Kinase 1 (ACVRL1/ALK1) Expression in the Rat and Human Hippocampus: Decline in CA3 During Progression of Alzheimer's Disease. %A Adams, Stephanie L %A Benayoun, Laurent %A Tilton, Kathy %A Mellott, Tiffany J %A Seshadri, Sudha %A Blusztajn, Jan Krzysztof %A Delalle, Ivana %X

The pathophysiology of Alzheimer's disease (AD) includes signaling defects mediated by the transforming growth factor β-bone morphogenetic protein-growth and differentiation factor (TGFβ-BMP-GDF) family of proteins. In animal models of AD, administration of BMP9/GDF2 improves memory and reduces amyloidosis. The best characterized type I receptor of BMP9 is ALK1. We characterized ALK1 expression in the hippocampus using immunohistochemistry. In the rat, ALK1 immunoreactivity was found in CA pyramidal neurons, most frequently and robustly in the CA2 and CA3 fields. In addition, there were sporadic ALK1-immunoreactive cells in the stratum oriens, mainly in CA1. The ALK1 expression pattern in human hippocampus was similar to that of rat. Pyramidal neurons within the CA2, CA3, and CA4 were strongly ALK1-immunoreactive in hippocampi of cognitively intact subjects with no neurofibrillary tangles. ALK1 signal was found in the axons of alveus and fimbria, and in the neuropil across CA fields. Relatively strongest ALK1 neuropil signal was observed in CA1 where pyramidal neurons were occasionally ALK1-immunoractive. As in the rat, horizontally oriented neurons in the stratum oriens of CA1 were both ALK1- and GAD67-immunoreactive. Analysis of ALK1 immunoreactivity across stages of AD pathology revealed that disease progression was characterized by overall reduction of the ALK1 signal in CA3 in advanced, but not early, stages of AD. These data suggest that the CA3 pyramidal neurons may remain responsive to the ALK1 ligands, e.g., BMP9, during initial stages of AD and that ALK1 may constitute a therapeutic target in early and moderate AD.

%B J Alzheimers Dis %V 63 %P 1433-1443 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843236?dopt=Abstract %R 10.3233/JAD-171065 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Immunotherapy of Mild Cognitive Impairment by ω-3 Supplementation: Why Are Amyloid-β Antibodies and ω-3 Not Working in Clinical Trials? %A Fiala, Milan %A Restrepo, Lucas %A Pellegrini, Matteo %X

This article reviews the basic tenets of a clinical approach to effective immunotherapy of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). Although one randomized controlled study in early MCI patients by fish-derived omega-3 fatty acids (ω-3) showed slowing of disease progression, large clinical trials with different products have failed to show cognitive effects. Macrophages of healthy subjects phagocytize and degrade amyloid-β1 - 42 (Aβ) in the brain tissues, whereas macrophages of patients with AD and MCI are functionally defective. ω-3 and ω-3-derived specialized proresolving mediators (SPMs), such as resolvin D1, have powerful biochemical and immunological effects, which may repair the functions of MCI patients' macrophages in the brain's clearance of Aβ. Unfortunately, ω-3 products on the market have a variable quality. Nutritional supplementation with a combination drink called Smartfish with an emulsion of ω-3 and other fatty acids, antioxidants, 1,25-dihydroxy vitamin D3, and resveratrol improved the innate immune system of MCI patients by modulation of macrophage type to the pro-phagocytic M1-M2 type with an effective unfolded protein response against endoplasmic reticulum stress. Some MCI patients maintained their initial cognitive status for three years on Smartfish supplementation. Future randomized clinical trials should investigate the immune effects of ω-3, 1,25-dihydroxy vitamin D3, and SPMs on macrophage type, function, and biochemistry in parallel with cognitive effects.

%B J Alzheimers Dis %V 62 %P 1013-1022 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103035?dopt=Abstract %R 10.3233/JAD-170579 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Impact of a Shared Decision-Making Training Program on Dementia Care Planning in Long-Term Care. %A Mariani, Elena %A Chattat, Rabih %A Ottoboni, Giovanni %A Koopmans, Raymond %A Vernooij-Dassen, Myrra %A Engels, Yvonne %X

BACKGROUND: Shared decision-making (SDM) can be a way for staff to adopt international recommendations advocating the involvement of nursing home residents and their family members in care planning and the development of personalized care plans.

OBJECTIVE: The main aim was to analyze the effects of training nursing home staff in the implementation of SDM on agreement of residents' 'life-and-care plans' with the recommendations (primary outcome) and on family caregivers' quality of life and sense of competence, and staff's job satisfaction (secondary outcomes).

METHODS: In the intervention condition, staff attended a training program on the use of SDM with residents and family caregivers in the care planning process. In the control condition, care planning as usual took place. For the primary outcome, in-depth qualitative and quantitative analyses of the care plans were performed. Multivariate Permutation Tests were applied to assess the impact on secondary outcomes.

RESULTS: Forty-nine residents and family caregivers and 34 professionals were involved. Overall, many of the care plans developed during the intervention showed a high level of agreement with the care planning recommendations. Both Italian and Dutch care plans showed improvement in the number of clear problem statements (p < 0.001). In Italy, significant improvements (p < 0.05) were also found regarding specific care objectives, documentation of objectives met, and of residents and families' involvement. No impact was found on secondary outcomes.

CONCLUSION: The involvement of residents and family caregivers in care planning contributed to an improvement of the residents' care plans, but it did not have an effect on family caregivers and staff outcomes.

%B J Alzheimers Dis %V 64 %P 1123-1135 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010130?dopt=Abstract %R 10.3233/JAD-180279 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impact of a Virtual Dementia Experience on Medical and Pharmacy Students' Knowledge and Attitudes Toward People with Dementia: A Controlled Study. %A Gilmartin-Thomas, Julia F-M %A McNeil, John %A Powell, Anne %A Malone, Daniel T %A Wolfe, Rory %A Larson, Ian C %A O'Reilly, Claire L %A Kirkpatrick, Carl M %A Kipen, Eva %A Petrovich, Tanya %A Bell, J Simon %K Australia %K Curriculum %K Dementia %K Female %K Health Knowledge, Attitudes, Practice %K Humans %K Male %K Students, Medical %K Students, Pharmacy %K Virtual Reality %K Young Adult %X

BACKGROUND: Clinical practice guidelines for dementia highlight the importance of providing patient-centered care. This can be achieved by improving health professionals' attitudes and knowledge toward people with dementia.

OBJECTIVE: Quantitatively evaluate the impact of a virtual dementia experience on medical and pharmacy students' knowledge and attitudes toward people with dementia.

METHODS: A non-randomized controlled study from September-October 2016. The intervention group received a 1.5-hour multisensory, virtual simulation of light, sound, color, and visual content to experience the cognitive and perceptual difficulties faced by people with dementia. Controls participated in the standard curriculum only. All students were invited to complete the 20-item Dementia Attitudes Scale (DAS) pre- and post-intervention.

RESULTS: A total of 278 students (n = 64 medical, n = 214 pharmacy) were analyzed (n = 80 intervention, n = 198 control). The majority of students were female (n = 184, 66.2%), with an average age of 22.5 years. The intervention improved the DAS total score and subdomains of comfort and knowledge (p < 0.001).

CONCLUSION: The intervention had a positive impact on medical and pharmacy students' knowledge and attitudes toward people with dementia.

%B J Alzheimers Dis %V 62 %P 867-876 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480198?dopt=Abstract %R 10.3233/JAD-170982 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impact of Amyloid PET Imaging in the Memory Clinic: A Systematic Review and Meta-Analysis. %A Shea, Yat-Fung %A Barker, Warren %A Greig-Gusto, Maria T %A Loewenstein, David A %A Duara, Ranjan %A DeKosky, Steven T %X

BACKGROUND: Patients with cognitive impairment or dementias of uncertain etiology are frequently referred to a memory disorders specialty clinic. The impact of and role for amyloid PET imaging (Aβ-PET) may be most appropriate in this clinical setting.

OBJECTIVE: The primary objective of this study was to perform a systematic review and meta-analysis of the impact of Aβ-PET on etiological diagnosis and clinical management in the memory clinic setting.

METHODS: A search of the literature on the impact of Aβ-PET in the memory clinic setting between 1 January 2004 and 12 February 2018 was conducted. Meta-analysis using a random effects model was performed to determine the pooled estimate of the impact of Aβ-PET in the changes of diagnoses and changes in management plan.

RESULTS: After rigorous review, results from 13 studies were extracted, involving 1,489 patients. Meta-analysis revealed a pooled effect of change in diagnoses of 35.2% (95% CI 24.6-47.5). Sub-analyses showed that the pooled effect in change in diagnoses if Aβ-PET was used under the appropriate use criteria (AUC) or non-AUC criteria were 47.8% (95% CI 25.9-70.5) and 29.6% (95% CI: 21.5-39.3), respectively. The pooled effect of a change of diagnosis from Alzheimer's disease (AD) to non-AD and from non-AD to AD were 22.7% (95% CI: 17.1-29.5) and 25.6% (95% CI: 17.6-35.8), respectively. The pooled effect leading to a change of management was 59.6% (95% CI 39.4-77.0).

CONCLUSIONS: Aβ-PET has a highly significant impact on both changes in diagnosis and management among patients being seen at a specialty memory clinic.

%B J Alzheimers Dis %V 64 %P 323-335 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889075?dopt=Abstract %R 10.3233/JAD-180239 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Impact of APOE ɛ4 in Alzheimer's Disease Differs According to Age. %A Kim, Jaeho %A Park, Seongbeom %A Yoo, Heejin %A Jang, Hyemin %A Kim, Yeshin %A Kim, Ko Woon %A Jang, Young Kyoung %A Lee, Jin San %A Kim, Sung Tae %A Kim, Seonwoo %A Lee, Jong Min %A Ki, Chang-Seok %A Na, Duk L %A Seo, Sang Won %A Kim, Hee Jin %K Age Factors %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Atrophy %K Brain %K Case-Control Studies %K Cognition %K Female %K Heterozygote %K Humans %K Magnetic Resonance Imaging %K Male %K Memory %K Middle Aged %K Republic of Korea %X

We evaluated how the impact of apolipoprotein E4 (APOE4) differs according to age in Alzheimer's disease (AD) patients. We recruited 846 AD patients and 815 cognitively normal controls and categorized into three groups with respect to their age (<65, 65-74, and ≥75 years). We evaluated the risk of AD in APOE4 carriers and compared cortical thickness and cognitive function according to APOE4 status in each age group. At the point of this study, in young (<65 years) AD, APOE4 noncarriers had the most severe frontal and perisylvian atrophy, while in old (≥75 years) AD, APOE4 carriers had the most severe medial temporal atrophy. In AD under 75 years, APOE4 noncarriers and heterozygotes showed worse performance in language, visuospatial, and frontal function compared to homozygotes, while, in old (≥75 years) AD, APOE4 homozygotes showed worse performance in memory compared to noncarriers. As the detrimental effects of APOE4 seen in older AD patients were not found in younger AD patients, we suggest that some unrevealed factors are associated with cortical atrophy and non-amnestic cognitive dysfunction in young AD with APOE4 noncarriers.

%B J Alzheimers Dis %V 61 %P 1377-1385 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376853?dopt=Abstract %R 10.3233/JAD-170556 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Impact of Creative Arts in Alzheimer's Disease and Dementia Public Health Education. %A Burns, Nicole C %A Watts, Amber %A Perales, Jaime %A Montgomery, Robert Neal %A Morris, Jill K %A Mahnken, Jonathan D %A Lowther, Johnna %A Vidoni, Eric D %X

Previous research involving dramatic performances about Alzheimer's disease and dementia perception have targeted health care workers or caretakers. We examined the influence of a theater performance on the emotional affect of a general audience to determine the utility of this type of theater in large-scale public health education efforts. Our study included 147 participants that attended a self-revelatory theater performance based on the social/relationship experiences of those with dementia and those who care for them. This type of theater engages the audience and actors in a dual transformative process, supporting the emotional growth of all involved. Participants completed pre- and post-performance questionnaires regarding their beliefs and feelings surrounding the topic of dementia and the importance of the Arts for educating on issues surrounding dementia care. We tested for change in emotional affect pre- and post-performance using sensitivity and center of gravity statistical analyses. We found a significant change in emotional affect from an initial strong negative affect to slightly more positive/relaxed view after viewing the performance. Findings support self-revelatory theater as a resource to destigmatize preconceived notions of dementia. Large-scale community health education efforts could benefit from using this style of theater to elicit a change in audience perception of disease realities.

%B J Alzheimers Dis %V 63 %P 457-463 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578491?dopt=Abstract %R 10.3233/JAD-180092 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Impact of Hospitalization on Readmission, Institutionalization, and Mortality of People with Dementia: A Systematic Review and Meta-Analysis. %A Lehmann, Jana %A Michalowsky, Bernhard %A Kaczynski, Anika %A Thyrian, Jochen René %A Schenk, Nele Sophie %A Esser, Alexander %A Zwingmann, Ina %A Hoffmann, Wolfgang %X

BACKGROUND: People with dementia (PwD) are at a high risk of hospitalization. Hospitals are often not adequately equipped for PwD and discharges often come unexpected. Therefore, PwD are at a risk of adverse outcomes. However, information about those outcomes is rare but crucial for the development of preventive strategies.

OBJECTIVES: To conduct a quantitative systematic review and meta-analyses on the impact of a hospitalization on readmission, institutionalization, and mortality in PwD. To identify factors associated with these outcomes.

METHODS: PubMed, CENTRAL, and ScienceDirect were searched for studies including terms for dementia, hospital, readmission, institutionalization, and mortality. Relevant were assessed by a quality criteria sheet. Results were summarized in a table. Meta-analysis was conducted with Review Manager 5.3.

RESULTS: The search yielded 1,108 studies; 20 fulfilled the inclusion criteria and 10 studies were eligible for meta-analyses. The incidence and relative risk (RR) of mortality (RR 1.74 CI95 % 1.50, 2.05) and institutionalization (RR: 2.16 CI95 % 1.31, 3.56) of PwD was significantly higher when compared to people without dementia. Results according to readmission rate were inconsistent. Factors significantly associated with the examined adverse outcomes were severity of dementia, number of medications, and deficits in daily living activities.

CONCLUSION: Hospitalization of PwD lead to adverse outcomes. An improvement in the identification of and care for PwD in the acute setting as well as in after care in the community setting, especially in the interface between both settings, is required to prevent adverse outcomes in hospitalized PwD.

%B J Alzheimers Dis %V 64 %P 735-749 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966191?dopt=Abstract %R 10.3233/JAD-171128 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impact of Mild Cognitive Impairment on Mortality and Cause of Death in the Elderly. %A Bae, Jong Bin %A Han, Ji Won %A Kwak, Kyung Phil %A Kim, Bong Jo %A Kim, Shin Gyeom %A Kim, Jeong Lan %A Kim, Tae Hui %A Ryu, Seung-Ho %A Moon, Seok Woo %A Park, Joon Hyuk %A Youn, Jong Chul %A Lee, Dong Young %A Lee, Dong Woo %A Lee, Seok Bum %A Lee, Jung Jae %A Jhoo, Jin Hyeong %A Kim, Ki Woong %X

BACKGROUND: Mild cognitive impairment (MCI) is a cognitive state that lies on the continuum between normal aging and dementia, and the prevalence of MCI is higher than dementia. However, the risk for mortality of people with MCI has been far less studied than that of people with dementia, and the population attributable risk percent (PAR%) of death attributable to MCI has not been estimated yet.

OBJECTIVE: To investigate the impact of MCI on mortality and the cause of death in the elderly, and to estimate the PAR% of deaths attributable to MCI.

METHODS: Data came from 7,315 elderly subjects aged ≥60 years without dementia from two cohort studies with diagnostic assessments of MCI at baseline. Deaths among participants were confirmed through the nationwide mortality database of Statistics Korea.

RESULTS: MCI increased the risk of mortality in a multivariate Cox proportional model adjusting for age, sex, education, smoking, alcohol drinking, chronic illness, depression, vascular components, and cohort (hazard ratio = 1.59, 95% confidence interval 1.30, 1.94). PAR% of death attributable to MCI was 10.7% for age 65-74 years, 16.0% for age 75-84 years, and 24.2% for age ≥85 years. In the elderly with MCI, mortality risks from cerebrovascular disease, respiratory disease, and external causes were higher than in the cognitively normal elderly.

CONCLUSIONS: Our results suggest that the mortality risk of MCI in Asian countries may be comparable to that in Western countries, and MCI can contribute to the death of the elderly as much as dementia.

%B J Alzheimers Dis %V 64 %P 607-616 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914024?dopt=Abstract %R 10.3233/JAD-171182 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Impact of Music on the Self in Dementia. %A Baird, Amee %A Thompson, William Forde %K Consciousness %K Dementia %K Humans %K Music %K Music Therapy %K Personality %X

In this review, we consider how the onset and progression of dementia can disrupt one's sense of self, and propose that music is an ideal tool for alleviating this distressing symptom. Various aspects of the self can be impaired in people with dementia, depending on how the self is defined. There are anecdotal reports that music can 'bring people back to themselves' in the face of dementia, but there have been scarce empirical investigations of this topic. Motivated by a consideration of the existing literature, we outline a novel theoretical framework that accounts for the relationship between music and the self in people with dementia. We propose that music has a number of 'design features' that make it uniquely equipped to engage multiple aspects of the self. We suggest that each design feature interacts with different aspects of the self to varying degrees, promoting overall wellbeing. We discuss how existing research on music and dementia fits within this framework, and describe two case studies in which music was an ideal stimulus for reaffirming their sense of self. Our framework may be useful for the diagnosis and treatment of impairments of self in people with dementia, and highlights how music, given its ability to engage all aspects of the self simultaneously, can result in an overall enhanced sense of self.

%B J Alzheimers Dis %V 61 %P 827-841 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332051?dopt=Abstract %R 10.3233/JAD-170737 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impact of Olfactory Priming on Food Intake in an Alzheimer's Disease Unit. %A Sulmont-Rossé, Claire %A Gaillet, Marie %A Raclot, Carine %A Duclos, Michel %A Servelle, Maud %A Chambaron, Stéphanie %X

Alzheimer's disease (AD) is often associated with feeding difficulties and changes in eating behavior with may lead to malnutrition. In French nursing homes, AD patients may live in special care units that better meet dementia residents' needs. However, meals are often delivered to AD patients by using meal trays coming from central kitchens. This led to the disappearance of cues that could help residents to foresee mealtime, such as the smell of food odors. The aim of the present study was to assess the impact of odorizing the dining room of AD Units with a meat odor before lunch on subsequent food intake and eating behavior. Thirty-two residents (>75 years old) from three AD Units were included in the study. They participated in two control lunches and two primed lunches, for which a meat odor was diffused in the dining room 15 minutes before the arrival of the meal tray (olfactory priming). Results of the first replication showed a significant effect of olfactory priming, with a 25% increase in meat and vegetable consumption compared to the control condition. Behavioral measurements also showed a significant increase of resident's interest toward the meal in the primed lunch. However, this effect was no longer observed when the priming session was replicated two weeks later with the same priming odor and the same menu. Although further research is needed to understand why this priming effect cannot be replicated, our experiment is one of the very first to investigate the effect of food odor priming on subsequent food intake in AD patients in a real-life setting.

%B J Alzheimers Dis %V 66 %P 1497-1506 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30452411?dopt=Abstract %R 10.3233/JAD-180465 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impact of Osteoporosis on the Risk of Dementia in Almost 60,000 Patients Followed in General Practices in Germany. %A Kostev, Karel %A Hadji, Peyman %A Jacob, Louis %X

BACKGROUND: There has been in recent decades a growing interest in the relationship between osteoporosis and cognitive decline.

OBJECTIVE: The goal of this study was to analyze the impact of osteoporosis on the risk of dementia in patients followed for up to 20 years in general practices in Germany.

METHODS: This study included patients who received an initial diagnosis of osteoporosis and were followed by 1,215 general practitioners in Germany between January 1993 and December 2012 (index date). Controls were matched (1:1) to osteoporosis patients using propensity scores based on age, gender, index year, comorbidities, and co-therapies. Kaplan-Meier curves were performed to study the development of dementia separately in men and women with or without osteoporosis within 20 years of the index date. Cox proportional regression models were used to estimate the relationship between osteoporosis and dementia in men and women.

RESULTS: The present study included 29,983 cases and 29,983 controls. After 20 years of follow-up, 20.5% of women with osteoporosis and 16.4% of controls had been diagnosed with dementia (log-rank p-value <0.001). At the end of the follow-up period, dementia was found in 22.0% of men previously diagnosed with osteoporosis and 14.9% of men without this chronic condition (log-rank p-value <0.001). Osteoporosis was associated with a 1.2-fold increase in the risk of being diagnosed with dementia in women and a 1.3-fold increase in the risk of being diagnosed with dementia in men.

CONCLUSIONS: There was a positive association between osteoporosis and dementia in patients followed in general practices in Germany.

%B J Alzheimers Dis %V 65 %P 401-407 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056429?dopt=Abstract %R 10.3233/JAD-180569 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impact of Total Knee Arthroplasty with General Anesthesia on Brain Networks: Cognitive Efficiency and Ventricular Volume Predict Functional Connectivity Decline in Older Adults. %A Huang, Haiqing %A Tanner, Jared %A Parvataneni, Hari %A Rice, Mark %A Horgas, Ann %A Ding, Mingzhou %A Price, Catherine %X

Using resting state functional magnetic resonance imaging (RS-fMRI), we explored: 1) pre- to post-operative changes in functional connectivity in default mode, salience, and central executive networks after total knee arthroplasty (TKA) with general anesthesia, and 2) the contribution of cognitive/brain reserve metrics these resting state functional declines. Individuals age 60 and older electing unilateral total knee arthroplasty (TKA; n = 48) and non-surgery peers with osteoarthritis (n = 45) completed baseline cognitive testing and baseline and post-surgery (post-baseline, 48-h post-surgery) brain MRI. We acquired cognitive and brain estimates for premorbid (vocabulary, reading, education, intracranial volume) and current (working memory, processing speed, declarative memory, ventricular volume) reserve. Functional network analyses corrected for pain severity and pain medication. The surgery group declined in every functional network of interest (p < 0.001). Relative to non-surgery peers, 23% of surgery participants declined in at least one network and 15% of the total TKA sample declined across all networks. Larger preoperative ventricular volume and lower scores on preoperative metrics of processing speed and working memory predicted default mode network connectivity decline. Premorbid cognitive and premorbid brain reserve did not predict decline. Within 48 hours after surgery, at least one fourth of the older adult sample showed significant functional network decline. Metrics of current brain status (ventricular volume), working memory, and processing speed predicted the severity of default mode network connectivity decline. These findings demonstrate the relevance of preoperative cognition and brain integrity on acute postoperative functional network change.

%B J Alzheimers Dis %V 62 %P 319-333 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439328?dopt=Abstract %R 10.3233/JAD-170496 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impact of Untimely Access to Formal Care on Costs and Quality of Life in Community Dwelling People with Dementia. %A Janssen, Niels %A Handels, Ron L %A Sköldunger, Anders %A Woods, Bob %A Jelley, Hannah %A Edwards, Rhiannon Tudor %A Orrell, Martin %A Selbæk, Geir %A Røsvik, Janne %A Gonçalves-Pereira, Manuel %A Marques, Maria J %A Zanetti, Orazio %A Portolani, Elisa %A Irving, Kate %A Hopper, Louise %A Meyer, Gabriele %A Bieber, Anja %A Stephan, Astrid %A Kerpershoek, Liselot %A Wolfs, Claire A G %A de Vugt, Marjolein E %A Verhey, Frans R J %A Wimo, Anders %X

BACKGROUND: Access to formal care is not always timely and a better understanding on the impact of untimely access is needed.

OBJECTIVE: To examine, from a societal perspective, the impact of untimely access to formal care in terms of total costs and quality of life over one year in community dwelling people with dementia.

METHODS: Within the Actifcare study, needs, resource use, and quality of life were observed for one year in a cohort of 451 community dwelling people with dementia in 8 European countries. Untimely access to care was operationalized as having at least one unmet need for care identified by the Camberwell Assessment of Need for the Elderly (CANE) instrument. Two regression models were built for both total costs and quality of life measured by the EQ-5D-5L, one using sum of unmet needs and one using a predefined selection of need items.

RESULTS: Unmet needs were not associated with higher total costs but they were associated with a lower quality of life of people with dementia. Of all CANE items, only an unmet need for "company" was significantly related to lower total costs.

CONCLUSION: Total costs did not seem to differ between participants with unmet and met needs. Only few associations between specific unmet needs and costs and quality of life were found. Furthermore, quality of life of people with dementia decreases when multiple unmet needs are experienced, indicating that assessing and meeting needs is important to improve quality of life.

%B J Alzheimers Dis %V 66 %P 1165-1174 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400096?dopt=Abstract %R 10.3233/JAD-180531 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impaired IL-17 Production in Gut-Residing Immune Cells of 5xFAD Mice with Alzheimer's Disease Pathology. %A Saksida, Tamara %A Koprivica, Ivan %A Vujičić, Milica %A Stošić-Grujičić, Stanislava %A Perović, Milka %A Kanazir, Selma %A Stojanović, Ivana %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K B-Lymphocytes %K Disease Models, Animal %K Female %K Interleukin-17 %K Lymph Nodes %K Male %K Mice %K Mice, Transgenic %K MicroRNAs %K Peyer's Patches %K Th17 Cells %X

Alzheimer's disease (AD) is characterized by accumulation of amyloid-β plaques that further promotes microglia-mediated neuroinflammatory responses and inflammation in the brain. Emerging data are revealing the relation between gut-associated lymphoid tissue (GALT) cells and CNS, as effector cells primed in the gut might home to the brain. This study aimed to determine cell composition of GALT in 5xFAD mice, an established model for AD. Immune cells isolated from Peyer's patches (PP) and mesenteric lymph nodes (MLN) were stained with surface and intracellular markers for T helper (Th) subpopulations, B lymphocytes and macrophages and analyzed cytofluorimetrically, while cytokine expression and production were determined by qPCR and ELISA, respectively. Inflammation was detected in GALT of 5xFAD mice with established AD pathology. Although the production of IFN-γ, IL-4, and IL-10 was comparable between the strains, lower IL-17 production was observed in PP and MLN cells. This phenomenon could not be attributed to a lower abundance of Th17 cells, or cytokines that initiate their formation or propagation (TGF-β, IL-6, and IL-23). Also, reduced IL-17 production was not a consequence of altered Il-17 mRNA transcription or deficiency of Rorγt, a key transcription factor for IL-17. However, the expression of miR-155 (a non-coding micro RNA that promotes the development of Th17 cells), was significantly lower in MLN cells of 5xFAD mice. In contrast, mice without AD neuropathology did not have inflammation in GALT or altered Th17 numbers, nor decreased IL-17 production. In conclusion, the observed changes in GALT of 5xFAD mice mirror the disease progression and might reflect inadequate immune surveillance in the gut and lead to enhanced AD pathology.

%B J Alzheimers Dis %V 61 %P 619-630 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254086?dopt=Abstract %R 10.3233/JAD-170538 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impaired Spike Timing Dependent Cortico-Cortical Plasticity in Alzheimer's Disease Patients. %A Di Lorenzo, Francesco %A Ponzo, Viviana %A Motta, Caterina %A Bonní, Sonia %A Picazio, Silvia %A Caltagirone, Carlo %A Bozzali, Marco %A Martorana, Alessandro %A Koch, Giacomo %X

BACKGROUND: Mechanisms of cortical plasticity have been recently investigated in Alzheimer's disease (AD) patients with transcranial magnetic stimulation protocols showing a clear impairment of long-term potentiation (LTP) cortical-like plasticity mechanisms.

OBJECTIVE: We aimed to investigate mechanisms of cortico-cortical spike-timing dependent plasticity (STDP) in AD patients investigating the connections between posterior parietal cortex (PPC) and primary motor cortex (M1).

METHODS: We used a cortico-cortical paired associative stimulation (cc-PAS) protocol to repeatedly activate the connection between PPC and M1 of the left-dominant hemisphere in a sample of fifteen AD patients and ten age-matched healthy subjects. PPC transcranial magnetic stimulation preceded (ccPAS +5) or followed M1 stimulation (ccPAS - 5) by 5 ms. Motor-evoked potentials (MEPs) were collected to assess the time course of the after effects of cc-PAS protocol measuring MEP amplitude as index of cortico-cortical associative plasticity.

RESULTS: In healthy subjects, ccPAS - 5 protocol induced the expected long-lasting increase of MEP amplitude compatible with LTP-like cortical plasticity while PAS +5 protocol induced the opposite effect. AD patients did not show any significant modification of the amplitude of MEP after both ccPAS protocols.

CONCLUSIONS: Our study shows that in AD patients the time-locked activation of human cortico-cortical connections is not able to form STDP, reflecting an impairment of a multi-factor plasticity process.

%B J Alzheimers Dis %V 66 %P 983-991 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30372679?dopt=Abstract %R 10.3233/JAD-180503 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Implementation of an Occupational Therapy Program for Alzheimer's Disease Patients in France: Patients' and Caregivers' Perspectives. %A Corvol, Aline %A Netter, Alix %A Campeon, Arnaud %A Somme, Dominique %X

BACKGROUND: The French National Alzheimer Plan 2008-2012 created specialized Alzheimer teams, which provide up to 15 sessions of cognitive rehabilitation in the patient's home for 3 months. Sessions are conducted by an occupational therapist and a gerontological nursing assistant.

OBJECTIVES: As the patient's experience is one determinant of successful implementation, we explored the usefulness of these teams as viewed by the patient and his or her main caregiver.

METHODS: Thirteen patients and their caregiver, previously assisted by a specialized Alzheimer team, were individually given semi-structured interviews (n = 26, duration 20 to 180 minutes).

RESULTS: Our study showed that although patients and caregiver had no initial expectations, most of them appreciated the support provided by the specialized Alzheimer teams. Patients valued the "human" component, and favored interventions that improved quality of life over those intended to maintain functional capacities. Caregivers observed improved mood and behavior in patients. Those involved in sessions felt empowered by contact with a specialized Alzheimer team. We discuss how patients' and caregivers' feedback influenced the implementation process through comprehensive use of the five dimensions of the RE-AIM framework.

CONCLUSION: Whereas intervention by specialized Alzheimer teams was largely accepted by health care professionals, patients, and caregivers, its effectiveness is questioned in view of its deviation from the evidence-based model. Interviews with patients and caregivers shed light on some reasons for this deviation, as what they value in the intervention differs from the functional focus of the model.

%B J Alzheimers Dis %V 62 %P 157-164 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439340?dopt=Abstract %R 10.3233/JAD-170765 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Improvement of Main Cognitive Functions in Patients with Alzheimer's Disease after Treatment with Coconut Oil Enriched Mediterranean Diet: A Pilot Study. %A de la Rubia Ortí, Jose Enrique %A García-Pardo, María Pilar %A Drehmer, Eraci %A Sancho Cantus, David %A Julián Rochina, Mariano %A Aguilar, Maria Asunción %A Hu Yang, Iván %X

BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder (mainly in women), and new therapies are needed. In this way, ketone bodies are a direct source of cellular energy and can be obtained from coconut oil, postulating that coconut oil could be a new non-pharmacological alternative in AD patients.

OBJECTIVE: The aim of this study is to detect changes in the main cognitive functions of patients with AD after following a coconut oil enriched Mediterranean diet, and to determine whether there are differences in function of stage or sex.

METHODS: A prospective, longitudinal, qualitative, analytic, experimental study was carried out in 44 patients with AD, who were randomly divided into two homogenous groups of 22 patients each: an experimental group of patients who followed a coconut oil enriched Mediterranean diet for 21 days and a control group. In order to determine the cognitive changes after the intervention, we carried out the 7 Minute Screen, which analyses temporal orientation, visuospatial and visuoconstructive abilities, and semantic and episodic memory.

RESULTS: After intervention with coconut oil, improvements in episodic, temporal orientation, and semantic memory were observed, and it seems that the positive effect is more evident in women with mild-moderate state, although other improvements in males and severe state were also shown.

CONCLUSIONS: The isocaloric coconut oil enriched Mediterranean diet seems to improve cognitive functions in patients with AD, with differences according to patient sex and degree of severity of the disease, although more studies in this line are needed.

%B J Alzheimers Dis %V 65 %P 577-587 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056419?dopt=Abstract %R 10.3233/JAD-180184 %0 Journal Article %J J Alzheimers Dis %D 2018 %T In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer's Disease. %A Schartmann, Elena %A Schemmert, Sarah %A Niemietz, Nicole %A Honold, Dominik %A Ziehm, Tamar %A Tusche, Markus %A Elfgen, Anne %A Gering, Ian %A Brener, Oleksandr %A Shah, Nadim Joni %A Langen, Karl-Josef %A Kutzsche, Janine %A Willbold, Dieter %A Willuweit, Antje %X

Diffusible amyloid-β (Aβ) oligomers are currently presumed to be the most cytotoxic Aβ assembly and held responsible to trigger the pathogenesis of Alzheimer's disease (AD). Thus, Aβ oligomers are a prominent target in AD drug development. Previously, we reported on our solely D-enantiomeric peptide D3 and its derivatives as AD drug candidates. Here, we compare one of the most promising D3 derivatives, ANK6, with its tandem version (tANK6), and its head-to-tail cyclized isoform (cANK6r). In vitro tests investigating the D-peptides' potencies to inhibit Aβ aggregation, eliminate Aβ oligomers, and reduce Aβ-induced cytotoxicity revealed that all three D-peptides efficiently target Aβ. Subsequent preclinical pharmacokinetic studies of the three all-D-peptides in wildtype mice showed promising blood-brain barrier permeability with cANK6r yielding the highest levels in brain. The peptides' potencies to lower Aβ toxicity and their remarkable brain/plasma ratios make them promising AD drug candidates.

%B J Alzheimers Dis %V 64 %P 859-873 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966196?dopt=Abstract %R 10.3233/JAD-180165 %0 Journal Article %J J Alzheimers Dis %D 2018 %T In vivo Depiction of α7 Nicotinic Receptor Loss for Cognitive Decline in Alzheimer's Disease. %A Nakaizumi, Kyoko %A Ouchi, Yasuomi %A Terada, Tatsuhiro %A Yoshikawa, Etsuji %A Kakimoto, Akihiro %A Isobe, Takashi %A Bunai, Tomoyasu %A Yokokura, Masamichi %A Suzuki, Katsuaki %A Magata, Yasuhiro %K Adult %K Aged %K alpha7 Nicotinic Acetylcholine Receptor %K Alzheimer Disease %K Brain %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Humans %K Male %K Middle Aged %K Positron-Emission Tomography %K Young Adult %X

BACKGROUND: The α7 subtype of the nicotinic acetylcholine receptor (nAChR) is considered important in higher cognitive functions, and cholinergic loss underpins the pathophysiology of Alzheimer's disease (AD). However, the relationships between α7 nAChR function and clinical functions or amyloid-β (Aβ) deposition remain to be explored in the living AD brain.

OBJECTIVE: We aimed to elucidate the relationship between α7 nAChR availability in the specific cholinergic region and cognitive decline in the Aβ-confirmed AD brain.

METHODS: Twenty AD patients and ten age-matched healthy subjects were examined. The α7-nAChR availability and Aβ deposition were evaluated using positron emission tomography with an α7 nAChR radiotracer 11C-(R)-MeQAA and 11C-Pittsburg compound B (11C-PiB), respectively. Semi-quantified values of tracer binding were estimated with a simplified reference tissue method for BPND of 11C-(R)-MeQAA and a tissue ratio method for SUVR of 11C-PiB. These parameters and clinical scores were compared voxel-wise using a statistical parametric mapping method.

RESULTS: The levels of 11C-(R)-MeQAA BPND in the temporal and prefrontal cholinergic projection regions were significantly lower in AD, and negative correlations were found between 11C-PiB SUVR and 11C-(R)-MeQAA BPND in the region of the nucleus basalis magnocellularis and medial prefrontal cortex. Levels of 11C-(R)-MeQAA BPND were significantly correlated with memory and frontal function scores in AD.

CONCLUSION: The association between Aβ burden and α7-nAChR reduction in the basal forebrain cholinergic system was highlighted in relation to cognitive decline in AD. This suggests that Aβ-linked α7-nAChR reduction is clinico-pathophyisologically important for considering a good therapeutic target in AD.

%B J Alzheimers Dis %V 61 %P 1355-1365 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376856?dopt=Abstract %R 10.3233/JAD-170591 %0 Journal Article %J J Alzheimers Dis %D 2018 %T In Vivo MRI of Amyloid Plaques in a Cholesterol-Fed Rabbit Model of Alzheimer's Disease. %A Chen, Yuanxin %A Lim, Patrick %A Rogers, Kem A %A Rutt, Brian K %A Ronald, John A %X

Hypercholesterolemia has been identified as a risk factor for Alzheimer's disease. In this study, rabbits were fed either a cholesterol diet or normal chow diet for 24 months. At endpoint, in vivo MRI was performed at the field strength of 3 Tesla using fast imaging employing steady state acquisition without (FIESTA) or with susceptibility-weighted post-processing (SWI-FIESTA) and susceptibility-weighted imaging with multi-echo acquisition (SWAN). This imaging revealed signal voids/hypointensities throughout the cortex, sub-cortex, and hippocampus of cholesterol-fed animals compared to control animals. Quantitative image analysis corroborated these qualitative findings and highlighted that SWI processing of FIESTA images significantly improved the detectability of plaques (p < 0.05). Aβ immunostaining and Prussian blue staining for iron demonstrated that the voids in MR images corresponded to iron-laden Aβ-positive plaques. This study demonstrates non-invasive in vivo visualization of Aβ plaques in a diet-induced large animal model of Alzheimer's disease. This work lays the foundation for future work focusing on longitudinal monitoring of plaque formation in this model and the effects of diet or drug interventions.

%B J Alzheimers Dis %V 64 %P 911-923 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966200?dopt=Abstract %R 10.3233/JAD-180207 %0 Journal Article %J J Alzheimers Dis %D 2018 %T In Vivo Visualization of Tau Accumulation, Microglial Activation, and Brain Atrophy in a Mouse Model of Tauopathy rTg4510. %A Ishikawa, Ai %A Tokunaga, Masaki %A Maeda, Jun %A Minamihisamatsu, Takeharu %A Shimojo, Masafumi %A Takuwa, Hiroyuki %A Ono, Maiko %A Ni, Ruiqing %A Hirano, Shigeki %A Kuwabara, Satoshi %A Ji, Bin %A Zhang, Ming-Rong %A Aoki, Ichio %A Suhara, Tetsuya %A Higuchi, Makoto %A Sahara, Naruhiko %K Animals %K Atrophy %K Benzothiazoles %K Brain %K Disease Models, Animal %K Female %K Magnetic Resonance Imaging %K Male %K Mice %K Mice, Transgenic %K Microglia %K Positron-Emission Tomography %K Receptors, GABA %K tau Proteins %K Tauopathies %X

BACKGROUND: Tau imaging using PET is a promising tool for the diagnosis and evaluation of tau-related neurodegenerative disorders, but the relationship among PET-detectable tau, neuroinflammation, and neurodegeneration is not yet fully understood.

OBJECTIVE: We aimed to elucidate sequential changes in tau accumulation, neuroinflammation, and brain atrophy by PET and MRI in a tauopathy mouse model.

METHODS: rTg4510 transgenic (tg) mice expressing P301L mutated tau and non-tg mice were examined with brain MRI and PET imaging (analyzed numbers: tg = 17, non-tg = 13; age 2.5∼14 months). As PET probes, [11C]PBB3 (Pyridinyl-Butadienyl-Benzothiazole 3) and [11C]AC-5216 were used to visualize tau pathology and 18-kDa translocator protein (TSPO) neuroinflammation. Tau pathology and microglia activation were subsequently analyzed by histochemistry.

RESULTS: PET studies revealed age-dependent increases in [11C]PBB3 and [11C]AC-5216 signals, which were correlated with age-dependent volume reduction in the forebrain on MRI. However, the increase in [11C]PBB3 signals reached a plateau at age 7 months, and therefore its significant correlation with [11C]AC-5216 disappeared after age 7 months. In contrast, [11C]AC-5216 showed a strong correlation with both age and volume reduction until age 14 months. Histochemical analyses confirmed the relevance of pathological tau accumulation and elevated TSPO immunoreactivity in putative microglia.

CONCLUSION: Our results showed that tau accumulation is associated with neuroinflammation and brain atrophy in a tauopathy mouse model. The time-course of the [11C]PBB3- and TSPO-PET finding suggests that tau deposition triggers progressive neuroinflammation, and the sequential changes can be evaluated in vivo in mouse brains.

%B J Alzheimers Dis %V 61 %P 1037-1052 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332041?dopt=Abstract %R 10.3233/JAD-170509 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Incidence and Prevalence of Antiepileptic Medication Use in Community-Dwelling Persons with and without Alzheimer's Disease. %A Sarycheva, Tatyana %A Taipale, Heidi %A Lavikainen, Piia %A Tiihonen, Jari %A Tanskanen, Antti %A Hartikainen, Sirpa %A Tolppanen, Anna-Maija %X

BACKGROUND: Although antiepileptic drugs (AEDs) have a potential for adverse drug reactions in older populations, little is known about their use in relation to Alzheimer's disease (AD) diagnosis.

OBJECTIVES: In this study, we investigated the incidence and prevalence of AED use in relation to AD diagnosis.

METHODS: The MEDALZ-study includes all Finnish persons who received clinically verified AD diagnoses (n = 70,718) during 2005-2011 and a matched comparison cohort without AD (n = 70,718). AD diagnoses were identified from the Special Reimbursement Register. We used the Prescription Register to identify dispensed AEDs. Incident AED users were identified with a one-year washout period 9-10 years before AD diagnosis, and incidence rates per 100 person-years were calculated for each six-month period from nine years before to five years after AD diagnosis. Prevalence was assessed as proportion using AEDs during each six-month time period for incident use.

RESULTS: Persons with AD were more likely to use AEDs during the study period (4.3%) than persons without AD (3.2%). The incidence and prevalence of AED use was higher among persons with AD and increased around the time of AD diagnosis. Epilepsy diagnoses did not explain these differences. Persons with AD were more likely to use older AEDs.

CONCLUSION: Our study highlights the need to balance effective symptom control with the possible risks of treatment.

%B J Alzheimers Dis %V 66 %P 387-395 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282366?dopt=Abstract %R 10.3233/JAD-180594 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increased Albumin Oxidation in Cerebrospinal Fluid and Plasma from Alzheimer's Disease Patients. %A Costa, Montserrat %A Horrillo, Raquel %A Ortiz, Ana María %A Pérez, Alba %A Mestre, Anna %A Ruiz, Agustin %A Boada, Merce %A Grancha, Salvador %X

BACKGROUND: Oxidative stress in the brain and peripheral systems is considered a major player in Alzheimer's disease (AD). Albumin is the main transporter and the main extracellular antioxidant in the human body.

OBJECTIVE: Here we explore for the first time the oxidation status of cerebrospinal fluid (CSF) and plasma albumin in AD in comparison to healthy subjects.

METHODS: Plasma and CSF samples were obtained from mild-moderate AD patients and control healthy age-matched donors. Albumin redox state forms (reduced: HMA; reversibly oxidized: HNA1; irreversibly oxidized: HNA2) were determined by HPLC. Albumin post-translational modifications (PTM) analysis was performed by mass spectrometry.

RESULTS: HPLC showed less HMA in AD plasma than in controls (54.1% versus 65.2% ; p < 0.0001), mainly at expense of HNA1 (42.8% versus 32.5% ; p < 0.0001). In AD CSF, HMA was drastically decreased compared to controls (9.6% versus 77.4% ; p < 0.0001), while HNA2 was increased (52.8% versus 7.4% ; p < 0.0001). In AD patients but not in healthy controls, CSF albumin was much more irreversibly oxidized than in plasma (close to 20-fold increase in HNA2). PTM analysis showed that AD CSF albumin samples behave as a differentiated cluster, thus confirming the albumin oxidative pattern observed by HPLC.

CONCLUSION: CSF albumin oxidation in AD patients was dramatically increased comparing to healthy controls, while in plasma this increase was smaller. CSF albumin in AD patients was much more oxidized than in plasma, but this effect was not observed in healthy controls. These results suggest that albumin oxidation, especially in CSF, and its role in AD deserves further investigation.

%B J Alzheimers Dis %V 63 %P 1395-1404 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782326?dopt=Abstract %R 10.3233/JAD-180243 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increased Foxo3a Nuclear Translocation and Activity is an Early Neuronal Response to βγ-Secretase-Mediated Processing of the Amyloid-β Protein Precursor: Utility of an AβPP-GAL4 Reporter Assay. %A Law, Bernard M %A Guest, Amy L %A Pullen, Matthew W J %A Perkinton, Michael S %A Williams, Robert J %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Disease Models, Animal %K Forkhead Box Protein O3 %K Mice %K Mutagenesis, Site-Directed %K Mutation %K Neurons %K Phosphorylation %K Protein Transport %K Signal Transduction %X

Sequential cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (β-secretase) followed by theγ-secretase complex, is strongly implicated in Alzheimer's disease (AD) but the initial cellular responses to these cleavage events are not fully defined. β-secretase-mediated AβPP processing yields an extracellular domain (sAβPPβ) and a C-terminal fragment of AβPP of 99 amino acids (C99). Subsequent cleavage by γ-secretase produces amyloid-β (Aβ) and an AβPP intracellular domain (AICD). A cellular screen based on the generation of AICD from an AβPP-Gal4 fusion protein was adapted by introducing familial AD (FAD) mutations into the AβPP sequence and linking the assay to Gal4-UAS driven luciferase and GFP expression, to identify responses immediately downstream of AβPP processing in neurons with a focus on the transcription factor Foxo3a which has been implicated in neurodegeneration. The K670N/M671L, E682K, E693G, and V717I FAD mutations and the A673T protective mutation, were introduced into the AβPP sequence by site directed mutagenesis. When expressed in mouse cortical neurons, AβPP-Gal4-UAS driven luciferase and GFP expression was substantially reduced by γ-secretase inhibitors, lowered by β-secretase inhibitors, and enhanced by α-secretase inhibitors suggesting that AICD is a product of the βγ-secretase pathway. AβPP-Gal4-UAS driven GFP expression was exploited to identify individual neurons undergoing amyloidogenic AβPP processing, revealing increased nuclear localization of Foxo3a and enhanced Foxo3a-mediated transcription downstream of AICD production. Foxo3a translocation was not driven by AICD directly but correlated with reduced Akt phosphorylation. Collectively this suggests that βγ-secretase-mediated AβPP processing couples to Foxo3a which could be an early neuronal signaling response in AD.

%B J Alzheimers Dis %V 61 %P 673-688 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254083?dopt=Abstract %R 10.3233/JAD-170393 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increased Insoluble Amyloid-β Induces Negligible Cognitive Deficits in Old AppNL/NL Knock-In Mice. %A Salas, Isabel H %A Callaerts-Vegh, Zsuzsanna %A D'Hooge, Rudi %A Saido, Takaomi C %A Dotti, Carlos G %A De Strooper, Bart %X

Commonly used Alzheimer's disease mouse models are based on the ectopic overexpression of the human amyloid precursor protein (APP) gene, together with a mutant presenilin gene. Surprisingly, humanized APP knock-in mouse models carrying a single APP Swedish mutation (AppNL), failed to develop amyloid plaque aggregation or cognitive deficits. Here we characterized the effect of this mutation in more advanced ages. We show that 24-month-old AppNL/NL mice, despite presenting an age dependent increase in insoluble amyloid-β oligomers in the prefrontal cortex, they do not develop amyloid plaque deposition, reactive gliosis, or cognitive deficits.

%B J Alzheimers Dis %V 66 %P 801-809 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320577?dopt=Abstract %R 10.3233/JAD-180410 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increased Prevalence of Obesity/Type 2 Diabetes and Lower Levels of Lithium in Rural Texas Counties May Explain Greater Alzheimer's Disease Risk. %A Baranowski, Bradley J %A Hayward, Grant C %A Fajardo, Val A %A MacPherson, Rebecca E K %X

BACKGROUND/OBJECTIVE: To compare Alzheimer's disease (AD) mortality rates and coinciding risk factors in rural and urban Texas populations.

METHODS: 155 Texas counties were divided into 73 rural and 82 urban areas using the U.S. Census Bureau definition of rurality. Changes in age-adjusted AD mortality across these counties were calculated using a 7-year aggregation model from 2000-2006 and 2009-2015. Data pertaining to gender, race, education, obesity, diabetes, physical inactivity, and lithium concentrations in tap water were also collected from readily available databases.

RESULTS: Change in age-adjusted AD mortality was higher in rural counties (9.5±1.4) versus urban (5.9±1.1) over the time period examined. Similarly, obesity (30.2±0.2% ), diabetes (11.0±0.1% ), and physical inactivity (29.4±0.2% ) levels were significantly higher in rural populations compared to urban (29.1±0.2%, 9.7±0.1%, and 26.7±0.3, respectively). In contrast, the percent of population with some college education (40.1±0.7% ) was lower compared to urban (29.4±0.2% and 44.4±0.9%, respectively). Lithium concentrations in tap water was significantly lower in rural counties compared to urban (63.3±8.2 and 33.4±4.7μg/L, respectively). No significant differences were observed among females and however, we did find significant differences in the percent of African American and Hispanics. Correlational analysis uncovered a negative association between education status and AD mortality over time (r = -0.17). Further analysis controlling for physical inactivity, education, and trace lithium concentrations results in a loss of statistical significance.

CONCLUSIONS: AD mortality rates are higher in rural counties when compared to urban counties, and this may be linked to greater physical inactivity, obesity, and diabetes, as well as lower trace lithium levels in tap water.

%B J Alzheimers Dis %V 64 %P 303-308 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865052?dopt=Abstract %R 10.3233/JAD-171150 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increased Risk of Dementia in Subjective Cognitive Decline if CT Brain Changes are Present. %A Sacuiu, Simona %A Eckerström, Marie %A Johansson, Lena %A Kern, Silke %A Sigström, Robert %A Xinxin, Guo %A Östling, Svante %A Skoog, Ingmar %X

BACKGROUND: Subjective cognitive decline (SCD) has low predictive value for incident dementia.

OBJECTIVES: We examined whether CT detectable brain changes add predictive value to SCD in a population sample with high scores on the Mini-Mental State Examination.

METHODS: Subjective reports of memory and executive function were gathered in a non-demented population sample ≥70 years (n = 921). CT-brain was performed at baseline (n = 626). Brain atrophy, infarcts, and white matter lesions (WMLs) were classified using visual ratings. Dementia incidence was evaluated periodically during 12 years.

RESULTS: The prevalence of SCD was 32.5% among individuals without dementia. During follow-up, 151 individuals (16.4%) developed dementia. The risk of dementia was increased in SCD, and increased further with WMLs and cortical atrophy present. However, the positive predictive values for incident dementia were low, 25% in SCD and 41% in SCD with WMLs and cortical atrophy.

CONCLUSION: Our observations add clinical value to the use of SCD and CT to select relevant populations for interventions against dementia, but more stringent screening methods are necessary to reach individuals at risk.

%B J Alzheimers Dis %V 66 %P 483-495 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320572?dopt=Abstract %R 10.3233/JAD-180073 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increased Serum Acylated Ghrelin Levels in Patients with Mild Cognitive Impairment. %A Cao, Xi %A Zhu, Min %A He, Yan %A Chu, Wenzheng %A Du, Yifeng %A Du, Heng %K Aged %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Ghrelin %K Humans %K Male %K Middle Aged %K Risk Factors %X

Ghrelin is a stomach-derived circulating hormone. In addition to its function as an orexigenic stimulant, the role of ghrelin in the consolidation of learning and memory has been implicated in recent years. However, the status of circulating acylated ghrelin (AG, that is, the functional form of ghrelin) in the symptomatic predementia stage of Alzheimer's disease (AD) has rarely been investigated. In the current study, we examined the serum levels of acylated and total ghrelin in 22 patients with mild cognitive impairment (MCI) and 30 cognitively normal controls. We have found that patients with MCI had significantly increased serum AG levels, which were inversely associated with defected short- and long-term memory as well as language skills. Of note, the levels of total circulating ghrelin were similar between the two groups. Intriguingly, serum AG but not total ghrelin was associated with AD risk factors including the age, hypertension, and hyperlipidemia. Therefore, circulating AG may serve as a potential early systemic biomarker for AD-related cognitive impairments. Nevertheless, the simplest interpretation of the results is that the levels of circulating AG are associated with cognitive impairments in patients with MCI, thereby forming the groundwork for our future studies on the systemic mechanisms of AD pertaining to the ghrelin system.

%B J Alzheimers Dis %V 61 %P 545-552 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226871?dopt=Abstract %R 10.3233/JAD-170721 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increased Vulnerability of the Hippocampus in Transgenic Mice Overexpressing APP and Triple Repeat Tau. %A Arner, Andrew %A Rockenstein, Edward %A Mante, Michael %A Florio, Jazmin %A Masliah, Deborah %A Salehi, Bahar %A Adame, Anthony %A Overk, Cassia %A Masliah, Eliezer %A Rissman, Robert A %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Disease Models, Animal %K Female %K Glycogen Synthase Kinase 3 %K Hippocampus %K Humans %K Male %K Mice %K Mice, Transgenic %K Neocortex %K tau Proteins %K Tauopathies %X

Alzheimer's disease (AD) is the most common tauopathy, characterized by progressive accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. While pathology associated with the 4-repeat (4R) tau isoform is more abundant in corticobasal degeneration and progressive supranuclear palsy, both 3R and 4R tau isoforms accumulate in AD. Many studies have investigated interactions between Aβ and 4R tau in double transgenic mice, but few, if any, have examined the effects of Aβ with 3R tau. To examine this relationship, we crossed our APP751 mutant line with our recently characterized 3R tau mutant model to create a bigenic line (hAPP-3RTau) to model AD neuropathology. Mice were analyzed at 3 and 6 months of age for pathological and behavioral endpoints. While both the 3RTau and the hAPP-3RTau mice showed neuronal loss, increased tau aggregation, Aβ plaques and exhibited more behavioral deficits compared to the non-tg control, the bigenic mice often displaying relatively worsening levels. We found that even in young animals we found that the presence of APP/Aβ increased the accumulation of 3R tau in the neocortex and hippocampus. This observation was accompanied by activation of GSK3 and neurodegeneration in the neocortex and CA1 region. These results suggest that in addition to 4R tau, APP/Aβ may also enhance accumulation of 3R tau, a process which may be directly relevant to pathogenic pathways in AD. Our results demonstrate that this bigenic model closely parallels the pathological course of AD and may serve as a valuable model for testing new pharmacological interventions.

%B J Alzheimers Dis %V 61 %P 1201-1219 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332037?dopt=Abstract %R 10.3233/JAD-170388 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increasing Diagnostic Accuracy of Mild Cognitive Impairment due to Alzheimer's Disease by User-Independent, Web-Based Whole-Brain Volumetry. %A Hedderich, Dennis M %A Spiro, Judith E %A Goldhardt, Oliver %A Kaesmacher, Johannes %A Wiestler, Benedikt %A Yakushev, Igor %A Zimmer, Claus %A Boeckh-Behrens, Tobias %A Grimmer, Timo %X

BACKGROUND: Volumetric quantification of structural MRI has been shown to increase the diagnostic accuracy of patients with mild cognitive impairment (MCI); however, its implementation in clinical routine is usually technically difficult and time-consuming.

OBJECTIVE: The purpose of this study was to investigate whether volumetric information obtained from the free and easy-to-use online tool volBrain can improve correct identification of MCI patients with Alzheimer's disease (AD) compared to visual reading.

METHODS: The study cohort consisted of 27 patients with MCI due to AD (AD positive) as determined by biomarker information and 26 cognitively normal controls (CN). Three blinded readers, 2 radiologists and 1 clinical dementia expert, assessed the patients' MRI regarding brain atrophy and probability of underlying AD two times, without and with supporting volumetric information from volBrain. To assess diagnostic accuracy of volBrain measures alone, a simple sum score based on basic volumetric measures was developed and tested.

RESULTS: Correct patient classification by readers 1, 2, and 3 without a volumetric report was 73.6%, 77.4%, and 83.0%. With a volumetric report, correct classification increased for the radiological readers to 77.4% and 81.1%, respectively and decreased to 77.4% for reader 3. Usage of the volumetric report alone yielded the highest diagnostic accuracy of 84.9%. Diagnostic confidence increased significantly for radiological readers.

CONCLUSION: Volumetric information from volBrain increases the radiologist's diagnostic performance and confidence in identifying MCI patients with AD. We propose that such tools may be implemented in the routine diagnostic work-up of patients with suspected AD.

%B J Alzheimers Dis %V 65 %P 1459-1467 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30175976?dopt=Abstract %R 10.3233/JAD-180532 %0 Journal Article %J J Alzheimers Dis %D 2018 %T INDEL Length and Haplotypes in the β-Synuclein Gene: A Key to Differentiate Dementia with Lewy Bodies? %A Gámez-Valero, Ana %A Canet-Pons, Julia %A Urbizu, Aintzane %A Anillo, Ana %A Santos, Cristina %A Ariza, Aurelio %A Beyer, Katrin %X

Lewy body diseases (LBD) include Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and together with Alzheimer's disease (AD) they show an important neuropathological and clinical overlap. The human alpha- and beta-synuclein genes (SNCA and SNCB) are key factors for the development of Lewy body diseases. Here, we aimed to analyze the genotype distribution of potentially functional SNPs in SNCA and SNCB, perform haplotype analysis for SNCB, and to identify functional insertion and deletion (INDEL) variations within the regulatory region of SNCB which might be responsible for the drastically diminished beta-synuclein levels reported for pure DLB. Thus, we genotyped brain samples from AD, DLB, PD, and healthy controls for two SNCA and four SNCB SNPs. We also analyzed INDEL variations upstream of SNCB, determined SNCB expression levels, and correlated INDEL lengths with expression levels. Applying Fisher's exact, chi-square, ANOVA tests, and the ΔΔCt method, we found disease-specific genotype distribution of SNCA and SNCB SNPs. Additionally, we identified three INDEL variations upstream of SNCB and showed that the INDEL allele lengths were associated with SNCB expression levels. INDEL alleles associated with low SNCB expression were accumulated in pure DLB. Finally, one major and four minor DLB specific SNCB haplotypes were identified with Haploview and Arlequin. In summary, our study showed that different SNCA and SNCB genotypes are associated with the development of either PD or DLB, and that the frequencies of genotypes associated with low SNCB expression are elevated in DLB.

%B J Alzheimers Dis %V 65 %P 207-219 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040713?dopt=Abstract %R 10.3233/JAD-180074 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Independent Associations of Physical Activity and Sleep with Cognitive Function in Older Adults. %A Falck, Ryan S %A Best, John R %A Davis, Jennifer C %A Liu-Ambrose, Teresa %X

BACKGROUND: Current evidence suggests physical activity (PA) and sleep are important for cognitive health; however, few studies examining the role of PA and sleep for cognitive health have measured these behaviors objectively.

OBJECTIVE: We cross-sectionally examined whether 1) higher PA is associated with better cognitive performance independently of sleep quality; 2) higher sleep quality is associated with better cognitive performance independently of PA; and 3) whether higher PA is associated with better sleep quality.

METHODS: We measured PA, subjective sleep quality using the Pittsburgh Sleep Quality Index (PSQI), and objective sleep quality (i.e., fragmentation, efficiency, duration, and latency) using the MotionWatch8© in community-dwelling adults (N = 137; aged 55+). Cognitive function was indexed using the Alzheimer's Disease Assessment Scale-Plus. Correlation analyses were performed to determine relationships between PA, sleep quality, and cognitive function. We then used latent variable modelling to examine the relationships of PA with cognitive function independently of sleep quality, sleep quality with cognitive function independently of PA, and PA with sleep quality.

RESULTS: We found greater PA was associated with better cognitive performance independently of 1) PSQI (β= -0.03; p < 0.01); 2) sleep fragmentation (β= -0.02; p < 0.01); 3) sleep duration (β= -0.02; p < 0.01); and 4) sleep latency (β= -0.02; p < 0.01). In addition, better sleep efficiency was associated with better cognitive performance independently of PA (β= -0.01; p = 0.04). We did not find any associations between PA and sleep quality.

CONCLUSIONS: PA is associated with better cognitive performance independently of sleep quality, and sleep efficiency is associated with better cognitive performance independently of PA. However, PA is not associated with sleep quality and thus PA and sleep quality may be related to cognitive performance through independent mechanisms.

%B J Alzheimers Dis %V 63 %P 1469-1484 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782311?dopt=Abstract %R 10.3233/JAD-170936 %0 Journal Article %J J Alzheimers Dis %D 2018 %T An Inducible Alpha-Synuclein Expressing Neuronal Cell Line Model for Parkinson's Disease1. %A Vasquez, Velmarini %A Mitra, Joy %A Perry, George %A Rao, K S %A Hegde, Muralidhar L %X

Altered expression of α-synuclein is linked to Parkinson's disease (PD). A major challenge to explore how the increased α-synuclein affect neurotoxicity is the lack of a suitable human neuronal cell model that mimics this scenario. Its expression in neural precursors affects their differentiation process, in addition to the neuronal adaptability and variability in maintaining a constant level of expression across passages. Here, we describe an SH-SY5Y line harboring Tet-ON SNCA cDNA cassette that allows for induction of controlled α-synuclein expression after neuronal differentiation, which can be an important tool for PD research.

%B J Alzheimers Dis %V 66 %P 453-460 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320583?dopt=Abstract %R 10.3233/JAD-180610 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Induction of Amyloid-β42 Production by Fipronil and Other Pyrazole Insecticides. %A Cam, Morgane %A Durieu, Emilie %A Bodin, Marion %A Manousopoulou, Antigoni %A Koslowski, Svenja %A Vasylieva, Natalia %A Barnych, Bogdan %A Hammock, Bruce D %A Bohl, Bettina %A Koch, Philipp %A Omori, Chiori %A Yamamoto, Kazuo %A Hata, Saori %A Suzuki, Toshiharu %A Karg, Frank %A Gizzi, Patrick %A Haber, Vesna Erakovic %A Bencetic Mihaljevic, Vlatka %A Tavcar, Branka %A Portelius, Erik %A Pannee, Josef %A Blennow, Kaj %A Zetterberg, Henrik %A Garbis, Spiros D %A Auvray, Pierrick %A Gerber, Hermeto %A Fraering, Jeremy %A Fraering, Patrick C %A Meijer, Laurent %X

Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products, we screened a library of 3500 + compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.

%B J Alzheimers Dis %V 62 %P 1663-1681 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504531?dopt=Abstract %R 10.3233/JAD-170875 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Inflammatory Cytokine, IL-1β, Regulates Glial Glutamate Transporter via microRNA-181a in vitro. %A Zumkehr, Joannee %A Rodriguez-Ortiz, Carlos J %A Medeiros, Rodrigo %A Kitazawa, Masashi %X

Glutamate overload triggers synaptic and neuronal loss that potentially contributes to neurodegenerative diseases including Alzheimer's disease (AD). Glutamate clearance and regulation at synaptic clefts is primarily mediated by glial glutamate transporter 1 (GLT-1). We determined that inflammatory cytokines significantly upregulated GLT-1 through microRNA-181a-mediated post-transcriptional modifications. Unveiling the key underlying mechanisms modulating GLT-1 helps better understand its physiological and pathological interactions with cytokines. Primary murine astrocyte and neuron co-culture received 20 ng/mL IL-1β, TNF-α, or IL-6 for 48 h. Soluble proteins or total RNA were extracted after treatment for further analyses. Treatment with inflammatory cytokines, IL-1β and TNF-α, but not IL-6, significantly increased GLT-1 steady-state levels (p≤0.05) without affecting mRNA levels, suggesting the cytokine-induced GLT-1 was regulated through post-transcriptional modifications. Among the candidate microRNAs predicted to modulate GLT-1, only microRNA-181a was significantly decreased following the IL-1β treatment (p≤0.05). Co-treatment of microRNA-181a mimic in IL-1β-treated primary astrocytes and neurons effectively blocked the IL-1β-induced upregulation of GLT-1. Lastly, we attempted to determine the link between GLT-1 and microRNA-181a in human AD brains. A significant reduction of GLT-1 was found in AD hippocampus tissues, and the ratio of mature microRNA-181a over primary microRNA-181a had an increasing tendency in AD. MicroRNA-181a controls rapid modifications of GLT-1 levels in astrocytes. Cytokine-induced inhibition of microRNA-181a and subsequent upregulation of GLT-1 may have physiological implications in synaptic plasticity while aberrant maturation of microRNA-181a may be involved in pathological consequences in AD.

%B J Alzheimers Dis %V 63 %P 965-975 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710703?dopt=Abstract %R 10.3233/JAD-170828 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Influence of Butyrylcholinesterase in Progression of Mild Cognitive Impairment to Alzheimer's Disease. %A Gabriel, António José %A Almeida, Maria Rosário %A Ribeiro, Maria Helena %A Carneiro, Diogo %A Valério, Daniela %A Pinheiro, Ana Cristina %A Pascoal, Rui %A Santana, Isabel %A Baldeiras, Ines %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Biomarkers %K Butyrylcholinesterase %K Cognitive Dysfunction %K Disease Progression %K Female %K Genetic Predisposition to Disease %K Humans %K Kaplan-Meier Estimate %K Male %K Middle Aged %K Risk Factors %K tau Proteins %X

BACKGROUND: Several demographic and genetic prognostic factors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) have been recognized so far. The most frequent polymorphism of butyrylcholinesterase (BuChE), the K-variant, has been proposed as a risk factor for AD, but data regarding its influence on early disease progression is still limited.

OBJECTIVE: To investigate the influence of the BuChE-K variant in MCI progression to AD.

METHODS: 96 MCI patients were included in the study and were genotyped for BuChE-K variant and Apolipoprotein E (ApoE). Cerebrospinal fluid (CSF) BuChE activity, as well as the levels of AD biomarkers amyloid-β 42 (Aβ42), total and hyperphosphorylated tau (t-tau and p-tau) were also determined.

RESULTS: No significant differences were found in either BuChE-K variant or BuChE activity between MCI patients that progressed to AD (MCI-AD) and patients that remained stable during clinical follow-up (MCI-St). As expected, baseline CSF levels of Aβ42 were significantly lower and t-Tau, p-Tau, and ApoE ɛ4 allele frequency were significantly higher in MCI-AD patients. An association between the ApoE ɛ4 allele and the BuChE-K variant in MCI-AD, but not in MCI-St patients, was found with patients carrying both alleles presenting the highest incidence of progression and the lowest estimated time of progression to AD.

CONCLUSION: Although BuChE-K alone does not seem to play a major role in progression to AD in MCI patients, a synergistic effect with the ApoE ɛ4 allele was found, highlighting the importance of assessing these combined genotypes for evaluating risk progression in MCI patients.

%B J Alzheimers Dis %V 61 %P 1097-1105 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254094?dopt=Abstract %R 10.3233/JAD-170695 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Influence of Lewy Pathology on Alzheimer's Disease Phenotype: A Retrospective Clinico-Pathological Study. %A Roudil, Jennifer %A Deramecourt, Vincent %A Dufournet, Boris %A Dubois, Bruno %A Ceccaldi, Mathieu %A Duyckaerts, Charles %A Pasquier, Florence %A Lebouvier, Thibaud %X

BACKGROUND: Studies have shown the frequent coexistence of Lewy pathology (LP) in Alzheimer's Disease (AD).

OBJECTIVE: The aim of this study was to determine the influence of LP on the clinical and cognitive phenotype in a cohort of patients with a neuropathological diagnosis of AD.

METHODS: We reviewed neuropathologically proven AD cases, reaching Braak stages V and VI in the brain banks of Lille and Paris between 1993 and 2016, and classified them according to LP extension (amygdala, brainstem, limbic, or neocortical). We then searched patient files for all available clinical and neuropsychiatric features and neuropsychological data.

RESULTS: Thirty-three subjects were selected for this study, among which 16 were devoid of LP and 17 presented AD with concomitant LP. The latter were stratified into two subgroups according to LP distribution: 7 were AD with amygdala LP and 10 were AD with 'classical' (brainstem, limbic or neocortical) LP. When analyzing the incidence of each clinical feature at any point during the disease course, we found no significant difference in symptom frequency between the three groups. However, fluctuations appeared significantly earlier in patients with classical LP (2±3.5 years) than in patients without LP (7±1.7 years) or with amygdala LP (8±2.8 years; p < 0.01). There was no significant difference in cognitive profiles.

CONCLUSION: Our findings suggest that the influence of LP on the clinical phenotype of AD is subtle. Core features of dementia with Lewy bodies do not allow clinical diagnosis of a concomitant LP on a patient-to-patient basis.

%B J Alzheimers Dis %V 63 %P 1317-1323 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758938?dopt=Abstract %R 10.3233/JAD-170914 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Influence of Polypharmacy on the Initiation of Anti-Dementia Therapy in Germany. %A Bohlken, Jens %A Jacob, Louis %A van den Bussche, Hendrik %A Kostev, Karel %X

The goal of the present retrospective study was to focus on the potential influence of polypharmacy on the initiation of antidementia therapy in patients diagnosed with dementia in general practices in Germany. The current study sample included patients diagnosed with dementia in 1,217 general practices in Germany between 2014 and 2016 (index date). The primary outcome measure was the rate of prescription of anti-dementia drugs within one year following the index date. The explanatory variable was the number of different drugs prescribed at baseline per patient. Independent variables included age, sex, and type of dementia. Logistic regression analyses were conducted to study the impact of the number of different drugs prescribed at baseline per participant on the odds of receiving anti-dementia therapy (in all patients and in patients diagnosed with Alzheimer's disease). The study included 21,888 patients with all-cause dementia. Mean age was 80.2 years (SD = 7.3 years) and 61.4% of the study population were women. Individuals receiving six drugs or more at baseline were significantly less likely to be prescribed anti-dementia treatment when compared to those without any drug at baseline (6- 9 drugs: odds ratio [OR] = 0.75;≥10 drugs: OR = 0.58). In the subgroup of patients with Alzheimer's disease, the odds of being prescribed anti-dementia therapy were lower in individuals with four drugs or more, compared to patients who had not been prescribed any drugs at baseline (4- 5 drugs: OR = 0.60; 6- 9 drugs: OR = 0.49;≥10 drugs: OR = 0.36). There is a negative association between polypharmacy and antidementia therapy initiation in general practices in Germany.

%B J Alzheimers Dis %V 64 %P 827-833 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889071?dopt=Abstract %R 10.3233/JAD-180382 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Influence of the Val66Met Polymorphism of Brain-Derived Neurotrophic Factor on Neurological Function after Traumatic Brain Injury. %A Finan, John D %A Udani, Shreya V %A Patel, Vimal %A Bailes, Julian E %X

Functional outcomes after traumatic brain injury (TBI) vary widely across patients with apparently similar injuries. This variability hinders prognosis, therapy, and clinical innovation. Recently, single nucleotide polymorphism (SNPs) that influence outcome after TBI have been identified. These discoveries create opportunities to personalize therapy and stratify clinical trials. Both of these changes would propel clinical innovation in the field. This review focuses on one of most well-characterized of these SNPs, the Val66Met SNP in the brain-derived neurotrophic factor (BDNF) gene. This SNP influences neurological function in healthy subjects as well as TBI patients and patients with similar acute insults to the central nervous system. A host of other patient-specific factors including ethnicity, age, gender, injury severity, and post-injury time point modulate this influence. These interactions confound efforts to define a simple relationship between this SNP and TBI outcomes. The opportunities and challenges associated with personalizing TBI therapy around this SNP and other similar SNPs are discussed in light of these results.

%B J Alzheimers Dis %V 65 %P 1055-1064 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149456?dopt=Abstract %R 10.3233/JAD-180585 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Inhibition of Histone Acetylation by ANP32A Induces Memory Deficits. %A Chai, Gao-Shang %A Feng, Qiong %A Ma, Rong-Hong %A Qian, Xiao-Hang %A Luo, Dan-Ju %A Wang, Zhi-Hao %A Hu, Yu %A Sun, Dong-Sheng %A Zhang, Jun-Fei %A Li, Xiao %A Li, Xiao-Guang %A Ke, Dan %A Wang, Jian-Zhi %A Yang, Xi-Fei %A Liu, Gong-Ping %X

There is accumulating evidence that decreased histone acetylation is involved in normal aging and neurodegenerative diseases. Recently, we found that ANP32A, a key component of INHAT (inhibitor of acetyltransferases) that suppresses histone acetylation, increased in aged and cognitively impaired C57 mice and expressing wild-type human full length tau (htau) transgenic mice. Downregulating ANP32A restored cognitive function and synaptic plasticity through upregulation of the expressions of synaptic-related proteins via increasing histone acetylation. However, there is no direct evidence that ANP32A can induce neurodegeneration and memory deficits. In the present study, we overexpressed ANP32A in the hippocampal CA3 region of C57 mice and found that ANP32A overexpression induced cognitive abilities and synaptic plasticity deficits, with decreased synaptic-related protein expression and histone acetylation. Combined with our recent studies, our findings reveal that upregulated ANP32A induced-suppressing histone acetylation may underlie the cognitive decline in neurodegenerative disease, and suppression of ANP32A may represent a promising therapeutic approach for neurodegenerative diseases including Alzheimer's disease.

%B J Alzheimers Dis %V 63 %P 1537-1546 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782322?dopt=Abstract %R 10.3233/JAD-180090 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The In-Hospital Length of Stay after Hip Fracture in Octogenarians: Do Delirium and Dementia Shape a New Care Process? %A Monacelli, Fiammetta %A Pizzonia, Monica %A Signori, Alessio %A Nencioni, Alessio %A Giannotti, Chiara %A Minaglia, Cecilia %A Granello di Casaleto, Tommaso %A Podestà, Silvia %A Santolini, Federico %A Odetti, Patrizio %X

BACKGROUND: Hip fracture is a major health problem and a patient's biological age, comorbidity, and cognitive vulnerability have an impact on its related outcomes. Length of stay (LOS) for these highly vulnerable patients is rather long and the possible causes have not been clearly identified yet.

OBJECTIVE: We aimed to assess the main clinical factors associated with protracted LOS, focusing on delirium with or without dementia in older age hip fractured patients.

METHODS: 218 subjects (mean age 86.70±6.18 years), admitted to the Orthogeriatric Unit of the Ospedale Policlinico San Martino (Italy), were recruited. All patients received physical and comprehensive geriatric assessment. Days to surgery, days from surgery to rehabilitation, and LOS were recorded. In-hospital and three months' mortality were reported.

RESULTS: Prevalent delirium at hospital admission was of 3.1%. 35% of patients developed incident delirium. 56.4% were affected by dementia of Alzheimer-type. In addition, 52% of patients developed delirium superimposed to dementia. Mean LOS was 13.5±4.99 days. Namely, delirium, time to surgery, and complication rate disproportionally affected LOS. The analysis with 3 months mortality, based on cognitive vulnerability profiles, showed how delirium mainly affect short-term mortality in patients with dementia.

CONCLUSION: Our exploratory study originally pointed out the high incidence of delirium superimposed to dementia in orthogeriatric wards and how delirium turns to be a moderator of LOS. The results meet the need for additional research by virtue of a deeper understanding of the impact of delirium and dementia on orthogeriatric clinical management and outcomes.

%B J Alzheimers Dis %V 66 %P 281-288 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30248051?dopt=Abstract %R 10.3233/JAD-180153 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Innovative Biomarkers for Alzheimer's Disease: Focus on the Hidden Disease Biomarkers. %A Ghidoni, Roberta %A Squitti, Rosanna %A Siotto, Mariacristina %A Benussi, Luisa %X

The criteria for the clinical diagnosis of AD include the analysis of biomarkers of the underlying brain disease pathology; a set of cerebrospinal fluid (CSF) tests, amyloid-β1-42 (Aβ42), total-tau (t-tau), and phosphorylated tau (p-tau), are available and their performance in a clinical setting has been assessed in several studies. Thus, in dementia research, great advances have been made in the discovery of putative biomarkers; however, disappointingly, few of them have been translated into clinically applicable assays. To find biomarkers able to reliably detect AD pathology already at prodromal stages and in blood is even more important. Recent technical breakthroughs have provided ultrasensitive methods that allow the detection of brain-specific proteins in blood. In the present review, we will focus on the usefulness of ultrasensitive technologies for biomarker discovery and trace elements detection; moreover, we will review studies on circulating nano-compartments, a promising novel source of material for molecular diagnostics.

%B J Alzheimers Dis %V 62 %P 1507-1518 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504534?dopt=Abstract %R 10.3233/JAD-170953 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Integrating Sleep and Alzheimer's Disease Pathophysiology: Hints for Sleep Disorders Management. %A Proserpio, Paola %A Arnaldi, Dario %A Nobili, Flavio %A Nobili, Lino %X

Sleep represents an active phenomenon regulated by a highly integrated network of cortical and subcortical structures. This complex model results in disruptions at various levels during physiological aging and more deeply during neurodegenerative disorders, thus leading to different sleep alterations. In Alzheimer's disease (AD), sleep-wake abnormalities were described to occur even in the preclinical phase, thus suggesting they could be a possible AD biomarker. On the other hand, they also favor the progression of the disease. In this paper, we review current theories regarding sleep regulations and functions to highlight the pathophysiological mechanisms at the basis of the bidirectional relationship between sleep and AD. A better understanding of these complex interactions might also be useful to target both sleep disorder management and AD-related symptoms.

%B J Alzheimers Dis %V 63 %P 871-886 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710720?dopt=Abstract %R 10.3233/JAD-180041 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Interaction between Cytomegalovirus and Herpes Simplex Virus Type 1 Associated with the Risk of Alzheimer's Disease Development. %A Lövheim, Hugo %A Olsson, Jan %A Weidung, Bodil %A Johansson, Anders %A Eriksson, Sture %A Hallmans, Göran %A Elgh, Fredrik %K Aged %K Alzheimer Disease %K Antibodies, Viral %K Case-Control Studies %K Cytomegalovirus %K Cytomegalovirus Infections %K Enzyme-Linked Immunosorbent Assay %K Female %K Herpes Simplex %K Herpesvirus 1, Human %K Humans %K Immunoglobulin G %K Immunoglobulin M %K Logistic Models %K Male %K Middle Aged %X

BACKGROUND: Several environmental factors, including infectious agents, have been suggested to cause Alzheimer's disease (AD). Cytomegalovirus (CMV) has been associated with AD in several recent studies.

OBJECTIVE: To investigate whether carriage of CMV, alone or in combination with Herpes simplex virus (HSV), increased the risk of developing AD.

METHODS: Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years), taken an average of 9.6 years before AD diagnosis, and 360 age-, sex-, cohort-, and sampling date matched dementia-free controls were analyzed to detect anti-CMV (immunoglobulin [Ig] G and IgM), group-specific anti-HSV (IgG and IgM), and specific anti-HSV1 and HSV2 IgG antibodies by enzyme-linked immunosorbent assays. AD cases and dementia-free controls were compared using conditional logistic regression analyses.

RESULTS: The presence of anti-CMV IgG antibodies did not increase the risk of AD (odds ratio [OR], 0.857; p = 0.497). Among AD cases, an association between CMV and HSV1 carriage was detected (OR 7.145, p < 0.001); in a conditional logistic regression model, the interaction between CMV and HSV1 was associated with AD development (OR 5.662; p = 0.007).

CONCLUSION: The present findings do not support a direct relationship between CMV infection and the development of AD; however, an interaction between CMV and HSV1 was found to be associated significantly with AD development. These findings suggest that CMV infection facilitates the development of HSV1-associated AD, possibly via its effects on the immune system.

%B J Alzheimers Dis %V 61 %P 939-945 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254081?dopt=Abstract %R 10.3233/JAD-161305 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Interactions between Atrial Fibrillation, Cardiovascular Risk Factors, and ApoE Genotype in Promoting Cognitive Decline in Patients with Alzheimer's Disease: A Prospective Cohort Study. %A Falsetti, Lorenzo %A Viticchi, Giovanna %A Buratti, Laura %A Grigioni, Francesco %A Capucci, Alessandro %A Silvestrini, Mauro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Atherosclerosis %K Atrial Fibrillation %K Carotid Intima-Media Thickness %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Logistic Models %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Prospective Studies %K Risk Factors %K Tomography, X-Ray Computed %X

BACKGROUND: An association between non-valvular atrial fibrillation (NVAF) and cognitive impairment has been hypothesized.

OBJECTIVE: We sought to evaluate whether and how permanent NVAF (pNVAF) is associated with progression of cognitive impairment in patients with Alzheimer's disease (AD) in the presence of vascular or genetic risk factors.

METHODS: 310 consecutive patients affected by mild-moderate AD were included and followed for a 24-month period. At the end of the follow-up, based on the results of the neuropsychological evaluation patients were classified as stable or deteriorated to severe AD. Clinical history, therapy, time in therapeutic range for anticoagulation, Framingham cardiovascular risk profile (FCRP), CHA2DS2-VASc score, Mini-Mental State Examination (MMSE), ApoE genotype, brain CT-scan, carotid ultrasound, and ECG were collected. Binary logistic and path analysis were adopted to assess relationships between pNVAF, ApoE, and cognitive outcome.

RESULTS: Despite anticoagulant therapy, pNVAF was associated with lower entry MMSE, higher mean intima-media thickness (mIMT) and higher FCRP. Among patients carrying ApoE ɛ4 allele and affected by pNVAF, the lowest MMSE (14.90±7.62) and the highest mIMT (1.16±0.17 mm) and FCRP (26.24±3.96) values were detected. In this group, the risk of cognitive deterioration reached the highest probability. pNVAF was associated with an increased cognitive deterioration in subjects with high FCRP, CHA2DS2-VASc, or mIMT.

CONCLUSIONS: pNVAF seems to identify AD patients with a significant atherosclerotic burden and reduced cognitive performances. The interaction between pNVAF and ApoE ɛ4 genotype, especially with aggregated risk factors and an advanced stage of vascular damage is associated with higher risk of fast cognitive deterioration.

%B J Alzheimers Dis %V 62 %P 713-725 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480173?dopt=Abstract %R 10.3233/JAD-170544 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Interactive Effect of Depression and Cognitive Impairment on Olfactory Identification in Elderly People. %A Chen, Ben %A Zhong, Xiaomei %A Mai, Naikeng %A Peng, Qi %A Zhang, Min %A Chen, Xinru %A Wu, Zhangying %A Zou, Laiquan %A Liang, Wanyuan %A Ouyang, Cong %A Wu, Yujie %A Ning, Yuping %X

Olfactory identification (OI) deficits have been regarded as an indicator of cognitive impairment in the elderly, but few studies have analyzed the mixed effect of depression on OI. Since depression is common in the elderly and strongly associated with OI, we aimed to explore whether the comorbidity of depression and cognitive impairment may be associated with worse outcomes. In total, 153 elderly patients with depression and 154 normal elderly were recruited. Subjects underwent assessments of depression, cognitive function, and OI. Information on the factors that may affect OI performance was collected (age, sex, smoking history, diabetes, etc.). Correlation analysis showed that several factors had a significant influence on OI performance in the elderly, including severity of depression, cognitive scores, age, sex, and years of education (p < 0.05). Among the different cognitive domains, OI was positively associated with global cognition, memory, language, executive function, and attention performance (p < 0.05). The multiple linear regression analysis indicated that memory scores, age, HAMD scores, and sex were the most relevant factors to OI scores across all elderly participants. The factorial analysis suggested that elderly with comorbidity of depression and cognitive impairment (memory deficits or language deficits) had worse OI impairment, and there was an interactive effect of depression and memory deficits on OI in elderly people. The present study suggested that the coexistence of depressive symptoms and cognitive impairment was associated with worse OI in the elderly. Studies exploring the association between OI and cognitive function should include an assessment of depression and adjust the interactive effects of depression.

%B J Alzheimers Dis %V 66 %P 1645-1655 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30475771?dopt=Abstract %R 10.3233/JAD-180760 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Internal Consistency Over Time of Subjective Cognitive Decline: Drawing Preclinical Alzheimer's Disease Trajectories. %A Ávila-Villanueva, Marina %A Maestú, Fernando %A Fernández-Blázquez, Miguel A %X

BACKGROUND: Early intervention to prevent, or delay, the transition from healthy cognition to cognitive impairment in older adults is an important goal. In this way, it is critical to find sensitive, reproducible, and early markers to use low cost methods for the detection of that transition. One of those early markers for symptomatic manifestation of AD is subjective cognitive decline (SCD).

OBJECTIVE: To examine the internal consistency of the concept of SCD and to evaluate its clinical significance on the progression through the continuum of AD.

METHODS: 1,091 cognitively healthy individuals from the Vallecas Project cohort were followed for three years. Cognitive complaints were systematically collected and analyzed along with clinical data. All participants were classified in three groups at every visit based on specific features of their complaints.

RESULTS: Concordance analyses showed a good agreement in longitudinal classification of SCD. The Multi-state Markov Model highlighted a unidirectional transition from the status of no cognitive complaints to SCD. Interestingly, a more severe condition of SCD, namely SCD Plus, showed the highest risk of progression to mild cognitive impairment.

CONCLUSIONS: The concept of SCD is stable over time when it is operationally defined and consistently assessed. It provides not only a fast identification of individuals at higher risk of future mild cognitive impairment, but also it allows us to track longitudinal trajectories.

%B J Alzheimers Dis %V 66 %P 173-183 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30248053?dopt=Abstract %R 10.3233/JAD-180307 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Interrelationship between the Levels of C9orf72 and Amyloid-β Protein Precursor and Amyloid-β in Human Cells and Brain Samples. %A Leskelä, Stina %A Takalo, Mari %A Marttinen, Mikael %A Huber, Nadine %A Paananen, Jussi %A Mitra, Vikram %A Rauramaa, Tuomas %A Mäkinen, Petra %A Leinonen, Ville %A Soininen, Hilkka %A Pike, Ian %A Remes, Anne M %A Hiltunen, Mikko %A Haapasalo, Annakaisa %X

A subset of C9orf72 repeat expansion-carrying frontotemporal dementia patients display an Alzheimer-like decrease in cerebrospinal fluid amyloid-β (Aβ) biomarker levels. We report that downregulation of C9orf72 in non-neuronal human cells overexpressing amyloid-β protein precursor (AβPP) resulted in increased levels of secreted AβPP fragments and Aβ, while levels of AβPP or its C-terminal fragments (CTFs) remained unchanged. In neuronal cells, AβPP and C83 CTF levels were decreased upon C9orf72 knockdown, but those of secreted AβPP fragments or Aβ remained unchanged. C9orf72 protein levels significantly increased in human brain with advancing neurofibrillary pathology and positively correlated with brain Aβ42 levels. Our data suggest that altered C9orf72 levels may lead to cell-type specific alterations in AβPP processing, but warrant further studies to clarify the underlying mechanisms.

%B J Alzheimers Dis %V 62 %P 269-278 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439323?dopt=Abstract %R 10.3233/JAD-170362 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Intracellular Targeting of Heat Shock Proteins in Differentiated Human Neuronal Cells Following Proteotoxic Stress. %A Deane, Catherine A S %A Brown, Ian R %X

HSPA6 (Hsp70B') is an inducible member of the Hsp70 (HSPA) family of heat shock proteins that is present in the human genome and not found in mouse and rat. Hence it is lacking in current animal models of neurodegenerative diseases. To advance knowledge of the little studied HSPA6, differentiated human neuronal SH-SY5Y cells were treated with the proteotoxic stress-inducing agent MG132. A robust induction of HSPA6 was apparent which localized to the periphery of MG132-induced protein aggregates in the neuronal cytoplasm. Components of the protein disaggregation/refolding machine that co-operate with Hsp70 also targeted the periphery of cytoplasmic protein aggregates, including DNAJB1 (Hsp40-1), HSPH1 (Hsp105α), and HSPB1 (Hsp27). These data suggest that HSPA6 is involved in the response of human neuronal cells to proteotoxic stress that is a feature of neurodegenerative diseases which have been characterized as protein misfolding disorders. Constitutively expressed HSPA8 (Hsc70) also localized tothe periphery of cytoplasmic protein aggregates following the treatment of differentiated human neuronal cells with MG132. HSPA8 could provide a rapid response to proteotoxic stress in neuronal cells, circumventing the time required to upregulate inducible Hsps.

%B J Alzheimers Dis %V 66 %P 1295-1308 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412487?dopt=Abstract %R 10.3233/JAD-180536 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Intracranial Transplantation of Pancreatic Islets Attenuates Cognitive and Peripheral Metabolic Dysfunctions in a Rat Model of Sporadic Alzheimer's Disease. %A Bloch, Konstantin %A Gil-Ad, Irit %A Vanichkin, Alexey %A Hornfeld, Shay Henry %A Taler, Michal %A Dar, Shira %A Azarov, Dmitry %A Vardi, Pnina %A Weizman, Abraham %X

BACKGROUND: Alzheimer's disease (AD) is often associated with brain insulin resistance and peripheral metabolic dysfunctions. Recently, we developed a model of sporadic AD associated with obesity-related peripheral metabolic abnormalities in Lewis rats using intracerebroventricular administration of streptozotocin (icv-STZ).

OBJECTIVE: We aimed to assess the effect of intracranially grafted pancreatic islets on cognitive and peripheral metabolic dysfunctions in the icv-STZ Lewis rats.

METHODS: AD-like dementia associated with obesity was induced in inbred Lewis rats using a single icv-STZ. Two months after icv-STZ, syngeneic islets (100 islets per recipient) were implanted in the cranial subarachnoid cavity of icv-STZ rats. Morris water maze and marble burying tests were used for studying cognitive and behavioral functions. Central and peripheral metabolic alterations were assessed by histological and biochemical assays.

RESULTS: The icv-STZ induced increases in food intake, body weight, and blood levels of insulin and leptin without alteration of glucose homeostasis. Grafted islets reduced body weight gain, food consumption, peripheral insulin resistance, and hyperleptinemia. Biochemical and histological analysis of the brain revealed viable grafted islets expressing insulin and glucagon. The grafted islets did not affect expression of brain insulin receptors and peripheral glucose homeostasis. Two months after islet transplantation, cognitive and behavioral functioning in transplanted rats were significantly better than the sham-operated icv-STZ rats. No significant differences in the locomotor activity between transplanted and non-transplanted icv-STZ rats were found.

CONCLUSIONS: Intracranial islet transplantation attenuates cognitive decline and peripheral metabolic dysfunctions providing a novel therapeutic approach for sporadic AD associated with peripheral metabolic dysfunctions.

%B J Alzheimers Dis %V 65 %P 1445-1458 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30175977?dopt=Abstract %R 10.3233/JAD-180623 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Involvement of Activation of Asparaginyl Endopeptidase in Tau Hyperphosphorylation in Repetitive Mild Traumatic Brain Injury. %A Hu, Wen %A Tung, Yunn Chyn %A Zhang, Yanchong %A Liu, Fei %A Iqbal, Khalid %X

Traumatic brain injury (TBI) is an established risk factor for the development of neurodegeneration and dementia late in life. Repetitive mild TBI (r-mTBI) is directly associated with chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder characterized by focal perivascular to widespread Alzheimer-type neurofibrillary pathology of hyperphosphorylated tau. Studies in animal models have shown hyperphosphorylation of tau after TBI. However, the molecular mechanisms by which TBI leads to tau pathology are not understood. In this study, we employed western blots and immunohistochemistry to test, in triple-transgenic mouse model of Alzheimer's disease (3xTg-AD), the effect of r-mTBI on tau hyperphosphorylation and activation of asparaginyl endopeptidase (AEP), a cysteine proteinase which is known to be involved in tau hyperphosphorylation. We found that the level of active AEP was increased and correlated with the level of tau hyperphosphorylation following r-mTBI, and that fimbria showed increased immunoreactivity to phospho-tau. In addition, inhibitor 2 of protein phosphatase 2A (I2PP2A) was translocated from neuronal nucleus to the cytoplasm and colocalized with hyperphosphorylated tau. These data suggest the involvement of AEP-I2PP2A-PP2A-ptau pathway in tau pathology in TBI.

%B J Alzheimers Dis %V 64 %P 709-722 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889065?dopt=Abstract %R 10.3233/JAD-180177 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Involvement of the Cingulate Cortex in Anosognosia: A Multimodal Neuroimaging Study in Alzheimer's Disease Patients. %A Guerrier, Laura %A Le Men, Johanne %A Gane, Anaıs %A Planton, Mélanie %A Salabert, Anne-Sophie %A Payoux, Pierre %A Dumas, Hervé %A Bonneville, Fabrice %A Péran, Patrice %A Pariente, Jérémie %X

BACKGROUND: Anosognosia is a frequent symptom of Alzheimer's disease (AD), but its neural substrates remain in question.

OBJECTIVE: In this study, we combined neuroimaging with a neuropsychological evaluation to assess neural substrates of anosognosia.

METHODS: We prospectively recruited 30 patients with probable early-stage AD and matched healthy controls. Participants underwent MRI, FDG-PET, and a neuropsychological evaluation that includes an assessment of anosognosia. In the AD group, correlations between the anosognosia score, neuroimaging modalities, and neuropsychological performance were performed.

RESULTS: Atrophy and hypometabolism were correlated with the anosognosia score in the left dorsal anterior cingulate cortex. The anosognosia score was also correlated with atrophy of the cerebellar vermis, the left postcentral gyrus, and the right fusiform gyrus. No relation was found between anosognosia and the neuropsychological assessment.

DISCUSSION: Structural and metabolic alteration in the dorsal anterior cingulate cortex seems to be associated with a diminution of awareness in patients with early-stage AD.

%B J Alzheimers Dis %V 65 %P 443-453 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056422?dopt=Abstract %R 10.3233/JAD-180324 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Iron and Alzheimer's Disease: An Update on Emerging Mechanisms. %A Lane, Darius J R %A Ayton, Scott %A Bush, Ashley I %X

Iron is a crucial transition metal for life and is the most abundant transition metal in the brain. However, iron's biological utility as an effective redox cycling metal also endows it with the potential to catalyze production of noxious free radicals. This "Janus-faced" nature of iron demands a tight regulation of cellular its metabolism. This regulation is crucial in the CNS, where iron plays myriad keystone roles in CNS processes, including mitochondrial energy transduction, enzyme catalysis, mitochondrial function, myelination, neurotransmitter anabolism and catabolism. Aberrations in brain iron homeostasis can elevate levels of this redox-active metal, leading to mislocalization of the metal and catastrophic oxidative damage to sensitive cellular and subcellular structures. Iron dyshomeostasis has been strongly linked to the pathogenesis of Alzheimer's disease (AD), as well as other major neurodegenerative diseases. Despite the growing societal burden of AD, no disease-modifying therapy exists, necessitating continued investment into both drug-development and the fundamental science investigating the disease-causing mechanisms. Targeting iron dyshomeostasis in the brain represents a rational approach to treat the underlying disease. Here we provide an update on known and emerging iron-associated mechanisms involved in AD. We conclude with an overview of evidence suggesting that, in addition to apoptosis, neuronal loss in AD involves "ferroptosis", a newly discovered iron- and lipid-peroxidation-dependent form of regulated necrosis. The ferroptosis field is rapidly progressing and may provide key insights for future drug-development with disease-modifying potential in AD.

%B J Alzheimers Dis %V 64 %P S379-S395 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865061?dopt=Abstract %R 10.3233/JAD-179944 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Joint Assessment of Quantitative 18F-Florbetapir and 18F-FDG Regional Uptake Using Baseline Data from the ADNI. %A Ben Bouallègue, Fayçal %A Mariano-Goulart, Denis %A Payoux, Pierre %X

Joint analysis of amyloid and metabolic PET patterns across healthy, mild cognitive impairment (MCI), and Alzheimer's disease (AD) subjects was performed using baseline 18F-florbetapir and 18F-FDG PET of 684 subjects from the ADNI (251 normal, 204 stable MCI, 85 AD converters, and 144 AD). Correlation between regional amyloid and metabolic uptake was measured and predictive value of PET profile regarding AD conversion in cognitively impaired subjects was assessed using survival analysis and support vector machine classification (SVM). The highest correlations were found in the temporal cortex, precuneus, and posterior cingulum. With respect to normal controls, amyloid load increase was diffuse and early in MCI subjects, whereas metabolism decrease occurred later and predominated in temporo-parietal, precuneus, and cingulate cortices. Five-year AD conversion rates in cognitively impaired subjects were 5%, 22%, 42%, and 78% in amyloid-/FDG-, amyloid-/FDG+, amyloid+/FDG-, and amyloid+/FDG+ subjects respectively (mean follow-up 37±14 months). Using SVM, the combination of ADAS-cog score, amyloid PET, and FDG PET yielded better performance in predicting AD conversion (77% accuracy; 58% positive predictive value; 88% negative predictive value) than ADAS-cog (72%; 52%; 86%), amyloid PET (72%; 52%; 87%), and FDG PET (67%; 47%; 84%). This study attests the complementary value of amyloid and FDG PET in MCI assessment and the efficiency of combined cognitive, amyloid, and metabolic scores to predict AD conversion.

%B J Alzheimers Dis %V 62 %P 399-408 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439345?dopt=Abstract %R 10.3233/JAD-170833 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Kainic Acid Impairs the Memory Behavior of APP23 Mice by Increasing Brain Amyloid Load through a Tumor Necrosis Factor-α-Dependent Mechanism. %A Ruan, Yang %A Guo, Shi-Jie %A Wang, Xu %A Dong, Dong %A Shen, Dong-Hui %A Zhu, Jie %A Zheng, Xiang-Yu %X

Kainic acid (KA) was recently identified as an epileptogenic and neuroexcitotoxic agent that is responsible for inducing learning and memory deficits in various neurodegenerative diseases, such as Alzheimer's disease (AD). However, the mechanism by which KA acts upon AD remains unclear. To this end, we presently investigated the roles of KA in processing amyloid-β protein precursor (AβPP) and amyloid-β protein (Aβ) loads during the course of AD development and progression. Specifically, KA treatment clearly caused the upregulation of tumor necrosis factor α (TNF-α) via activation of the PI3-K/AKT, ERK1/2, and p65 pathways in glial cells. TNF-α secreted from glial cells was then found to be responsible for stimulating the expression of BACE-1 and PS1/2, which resulted in the production and deposition of Aβ in neurons. Finally, the accumulation and aggregation of Aβ lead to the cognitive decline of APP23 mice. These results indicate that KA accelerates the progression of AD by inducing the crosstalk between glial cells and neurons.

%B J Alzheimers Dis %V 64 %P 103-116 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782313?dopt=Abstract %R 10.3233/JAD-171137 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Ketogenic Medium Chain Triglycerides Increase Brain Energy Metabolism in Alzheimer's Disease. %A Croteau, Etienne %A Castellano, Christian-Alexandre %A Richard, Marie Anne %A Fortier, Mélanie %A Nugent, Scott %A Lepage, Martin %A Duchesne, Simon %A Whittingstall, Kevin %A Turcotte, Éric E %A Bocti, Christian %A Fülöp, Tamás %A Cunnane, Stephen C %X

BACKGROUND: In Alzheimer's disease (AD), it is unknown whether the brain can utilize additional ketones as fuel when they are derived from a medium chain triglyceride (MCT) supplement.

OBJECTIVE: To assess whether brain ketone uptake in AD increases in response to MCT as it would in young healthy adults.

METHODS: Mild-moderate AD patients sequentially consumed 30 g/d of two different MCT supplements, both for one month: a mixture of caprylic (55%) and capric acids (35%) (n = 11), followed by a wash-out and then tricaprylin (95%; n = 6). Brain ketone (11C-acetoacetate) and glucose (FDG) uptake were quantified by PET before and after each MCT intervention.

RESULTS: Brain ketone consumption doubled on both types of MCT supplement. The slope of the relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults. Both types of MCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization.

CONCLUSION: Ketones from MCT compensate for the brain glucose deficit in AD in direct proportion to the level of plasma ketones achieved.

%B J Alzheimers Dis %V 64 %P 551-561 %8 2018 Jun 19 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914035?dopt=Abstract %R 10.3233/JAD-180202 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Learning Processes and Brain Connectivity in A Cognitive-Motor Task in Neurodegeneration: Evidence from EEG Network Analysis. %A Vecchio, Fabrizio %A Miraglia, Francesca %A Quaranta, Davide %A Lacidogna, Giordano %A Marra, Camillo %A Rossini, Paolo Maria %X

Electroencephalographic (EEG) rhythms are linked to any kind of learning and cognitive performance including motor tasks. The brain is a complex network consisting of spatially distributed networks dedicated to different functions including cognitive domains where dynamic interactions of several brain areas play a pivotal role. Brain connectome could be a useful approach not only to mechanisms underlying brain cognitive functions, but also to those supporting different mental states. This goal was approached via a learning task providing the possibility to predict performance and learning along physiological and pathological brain aging. Eighty-six subjects (22 healthy, 47 amnesic mild cognitive impairment, 17 Alzheimer's disease) were recruited reflecting the whole spectrum of normal and abnormal brain connectivity scenarios. EEG recordings were performed at rest, with closed eyes, both before and after the task (Sensory Motor Learning task consisting of a visual rotation paradigm). Brain network properties were described by Small World index (SW), representing a combination of segregation and integration properties. Correlation analyses showed that alpha 2 SW in pre-task significantly predict learning (r  =  -0.2592, p < 0.0342): lower alpha 2 SW (higher possibility to increase during task and better the learning of this task), higher the learning as measured by the number of reached targets. These results suggest that, by means of an innovative analysis applied to a low-cost and widely available techniques (SW applied to EEG), the functional connectome approach as well as conventional biomarkers would be effective methods for monitoring learning progress during training both in normal and abnormal conditions.

%B J Alzheimers Dis %V 66 %P 471-481 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282357?dopt=Abstract %R 10.3233/JAD-180342 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Leisure-Time Physical Activity and the Risk of Incident Dementia: The Mayo Clinic Study of Aging. %A Krell-Roesch, Janina %A Feder, Nathanael T %A Roberts, Rosebud O %A Mielke, Michelle M %A Christianson, Teresa J %A Knopman, David S %A Petersen, Ronald C %A Geda, Yonas E %X

We conducted a prospective cohort study derived from the population-based Mayo Clinic Study of Aging. We investigated if leisure-time physical activity among individuals with mild cognitive impairment (MCI) was associated with a decreased risk of developing dementia. 280 persons aged≥70 years (median 81 years, 165 males) with MCI and available data from neurologic evaluation, neuropsychological testing, and questionnaire-based physical activity assessment, were followed for a median of 3 years to the outcomes of incident dementia or censoring variables. We conducted Cox proportional hazards regression analyses with age as a time scale and adjusted for sex, education, medical comorbidity, depression, and APOE ɛ4 status. Moderate intensity midlife physical activity among MCI participants was significantly associated with a decreased risk of incident dementia (HR = 0.64; 95% CI, 0.41-0.98). There was a non-significant trend for a decreased risk of dementia for light and vigorous intensity midlife physical activity, as well as light and moderate intensity late-life physical activity. In conclusion, we observed that physical activity may be associated with a reduced risk of dementia among individuals with MCI. Furthermore, intensity and timing of physical activity may be important factors when investigating this association.

%B J Alzheimers Dis %V 63 %P 149-155 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614667?dopt=Abstract %R 10.3233/JAD-171141 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Lentivirus-Mediated HDAC3 Inhibition Attenuates Oxidative Stress in APPswe/PS1dE9 Mice. %A Yu, Linjie %A Liu, Yi %A Jin, Yuexinzi %A Cao, Xiang %A Chen, Jian %A Jin, Jiali %A Gu, Yue %A Bao, Xinyu %A Ren, Zhuoying %A Xu, Yun %A Zhu, Xiaolei %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Disease Models, Animal %K Hippocampus %K Histone Deacetylases %K Lentivirus %K Male %K Maze Learning %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Neurons %K Oxidative Stress %K Plaque, Amyloid %K Primary Cell Culture %K Reactive Oxygen Species %K Spatial Memory %K tau Proteins %X

Amyloid-β (Aβ) induces a burst of oxidative stress and plays a critical role in the pathogenesis of Alzheimer's disease (AD). Our previous results have shown that histone deacetylase 3 (HDAC3) inhibition ameliorates spatial memory deficits and decreases the Aβ burden in the brains of 9-month-old APPswe/PS1dE9 (APP/PS1) mice. In this study, we investigated the role of HDAC3 inhibition in oxidative stress in vivo and in vitro models of AD. HDAC3 was detected mainly in the neurons, and HDAC3 inhibition significantly decreased reactive oxygen species generation and improved primary cortical neuron viability. In addition, HDAC3 inhibition attenuated spatial memory dysfunction in 6-month-old APP/PS1 mice, and decreased the apoptotic rate in the hippocampi as demonstrated by TUNEL staining. HDAC3 inhibition also reduced markers of lipid peroxidation, protein oxidation, and DNA/RNA oxidation in the hippocampi of APP/PS1 mice. Moreover, HDAC3 inhibition inactivated the c-Abl/MST1/YAP signaling pathway in the hippocampi of APP/PS1 mice. In conclusion, our data show that HDAC3 inhibition can attenuate spatial memory deficits and inhibit oxidative stress in APP/PS1 mice; these results indicate a potential strategy for AD treatment.

%B J Alzheimers Dis %V 61 %P 1411-1424 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376873?dopt=Abstract %R 10.3233/JAD-170844 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Level of Plasma Amyloid-β40 Is Correlated with Peripheral Transport Proteins in Cognitively Normal Adults: A Population-Based Cross-Sectional Study. %A Gao, Ling %A Jiang, Yu %A Wei, Shan %A Shang, Suhang %A Li, Pei %A Chen, Chen %A Dang, Liangjun %A Wang, Jin %A Huo, Kang %A Deng, Meiying %A Wang, Jingyi %A Zhang, Rong %A Qu, Qiumin %X

BACKGROUND: Transport proteins, soluble low-density lipoprotein receptor-related protein-1 (sLRP1), and soluble receptor of advanced glycation end products (sRAGE), play an important role in the clearance of plasma amyloid-β (Aβ). However, their relationship is not clear.

OBJECTIVE: The aim was to explore the relationship between plasma levels of sLRP1, sRAGE, and Aβ in a cross-sectional study.

METHODS: A total of 1,185 cognitively normal participants (age above 40) from a village in the suburbs of Xi'an, China were enrolled from October 8, 2014 to March 30, 2015. Plasma Aβ40, Aβ42, sLRP1, and sRAGE were tested using a commercial ELISA. Apolipoprotein E (APOE) genotyping was conducted using PCR and sequencing. The relationship between plasma levels of sLRP1, sRAGE, and Aβ was analyzed using Pearson's correlation analysis and multiple linear regression.

RESULTS: In the total population, Log sLRP1 and Log sRAGE were positively correlated with plasma Aβ40 (r= 0.103, p < 0.001; r= 0.064, p = 0.027, respectively), but neither were associated with plasma Aβ42. After multivariable adjustment in the regression model, Log sLRP1 and Log sRAGE were still positively related with plasma Aβ40 (β= 2.969, p < 0.001; β= 1.936, p = 0.017, respectively) but not Aβ42. Furthermore, the positive correlations between transport proteins and plasma Aβ40 remained significant only in APOEɛ4 non-carriers after Pearson's analysis and multiple regression analysis after stratification by gene status.

CONCLUSION: The concentrations of plasma sLRP1 and sRAGE had a significant impact on the level of plasma Aβ40 in cognitively normal adults, especially in APOEɛ4 non-carriers. However, the mechanism by which the transport proteins are involved in peripheral Aβ clearance and the relationship between transporters and amyloid burden in the brain needs further validation.

%B J Alzheimers Dis %V 65 %P 951-961 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103331?dopt=Abstract %R 10.3233/JAD-180399 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Lifetime Risk Factors for Functional and Cognitive Outcomes in Patients with Alzheimer's Disease. %A de Oliveira, Fabricio Ferreira %A de Almeida, Sandro Soares %A Chen, Elizabeth Suchi %A Smith, Marilia Cardoso %A Naffah-Mazzacoratti, Maria da Graça %A Bertolucci, Paulo Henrique Ferreira %X

Lifetime risk factors for cognitive and functional decline in Alzheimer's disease (AD) are not fully understood, and were prospectively evaluated in patients with low mean schooling from São Paulo, Brazil. Consecutive outpatients with late-onset AD were assessed for APOE haplotypes and the following potential baseline predictors: gender, schooling, age at dementia onset, lifetime urban living and sanitary conditions, occupational complexity, cognitive and physical activities, cerebrovascular risk factors (obesity, lifetime alcohol use and smoking, length of arterial hypertension, diabetes mellitus, and a dyslipidemic profile), use of a pacemaker, creatinine clearance, body mass index, waist circumference, head traumas with unconsciousness, treated systemic bacterial infections, amount of surgical procedures under general anesthesia, and family history of AD. Participants were followed from October 2010 to May 2017 for baseline risk factor associations with time since dementia onset for Clinical Dementia Rating and Mini-Mental State Examination score changes. For 227 patients (154 women, 119 APOE ε 4 carriers), later AD onset (mean 73.60±6.4 years-old, earlier for APOE ε 4/ε 4 carriers, p < 0.001) was the only variable hastening all endpoints, baseline creatinine clearance and lifetime alcohol use were hazardous for earlier cognitive and functional endpoints, women had earlier cognitive endpoints only, and schooling had a cumulative protective effect over later cognitive endpoints, particularly for carriers of APOE ε 4. Exclusively for carriers of APOE ε 4, head traumas with unconsciousness were hazardous for earlier cognitive endpoints, while lifetime sanitary conditions were protective regarding later cognitive endpoints. Functional and cognitive outcomes in AD represent probable interactions between effects of brain reserve and cerebral perfusion over neurodegeneration.

%B J Alzheimers Dis %V 65 %P 1283-1299 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149448?dopt=Abstract %R 10.3233/JAD-180303 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Link between Subjective Perceptions of Memory and Physical Function: Implications for Subjective Cognitive Decline. %A Cosentino, Stephanie %A Devanand, Davangere %A Gurland, Barry %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Executive Function %K Female %K Humans %K Linear Models %K Male %K Memory %K Neuropsychological Tests %K New York City %K Perception %X

Subjective impairment in memory is a frequently defining feature of subjective cognitive decline (SCD), a state hypothesized to precede objectively apparent cognitive symptoms of Alzheimer's disease (AD) and to hold promise as a non-invasive, inexpensive, preclinical indicator of AD. However, a full model of the factors that contribute to subjective memory (SM), and therefore to SCD, has yet to be articulated. While SM impairment is widely known to be associated with negative affect, the extent to which SM functioning may also reflect other factors, particularly subjective beliefs or perceptions about one's health, is not known. To examine the extent to which SM is associated with subjective perceptions of health more broadly, the current study investigated the link between SM and subjective physical functioning (independent of depressive affect, and objective cognitive and physical function) in an ethnically diverse sample of 471 older adults enrolled in the population-based Northern Manhattan Aging Project. 199 (42%) participants endorsed no difficulty on a 5-point SM index while 272 (58%) endorsed some degree of difficulty. As hypothesized, SM correlated with both depression and subjective physical function, but not with age, education, global cognition, or objective physical function. When objective and subjective physical function were entered in two separate, adjusted linear regressions predicting SM, only subjective physical function and depressive affect independently predicted SM. Subjective perceptions of memory appear to reflect individuals' broader health perceptions in part. Articulating the various correlates of SM will improve identification of SCD specific to preclinical AD.

%B J Alzheimers Dis %V 61 %P 1387-1398 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376850?dopt=Abstract %R 10.3233/JAD-170495 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Linking Atrial Fibrillation with Alzheimer's Disease: Epidemiological, Pathological, and Mechanistic Evidence. %A Ihara, Masafumi %A Washida, Kazuo %X

Many studies have shown a relationship between atrial fibrillation (AF) and vascular dementia. AF is a major risk factor for stroke, and stroke is the greatest risk factor for vascular dementia. However, the relationship between Alzheimer's disease (AD), the leading cause of dementia, and AF remains unclear. At least four epidemiological studies have reported AF significantly raises the risk of AD 1.5- to 2.5-fold. Chronic cerebral hypoperfusion, resulting from persistent AF, could explain the link as hypoperfusion may mechanistically exacerbate amyloid-β (Aβ) neuropathology, such as senile plaques and amyloid angiopathy, by upregulating Aβ-producing enzymes and lowering Aβ clearance efficiency. In addition, hypoperfusion may exacerbate tau pathology directly through upregulation of tau-phosphorylating enzymes and indirectly via the amyloid cascade. However, most neuropathological studies do not support the direct link between AD pathology and AF but rather suggests vascular neuropathology is related to, or coexistent with, AF and lowers the threshold for clinically-evident AD. Vascular neuropathology may thus mediate the link between AD and AF. From a treatment perspective, an observational study has shown that catheter ablation is associated with less incidence of AD in AF patients, suggesting rhythm-control suppresses hypoperfusion-induced AD neuropathology. In addition, rate-control may lower the rate of cognitive decline in cognitively impaired elderly subjects with AF. Further studies are warranted to clarify the mechanisms underlying the linkage between AF and AD. However, anticoagulation and rhythm-/rate-control against AF may hold promise even for AD patients.

%B J Alzheimers Dis %V 62 %P 61-72 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439352?dopt=Abstract %R 10.3233/JAD-170970 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Lipid Metabolism and Survival Across the Frontotemporal Dementia-Amyotrophic Lateral Sclerosis Spectrum: Relationships to Eating Behavior and Cognition. %A Ahmed, Rebekah M %A Highton-Williamson, Elizabeth %A Caga, Jashelle %A Thornton, Nicolette %A Ramsey, Eleanor %A Zoing, Margaret %A Kim, Woojin Scott %A Halliday, Glenda M %A Piguet, Olivier %A Hodges, John R %A Farooqi, I Sadaf %A Kiernan, Matthew C %K Adult %K Aged %K Amyotrophic Lateral Sclerosis %K Australia %K Body Mass Index %K Case-Control Studies %K Cholesterol %K Cholesterol, HDL %K Cognition %K Energy Intake %K Feeding Behavior %K Female %K Frontotemporal Dementia %K Humans %K Lipid Metabolism %K Male %K Middle Aged %K Neuropsychological Tests %K Survival Analysis %X

BACKGROUND: Patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exhibit changes in eating behavior that could potentially affect lipid levels.

OBJECTIVE: This study aimed to document changes in lipid metabolism across the ALS-FTD spectrum to identify potential relationships to eating behavior (including fat intake), cognitive change, body mass index (BMI), and effect on survival.

METHODS: One hundred and twenty-eight participants were recruited: 37 ALS patients, 15 ALS patients with cognitive and behavioral change (ALS-Plus), 13 ALS-FTD, 31 behavioral variant FTD, and 32 healthy controls. Fasting total cholesterol, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL) and triglyceride levels were measured and correlated to eating behavior (caloric, fat intake), cognitive change, and BMI; effect on survival was examined using cox regression analyses.

RESULTS: There was a spectrum of lipid changes from ALS to FTD with increased triglyceride (p < 0.001), total cholesterol/HDL ratio (p < 0.001), and lower HDL levels (p = 0.001) in all patient groups compared to controls. While there was no increase in total cholesterol levels, a higher cholesterol level was found to correlate with 3.25 times improved survival (p = 0.008). Triglyceride and HDL cholesterol levels correlated to fat intake, BMI, and measures of cognition and disease duration.

CONCLUSION: A spectrum of changes in lipid metabolism has been identified in ALS-FTD, with total cholesterol levels found to potentially impact on survival. These changes were mediated by changes in fat intake, and BMI, and may also be mediated by the neurodegenerative process, offering the potential to modify these factors to slow disease progression and improve survival.

%B J Alzheimers Dis %V 61 %P 773-783 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254092?dopt=Abstract %R 10.3233/JAD-170660 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Long Journey into Aging, Brain Aging, and Alzheimer's Disease Following the Oxidative Stress Tracks. %A Mecocci, Patrizia %A Boccardi, Virginia %A Cecchetti, Roberta %A Bastiani, Patrizia %A Scamosci, Michela %A Ruggiero, Carmelinda %A Baroni, Marta %K Aging %K Alzheimer Disease %K Animals %K Brain %K Humans %K Oxidative Stress %X

The Editors of the Journal of Alzheimer's Disease invited Professor Patrizia Mecocci to contribute a review article focused on the importance and implications of her research on aging, brain aging, and senile dementias over the last years. This invitation was based on an assessment that she was one of the journal's top authors and a strong supporter of the concept that oxidative stress is a major contributor to several alterations observed in age-related conditions (sarcopenia, osteoporosis) and, more significantly, in brain aging suggesting a pivotal role in the pathogenesis and progression of one of the most dramatic age-related diseases, Alzheimer's disease (AD). Her first pioneering research was on the discovery of high level of 8-hydroxy-2'-deoxyguanosine (OH8dG), a marker of oxidation in nucleic acids, in mitochondrial DNA isolated from cerebral cortex. This molecule increases progressively with aging and more in AD brain, supporting the hypothesis that oxidative stress, a condition of unbalance between the production of reactive oxygen species and antioxidants, gives a strong contribution to the high incidence of AD in old age subjects. OH8dG also increases in peripheral lymphocyte from AD subjects, suggesting that AD is not only a cerebral but also a systemic disease. The role of antioxidants, particularly vitamin E and zinc, were also studied in longevity and in cognitive decline and dementia. This review shows the main findings from Mecocci's laboratory related to oxidative stress in aging, brain aging, and AD and discusses the importance and implications of some of the major achievements in this field of research.

%B J Alzheimers Dis %V 62 %P 1319-1335 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170732?id=journal-of-alzheimers-disease%2Fjad170732 %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562533?dopt=Abstract %R 10.3233/JAD-170732 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Longitudinal Changes in Serum Glucose Levels are Associated with Metabolic Changes in Alzheimer's Disease Related Brain Regions. %A Burns, Christine M %A Kaszniak, Alfred W %A Chen, Kewei %A Lee, Wendy %A Bandy, Daniel J %A Caselli, Richard J %A Reiman, Eric M %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Blood Glucose %K Brain %K Brain Mapping %K Female %K Fluorodeoxyglucose F18 %K Heterozygote %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Positron-Emission Tomography %K Prospective Studies %K Radiopharmaceuticals %X

BACKGROUND: The association between longitudinal changes in serum glucose level and longitudinal changes in [18F] Fluorodeoxyglucose-PET (FDG PET) measurements of Alzheimer's disease (AD) risk are unknown.

OBJECTIVE: To investigate whether variation in serum glucose levels across time are associated with changes in FDG PET measurements of cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer's disease (AD).

METHODS: Participants are a subset of a prospective cohort study investigating FDG PET, apolipoprotein E (APOE) ɛ4, and risk for AD which includes data from baseline, interim, and follow up visits over 4.4±1.0-years. An automated brain-mapping algorithm was utilized to characterize and compare associations between longitudinal changes in serum glucose levels and longitudinal changes in rCMRgl.

RESULTS: This study included 80 adults aged 61.5±5 years, including 38 carriers and 42 non-carriers of the APOE ɛ4 allele. Longitudinal increases in serum glucose levels were associated with longitudinal CMRgl decline in the vicinity of parietotemporal, precuneus/posterior cingulate, and prefrontal brain regions preferentially affected by AD (p < 0.05, corrected for multiple comparisons). Findings remained significant when controlled for APOE ɛ4 status and baseline and advancing age.

CONCLUSIONS: Additional studies are needed to clarify and confirm the relationship between longitudinal changes in peripheral glucose and FDG PET measurements of AD risk. Future findings will set the stage on the use of FDG PET in the evaluation of possible interventions that target risk factors for the development of AD.

%B J Alzheimers Dis %V 62 %P 833-840 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480176?dopt=Abstract %R 10.3233/JAD-170767 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Longitudinal Modeling of Functional Decline Associated with Pathologic Alzheimer's Disease in Older Persons without Cognitive Impairment. %A Wang, Dai %A Schultz, Tim %A Novak, Gerald P %A Baker, Susan %A Bennett, David A %A Narayan, Vaibhav A %X

BACKGROUND: Therapeutic research on Alzheimer's disease (AD) has moved to intercepting the disease at the preclinical phase. Most drugs in late development have focused on the amyloid hypothesis.

OBJECTIVE: To understand the magnitude of amyloid-related functional decline and to identify the functional domains sensitive to decline in a preclinical AD population.

METHODS: Data were from the Religious Orders Study and the Rush Memory and Aging Project. Cognitive decline was measured by a modified version of the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite. The trajectories of functional decline, as measured by the instrumental and basic activities of daily living, were longitudinally modeled in 484 participants without cognitive impairment at baseline and having both a final clinical and a postmortem neuropathology assessment of AD.

RESULTS: Individuals with different final clinical diagnoses had different trajectories of cognitive and functional decline. Individuals with AD dementia, minor cognitive impairment, and no cognitive impairment had the most, intermediate, and least declines. While individuals with pathologic AD had significantly more cognitive decline over time than those without, the magnitude of difference in functional decline between these two groups was small. Functional domains such as handling finance and handling medications were more sensitive to decline.

CONCLUSION: Demonstrating the functional benefit of an amyloid-targeting drug represents a significant challenge as elderly people experience functional decline due to a wide range of reasons with limited manifestation attributable to AD neuropathology. More sensitive functional scales focusing on the functional domains sensitive to decline in preclinical AD are needed.

%B J Alzheimers Dis %V 62 %P 855-865 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480187?dopt=Abstract %R 10.3233/JAD-170903 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin. %A Cuberas-Borrós, Gemma %A Roca, Isabel %A Boada, Merce %A Tárraga, Lluís %A Hernandez, Isabel %A Buendia, Mar %A Rubio, Lourdes %A Torres, Gustavo %A Bittini, Ángel %A Guzmán-de-Villoria, Juan A %A Pujadas, Francesc %A Torres, Mireia %A Núñez, Laura %A Castell, Joan %A Páez, Antonio %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuroimaging %K Plasma Exchange %K Serum Albumin, Human %K Time Factors %K Tomography, Emission-Computed, Single-Photon %K Treatment Outcome %X

BACKGROUND: Recently, modifications of Aβ1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement.

OBJECTIVE: To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial.

METHODS: Patients received between 3 and 18 PE with albumin (Albutein® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline.

RESULTS: 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls.

CONCLUSIONS: Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion.

%B J Alzheimers Dis %V 61 %P 321-332 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154283?dopt=Abstract %R 10.3233/JAD-170693 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Longitudinal Study of Total and Phosphorylated α-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer's Disease and Mild Cognitive Impairment. %A Wang, Hua %A Stewart, Tessandra %A Toledo, Jon B %A Ginghina, Carmen %A Tang, Lu %A Atik, Anzari %A Aro, Patrick %A Shaw, Leslie M %A Trojanowski, John Q %A Galasko, Douglas R %A Edland, Steven %A Jensen, Poul H %A Shi, Min %A Zhang, Jing %K Aged %K Aged, 80 and over %K alpha-Synuclein %K Alzheimer Disease %K Biomarkers %K Cognitive Dysfunction %K Cross-Sectional Studies %K Disease Progression %K Executive Function %K Female %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Memory Disorders %K Multivariate Analysis %K Neuropsychological Tests %K Phosphorylation %K tau Proteins %X

Alzheimer's disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson's disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total α-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-β1-42 (Aβ42), tau, and phosphorylated tau (p-tau181)] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer's Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total α-synuclein, pS129, Aβ42, tau, and p-tau181. pS129, but not total α-synuclein, was weakly associated with diagnosis at baseline when t-tau/Aβ42 was included in the statistical model (β= 0.0026, p = 0.041, 95% CI [(0.0001)-(0.005)]). CSF α-synuclein predicted Alzheimer's Disease Assessment Scale-Cognitive (β= -0.59, p = 0.0015, 95% CI [(-0.96)-(-0.23)]), memory (β= 0.4, p = 0.00025, 95% CI [(0.16)-(0.59)]), and executive (0.62,<0.0001, 95% CI [(0.31)-(0.93)]) function composite scores, and progression from MCI to AD (β= 0.019, p = 0.0011, 95% CI [(0.002)-(0.20)]). pS129 was associated with executive function (β= -2.55, p = 0.0085, 95% CI [(-4.45)-(-0.66)]). Lower values in the mismatch between α-synuclein and p-tau181 predicted faster cognitive decline (β= 0.64, p = 0.0012, 95% CI [(0.48)-(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The α-synuclein-p-tau181-Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further.

%B J Alzheimers Dis %V 61 %P 1541-1553 %8 2018 Jan 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376878?dopt=Abstract %R 10.3233/JAD-171013 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer's Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study. %A Salloway, Stephen P %A Sperling, Reisa %A Fox, Nick C %A Sabbagh, Marwan N %A Honig, Lawrence S %A Porsteinsson, Anton P %A Rofael, Hany %A Ketter, Nzeera %A Wang, Daniel %A Liu, Enchi %A Carr, Stephen %A Black, Ronald S %A Brashear, H Robert %X

BACKGROUND: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized.

OBJECTIVES: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab.

METHODS: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the parent studies.

RESULTS: A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups.

CONCLUSIONS: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.

%B J Alzheimers Dis %V 64 %P 689-707 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914022?dopt=Abstract %R 10.3233/JAD-171157 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Long-Term Severe Mental Disorders Preceding Behavioral Variant Frontotemporal Dementia: Frequency and Clinical Correlates in an Outpatient Sample. %A Gambogi, Leandro Boson %A Guimarães, Henrique Cerqueira %A de Souza, Leonardo Cruz %A Caramelli, Paulo %X

BACKGROUND: The behavioral variant frontotemporal dementia (bvFTD) shares some clinical features with severe mental disorders, such as bipolar affective disorder (BAD), schizophrenia (SCZ), and schizoaffective disorder (SZA), and at least for a small subgroup of patients, these conditions may share similar pathological genetic mutations.

OBJECTIVES: To investigate the frequency of a past medical history satisfying diagnostic criteria for BAD, SCZ, and SZA in a bvFTD outpatient sample, and to compare the clinical profile of patients with and without a positive history.

METHODS: Cross-sectional study in which participants were consecutively selected after receiving a diagnosis of probable bvFTD and had a caregiver interviewed with SCID-I. The sample was categorized into two groups: with (bvFTD+) or without (bvFTD-) prior medical history satisfying diagnostic criteria for BAD/SCZ/SZA. Subjects went through cognitive, functional, and neuropsychiatric evaluations.

RESULTS: Overall, 46 bvFTD patients were included; bvFTD+ patients accounted for 36.9% of the sample. The main nosology fulfilling criteria was BAD (76.5%). The groups differed in Neuropsychiatric Inventory scores (p = 0.01), use of antipsychotics (p = 0.01), family history of psychosis (p = 0.01), presence of primitive reflexes (p = 0.04), Frontal Assessment Battery performance (p = 0.01), Ekman's facial emotion recognition test (p = 0.03), frequency of apathy (p = 0.03), and stereotyped behavior (p = 0.01). All these parameters were more frequent/worse in the bvFTD+ group.

CONCLUSIONS: A prior medical history compatible with BAD/SCZ/SZA was found in more than 1/3 of this sample of bvFTD patients and was associated with subtle distinctive clinical features.

%B J Alzheimers Dis %V 66 %P 1577-1585 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30452412?dopt=Abstract %R 10.3233/JAD-180528 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Loss in PKC Epsilon Causes Downregulation of MnSOD and BDNF Expression in Neurons of Alzheimer's Disease Hippocampus. %A Sen, Abhik %A Nelson, Thomas J %A Alkon, Daniel L %A Hongpaisan, Jarin %X

Oxidative stress and amyloid-β (Aβ) oligomers have been implicated in Alzheimer's disease (AD). The growth and maintenance of neuronal networks are influenced by brain derived neurotrophic factor (BDNF) expression, which is promoted by protein kinase C epsilon (PKCɛ). We investigated the reciprocal interaction among oxidative stress, Aβ, and PKCɛ levels and subsequent PKCɛ-dependent MnSOD and BDNF expression in hippocampal pyramidal neurons. Reduced levels of PKCɛ, MnSOD, and BDNF and an increased level of Aβ were also found in hippocampal neurons from autopsy-confirmed AD patients. In cultured human primary hippocampal neurons, spherical aggregation of Aβ (amylospheroids) decreased PKCɛ and MnSOD. Treatment with t-butyl hydroperoxide (TBHP) increased superoxide, the oxidative DNA/RNA damage marker, 8-OHG, and Aβ levels, but reduced PKCɛ, MnSOD, BDNF, and cultured neuron density. These changes were reversed with the PKCɛ activators, bryostatin and DCPLA-ME. PKCɛ knockdown suppressed PKCɛ, MnSOD, and BDNF but increased Aβ. In cultured neurons, the increase in reactive oxygen species (ROS) associated with reduced PKCɛ during neurodegeneration was inhibited by the SOD mimetic MnTMPyP and the ROS scavenger NAc, indicating that strong oxidative stress suppresses PKCɛ level. Reduction of PKCɛ and MnSOD was prevented with the PKCɛ activator bryostatin in 5-6-month-old Tg2576 AD transgenic mice. In conclusion, oxidative stress and Aβ decrease PKCɛ expression. Reciprocally, a depression of PKCɛ reduces BDNF and MnSOD, resulting in oxidative stress. These changes can be prevented with the PKCɛ-specific activators.

%B J Alzheimers Dis %V 63 %P 1173-1189 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710707?dopt=Abstract %R 10.3233/JAD-171008 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Lost in Translation? Finding Our Way To Effective Alzheimer's Disease Therapies. %A Quinn, Joseph F %X

Efforts over the past two decades to develop effective disease-modifying treatments for Alzheimer's disease have been disappointing, while parallel efforts in another chronic neurologic disease, multiple sclerosis, have been remarkably productive. In an effort to advance development of therapeutics for Alzheimer's disease, these two fields are contrasted in terms of the utility of animal models, definition of study populations, and utility of biomarkers. Possible solutions are suggested, and the review concludes with description of some active peer-reviewed, publicly funded clinical studies which address some of the identified weaknesses in past clinical trials for age-related dementia.

%B J Alzheimers Dis %V 64 %P S33-S39 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758942?dopt=Abstract %R 10.3233/JAD-179930 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Low Accuracy of Brief Cognitive Tests in Tracking Longitudinal Cognitive Decline in an Asian Elderly Cohort. %A Phua, April Ka Sin %A Hiu, Shaun Kuan Wei %A Goh, Win King %A Ikram, Mohammad Kamran %A Venketasubramanian, Narayanaswamy %A Tan, Boon Yeow %A Chen, Christopher Li-Hsian %A Xu, Xin %X

BACKGROUND: Researchers have questioned the utility of brief cognitive tests such as the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in serial administration and suggested that brief cognitive tests may not accurately track changes in Global Cognition.

OBJECTIVE: To examine the accuracy of longitudinal changes on brief cognitive tests in reflecting progression in Global Cognition measured using comprehensive neuropsychological assessments.

METHODS: Two hundred and seven participants were assessed with the MMSE, MoCA, and a validated comprehensive neuropsychological battery. Global z-scores on the battery were derived and used to assess overall and significant (≥0.5 standard deviation) decline on Global Cognition. Different patterns of decline on MMSE/MoCA were classified. Accuracy was examined using receiver operating characteristic curve, and sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were reported.

RESULTS: The overall ability of MMSE/MoCA change scores to discriminate participants who did and did not decline on Global Cognition was fair-to-moderate (AUC [95% CI] = 0.71 [0.64-0.78] & 0.73 [0.66-0.80] for overall decline; 0.78 [0.70-0.85] & 0.80 [0.73-0.86] for significant decline, respectively). Changes in MMSE/MoCA had low accuracy in identifying significant Global Cognitive Decline (PPV = 0.41 & 0.46, respectively) but high accuracy in ruling out significant decline and identifying cognitively stable participants (NPV = 0.89 & 0.88, respectively).

CONCLUSION: There is limited utility in brief cognitive tests for tracking cognitive decline. Instead, they should be used for identifying participants who remain cognitively stable on follow up. These results accentuate the importance of acknowledging the limitations of brief cognitive tests when assessing cognitive change.

%B J Alzheimers Dis %V 62 %P 409-416 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439344?dopt=Abstract %R 10.3233/JAD-170831 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Low Cerebrospinal Fluid Aβ42 and Aβ40 are Related to White Matter Lesions in Cognitively Normal Elderly. %A Skoog, Ingmar %A Kern, Silke %A Zetterberg, Henrik %A Östling, Svante %A Börjesson-Hanson, Anne %A Guo, Xinxin %A Blennow, Kaj %X

BACKGROUND: Low cerebrospinal fluid (CSF) levels of Aβ42 may be the earliest manifestation of Alzheimer's disease (AD). Knowledge on how CSF Aβ interacts with different brain pathologies early in the disease process is limited. We examined how CSF Aβ markers relate to brain atrophy and white matter lesions (WMLs) in octogenarians with and without dementia to explore the earliest pathogenetic pathways of AD in the oldest old.

OBJECTIVE: To study CSF amyloid biomarkers in relation to brain atrophy and WMLs in 85-year-olds with and without dementia.

METHODS: 53 octogenarians took part in neuropsychiatric examinations and underwent both a lumbar puncture and a brain CT scan. CSF levels of Aβ42 and Aβ40 were examined in relation to cerebral atrophy and WMLs. Dementia was diagnosed.

RESULTS: In 85-year-olds without dementia, lower levels of both CSF Aβ42 and CSF Aβ40 were associated with WMLs. CSF Aβ42 also correlated with measures of central atrophy, but not with cortical atrophy. In participants with dementia, lower CSF levels of Aβ42 were related to frontal, temporal, and parietal cortical atrophy but not to WMLs.

CONCLUSIONS: Our findings may suggest that there is an interrelationship between Aβ and subcortical WMLs in older persons without dementia. After onset of dementia, low CSF Aβ42, probably representing amyloid deposition in plaques, is associated with cortical atrophy. WMLs may be an earlier manifestation of Aβ deposition than cortical degeneration.

%B J Alzheimers Dis %V 62 %P 1877-1886 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614655?dopt=Abstract %R 10.3233/JAD-170950 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Low Prevalence of Cancer in Patients with Frontotemporal Lobar Degeneration. %A Katisko, Kasper %A Haapasalo, Annakaisa %A Koivisto, Anne %A Krüger, Johanna %A Hartikainen, Päivi %A Korhonen, Ville %A Helisalmi, Seppo %A Herukka, Sanna-Kaisa %A Remes, Anne M %A Solje, Eino %K Aged %K Alzheimer Disease %K C9orf72 Protein %K DNA Repeat Expansion %K Female %K Finland %K Frontotemporal Lobar Degeneration %K Heterozygote %K Humans %K Male %K Middle Aged %K Neoplasms %K Prevalence %X

Several studies have reported reduced risk of cancer in patients with Alzheimer's disease (AD) or Parkinson's disease. The relationship between cancer and frontotemporal lobar degeneration (FTLD) has not been previously reported. Here, our aim was to evaluate the occurrence of cancer in Finnish FTLD patients with a high proportion of C9ORF72 repeat expansion carriers in comparison to age- and sex-matched group of AD patients and control subjects classified as not cognitively impaired (NCI). The prevalence of cancer was 9.7% in FTLD, 18.7% in AD, and 17.4% in NCI (FTLD versus AD p = 0.012, FTLD versus NCI p = 0.029) groups. No differences were observed between C9ORF72 repeat expansion carriers and non-carriers inside the FTLD group. To our knowledge, this is the first study showing significantly lower prevalence of cancer in FTLD patients compared to patients with AD or NCI subjects. Our data suggest an inverse association between neurodegeneration and cancer and that FTLD-specific mechanisms may underlie the especially strong inverse association observed in this study.

%B J Alzheimers Dis %V 62 %P 789-794 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480183?dopt=Abstract %R 10.3233/JAD-170854 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Lower Serum Antibodies Against Tau Protein and Heavy Neurofilament in Alzheimer's Disease. %A Bartos, Ales %A Fialová, Lenka %A Švarcová, Jana %X

BACKGROUND: Unlike antibodies against amyloid-β, little is known about serum antibodies to neuron-specific cytoskeletal proteins in patients with Alzheimer's disease (AD).

OBJECTIVE: We aimed to study IgG autoantibodies against tau protein, light (NFL) and heavy subunits (NFH) of neurofilaments in serum of AD patients and elderly controls and to explore the evolution of antineurocytoskeletal antibody levels over time.

METHODS: Antibodies against three targets (tau, NFL, and NFH) were measured using ELISA in 100 serum samples from 51 cognitively normal elderly controls and 49 patients with AD. Our primary cross-sectional design was further extended to monitor fluctuations over 1-2 years in a subset of individuals.

RESULTS: The AD patients had lower levels of anti-tau antibodies (p = 0.03) and even lower anti-NFH antibodies (p = 0.005) than those in the control group at baseline. On the contrary, anti-NFL antibodies or total IgG concentrations in serum did not differ. All three antibodies remained stable in both groups except for a selective and significant anti-tau decline in AD patients (p = 0.03).

CONCLUSIONS: The different responses to these antigens suggest some antibody selectivity in AD. The significant decline was observed for only serum anti-tau antibodies in AD patients over time and it corresponds to lower anti-tau levels in these patients. Our findings indicate a special feature of disease-relevant antigens and humoral autoimmunity in AD.

%B J Alzheimers Dis %V 64 %P 751-760 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966192?dopt=Abstract %R 10.3233/JAD-180039 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mapping the Proxies of Memory and Learning Function in Senior Adults with High-performing, Normal Aging and Neurocognitive Disorders. %A Lu, Hanna %A Ni, Xi %A Fung, Ada W T %A Lam, Linda C W %X

BACKGROUND: Memory and learning, as the core brain function, shows controversial results across studies focusing on aging and dementia. One of the reasons is because of the multi-faceted nature of memory and learning. However, there is still a dearth of comparable proxies with psychometric and morphometric portrait in clinical and non-clinical populations.

OBJECTIVE: We aim to investigate the proxies of memory and learning function with direct and derived measures and examine their associations with morphometric features in senior adults with different cognitive status.

METHODS: Based on two modality-driven tests, we assessed the component-specific memory and learning in the individuals with high performing (HP), normal aging, and neurocognitive disorders (NCD) (n = 488). Structural magnetic resonance imaging was used to measure the regional cortical thickness with surface-based morphometry analysis in a subsample (n = 52).

METHODS: Compared with HP elderly, the ones with normal aging and minor NCD showed declined recognition memory and working memory, whereas had better learning performance (derived scores). Meanwhile, major NCD patients showed more breakdowns of memory and learning function. The correlation between proxies of memory and learning and cortical thickness exhibited the overlapped and unique neural underpinnings.

CONCLUSIONS: The proxies of memory and learning could be characterized by component-specific constructs with psychometric and morphometric bases. Overall, the constructs of memory are more likely related to the pathological changes, and the constructs of learning tend to reflect the cognitive abilities of compensation.

%B J Alzheimers Dis %V 64 %P 815-826 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914037?dopt=Abstract %R 10.3233/JAD-180225 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mechanism of Tau Hyperphosphorylation Involving Lysosomal Enzyme Asparagine Endopeptidase in a Mouse Model of Brain Ischemia. %A Basurto-Islas, Gustavo %A Gu, Jin-Hua %A Tung, Yunn Chyn %A Liu, Fei %A Iqbal, Khalid %X

Dementias including Alzheimer's disease (AD) are multifactorial disorders that involve several different etiopathogenic mechanisms. Cerebral ischemia has been suspected in the altered regulation of protein kinases and phosphatases that leads to hyperphosphorylation of tau and further neurofibrillary pathology, a key hallmark of AD and related neurodegenerative diseases. However, the deregulation of these enzymes and their relationship with ischemia and AD remain unclear. Previously, we reported a mechanism by which the lysosomal enzyme asparagine endopeptidase (AEP) is associated with brain acidosis and AD. In this study, we subjected mice to middle cerebral artery occlusion and found that compared with wild type mice, the ischemia-induced brain injury and motor deficit in AEP-knockout mice are reduced, probably because ischemia activates AEP. AEP cleaves inhibitor 2 of protein phosphatase 2A (I2PP2A), which translocates from the neuronal nucleus to the cytoplasm and produces hyperphosphorylation of tau through inhibition of PP2A. These findings suggest a possible mechanism of tau pathology associated with ischemia.

%B J Alzheimers Dis %V 63 %P 821-833 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689717?dopt=Abstract %R 10.3233/JAD-170715 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Medical and Research Consent Decision-Making Capacity in Patients with Alzheimer's Disease: A Systematic Review. %A van Duinkerken, Eelco %A Farme, Juliana %A Landeira-Fernandez, Jesus %A Dourado, Marcia C %A Laks, Jerson %A Mograbi, Daniel C %X

The capacity to make decisions is an important feature of daily living, which is closely linked to proper cognitive functioning. In conditions in which cognitive functioning becomes compromised, such as in Alzheimer's disease (AD), decision-making capacity can also get affected. Especially in AD, this has important implications, since over the course of the condition many important clinical decisions have to be made. For caregivers as well as physicians, it is sometimes difficult to determine how and when to intervene in the decision-making process. The aim of this systematic literature review was to identify studies that have evaluated medical and research consent decision-making capacity in patients with AD. Studies consistently show that decision-making capabilities are impaired in patients with AD. The cognitive and neuronal correlates of this process are, however, poorly studied. The few studies that investigated correlations have shown worse cognitive performance, mainly on the MMSE, to be related to poorer decision-making capacity. As most of these correlations have been performed in groups combining patients and controls, it remains unknown if these associations are disease specific. There is a need to study more systematically the decision-making process in relation to cognitive functioning and neural correlates to be able to develop a framework of decision-making capacity in AD, ultimately aiding clinicians and caregivers to understand and evaluate those capabilities in patients.

%B J Alzheimers Dis %V 65 %P 917-930 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103326?dopt=Abstract %R 10.3233/JAD-180311 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Medical Comorbidity in Alzheimer's Disease: A Nested Case-Control Study. %A Wang, Jen-Hung %A Wu, Ya-Ju %A Tee, Boon Lead %A Lo, Raymond Y %X

BACKGROUND: Little is known about the distribution of medical comorbidities in Alzheimer's disease (AD).

OBJECTIVE: We aimed to describe the comorbidity pattern of AD in a nested case-control study.

METHODS: Incident AD cases were identified by International Classification of Diseases codes in a random sample of 2 million individuals in Taiwan National Health Insurance program during 2001-2011. We further restricted cases to those treated with AD drugs of approved reimbursement. We sampled a set of age- and sex-matched control subjects (2:1 ratio) and employed conditional logistic regression to estimate the associations between pre-specified 14 comorbidities and AD. The clusters of multiple chronic diseases were then identified by exploratory factor analysis.

RESULTS: A total of 2,618 AD cases were identified during 2001-2011 with a mean age of 76.1 years and female preponderance (59%). The most common 5 comorbidities in AD were hypertension (55.1%), osteoarthritis (38.2%), depression (32.3%), diabetes mellitus (DM) (25.7%), and cerebrovascular disease (CVD) (22.7%). After adjusting for age and sex, DM, osteoporosis, depression, and CVD were significantly associated with AD. The number of comorbidity was 3-fold greater in the AD group. The cluster of hypertension, DM, and hyperlipidemia was the most common combination in old age, whereas the cluster osteoarthritis and osteoporosis was the only multimorbidity pattern significantly associated with AD.

CONCLUSION: Multimorbidity is common in AD. Depression, CVD, osteoporosis, and DM are associated with incident AD, supporting that their co-existence is a typical feature of AD at old age. Comorbidity care should be integrated into current management for patients with AD.

%B J Alzheimers Dis %V 63 %P 773-781 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660933?dopt=Abstract %R 10.3233/JAD-170786 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mediterranean Diet, Its Components, and Amyloid Imaging Biomarkers. %A Vassilaki, Maria %A Aakre, Jeremiah A %A Syrjanen, Jeremy A %A Mielke, Michelle M %A Geda, Yonas E %A Kremers, Walter K %A Machulda, Mary M %A Alhurani, Rabe E %A Staubo, Sara C %A Knopman, David S %A Petersen, Ronald C %A Lowe, Val J %A Jack, Clifford R %A Roberts, Rosebud O %X

BACKGROUND: There is accumulating evidence suggesting that diet may play a role in preventing or delaying cognitive decline and dementia, but the underlying biological mechanisms are not well understood.

OBJECTIVES: To examine the cross-sectional associations of the Mediterranean diet (MeDi) and its components with 11C-PiB-PET scan measures of amyloid-β (Aβ) deposition.

METHODS: The study consisted of 278 Mayo Clinic Study of Aging participants 70+ years old, who were cognitively unimpaired (CU) at the time of completion of the Food Frequency Questionnaire (FFQ) and when they underwent PET imaging. Adherence to the MeDi was assessed by computing the MeDi score for each participant. All scans were performed after the FFQ completion; median [IQR] time between FFQ and Aβ PET was 3.5 (1.4) years. Z-scores were created for component, macro- and micronutrients measured. Linear and logistic regression models were adjusted for age, sex, education, apolipoprotein E (APOE) ɛ4 allele carrier status, time interval between the FFQ completion and PET scan, and total energy intake.

RESULTS: Participants' median age at FFQ was 77.7 years (55.8% men; 26.6% with an APOE ɛ4 allele). Higher MeDi score (linear regression slope (beta):-0.035, p = 0.012; per standard deviation increase), vegetable intake (beta:-0.043, p = 0.002), intake of vitamin A (beta:-0.041, p = 0.003) or β-carotene (beta: -0.039, p = 0.005) from food sources and moderate alcohol consumption (beta: -0.074, p = 0.03) were associated with lower 11C-PiB standardized uptake value ratio.

CONCLUSION: Findings are consistent with previous studies suggesting that higher adherence to a MeDi pattern and higher vegetable consumption are associated with better neuroimaging biomarker profile. Prospective studies are needed to validate current findings.

%B J Alzheimers Dis %V 64 %P 281-290 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889074?dopt=Abstract %R 10.3233/JAD-171121 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Melatonin in Synaptic Impairments of Alzheimer's Disease. %A Shi, Yan %A Fang, Ying-Yan %A Wei, Yu-Ping %A Jiang, Qian %A Zeng, Peng %A Tang, Na %A Lu, Youming %A Tian, Qing %X

Alzheimer's disease (AD) underlies dementia for millions of people worldwide with no effective treatment. The dementia of AD is thought stem from the impairments of the synapses because of their critical roles in cognition. Melatonin is a neurohormone mainly released by the pineal gland in a circadian manner and it regulates brain functions in various manners. It is reported that both the melatonin deficit and synaptic impairments are present in the very early stage of AD and strongly contribute to the progress of AD. In the mammalian brains, the effects of melatonin are mainly relayed by two of its receptors, melatonin receptor type 1a (MT1) and 1b (MT2). To have a clear idea on the roles of melatonin in synaptic impairments of AD, this review discussed the actions of melatonin and its receptors in the stabilization of synapses, modulation of long-term potentiation, as well as their contributions in the transmissions of glutamatergic, GABAergic and dopaminergic synapses, which are the three main types of synapses relevant to the synaptic strength. The synaptic protective roles of melatonin in AD treatment were also summarized. Regarding its protective roles against amyloid-β neurotoxicity, tau hyperphosphorylation, oxygenation, inflammation as well as synaptic dysfunctions, melatonin may be an ideal therapeutic agent against AD at early stage.

%B J Alzheimers Dis %V 63 %P 911-926 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710712?dopt=Abstract %R 10.3233/JAD-171178 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Memantine for the Treatment of Dementia: A Review on its Current and Future Applications. %A Folch, Jaume %A Busquets, Oriol %A Ettcheto, Miren %A Sánchez-López, Elena %A Castro-Torres, Ruben Dario %A Verdaguer, Ester %A Garcia, Maria Luisa %A Olloquequi, Jordi %A Casadesus, Gemma %A Beas-Zarate, Carlos %A Pelegri, Carme %A Vilaplana, Jordi %A Auladell, Carme %A Camins, Antoni %X

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.

%B J Alzheimers Dis %V 62 %P 1223-1240 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254093?dopt=Abstract %R 10.3233/JAD-170672 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Memory Binding Test Predicts Incident Dementia: Results from the Einstein Aging Study. %A Mowrey, Wenzhu B %A Lipton, Richard B %A Katz, Mindy J %A Ramratan, Wendy S %A Loewenstein, David A %A Zimmerman, Molly E %A Buschke, Herman %X

BACKGROUND: The Memory Binding Test (MBT) demonstrated good cross-sectional discriminative validity and predicted incident aMCI.

OBJECTIVE: To assess whether the MBT predicts incident dementia better than a conventional list learning test in a longitudinal community-based study.

METHODS: As a sub-study in the Einstein Aging Study, 309 participants age≥70 initially free of dementia were administered the MBT and followed annually for incident dementia for up to 13 years. Based on previous work, poor memory binding was defined using an optimal empirical cut-score of≤17 on the binding measure of the MBT, Total Items in the Paired condition (TIP). Cox proportional hazards models were used to assess predictive validity adjusting for covariates. We compared the predictive validity of MBT TIP to that of the free and cued selective reminding test free recall score (FCSRT-FR; cut-score:≤24) and the single list recall measure of the MBT, Cued Recalled from List 1 (CR-L1; cut-score:≤12).

RESULTS: Thirty-five of 309 participants developed incident dementia. When assessing each test alone, the hazard ratio (HR) for dementia was significant for MBT TIP (HR = 8.58, 95% CI: (3.58, 20.58), p < 0.0001), FCSRT-FR (HR = 4.19, 95% CI: (1.94, 9.04), p = 0.0003) and MBT CR-L1 (HR = 2.91, 95% CI: (1.37, 6.18), p = 0.006). MBT TIP remained a significant predictor of dementia (p = 0.0002) when adjusting for FCSRT-FR or CR-L1.

CONCLUSIONS: Older adults with poor memory binding as measured by the MBT TIP were at increased risk for incident dementia. This measure outperforms conventional episodic memory measures of free and cued recall, supporting the memory binding hypothesis.

%B J Alzheimers Dis %V 62 %P 293-304 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439336?dopt=Abstract %R 10.3233/JAD-170714 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Memory Loss and the Onset of Alzheimer's Disease Could Be Under the Control of Extracellular Heat Shock Proteins. %A Arispe, Nelson %A De Maio, Antonio %X

Alzheimer's disease (AD) is a major contemporary and escalating malady in which amyloid-β (Aβ) peptides are the most likely causative agent. Aβ peptides spontaneously tend to aggregate in extracellular fluids following a progression from a monomeric state, through intermediate forms, ending in amyloid fibers and plaques. It is generally accepted now that the neurotoxic agents leading to cellular death, memory loss, and other AD characteristics are the Aβ intermediate aggregated states. However, Aβ peptides are continuously produced, released into the extracellular space, and rapidly cleared from healthy brains. Coincidentally, members of the heat shock proteins (hsp) family are present in the extracellular medium of healthy cells and body fluids, opening the possibility that hsps and Aβ could meet and interact in the extracellular milieu of the brain. In this perspective and reflection article, we place our investigation showing that the presence of Hsp70s mitigate the formation of low molecular weight Aβ peptide oligomers resulting in a reduction of cellular toxicity, in context of the current understanding of the disease. We propose that it may be an inverse relationship between the presence of Hsp70, the stage of Aβ oligomers, neurotoxicity, and the incidence of AD, particularly since the expression and circulating levels of hsp decrease with aging. Combining these observations, we propose that changes in the dynamics of Hsp70s and Aβ concentrations in the circulating brain fluids during aging defines the control of the formation of Aβ toxic aggregates, thus determining the conditions for neuron degeneration and the incidence of AD.

%B J Alzheimers Dis %V 63 %P 927-934 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689729?dopt=Abstract %R 10.3233/JAD-180161 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mental States in Moving Shapes: Distinct Cortical and Subcortical Contributions to Theory of Mind Impairments in Dementia. %A Synn, Artemis %A Mothakunnel, Annu %A Kumfor, Fiona %A Chen, Yu %A Piguet, Olivier %A Hodges, John R %A Irish, Muireann %K Aged %K Alzheimer Disease %K Brain %K Case-Control Studies %K Female %K Frontotemporal Dementia %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Memory, Episodic %K Mentalization %K Middle Aged %K Neuropsychological Tests %K Task Performance and Analysis %K Theory of Mind %X

Impaired capacity for Theory of Mind (ToM) represents one of the hallmark features of the behavioral variant of frontotemporal dementia (bvFTD) and is suggested to underpin an array of socioemotional disturbances characteristic of this disorder. In contrast, while social processing typically remains intact in Alzheimer's disease (AD), the cognitive loading of socioemotional tasks may adversely impact mentalizing performance in AD. Here, we employed the Frith-Happé animations as a dynamic on-line assessment of mentalizing capacity with reduced incidental task demands in 18 bvFTD, 18 AD, and 25 age-matched Controls. Participants viewed silent animations in which geometric shapes interact in Random, Goal-Directed, and ToM conditions. An exclusive deficit in ToM classification was observed in bvFTD relative to Controls, while AD patients were impaired in the accurate classification of both Random and ToM trials. Correlation analyses revealed robust associations between ToM deficits and carer ratings of affective empathy disruption in bvFTD, and with episodic memory dysfunction in AD. Voxel-based morphometry analyses further identified dissociable neural correlates contingent on patient group. A distributed network of medial prefrontal, frontoinsular, striatal, lateral temporal, and parietal regions were implicated in the bvFTD group, whereas the right hippocampus correlated with task performance in AD. Notably, subregions of the cerebellum, including lobules I-IV and V, bilaterally were implicated in task performance irrespective of patient group. Our findings reveal new insights into the mechanisms potentially mediating ToM disruption in dementia syndromes, and suggest that the cerebellum may play a more prominent role in social cognition than previously appreciated.

%B J Alzheimers Dis %V 61 %P 521-535 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170809?id=journal-of-alzheimers-disease%2Fjad170809 %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29172002?dopt=Abstract %R 10.3233/JAD-170809 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mesenchymal Stem Cell-Derived Extracellular Vesicles Suppresses iNOS Expression and Ameliorates Neural Impairment in Alzheimer's Disease Mice. %A Wang, Shan-Shan %A Jia, Jianjun %A Wang, Zhenfu %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Cells, Cultured %K Disease Models, Animal %K Extracellular Vesicles %K Humans %K Male %K Mesenchymal Stem Cells %K Mice %K Mice, Transgenic %K Neuronal Plasticity %K Neurons %K Nitric Oxide Synthase Type II %K Synaptic Transmission %X

BACKGROUND: Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been reported to exhibit therapeutic effects in various animal models of neurological diseases, such as stroke and hypoxic-ischemic brain injury.

OBJECTIVE: The present study investigated the potential beneficial effect of MSC-derived EVs in an animal model of Alzheimer's disease (AD).

METHODS: APP/PS1 mice and their non-transgenic littermates (WT) received intracerebroventricle injection of MSC-derived EVs once per two days for two weeks. Then novel object recognition and water maze tasks were carried out to measure the cognitive behaviors. Electrophysiological tests were carried out to measure hippocampal synaptic plasticity. Inducible nitric oxide synthase (iNOS) mRNA and protein levels were measured by qRT-PCR and western blotting in primary cultured neurons treated with amyloid-β peptide (Aβ) or prepared from APP/PS1 mice.

RESULTS: Treatment with MSC-derived EVs alleviates exogenous Aβ-induced iNOS mRNA and protein expression. In cultured primary neurons prepared from APP/PS1 pups, iNOS mRNA and protein levels were significantly reduced when treated with MSC-derived EVs. MSC-derived EVs improved cognitive behavior, rescued impairment of CA1 synaptic transmission, and long-term potentiation in APP/PS1 mice.

CONCLUSION: MSC-derived EVs possessed beneficial effects in a mouse model of AD, probably by suppressing Aβ induced iNOS expression.

%B J Alzheimers Dis %V 61 %P 1005-1013 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254100?dopt=Abstract %R 10.3233/JAD-170848 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Meta-Analysis of Personality Traits in Alzheimer's Disease: A Comparison with Healthy Subjects. %A D'Iorio, Alfonsina %A Garramone, Federica %A Piscopo, Fausta %A Baiano, Chiara %A Raimo, Simona %A Santangelo, Gabriella %K Alzheimer Disease %K Case-Control Studies %K Humans %K Personality %K Personality Inventory %X

BACKGROUND: The role of specific personality traits as factor risks of Alzheimer's disease (AD) has been consistently found, whereas personality traits specifically related to AD (after the diagnosis) have not been outlined yet.

OBJECTIVE: A meta-analysis of published studies was performed to determine whether AD patients have a distinctive personality trait profile compared to healthy subjects (HC), similar to or different from a premorbid personality profile consistently reported in previous studies.

METHODS: A systematic literature search was performed using PsycInfo (PROQUEST), PubMed, and Scopus. The meta-analysis pooled results from primary studies using Hedges' g unbiased approach.

RESULTS: The meta-analysis included 10 primary studies and revealed that, when the personality was evaluated by informant-rated measures, AD patients had significantly higher levels of Neuroticism, lower levels of Openness, Agreeableness, Conscientiousness, and Extraversion than HCs. When the personality was evaluated by self-rated measures, the results obtained from informants were confirmed for Neuroticism, Openness, and Extraversion but not for Agreeableness and Conscientiousness where AD patients and HCs achieved similar scores.

CONCLUSIONS: The meta-analysis revealed that high Neuroticism and low Openness and Extraversion are distinctive personality traits significantly associated with a diagnosis of AD when evaluated both self-rated and informant-rated measures. This personality trait profile is similar to premorbid one, which contributes to development of AD over time. Therefore, our findings indirectly support the idea of specific premorbid personality traits as harbingers of AD.

%B J Alzheimers Dis %V 62 %P 773-787 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480186?dopt=Abstract %R 10.3233/JAD-170901 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Meta-Analysis of the Association between Variants in ABCA7 and Alzheimer's Disease. %A Ma, Fang-Chen %A Wang, Hui-Fu %A Cao, Xi-Peng %A Tan, Chen-Chen %A Tan, Lan %A Yu, Jin-Tai %X

The ATP-binding cassette transporter A7 (ABCA7) was identified as a known risk factor for Alzheimer's disease (AD). However, the relation between ABCA7 and AD was still inconsistent across these studies. Here, our meta-analysis aimed at confirming the association of ABCA7 with AD. Finally, 16 case-control studies (63747 versus 85833) were retrieved from PubMed and other databases. Three common loci were confirmed to increase the risk of AD (rs3764650: OR = 1.20, 95% CI = 1.16-1.24; rs3752246: OR = 1.13,95% CI = 1.08-1.19; rs4147929: OR = 1.17, 95% CI = 1.10-1.24), but the associations varied among the different races. Furthermore, ABCA7 loss-of-function (LOF) mutations conferred a higher risk for AD than did the above variants (LOF: OR = 1.78, 95%  = 1.43-2.22). In conclusion, ABCA7 genetic variants, especially the LOF mutations, were significantly associated with the risk of AD.

%B J Alzheimers Dis %V 63 %P 1261-1267 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782324?dopt=Abstract %R 10.3233/JAD-180107 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Metabolic Dysfunction in Alzheimer's Disease: From Basic Neurobiology to Clinical Approaches. %A Clarke, Julia R %A Ribeiro, Felipe C %A Frozza, Rudimar L %A De Felice, Fernanda G %A Lourenco, Mychael V %X

Clinical trials have extensively failed to find effective treatments for Alzheimer's disease (AD) so far. Even after decades of AD research, there are still limited options for treating dementia. Mounting evidence has indicated that AD patients develop central and peripheral metabolic dysfunction, and the underpinnings of such events have recently begun to emerge. Basic and preclinical studies have unveiled key pathophysiological mechanisms that include aberrant brain stress signaling, inflammation, and impaired insulin sensitivity. These findings are in accordance with clinical and neuropathological data suggesting that AD patients undergo central and peripheral metabolic deregulation. Here, we review recent basic and clinical findings indicating that metabolic defects are central to AD pathophysiology. We further propose a view for future therapeutics that incorporates metabolic defects as a core feature of AD pathogenesis. This approach could improve disease understanding and therapy development through drug repurposing and/or identification of novel metabolic targets.

%B J Alzheimers Dis %V 64 %P S405-S426 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562518?dopt=Abstract %R 10.3233/JAD-179911 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Metabolic Syndrome and Amyloid Accumulation in the Aging Brain. %A Gomez, Gabriela %A Beason-Held, Lori L %A Bilgel, Murat %A An, Yang %A Wong, Dean %A Studenski, Stephanie %A Ferrucci, Luigi %A Resnick, Susan M %X

BACKGROUND: Recent studies show links between metabolic syndrome and Alzheimer's disease (AD) neuropathology. Understanding the link between vascular-related health conditions and dementia will help target at risk populations and inform clinical strategies for early detection and prevention of AD.

OBJECTIVE: To determine whether metabolic syndrome is associated with global cerebral amyloid-β (Aβ) positivity and longitudinal Aβ accumulation.

METHODS: Prospective study of 165 participants who underwent (11)C-Pittsburgh compound B (PiB) PET neuroimaging to measure Aβ, from June 2005 to May 2016. Metabolic syndrome was defined using the revised Third Adults Treatment Panel of the National Cholesterol Education Program criteria. Participants were classified as PiB+/- . Linear mixed effects models assessed the relationships between baseline metabolic syndrome and PiB status and regional Aβ change over time.

RESULTS: A total of 165 cognitively normal participants of the Baltimore Longitudinal Study of Aging (BLSA) Neuroimaging substudy, aged 55-92 years (mean baseline age = 76.4 years, 85 participants were male), received an average of 2.5 PET-PiB scans over an average interval of 2.6 (3.08 SD) years between first and last visits. Metabolic syndrome was not associated with baseline PiB positivity or concurrent regional Aβ. Metabolic syndrome was associated with increased rates of Aβ accumulation in superior parietal and precuneus regions over time in the PiB+ group. Elevated fasting glucose and blood pressure showed individual associations with accelerated Aβ accumulation.

CONCLUSION: Metabolic syndrome was associated with accelerated Aβ accumulation in PiB+ individuals and may be an important factor in the progression of AD pathology.

%B J Alzheimers Dis %V 65 %P 629-639 %8 2018 Jul 30 %G eng %N 2 %& 629 %R 10.3233/JAD-180297 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Metabolic Syndrome, Brain Insulin Resistance, and Alzheimer's Disease: Thioredoxin Interacting Protein (TXNIP) and Inflammasome as Core Amplifiers. %A Nasoohi, Sanaz %A Parveen, Kehkashan %A Ishrat, Tauheed %X

Empirical evidence indicates a strong association between insulin resistance and pathological alterations related to Alzheimer's disease (AD) in different cerebral regions. While cerebral insulin resistance is not essentially parallel with systemic metabolic derangements, type 2 diabetes mellitus (T2DM) has been established as a risk factor for AD. The circulating "toxic metabolites" emerging in metabolic syndrome may engage several biochemical pathways to promote oxidative stress and neuroinflammation leading to impair insulin function in the brain or "type 3 diabetes". Thioredoxin-interacting protein (TXNIP) as an intracellular amplifier of oxidative stress and inflammasome activation may presumably mediate central insulin resistance. Emerging data including those from our recent studies has demonstrated a sharp TXNIP upregulation in stroke, aging and AD and well underlining the significance of this hypothesis. With the main interest to illustrate TXNIP place in type 3 diabetes, the present review primarily briefs the potential mechanisms contributing to cerebral insulin resistance in a metabolically deranged environment. Then with a particular focus on plausible TXNIP functions to drive and associate with AD pathology, we present the most recent evidence supporting TXNIP as a promising therapeutic target in AD as an age-associated dementia.

%B J Alzheimers Dis %V 66 %P 857-885 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30372683?dopt=Abstract %R 10.3233/JAD-180735 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Metabolomics Analyses of Saliva Detect Novel Biomarkers of Alzheimer's Disease. %A Huan, Tao %A Tran, Tran %A Zheng, Jiamin %A Sapkota, Shraddha %A MacDonald, Stuart W %A Camicioli, Richard %A Dixon, Roger A %A Li, Liang %X

Using a non-invasive biofluid (saliva), we apply a powerful metabolomics workflow for unbiased biomarker discovery in Alzheimer's disease (AD). We profile and differentiate Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD groups. The workflow involves differential chemical isotope labeling liquid chromatography mass spectrometry using dansylation derivatization for in-depth profiling of the amine/phenol submetabolome. The total sample (N = 109) was divided in to the Discovery Phase (DP) (n = 82; 35 CN, 25 MCI, 22 AD) and a provisional Validation Phase (VP) (n = 27; 10 CN, 10 MCI, 7 AD). In DP we detected 6,230 metabolites. Pairwise analyses confirmed biomarkers for AD versus CN (63), AD versus MCI (47), and MCI versus CN (2). We then determined the top discriminating biomarkers and diagnostic panels. A 3-metabolite panel distinguished AD from CN and MCI (DP and VP: Area Under the Curve [AUC] = 1.000). The MCI and CN groups were best discriminated with a 2-metabolite panel (DP: AUC = 0.779; VP: AUC = 0.889). In addition, using positively confirmed metabolites, we were able to distinguish AD from CN and MCI with good diagnostic performance (AUC > 0.8). Saliva is a promising biofluid for both unbiased and targeted AD biomarker discovery and mechanism detection. Given its wide availability and convenient accessibility, saliva is a biofluid that can promote diversification of global AD biomarker research.

%B J Alzheimers Dis %V 65 %P 1401-1416 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30175979?dopt=Abstract %R 10.3233/JAD-180711 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Metals and Alzheimer's Disease: How Far Have We Come in the Clinic? %A Adlard, Paul A %A Bush, Ashley I %X

It is estimated that by the year 2050 there will be more than 1.5 billion people globally over the age of 65 years. Aging is associated with changes to a number of different cellular processes which are driven by a variety of factors that contribute to the characteristic decline in function that is seen across multiple physiological domains/tissues in the elderly (including the brain). Importantly, aging is also the primary risk factor for the development of neurodegenerative disorders such as Alzheimer's disease. As such, there is an urgent need to provide a greater understanding of both the pathogenesis and treatment of these devastating neurodegenerative disorders. One of the key cellular processes that becomes dysregulated with age and participates both directly and indirectly in age-related dysfunction, is metal homeostasis and the neurochemistry of metalloproteins, the basic science of which has been extensively reviewed in the past. In this review, we will focus on the human clinical intervention trials that have been conducted over approximately the last four decades that have attempted to establish the efficacy of targeting metal ions in the treatment of AD.

%B J Alzheimers Dis %V 62 %P 1369-1379 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562528?dopt=Abstract %R 10.3233/JAD-170662 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis. %A Campbell, Jared M %A Stephenson, Matthew D %A de Courten, Barbora %A Chapman, Ian %A Bellman, Susan M %A Aromataris, Edoardo %X

BACKGROUND: Metformin, a first line antihyperglycemic medication, is an AMPK activator and has been hypothesized to act as a geroprotective agent. Studies on its association with various classifications of age-related cognitive decline have shown mixed results with positive and negative findings.

OBJECTIVE: To synthesize the best available evidence on the association of metformin-use with risk, progression, and severity of dementia.

METHOD: Eligible research investigated the effect of metformin on dementia, Alzheimer's disease, or any measure of cognitive impairment compared to any control group who were not receiving metformin. The initial search resulted in 862 citations from which 14 studies (seven cohort, four cross-sectional, two RCTs, and one case control) were included.

RESULTS: Meta-analysis of three studies showed that cognitive impairment was significantly less prevalent in diabetic metformin (Odds ratio = 0.55, 95% CI 0.38 to 0.78), while six studies showed that dementia incidence was also significantly reduced (Hazard ratio = 0.76, 95% CI 0.39 to 0.88). Mini-Mental State Examination scores were not significantly affected by metformin-use, although both RCTs showed that metformin had a neuroprotective effect compared to placebo. Some studies found negative or neutral effects for metformin use by people with diabetes; the potential mechanism of metformin-induced vitamin B12 deficiency is discussed.

CONCLUSIONS: Metformin should continue to be used as a first line therapy for diabetes in patients at risk of developing dementia or Alzheimer's disease. The use of metformin by individuals without diabetes for the prevention of dementia is not supported by the available evidence.

%B J Alzheimers Dis %V 65 %P 1225-1236 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149446?dopt=Abstract %R 10.3233/JAD-180263 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Methylenetetrahydrofolate Reductase Deficiency Deregulates Regional Brain Amyloid-β Protein Precursor Expression and Phosphorylation Levels. %A Hoffman, Alexander %A Taleski, Goce %A Qian, Helena %A Wasek, Brandi %A Arning, Erland %A Bottiglieri, Teodoro %A Sontag, Jean-Marie %A Sontag, Estelle %X

Deregulation of the amyloid-β protein precursor (AβPP) plays a critical role in the neurodegenerative cascade of Alzheimer's disease (AD). Significantly, common functional polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene are a risk factor for the development of late-onset AD. Reduced MTHFR activity is associated with alterations in folate and homocysteine metabolism. Here, we first show that in young MTHFR knockout mice, mild and severe MTHFR deficiency markedly increase cortical and hippocampal AβPP phosphorylation at the regulatory Thr668 site. However, the hippocampus is especially vulnerable to the effects of aging and mild MTHFR deficiency. Notably, the effects of severe MTHFR deficiency in young mice are recapitulated by prolonged dietary folate deficiency in old mice, which leads to regional brain accumulation of cystathionine due to impaired methylation of homocysteine. The incremental AβPP phosphorylation at Thr668 mediated by severe genetic-or diet-induced impairment of the folate cycle correlates with enhanced accumulation of demethylated protein phosphatase 2A (PP2A), and activation of glycogen synthase kinase-3β (GSK-3β). Lastly, we show that severe disturbances in folate metabolism can also affect AβPP expression levels in a brain region specific manner. Together our findings identify a novel link between genetic MTHFR deficiency, activation of GSK-3β, demethylation of PP2A, and enhanced phosphorylation of AβPP at Thr668, which is known to critically influence neuronal AβPP function and pathological amyloidogenic processing. Deregulation of AβPP provides a novel mechanism by which common human MTHFR polymorphisms may interact with dietary folate deficiency to alter neuronal homeostasis and increase the risk for sporadic AD.

%B J Alzheimers Dis %V 64 %P 223-237 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865064?dopt=Abstract %R 10.3233/JAD-180032 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Microglia CREB-Phosphorylation Mediates Amyloid-β-Induced Neuronal Toxicity. %A Gao, Yuan %A Liu, En-Jie %A Wang, Wei-Jin %A Wang, Ya-Li %A Li, Xiao-Guang %A Wang, Xin %A Li, Shi-Hong %A Zhang, Shu-Juan %A Li, Meng-Zhu %A Zhou, Qiu-Zhi %A Long, Xiao-Bing %A Zhang, Hua-Qiu %A Wang, Jian-Zhi %X

Extracellular accumulation of amyloid-β (Aβ) forming senile plaques is one of the hallmark pathologies in Alzheimer's disease (AD), while the mechanisms underlying the neuronal toxic effect of Aβ are not fully understood. Here, we found that intracerebroventricular infusion of the aged Aβ42 in mice only induces memory deficit at 24 h but not at 7 days. Interestingly, a remarkably increased CREB (cAMP response element-binding protein) Ser133-phosphorylation (pS133-CREB) with microglial activation was detected at 24 h but not at 7 days after Aβ infusion. Aβ treatment for 24 h increased pS133-CREB level in microglia of the hippocampal non-granular cell layers with remarkably decreased pS133-CREB immunoreactivity in neurons of the hippocampal granular cell layers, including CA1, CA3, and DG subsets. Inhibition of microglia activation by minocycline or CREB phosphorylation by H89, an inhibitor of protein kinase A (PKA), abolished Aβ-induced microglia CREB hyperphosphorylation with restoration of neuronal function and attenuation of inflammatory response, i.e., reduced levels of interleukin-6 (IL6) and pCREB binding of matrix metalloproteinase-9 (MMP9) DNA. Finally, treatment of the primary hippocampal neurons with Aβ-potentiated microglia media decreased neuronal GluN1 and GluA2 levels, while simultaneous inhibition of PKA restored the levels. These novel findings reveal that intracerebroventricular infusion of Aβ only induces transient memory deficit in mice and the molecular mechanisms involve a stimulated microglial CREB phosphorylation.

%B J Alzheimers Dis %V 66 %P 333-345 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282353?dopt=Abstract %R 10.3233/JAD-180286 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Microglial Activation During Pathogenesis of Tauopathy in rTg4510 Mice: Implications for the Early Diagnosis of Tauopathy. %A Sahara, Naruhiko %A Maeda, Jun %A Ishikawa, Ai %A Tokunaga, Masaki %A Suhara, Tetsuya %A Higuchi, Makoto %X

Tauopathy is characterized by the fibrillar tau accumulation in neurons and glial cells. In order to advance our understanding of the causative mechanisms of tauopathy, neuroinflammation, which has been suggested to play important roles in disease progression, will require particular attention. Neuroinflammation is characterized predominantly by microglial activation. At present, it is still under debate whether microglial activation is a cause or a result of neurodegeneration. To search for a temporal relationship between neurodegeneration and neuroinflammation, our group demonstrated that in vivo imaging (e.g., tau-PET, TSPO-PET, and volumetric MRI) of tauopathy mice strongly supports the evidence of microglial activation along with both pathological tau accumulation and brain atrophy. Both in vivo imaging and histochemical analysis confirmed that microglial TSPO accumulation was the late event during the pathogenesis of tauopathy. On the other hand, it is known that purinergic receptor P2Y12 as a marker of homeostatic microglia cells was reduced at an early stage of disease progression. In this review, we will introduce a phenotypic change of microglia in a mouse model of tauopathy and propose novel approaches to the establishment of imaging biomarkers, thereby targeting the early diagnosis of tauopathy.

%B J Alzheimers Dis %V 64 %P S353-S359 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865054?dopt=Abstract %R 10.3233/JAD-179933 %0 Journal Article %J J Alzheimers Dis %D 2018 %T microRNA 221 Targets ADAM10 mRNA and is Downregulated in Alzheimer's Disease. %A Manzine, Patricia R %A Pelucchi, Silvia %A Horst, Maria A %A Vale, Francisco A C %A Pavarini, Sofia C I %A Audano, Matteo %A Mitro, Nico %A Di Luca, Monica %A Marcello, Elena %A Cominetti, Márcia R %K ADAM10 Protein %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cell Line, Tumor %K Cohort Studies %K Down-Regulation %K Female %K Humans %K Male %K MicroRNAs %K Middle Aged %K Neuroblastoma %K Psychiatric Status Rating Scales %K RNA, Messenger %K ROC Curve %K Transfection %X

ADAM10 is the α-secretase that cleaves amyloid-β protein precursor in the non-amyloidogenic pathway in Alzheimer's disease (AD) and is known to be regulated by different microRNAs (miRNAs), which are post-transcriptional regulators related to several biological and pathological processes, including AD. Here we proposed to explore and validate miRNAs that have direct or indirect relations to the AD pathophysiology and ADAM10 gene. Approximately 700 miRNAs were analyzed and 21 differentially expressed miRNAs were validated in a sample of 21 AD subjects and 17 cognitively healthy matched controls. SH-SY5Y cells were transfected with miR-144-5p, miR-221, and miR-374 mimics and inhibitors, and ADAM10 protein levels were evaluated. miR-144-5p, miR-221, and miR-374 were downregulated in AD. The overexpression of miR-221 in SH-SY5Y cells resulted in ADAM10 reduction and its inhibition in ADAM10 increased. These findings show that miR-221 can be a new potential therapeutic target for increasing ADAM10 levels in AD. In addition, these results can contribute to the better understanding of ADAM10 post-transcriptional regulation.

%B J Alzheimers Dis %V 61 %P 113-123 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036829?dopt=Abstract %R 10.3233/JAD-170592 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Midlife Physical Activity, Psychological Distress, and Dementia Risk: The HUNT Study. %A Zotcheva, Ekaterina %A Bergh, Sverre %A Selbæk, Geir %A Krokstad, Steinar %A Håberg, Asta Kristine %A Strand, Bjørn Heine %A Ernstsen, Linda %X

BACKGROUND: Physical activity (PA) is associated with a decreased dementia risk, whereas psychological distress (distress) is linked to an increased dementia risk.

OBJECTIVE: We investigated independent and joint associations of midlife moderate-to-vigorous PA (MVPA) and distress with incident dementia.

METHODS: Our study comprised 28,916 participants aged 30-60 years from the Nord-Trøndelag Health Study (HUNT1, 1984-1986). Data on MVPA and distress from HUNT1 was linked to the Health and Memory Study in Nord-Trøndelag for dementia case identification. Participants were followed from 1995 until 2011. We used adjusted Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI).

RESULTS: In fully adjusted analyses, MVPA was associated with a reduced dementia risk (HR 0.81, 95% CI 0.62-1.06), compared to no MVPA. Distress was associated with an increased dementia risk (HR 1.30, 95% CI 0.99-1.70). Compared to distressed participants not taking part in MVPA, non-distressed no-MVPA participants had a reduced dementia risk (HR 0.72, 95% CI 0.54-0.96). The same applied to distressed MVPA participants (HR 0.50, 95% CI 0.22-1.14), and non-distressed MVPA participants (HR 0.63, 95% CI 0.44-0.90). Our results indicated an additive interaction between MVPA and distress on dementia risk.

CONCLUSION: Our results suggest that midlife MVPA reduces risk of incident dementia among both distressed and non-distressed individuals.

%B J Alzheimers Dis %V 66 %P 825-833 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320592?dopt=Abstract %R 10.3233/JAD-180768 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Minor Hallucinations in Alzheimer's Disease. %A Ruiz, Maria %A Arias, Alfonso %A Sánchez-Llanos, Ernesto %A Gil, Maria Pilar %A López-Ortega, Ricard %A Dakterzada, Faridé %A Purroy, Francisco %A Piñol-Ripoll, Gerard %X

BACKGROUND: Hallucinations may have a broad spectrum and include so-called minor hallucinations (MHs). MHs include passage hallucinations (PHs), visual illusions, and presence hallucinations (PrHs).

OBJECTIVE: To determine the prevalence and characteristics of MHs in Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) patients, and to describe their potential relationship with cognition, behavioral symptoms, and use of psychoactive drugs.

METHODS: We have recruited prospectively and consecutively 268 subjects (90 AD mild-moderate drug-naïve patients, 78 aMCI, and 100 controls). All patients responded to a semi-structured questionnaire in order to rate psychotic phenomena. Clinical, neuropsychological, and demographic data of patients with and without MH were compared with those of age, sex, and education-matched controls.

RESULTS: The prevalence of MHs was 21.1% (19) in AD, 12.8% (10) in aMCI, and 3% (3) in controls (p < 0.01). The most frequent MH was PrH (9.3%), followed by PH (4.9%) and illusion (0.7%). Eight (27.8%) patients had more than one MH. After adjusting for age and gender, there was a negative correlation between the presence of MHs and MMSE score (r = -0.261; p < 0.01) and a positive correlation between MHs and Neuropsychiatric Inventory score (r = 0.237; p < 0.01). We did not observe a significant relationship between presence of MHs and the consumption of psychoactive drugs (p > 0.05).

CONCLUSION: We have shown that the presence of MHs in patients with newly diagnosed, untreated AD and aMCI is more than controls. MHs were correlated with other behavioral symptoms and a worse cognitive performance. We suggest the specific interrogation for MHs as a clinical feature for this population.

%B J Alzheimers Dis %V 64 %P 543-549 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889069?dopt=Abstract %R 10.3233/JAD-180234 %0 Journal Article %J J Alzheimers Dis %D 2018 %T miRNA 933 Expression by Endothelial Cells is Increased by 27-Hydroxycholesterol and is More Prevalent in Plasma from Dementia Patients. %A Dias, Irundika H K %A Brown, Caroline L %A Shabir, Kiran %A Polidori, M Cristina %A Griffiths, Helen R %X

Alzheimer's disease (AD) etiology is complex; gene and environmental risk factors may interact to predispose to disease. From single nucleotide polymorphism analyses and genome-wide association studies, a number of candidate risk genes for the onset of AD have been identified and cluster around lipid metabolism and inflammation. We hypothesized that endothelial cells which line the blood-brain barrier are likely to be critical mediators of systemic metabolism within the brain. Therefore, we have studied the effect of 27 hydroxycholesterol (27-OHC) on microvascular endothelial cell (HMVEC) redox state, inflammatory cytokine secretion, and microRNA (miR) expression. Using a transwell method, we have studied directional secretion profiles for the proinflammatory cytokines TNFα and IL-6 and confirmed that 27-OHC induces discrete and directional inflammatory molecular signatures from HMVEC. The lipids caused depletion of cellular glutathione and cytokine secretion is HMVEC-redox state-dependent. Discovery miR expression change in HMVEC with and without 27-OHC treatment was undertaken. We selected three genes for further analysis by qPCR; miR-144 and 146 expression, which are anti-inflammatory and redox regulating modulators, were not affected significantly by 27-OHC. However, increased expression of a putative neurotrophic regulatory factor miR933 in HMVEC with 27-OHC was confirmed by qPCR. In plasma from patients with dementia, all three miR were found at significantly elevated levels compared to healthy older adults. These data highlight that 27-OHC has an important regulatory effect on endothelial microvascular cells to increase expression of a miR (-933) and secretion of inflammatory cytokines that are elevated in plasma from dementia patients.

%B J Alzheimers Dis %V 64 %P 1009-1017 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966198?dopt=Abstract %R 10.3233/JAD-180201 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mitochondria and Mitochondrial Cascades in Alzheimer's Disease. %A Swerdlow, Russell H %X

Decades of research indicate mitochondria from Alzheimer's disease (AD) patients differ from those of non-AD individuals. Initial studies revealed structural differences, and subsequent studies showed functional deficits. Observations of structure and function changes prompted investigators to consider the consequences, significance, and causes of AD-related mitochondrial dysfunction. Currently, extensive research argues mitochondria may mediate, drive, or contribute to a variety of AD pathologies. The perceived significance of these mitochondrial changes continues to grow, and many currently believe AD mitochondrial dysfunction represents a reasonable therapeutic target. Debate continues over the origin of AD mitochondrial changes. Some argue amyloid-β (Aβ) induces AD mitochondrial dysfunction, a view that does not challenge the amyloid cascade hypothesis and that may in fact help explain that hypothesis. Alternatively, data indicate mitochondrial dysfunction exists independent of Aβ, potentially lies upstream of Aβ deposition, and suggest a primary mitochondrial cascade hypothesis that assumes mitochondrial pathology hierarchically supersedes Aβ pathology. Mitochondria, therefore, appear at least to mediate or possibly even initiate pathologic molecular cascades in AD. This review considers studies and data that inform this area of AD research.

%B J Alzheimers Dis %V 62 %P 1403-1416 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036828?dopt=Abstract %R 10.3233/JAD-170585 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mitochondrial Dysfunction as a Predictor and Driver of Alzheimer's Disease-Like Pathology in OXYS Rats. %A Tyumentsev, Mikhail A %A Stefanova, Natalia A %A Muraleva, Natalia A %A Rumyantseva, Yulia V %A Kiseleva, Elena %A Vavilin, Valentin A %A Kolosova, Nataliya G %X

Growing evidence suggests that mitochondrial dysfunction is an early event in sporadic Alzheimer's disease (AD), but the impact of mitochondrial dysfunction on the transition from healthy aging to AD remains elusive. Here we estimated the influence of mitochondrial dysfunction on the initiation of AD signs in OXYS rats, which simulate key characteristics of sporadic AD. We assessed the mitochondrial ultrastructure of pyramidal neurons of the hippocampus at the age preceding the development (age 20 days), during manifestation (4-5 months), and at the well-pronounced stages (18-24 months) of the AD-like pathology in OXYS rats. Ultrastructural alterations were collated with the amounts of proteins mediating mitochondrial dynamics [mitofusins (MFN1 and MFN2) and dynamin-1-like protein (DRP1)]; with activity of respiratory chain complexes I, IV, and V in the hippocampal mitochondria; with reactive oxygen species (ROS) production; and with expression of uncoupling protein 2 (UCP2) regulating ROS production. Already at the preclinical stage, OXYS rats showed some characteristic changes in hippocampal mitochondria, which increased in size with the manifestation and progression of AD-like pathology, including decreased activity of respiratory complexes against the background of greater fusion and formation of larger mitochondria. Signs of AD developed simultaneously with increasing dysfunction of mitochondria, with a dramatic decrease in their number, and with increased fission but without upregulation of ROS production (observed only in 20-day-old OXYS rats). Summarizing the data from our present and previous studies, we conclude that mitochondrial dysfunction appears to mediate or possibly even initiate pathological molecular cascades of AD-like pathology in OXYS rats and can be considered a predictor of the early development of the late-onset form of AD in humans.

%B J Alzheimers Dis %V 63 %P 1075-1088 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710722?dopt=Abstract %R 10.3233/JAD-180065 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mitochondrial Function, Dynamics, and Permeability Transition: A Complex Love Triangle as A Possible Target for the Treatment of Brain Aging and Alzheimer's Disease. %A Stockburger, Carola %A Eckert, Schamim %A Eckert, Gunter P %A Friedland, Kristina %A Müller, Walter E %X

Because of the failure of all amyloid-β directed treatment strategies for Alzheimer's disease (AD), the concept of mitochondrial dysfunction as a major pathomechanism of the cognitive decline in aging and AD has received substantial support. Accordingly, improving mitochondrial function as an alternative strategy for new drug development became of increasing interest and many different compounds have been identified which improve mitochondrial function in preclinical in vitro and in vivo experiments. However, very few if any have been investigated in clinical trials, representing a major drawback of the mitochondria directed drug development. To overcome these problems, we used a top-down approach by investigating several older antidementia drugs with clinical evidence of therapeutic efficacy. These include EGb761® (standardized ginkgo biloba extract), piracetam, and Dimebon. All improve experimentally many aspects of mitochondrial dysfunction including mitochondrial dynamics and also improve cognition and impaired neuronal plasticity, the functionally most relevant consequences of mitochondrial dysfunction. All partially inhibit opening events of the mitochondrial permeability transition pore (mPTP) which previously has mainly been discussed as a mechanism relevant for the induction of apoptosis. However, as more recent work suggests the mPTP as a master regulator of many mitochondrial functions, our data suggest the mPTP as a possible relevant drug target within the love triangle between mPTP regulation, mitochondrial dynamics, and mitochondrial function including regulation of neuronal plasticity. Drugs interfering with mPTP function will improve not only mitochondrial impairment in aging and AD but also will have beneficial effects on impaired neuronal plasticity, the pathomechanism which correlates best with functional deficits (cognition, behavior) in aging and AD.

%B J Alzheimers Dis %V 64 %P S455-S467 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504539?dopt=Abstract %R 10.3233/JAD-179915 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mitochondrial Translocase of the Outer Membrane Alterations May Underlie Dysfunctional Oxidative Phosphorylation in Alzheimer's Disease. %A Chai, Yuek Ling %A Xing, Huayang %A Chong, Joyce R %A Francis, Paul T %A Ballard, Clive G %A Chen, Christopher P %A Lai, Mitchell K P %K Aged, 80 and over %K Alzheimer Disease %K Autopsy %K Brain %K Female %K Humans %K Male %K Mitochondria %K Mitochondrial Membrane Transport Proteins %K Multivariate Analysis %K Oxidative Phosphorylation %X

BACKGROUND: The translocase of the outer membrane (TOM) is a vital mitochondrial transport system facilitating the importation of nuclear encoded proteins into the organelle. While mitochondrial dysfunction, including perturbation of oxidative phosphorylation (OXPHOS) complex, is evident in Alzheimer's disease (AD), it remains unclear whether the observed OXPHOS deficits may be associated with TOM alterations.

OBJECTIVES: To correlate TOM subunits with OXPHOS complex proteins in AD.

METHODS: Postmortem neocortex (BA40) from AD and age-matched controls were processed to obtain mitochondrial enriched homogenates for the measurement of Tom20, Tom22, Tom40, and Tom70 as well as components of OXPHOS complex I-V by immunoblotting.

RESULTS: Tom20 and Tom70 immunoreactivities were significantly reduced in AD, as were components of OXPHOS complex I and III. Both Tom20 and Tom70 positively correlated with complex III and V, while Tom20 also correlated withcomplex IV.

CONCLUSION: Reductions in certain TOM subunits and their correlations with specific OXPHOS complex proteins suggest that an impaired mitochondrial transportation system may contribute to previously observed oxidative phosphorylation deficits in AD. Follow-up studies are needed to corroborate the present correlative study.

%B J Alzheimers Dis %V 61 %P 793-801 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254089?dopt=Abstract %R 10.3233/JAD-170613 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Modeling Prion-Like Processing of Tau Protein in Alzheimer's Disease for Pharmaceutical Development. %A Wischik, Claude M %A Schelter, Björn O %A Wischik, Damon J %A Storey, John M D %A Harrington, Charles R %X

Following our discovery of a fragment from the repeat domain of tau protein as a structural constituent of the PHF-core in Alzheimer's disease (AD), we developed an assay that captured several key features of the aggregation process. Tau-tau binding through the core tau fragment could be blocked by the same diaminophenothiazines found to dissolve proteolytically stable PHFs isolated from AD brain. We found that the PHF-core tau fragment is inherently capable of auto-catalytic self-propagation in vitro, or "prion-like processing", that has now been demonstrated for several neurodegenerative disorders. Here we review the findings that led to the first clinical trials to test tau aggregation inhibitor therapy in AD as a way to block this cascade. Although further trials are still needed, the results to date suggest that a treatment targeting the prion-like processing of tau protein may have a role in both prevention and treatment of AD.

%B J Alzheimers Dis %V 62 %P 1287-1303 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226873?dopt=Abstract %R 10.3233/JAD-170727 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Montreal Cognitive Assessment: Normative Data from a German-Speaking Cohort and Comparison with International Normative Samples. %A Thomann, Alessandra E %A Goettel, Nicolai %A Monsch, Raphael J %A Berres, Manfred %A Jahn, Thomas %A Steiner, Luzius A %A Monsch, Andreas U %X

BACKGROUND: The Montreal Cognitive Assessment (MoCA) is used to evaluate multiple cognitive domains in elderly individuals. However, it is influenced by demographic characteristics that have yet to be adequately considered.

OBJECTIVE: The aim of our study was to investigate the effects of age, education, and sex on the MoCA total score and to provide demographically adjusted normative values for a German-speaking population.

METHODS: Subjects were recruited from a registry of healthy volunteers. Cognitive health was defined using the Mini-Mental State Examination (score ≥27/30 points) and the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (total score ≥85.9 points). Participants were assessed with the German version of the MoCA. Normative values were developed based on regression analysis. Covariates were chosen using the Predicted Residual Sums of Squares approach.

RESULTS: The final sample consisted of 283 participants (155 women, 128 men; mean (SD) age = 73.8 (5.2) years; education = 13.6 (2.9) years). Thirty-one percent of participants scored below the original cut-off (<26/30 points). The MoCA total score was best predicted by a regression model with age, education, and sex as covariates. Older age, lower education, and male sex were associated with a lower MoCA total score (p < 0.001).

CONCLUSION: We developed a formula to provide demographically adjusted standard scores for the MoCA in a German-speaking population. A comparison with other MoCA normative studies revealed considerable differences with respect to selection of volunteers and methods used to establish normative data.

%B J Alzheimers Dis %V 64 %P 643-655 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29945351?dopt=Abstract %R 10.3233/JAD-180080 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Moringa Oleifera Alleviates Homocysteine-Induced Alzheimer's Disease-Like Pathology and Cognitive Impairments. %A Mahaman, Yacoubou Abdoul Razak %A Huang, Fang %A Wu, Mengjuan %A Wang, Yuman %A Wei, Zhen %A Bao, Jian %A Salissou, Maibouge Tanko Mahamane %A Ke, Dan %A Wang, Qun %A Liu, Rong %A Wang, Jian-Zhi %A Zhang, Bin %A Chen, Dan %A Wang, Xiaochuan %X

Alzheimer's disease (AD) is multifactorial with unclear etiopathology. Due to the complexity of AD, many attempted single therapy treatments, like Aβ immunization, have generally failed. Therefore, there is a need for drugs with multiple benefits. Naturally occurring phytochemicals with neuroprotective, anti-amyloidogenic, antioxidative, and anti-inflammatory properties could be a possible way out. In this study, the effect of Moringa oleifera (MO), a naturally occurring plant with high antioxidative, anti-inflammatory, and neuroprotective effects, was evaluated on hyperhomocysteinemia (HHcy) induced AD-like pathology in rats. Homocysteine (Hcy) injection for 14 days was used to induce AD-like pathology. Simultaneous MO extract gavage followed the injection as a preventive treatment or, after injection completion, MO gavage was performed for another 14 days as a curative treatment. MO was found to not only prevent but also rescue the oxidative stress and cognitive impairments induced by Hcy treatment. Moreover, MO recovered the decreased synaptic proteins PSD93, PSD95, Synapsin 1 and Synaptophysin, and improved neurodegeneration. Interestingly, MO decreased the Hyc-induced tau hyperphosphorylation at different sites including S-199, T-231, S-396, and S-404, and at the same time decreased Aβ production through downregulation of BACE1. These effects in HHcy rats were accompanied by a decrease in calpain activity under MO treatment, supporting that calpain activation might be involved in AD pathogenesis in HHcy rats. Taken together, our data, for the first time, provided evidence that MO alleviates tau hyperphosphorylation and Aβ pathology in a HHcy AD rat model. This and previous other studies support MO as a good candidate for, and could provide new insights into, the treatment of AD and other tauopathies.

%B J Alzheimers Dis %V 63 %P 1141-1159 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710724?dopt=Abstract %R 10.3233/JAD-180091 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Morphological and Pathological Characteristics of Brain in Diabetic Encephalopathy. %A Chen, Rui %A Shi, Jiangwei %A Yin, Qingsheng %A Li, Xiaojin %A Sheng, Yanyuan %A Han, Juan %A Zhuang, Pengwei %A Zhang, Yanjun %X

Diabetes mellitus is a metabolic disease often accompanied by a series of complications, such as diabetic nephropathy, retinopathy, and diabetic foot. The survival time of diabetics has been significantly prolonged due to advancements in medicine. However, the prolonged survival time for diabetics can increase the prevalence of diabetic central nervous system disease. Diabetic encephalopathy (DE) has become one of the main complications of the disease, and the main clinical manifestation of DE is cognitive dysfunction. However, the typical morphological and pathological characteristics of the brain in DE are rarely systematically reported. Thus, this phenomenon severely restricts the diagnosis and treatment of DE. This article presents a description of the pathology characteristics of DE, including atrophy of the brain (gray matter, white matter, and hippocampus), changes in cerebrovascular morphology and function, impairment of synaptic plasticity, and dysfunction of neuroglia. In addition, abnormalities in the glymphatic clearance system of the brain are closely related to the progression of DE. A review of typical brain morphological and pathological characteristics would aid in the diagnosis and treatment of DE.

%B J Alzheimers Dis %V 65 %P 15-28 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040723?dopt=Abstract %R 10.3233/JAD-180314 %0 Journal Article %J J Alzheimers Dis %D 2018 %T MRI-Based Screening of Preclinical Alzheimer's Disease for Prevention Clinical Trials. %A Casamitjana, Adrià %A Petrone, Paula %A Tucholka, Alan %A Falcon, Carles %A Skouras, Stavros %A Molinuevo, José Luis %A Vilaplana, Verónica %A Gispert, Juan Domingo %X

The identification of healthy individuals harboring amyloid pathology represents one important challenge for secondary prevention clinical trials in Alzheimer's disease (AD). Consequently, noninvasive and cost-efficient techniques to detect preclinical AD constitute an unmet need of critical importance. In this manuscript, we apply machine learning to structural MRI (T1 and DTI) of 96 cognitively normal subjects to identify amyloid-positive ones. Models were trained on public ADNI data and validated on an independent local cohort. Used for subject classification in a simulated clinical trial setting, the proposed method is able to save 60% of unnecessary CSF/PET tests and to reduce 47% of the cost of recruitment. This recruitment strategy capitalizes on available MR scans to reduce the overall amount of invasive PET/CSF tests in prevention trials, demonstrating a potential value as a tool for preclinical AD screening. This protocol could foster the development of secondary prevention strategies for AD.

%B J Alzheimers Dis %V 64 %P 1099-1112 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010132?dopt=Abstract %R 10.3233/JAD-180299 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Multicenter Resting State Functional Connectivity in Prodromal and Dementia Stages of Alzheimer's Disease. %A Teipel, Stefan J %A Metzger, Coraline D %A Brosseron, Frederic %A Buerger, Katharina %A Brueggen, Katharina %A Catak, Cihan %A Diesing, Dominik %A Dobisch, Laura %A Fliebach, Klaus %A Franke, Christiana %A Heneka, Michael T %A Kilimann, Ingo %A Kofler, Barbara %A Menne, Felix %A Peters, Oliver %A Polcher, Alexandra %A Priller, Josef %A Schneider, Anja %A Spottke, Annika %A Spruth, Eike J %A Thelen, Manuela %A Thyrian, René J %A Wagner, Michael %A Düzel, Emrah %A Jessen, Frank %A Dyrba, Martin %X

BACKGROUND: Alterations of intrinsic networks from resting state fMRI (rs-fMRI) have been suggested as functional biomarkers of Alzheimer's disease (AD).

OBJECTIVE: To determine the diagnostic accuracy of multicenter rs-fMRI for prodromal and preclinical stages of AD.

METHODS: We determined rs-fMRI functional connectivity based on Pearson's correlation coefficients and amplitude of low-frequency fluctuation in people with subjective cognitive decline, people with mild cognitive impairment, and people with AD dementia compared with healthy controls. We used data of 247 participants of the prospective DELCODE study, a longitudinal multicenter observational study, imposing a unified fMRI acquisition protocol across sites. We determined cross-validated discrimination accuracy based on penalized logistic regression to account for multicollinearity of predictors.

RESULTS: Resting state functional connectivity reached significant cross-validated group discrimination only for the comparison of AD dementia cases with healthy controls, but not for the other diagnostic groups. AD dementia cases showed alterations in a large range of intrinsic resting state networks, including the default mode and salience networks, but also executive and language networks. When groups were stratified according to their CSF amyloid status that was available in a subset of cases, diagnostic accuracy was increased for amyloid positive mild cognitive impairment cases compared with amyloid negative controls, but still inferior to the accuracy of hippocampus volume.

CONCLUSION: Even when following a strictly harmonized data acquisition protocol and rigorous scan quality control, widely used connectivity measures of multicenter rs-fMRI do not reach levels of diagnostic accuracy sufficient for a useful biomarker in prodromal stages of AD.

%B J Alzheimers Dis %V 64 %P 801-813 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914027?dopt=Abstract %R 10.3233/JAD-180106 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Multi-Center Study on Human Brain Glutathione Conformation using Magnetic Resonance Spectroscopy. %A Shukla, Deepika %A Mandal, Pravat K %A Ersland, Lars %A Grüner, Eli Renate %A Tripathi, Manjari %A Raghunathan, Partha %A Sharma, Ankita %A Chaithya, G R %A Punjabi, Khushboo %A Splaine, Christopher %X

Molecular dynamics simulation and in vitro nuclear magnetic resonance (NMR) studies on glutathione (GSH) indicated existence of closed and extended conformations. The present work in a multi-center research setting reports in-depth analysis of GSH conformers in vivo using a common magnetic resonance spectroscopy (MRS) protocol and signal processing scheme. MEGA-PRESS pulse sequence was applied on healthy subjects using 3T Philips MRI scanner (India) and 3T GE MRI scanner (Norway) using the same experimental parameters (echo time, repetition time, and selective 180° refocusing ON-pulse at 4.40 ppm and 4.56 ppm). All MRS data were processed at one site National Brain Research Center (NBRC) using in-house MRS processing toolbox (KALPANA) for consistency. We have found that both the closed and extended GSH conformations are present in human brain and the relative proportion of individual conformer peak depends on the specific selection of refocusing ON-pulse position in MEGA-PRESS pulse sequence. It is important to emphasize that in vivo experiments with different refocusing and inversion pulse positions, echo time, and voxel size, clearly evidence the presence of both the GSH conformations. The GSH conformer peak positions for the closed GSH (Cys-Hβ) peak at ∼2.80 ppm and extended GSH (Cys-Hβ) peak at ∼2.95 ppm remain consistent irrespective of the selective refocusing OFF-pulse positions. This is the first in vivo study where both extended and closed GSH conformers are detected using the MEGA-PRESS sequence employing the parameters derived from the high resolution in vitro NMR studies on GSH.

%B J Alzheimers Dis %V 66 %P 517-532 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30198874?dopt=Abstract %R 10.3233/JAD-180648 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Multi-Faceted Role of Melatonin in Neuroprotection and Amelioration of Tau Aggregates in Alzheimer's Disease. %A Balmik, Abhishek Ankur %A Chinnathambi, Subashchandrabose %X

Alzheimer's disease (AD) is one of the major age related neurodegenerative diseases whose pathology arises due to the presence of two distinct protein aggregates, viz., amyloid-β plaques in extracellular matrix and tau neurofibrillary tangles in neurons. Multiple factors play a role in AD pathology, which includes familial mutations, oxidative stress, and post-translational modifications. Melatonin is an endocrine hormone, secreted during darkness, derived from tryptophan, and produced mainly by the pineal gland. It is an amphipathic molecule, which makes it suitable to cross not only blood-brain barrier, but also to enter several other subcellular compartments like mitochondria and endoplasmic reticulum. In this context, the neuroprotective effect of melatonin may be attributed to its role as an antioxidant. Melatonin's pleiotropic function as an antioxidant and neuroprotective agent has been widely studied. However, its direct effect on the aggregation of tau and amyloid-β needs to be explored. Furthermore, an important aspect of its function is its ability to regulate the process of phosphorylation of tau by affecting the function of kinases and phosphatases. In this review, we are focusing on the pleiotropic function of melatonin on the aspect of its neuroprotective function in tau pathology, which includes antioxidant function, regulation of enzymes, including kinases and enzymes involved in free radical scavenging and mitochondrial protection.

%B J Alzheimers Dis %V 62 %P 1481-1493 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562506?dopt=Abstract %R 10.3233/JAD-170900 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Multimodal Neuroimaging in Alzheimer's Disease: Early Diagnosis, Physiopathological Mechanisms, and Impact of Lifestyle. %A Chételat, Gaël %X

Over the last ten years, we have conducted research in Alzheimer's disease (AD) using multimodal neuroimaging techniques to improve diagnosis, further our understanding of the pathological mechanisms underlying the disease, and support the development of innovative non-pharmacological preventive strategies. Our works emphasized the interest of hippocampal subfield volumetry in early diagnosis and the need for further development in this field including optimization, standardization, and automatization of the techniques. Also, we conducted several studies in cognitively intact at-risk elderly (e.g., subjective cognitive decline patients and APOE4 carriers) to better identify biomarkers associated with increased risk of developing AD. Regarding the physiopathological mechanisms, specific multimodal neuroimaging techniques allowed us to highlight the relevance of diaschisis, the mismatch between neurodegeneration and local Aβ deposition and the regional variation in the mechanisms underlying structural or functional alterations. Further works integrating other biomarkers known to play a role in the physiopathology of AD (tau, TDP-43, inflammation, etc.) in a longitudinal design would be useful to get a comprehensive understanding of their relative role, sequence, and causal relationships. Our works also highlighted the relevance of functional connectivity in further understanding the specificity of cognitive deficits in AD and how connectivity differentially influences the propagation of the different AD biomarkers. Finally, we conducted several studies on the links between lifestyle factors and neuroimaging biomarkers to unravel mechanisms of reserve. Further efforts are needed to better understand which lifestyle factor, or combination of factors, impact on AD pathology, and when, to help translating our knowledge to training programs that might prevent or delay brain and cognitive changes leading to AD dementia.

%B J Alzheimers Dis %V 64 %P S199-S211 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504542?dopt=Abstract %R 10.3233/JAD-179920 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Multi-Modality Sparse Representation for Alzheimer's Disease Classification. %A Kwak, Kichang %A Yun, Hyuk Jin %A Park, Gilsoon %A Lee, Jong-Min %X

BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are age-related neurodegenerative diseases characterized by progressive loss of memory and irreversible cognitive functions. The hippocampus, a brain area critical for learning and memory processes, is especially susceptible to damage at early stages of AD.

OBJECTIVE: We aimed to develop prediction model using a multi-modality sparse representation approach.

METHODS: We proposed a sparse representation approach to the hippocampus using structural T1-weighted magnetic resonance imaging (MRI) and 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) to distinguish AD/MCI from healthy control subjects (HCs). We considered structural and function information for the hippocampus and applied a sparse patch-based approach to effectively reduce the dimensions of neuroimaging biomarkers.

RESULTS: In experiments using Alzheimer's Disease Neuroimaging Initiative data, our proposed method demonstrated more reliable than previous classification studies. The effects of different parameters on segmentation accuracy were also evaluated. The mean classification accuracy obtained with our proposed method was 0.94 for AD/HCs, 0.82 for MCI/HCs, and 0.86 for AD/MCI.

CONCLUSION: We extracted multi-modal features from automatically defined hippocampal regions of training subjects and found this method to be discriminative and robust for AD and MCI classification. The extraction of features in T1 and FDG-PET images is expected to improve classification performance due to the relationship between brain structure and function.

%B J Alzheimers Dis %V 65 %P 807-817 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562503?dopt=Abstract %R 10.3233/JAD-170338 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Multi-Parametric Classification of Vascular Cognitive Impairment and Dementia: The Impact of Diverse Cerebrovascular Injury Biomarkers. %A Lang, Brittany %A Kindy, Mark S %A Kozel, F Andrew %A Schultz, Susan K %A Taheri, Saeid %X

Vascular cognitive impairment and dementia (VCID) is a diagnostic term applied to cognitively impaired individuals with heterogeneous cerebrovascular conditions affecting large and/or small vessels. Individual biomarkers have been identified as instrumental in relating VCID to specific underlying pathologies to better characterize this syndrome. Emerging research to refine panels of biomarkers will increase classification sensitivity and specificity. Refined VCID clustering based on the severity and pathology of vascular injury will permit the development of optimal prevention and treatment strategies. Here, we review recently reported data concerning the diversity of VCID-related pathology and attempts for VCID clustering based on biomarkers obtained from different sets of measurements. We discuss three major sets of biomarkers: 1) neuroimaging biomarkers, 2) neuropsychological performance measures, and 3) biochemical markers in current VCID clustering. Finally, we highlight the effect of blood-brain barrier health on cerebrovascular disease trajectory.

%B J Alzheimers Dis %V 62 %P 39-60 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439338?dopt=Abstract %R 10.3233/JAD-170733 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1. %A Jellinger, Kurt A %X

Multiple system atrophy (MSA) is an orphan, fatal, adult-onset neurodegenerative disorder of uncertain etiology that is clinically characterized by various combinations of parkinsonism, cerebellar, autonomic, and motor dysfunction. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, and autonomic nervous systems but also other parts of the central and peripheral nervous systems. The major clinical variants correlate with the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). While our knowledge of the molecular pathogenesis of this devastating disease is still incomplete, updated consensus criteria and combined fluid and imaging biomarkers have increased its diagnostic accuracy. The neuropathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein in both glia (mainly oligodendroglia) and neurons forming glial and neuronal cytoplasmic inclusions that cause cell dysfunction and demise. In addition, there is widespread demyelination, the pathogenesis of which is not fully understood. The pathogenesis of MSA is characterized by propagation of misfolded α-synuclein from neurons to oligodendroglia and cell-to-cell spreading in a "prion-like" manner, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, decreased neurotrophic factors, neuroinflammation, and energy failure. The combination of these mechanisms finally results in a system-specific pattern of neurodegeneration and a multisystem involvement that are specific for MSA. Despite several pharmacological approaches in MSA models, addressing these pathogenic mechanisms, no effective neuroprotective nor disease-modifying therapeutic strategies are currently available. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable biomarkers and targets for effective treatment of this hitherto incurable disorder is urgently needed.

%B J Alzheimers Dis %V 62 %P 1141-1179 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984582?dopt=Abstract %R 10.3233/JAD-170397 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Multisensory Stimulation and Individualized Music Sessions on Older Adults with Severe Dementia: Effects on Mood, Behavior, and Biomedical Parameters. %A Maseda, Ana %A Cibeira, Nuria %A Lorenzo-López, Laura %A González-Abraldes, Isabel %A Buján, Ana %A de Labra, Carmen %A Millán-Calenti, José Carlos %X

BACKGROUND: Multisensory stimulation and individualized music have shown to be good in handling the psychological and behavioral symptoms in people with severe dementia.

OBJECTIVE: Explore the effects of two nonpharmacological interventions, multisensory stimulation environment (MSSE) in a Snoezelen room and individualized music sessions, on mood, behavior, and biomedical parameters of institutionalized elderly patients with severe dementia.

METHODS: Randomized trial of 21 patients aged ≥65 years randomly assigned to two groups (MSSE and individualized music). Interventions administered in two-weekly sessions lasted 30 minutes for a period of 12 weeks. Main outcomes were recorded before, during, and at the end of the intervention.

RESULTS: Both groups had immediate positive effects on mood and behavior. Participants were more happy/more content (p < 0.001), talked more spontaneously (p = 0.009), related to people better (p = 0.002), were more attentive to/focused on their environment (p < 0.001), enjoyed themselves (p = 0.003), were less bored/inactive (p = 0.004), and more relaxed/content (p = 0.003). The MSSE group performed a better visual follow-up of the stimuli (p = 0.044), and the music group were more relaxed and happy (p = 0.003). A decrease in heart rate (p = 0.013) and an increase in oxygen saturation (p = 0.011) were observed from before to after interventions in both groups, with no significant differences between them.

CONCLUSIONS: Both interventions seem to be effective at managing mood and behavioral disturbances in the short term and at improving physiological rates, highlighting the efficacy of nonpharmacological treatments in patients with severe dementia.

%B J Alzheimers Dis %V 63 %P 1415-1425 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843244?dopt=Abstract %R 10.3233/JAD-180109 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Multivariate Approach for Alzheimer's Disease Detection Using Stationary Wavelet Entropy and Predator-Prey Particle Swarm Optimization. %A Zhang, Yudong %A Wang, Shuihua %A Sui, Yuxiu %A Yang, Ming %A Liu, Bin %A Cheng, Hong %A Sun, Junding %A Jia, Wenjuan %A Phillips, Preetha %A Górriz, Juan Manuel %X

BACKGROUND: The number of patients with Alzheimer's disease is increasing rapidly every year. Scholars often use computer vision and machine learning methods to develop an automatic diagnosis system.

OBJECTIVE: In this study, we developed a novel machine learning system that can make diagnoses automatically from brain magnetic resonance images.

METHODS: First, the brain imaging was processed, including skull stripping and spatial normalization. Second, one axial slice was selected from the volumetric image, and stationary wavelet entropy (SWE) was done to extract the texture features. Third, a single-hidden-layer neural network was used as the classifier. Finally, a predator-prey particle swarm optimization was proposed to train the weights and biases of the classifier.

RESULTS: Our method used 4-level decomposition and yielded 13 SWE features. The classification yielded an overall accuracy of 92.73±1.03%, a sensitivity of 92.69±1.29%, and a specificity of 92.78±1.51%. The area under the curve is 0.95±0.02. Additionally, this method only cost 0.88 s to identify a subject in online stage, after its volumetric image is preprocessed.

CONCLUSION: In terms of classification performance, our method performs better than 10 state-of-the-art approaches and the performance of human observers. Therefore, this proposed method is effective in the detection of Alzheimer's disease.

%B J Alzheimers Dis %V 65 %P 855-869 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731432?dopt=Abstract %R 10.3233/JAD-170069 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Music and Dementia: Individual Differences in Response to Personalized Playlists. %A Garrido, Sandra %A Stevens, Catherine J %A Chang, Esther %A Dunne, Laura %A Perz, Janette %X

Personalized music playlists are increasingly being used in health-care contexts to address the psychological and behavioral symptoms in people with dementia. However, there is little understanding of how people with different mental health histories and symptoms respond differently to music. A factorial experiment was conducted to investigate the influence of depression, anxiety, apathy, and cognitive decline on affective response to music. Ninety-nine people with dementia listened to three music playlists based on personal preferences. Activation of facial action units was measured, and behavioural responses continuously observed. Results demonstrated that people with high levels of depression and with symptoms of Alzheimer's type dementia demonstrated increased levels of sadness when listening to music. People with low depression but high levels of apathy demonstrated the highest behavioral evidence of pleasure during music listening, although behavioral evidence declined with severity of cognitive impairment. It is concluded that as well as accounting for personal preferences, music interventions for people with dementia need to take mental health history and symptoms into account.

%B J Alzheimers Dis %V 64 %P 933-941 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966193?dopt=Abstract %R 10.3233/JAD-180084 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mutation Screening of the CHCHD2 Gene for Alzheimer's Disease and Frontotemporal Dementia in Chinese Mainland Population. %A Che, Xiang-Qian %A Zhao, Qian-Hua %A Huang, Yue %A Li, Xia %A Ren, Ru-Jing %A Chen, Sheng-Di %A Guo, Qi-Hao %A Wang, Gang %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Asian Continental Ancestry Group %K Case-Control Studies %K China %K Female %K Frontotemporal Dementia %K Genetic Association Studies %K Humans %K Male %K Middle Aged %K Mitochondrial Proteins %K Mutation %K Transcription Factors %X

As an important multifunctional protein involved in regulation of mitochondrial metabolism, CHCHD2 was identified as a causative gene for Parkinson's disease (PD), yet the relationship between CHCHD2 and neurodegenerative dementia is not well understood. We directly sequenced the entire coding region of CHCHD2 gene in 150 AD patients, 84 FTD patients, and 417 controls. Four rare putative pathogenic variants of CHCHD2, including rs142444896 (c.5C>T, p.P2L), rs752705344 (c.15C>G, p.S5R), rs145190179 (c.94G>A, p.A32T), and rs182992574 (c.255T>A, p.S85R) were identified from a cohort composed of 150 AD and 84 FTD patients. These results suggest that CH CHD2 gene play an important role in other neurodegenerative disorders from our dementia study in China.

%B J Alzheimers Dis %V 61 %P 1283-1288 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376860?dopt=Abstract %R 10.3233/JAD-170692 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Nailfold Capillary Morphology in Alzheimer's Disease Dementia. %A Cousins, Clara C %A Alosco, Michael L %A Cousins, Henry C %A Chua, Alicia %A Steinberg, Eric G %A Chapman, Kimberly R %A Bing-Canar, Hanaan %A Tripodis, Yorghos %A Knepper, Paul A %A Stern, Robert A %A Pasquale, Louis R %X

BACKGROUND: Cerebrovascular disease (CVD) is highly comorbid with Alzheimer's disease (AD), yet its role is not entirely understood. Nailfold video capillaroscopy (NVC) is a noninvasive method of live imaging the capillaries near the fingernail's cuticle and may help to describe further vascular contributions to AD.

OBJECTIVE: To examine finger nailfold capillary morphology using NVC in subjects with AD dementia, mild cognitive impairment (MCI), and normal cognition (NC).

METHODS: We evaluated nailfold capillary hemorrhages, avascular zones ≥100 microns, and degree of tortuosity in 28 NC, 15 MCI, and 18 AD dementia subjects using NVC. Tortuosity was measured with a semi-quantitative rating scale. To assess the relation between nailfold capillary morphological features and diagnostic grouping, univariate and multivariable logistic regression models were fit to the data.

RESULTS: 56% of subjects with AD dementia compared to 14% with NC and 13% with MCI displayed moderate to severe tortuosity. Greater severity of tortuosity was associated with 10.6-fold (95% confidence interval [CI]: 2.4, 46.2; p = 0.0018) and 7.4-fold (95% CI: 1.3, 41.3; p = 0.023) increased odds of AD dementia relative to NC and MCI, respectively, after adjusting for multiple covariates.

CONCLUSION: Greater nailfold capillary tortuosity was found in participants with AD dementia compared to those with MCI or NC. These data provide preliminary evidence of a systemic microvasculopathy in AD that may be noninvasively and inexpensively evaluated through NVC.

%B J Alzheimers Dis %V 66 %P 601-611 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320588?dopt=Abstract %R 10.3233/JAD-180658 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Natural Benzofuran from the Patagonic Aleurodiscus vitellinus Fungus has Potent Neuroprotective Properties on a Cellular Model of Amyloid-β Peptide Toxicity. %A González-Ramírez, Mariela %A Gavilán, Javiera %A Silva-Grecchi, Tiare %A Cajas-Madriaga, Daniel %A Triviño, Sergio %A Becerra, José %A Saez-Orellana, Francisco %A Pérez, Claudia %A Fuentealba, Jorge %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Basidiomycota %K Benzofurans %K Cell Survival %K Hippocampus %K Neurons %K Neuroprotective Agents %K PC12 Cells %K Plaque, Amyloid %K Rats %X

Alzheimer's disease (AD) is characterized by amyloid plaques that form due to an increase in amyloid-β peptide (Aβ) aggregation. One strategy in the search of new treatments for AD focuses on compounds that decrease Aβ accumulation. Compounds containing a benzofuran ring have been described to play an important role in decreasing Aβ-induced toxicity; however, only synthetic benzofurans have been tested thus far. The aim of the present study was to examine the in vitro neuroprotective properties of fomannoxin (Fx), a natural benzofuran isolated from cultures of the Andean-Patagonian fungi Aleurodiscus vitellinus, and evaluate its effect on Aβ peptide. We tested the effect of Fx at a wide concentration range (10-11-10-4 M) in PC-12 cells, and found the compound did not alter cellular viability. Fx also showed a concentration-dependent effect on the Aβ-induced toxicity in PC12 cells, showing viability above 100% at 10-6 M. We then measured the effect of Fx (10-7-10-5 M) on the frequency of cytosolic Ca2+ transients in rat hippocampal neurons at both acute and chronic (24 h) times. Acute incubation with Fx increased the frequency of cytosolic Ca2+ transients to values around 200%, whereas chronic incubation with Fx increased the frequency of Ca2+ transients. Finally, the Aβ-induced decrease in intracellular Ca2+ transients was prevented when Fx (10-6 M) was co-incubated with Aβ (5×10-6 M). The results suggest a potent neuroprotective effect of this naturally occurring benzofuran against Aβ peptide toxicity that could be mediated by an interference with it binding to plasma membrane, and lead Fx as new chemical entity to develop pharmacological tools against Aβ peptide neurotoxicity.

%B J Alzheimers Dis %V 61 %P 1463-1475 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376877?dopt=Abstract %R 10.3233/JAD-170958 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Naturalistic Driving Study Investigating Self-Regulation Behavior in Early Alzheimer's Disease: A Pilot Study. %A Paire-Ficout, Laurence %A Lafont, Sylviane %A Conte, Fanny %A Coquillat, Amandine %A Fabrigoule, Colette %A Ankri, Joël %A Blanc, Frédéric %A Gabel, Cécilia %A Novella, Jean-Luc %A Morrone, Isabella %A Mahmoudi, Rachid %X

BACKGROUND: Because cognitive processes decline in the earliest stages of Alzheimer's disease (AD), the driving abilities are often affected. The naturalistic driving approach is relevant to study the driving habits and behaviors in normal or critical situations in a familiar environment of participants.

OBJECTIVE: This pilot study analyzed in-car video recordings of naturalistic driving in patients with early-stage AD and in healthy controls, with a special focus on tactical self-regulation behavior.

METHODS: Twenty patients with early-stage AD (Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria), and 21 healthy older adults were included in the study. Data collection equipment was installed in their personal vehicles. Two expert psychologists assessed driving performance using a specially designed Naturalistic Driving Assessment Scale (NaDAS), paying particular attention to tactical self-regulation behavior, and they recorded all critical safety events.

RESULTS: Poorer driving performance was observed among AD drivers: their tactical self-regulation behavior was of lower quality. AD patients had also twice as many critical events as healthy drivers and three times more "unaware" critical events.

CONCLUSION: This pilot study used a naturalistic approach to accurately show that AD drivers have poorer tactical self-regulation behavior than healthy older drivers. Future deployment of assistance systems in vehicles should specifically target tactical self-regulation components.

%B J Alzheimers Dis %V 63 %P 1499-1508 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782312?dopt=Abstract %R 10.3233/JAD-171031 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Nature of Tau-Associated Neurodegeneration and the Molecular Mechanisms. %A Yang, Ying %A Wang, Jian-Zhi %X

Neurodegeneration is defined as the progressive loss of structure or function of the neurons. As the nature of degenerative cell loss is currently not clear, there is no specific molecular marker to measure neurodegeneration. Therefore, researchers have been using apoptotic markers to measure neurodegeneration. However, neurodegeneration is completely different from apoptosis by morphology and time course. Lacking specific molecular marker has been the major hindrance in research of neurodegenerative disorders. Alzheimer's disease (AD) is the most common neurodegenerative disorder, and tau accumulation forming neurofibrillary tangles is a hallmark pathology in the AD brains, suggesting that tau must play a critical role in AD neurodegeneration. Here we review part of our published papers on tau-related studies, and share our thoughts on the nature of tau-associated neurodegeneration in AD.

%B J Alzheimers Dis %V 62 %P 1305-1317 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562535?dopt=Abstract %R 10.3233/JAD-170788 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Need to Separate Chronic Traumatic Encephalopathy Neuropathology from Clinical Features. %A Iverson, Grant L %A Keene, C Dirk %A Perry, George %A Castellani, Rudolph J %K Chronic Traumatic Encephalopathy %K Cognition Disorders %K Disease Progression %K Gait Disorders, Neurologic %K Humans %K Neurodegenerative Diseases %K Neuropathology %K Tremor %X

There is tremendous recent interest in chronic traumatic encephalopathy (CTE) in former collision sport athletes, civilians, and military veterans. This critical review places important recent research results into a historical context. In 2015, preliminary consensus criteria were developed for defining the neuropathology of CTE, which substantially narrowed the pathology previously reported to be characteristic. There are no agreed upon clinical criteria for diagnosis, although sets of criteria have been proposed for research purposes. A prevailing theory is that CTE is an inexorably progressive neurodegenerative disease within the molecular classification of the tauopathies. However, historical and recent evidence suggests that CTE, as it is presented in the literature, might not be pathologically or clinically progressive in a substantial percentage of people. At present, it is not known whether the emergence, course, or severity of clinical symptoms can be predicted by specific combinations of neuropathologies, thresholds for accumulation of pathology, or regional distributions of pathologies. More research is needed to determine the extent to which the neuropathology ascribed to long-term effects of neurotrauma is static, progressive, or both. Disambiguating the pathology from the broad array of clinical features that have been reported in recent studies might facilitate and accelerate research- and improve understanding of CTE.

%B J Alzheimers Dis %V 61 %P 17-28 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170654?id=journal-of-alzheimers-disease%2Fjad170654 %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103039?dopt=Abstract %R 10.3233/JAD-170654 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Negative 11C-PIB PET Predicts Lack of Alzheimer's Disease Pathology in Postmortem Examination. %A Scheinin, Noora M %A Gardberg, Maria %A Röyttä, Matias %A Rinne, Juha O %X

Our aim was to assess whether in vivo11C-PIB negative memory-impaired subjects may nonetheless exhibit brain Alzheimer's disease (AD) pathology. We re-evaluated the PET images and systematically characterized the postmortem neuropathology of six individuals who had undergone clinically indicated amyloid PET. The single case with negligible amyloid-β (Aβ) pathology had Lewy body disease, where concomitant AD changes are often seen. Further, the subject's plaques were predominantly diffuse. The predictive value of a negative 11C-PIB scan appears to be good, even in memory-impaired populations. Our results suggest that considerable neuritic Aβ plaque pathology in the absence of specific/cortical 11C-PIB binding upon PET is unlikely.

%B J Alzheimers Dis %V 63 %P 79-85 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614642?dopt=Abstract %R 10.3233/JAD-170569 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Negative Prospective Memory in Alzheimer's Disease: "Do Not Perform That Action". %A El Haj, Mohamad %A Coello, Yann %A Kapogiannis, Dimitrios %A Gallouj, Karim %A Antoine, Pascal %K Aged %K Alzheimer Disease %K Case-Control Studies %K Female %K Humans %K Inhibition (Psychology) %K Male %K Memory Disorders %K Memory, Episodic %K Mental Recall %K Neuropsychological Tests %X

Relatively to "standard" prospective memory, i.e., remembering to perform a future action, little is known about negative prospective memory, i.e., remembering not to perform a future action. This study investigated the latter ability in Alzheimer's disease (AD). AD participants and healthy older adults were asked to click on the keyboard or not to click on it when a cue word was encountered. Results showed more omissions (i.e., forgetting to click the keyboard when the instruction was to do so) in AD participants than in healthy older adults, suggesting a prospective memory deficit. Interestingly, more commissions (i.e., clicking the keyboard when the instruction was not to do so) were also observed in AD participants than in healthy older adults. Similar levels of commissions and omissions were observed in AD participants and in healthy older adults. Also, commissions and omissions were correlated with performance on an inhibition assessment task. Our findings reveal that AD is characterized by not only difficulty in the retrieval of recent information, but also difficulty to inhibit no-longer appropriate stimulus-response associations previously learned, suggesting a specific deficit of negative prospective memory in AD.

%B J Alzheimers Dis %V 61 %P 663-672 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226877?dopt=Abstract %R 10.3233/JAD-170807 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer's Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOEɛ4 Carriers. %A Sapkota, Shraddha %A Dixon, Roger A %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Brain-Derived Neurotrophic Factor %K Canada %K Catechol O-Methyltransferase %K Clusterin %K Cognitive Aging %K Cognitive Dysfunction %K Executive Function %K Female %K Genetic Predisposition to Disease %K Heterozygote %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Monomeric Clathrin Assembly Proteins %K Neuropsychological Tests %K Receptors, Complement 3b %X

BACKGROUND: Trajectories of complex neurocognitive phenotypes in preclinical aging may be produced differentially through selective and interactive combinations of genetic risk.

OBJECTIVE: We organize three possible combinations into a "network" of genetic risk indices derived from polymorphisms associated with normal and impaired cognitive aging, as well as Alzheimer's disease (AD). Specifically, we assemble and examine three genetic clusters relevant to non-demented cognitive trajectories: 1) Apolipoprotein E (APOE), 2) a Cognitive Aging Genetic Risk Score (CA-GRS; Catechol-O-methyltransferase + Brain-derived neurotrophic factor), and 3) an AD-Genetic Risk Score (AD-GRS; Clusterin + Complement receptor 1 + Phosphatidylinositol-binding clathrin assembly protein).

METHOD: We use an accelerated longitudinal design (n = 634; age range = 55-95 years) to test whether AD-GRS (low versus high) moderates the effect of increasing CA-GRS risk on executive function (EF) performance and change as stratified by APOE status (ɛ4+ versus ɛ4-).

RESULTS: APOEɛ4 carriers with high AD-GRS had poorer EF performance at the centering age (75 years) and steeper 9-year decline with increasing CA-GRS but this association was not present in APOEɛ4 carriers with low AD-GRS.

CONCLUSIONS: APOEɛ4 carriers with high AD-GRS are at elevated risk of cognitive decline when they also possess higher CA-GRS risk. Genetic risk from both common cognitive aging and AD-related indices may interact in intensification networks to differentially predict (1) level and trajectories of EF decline and (2) potential selective vulnerability for transitions into impairment and dementia.

%B J Alzheimers Dis %V 62 %P 887-900 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480189?dopt=Abstract %R 10.3233/JAD-170909 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neural Correlates of Sleep Disturbance in Alzheimer's Disease: Role of the Precuneus in Sleep Disturbance. %A Matsuoka, Teruyuki %A Imai, Ayu %A Fujimoto, Hiroshi %A Kato, Yuka %A Shibata, Keisuke %A Nakamura, Kaeko %A Yokota, Hajime %A Yamada, Kei %A Narumoto, Jin %X

BACKGROUND: Sleep disturbance may affect the development of Alzheimer's disease (AD), but the neural correlates of sleep disturbance in AD have not been fully clarified.

OBJECTIVE: To examine the factors associated with sleep disturbance in AD.

METHODS: A retrospective study was performed in 63 patients with AD. None of the patients had been prescribed antidementia or psychoactive drugs, and all underwent brain magnetic resonance imaging (MRI) before medication. Sleep disturbance was defined as a score of at least 1 point on the sleep disturbance subscale of the Neuropsychiatric Inventory (NPI). Whole brain image analysis was performed using SPM8 and VBM8. A two-sample t-test was used to compare patients with AD with (n = 19) and without (n = 44) sleep disturbance, with age and gender included as covariates. The statistical thresholds were set to an uncorrected p-value of 0.001 at the voxel level and a corrected p-value of 0.05 at the cluster level. In addition, pineal gland volume (PGV) measured using MRI, and white matter hyperintensity (WMH) assessed with the modified Fazekas scale were compared between patients with AD with and without sleep disturbance using independent group t-tests.

RESULTS: In whole brain analysis, the precuneus volume in patients with AD with sleep disturbance was significantly smaller than those without sleep disturbance. There were no significant differences in PGV and WMH between the two groups.

CONCLUSION: Sleep disturbance in AD was associated with reduction of precuneus volume. This suggests that the precuneus might be an important region in sleep disturbance in AD.

%B J Alzheimers Dis %V 63 %P 957-964 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710710?dopt=Abstract %R 10.3233/JAD-171169 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuroanatomical Comparison of the "Word" and "Picture" Versions of the Free and Cued Selective Reminding Test in Alzheimer's Disease. %A Slachevsky, Andrea %A Barraza, Paulo %A Hornberger, Michael %A Muñoz-Neira, Carlos %A Flanagan, Emma %A Henriquez, Fernando %A Bravo, Eduardo %A Farías, Mauricio %A Delgado, Carolina %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Cues %K Female %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Memory, Episodic %K Mental Recall %K Middle Aged %K Neuropsychological Tests %K Photic Stimulation %X

Episodic memory tests with cued recall, such as the Free and Cued Selective Reminding Test (FCSRT), allow for the delineation of hippocampal and prefrontal atrophy contributions to memory performance in Alzheimer's disease (AD). Both Word and Picture versions of the test exist but show different profiles, with the Picture version usually scoring higher across different cohorts. One possible explanation for this divergent performance between the different modality versions of the test might be that they rely on different sets of neural correlates. The current study explores this by contrasting the neural correlates of the Word and Picture versions of the FCSRT with voxel-based morphometry (VBM) in AD and healthy subjects. We predicted that the Picture version would be associated with different cortical regions than the Word version, which might be more hippocampal-centric. When comparing 35 AD patients and 34 controls, AD patients exhibited impairments on both versions of the FCSRT and both groups performed higher in the Picture version. A region of interest analysis based on prior work revealed significant correlations between free recall of either version with atrophy of the temporal pole and hippocampal regions. Thus, contrary to expectations, performance on both the Word and the Picture version of the FCSRT is associated with largely overlapping networks. Free recall is associated with hippocampal volume and might be properly considered as an indicator of hippocampal structural integrity.

%B J Alzheimers Dis %V 61 %P 589-600 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226861?dopt=Abstract %R 10.3233/JAD-160973 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuroepigenetics and Alzheimer's Disease: An Update. %A Zusso, Morena %A Barbierato, Massimo %A Facci, Laura %A Skaper, Stephen D %A Giusti, Pietro %X

Epigenetics is the study of changes in gene expression which may be triggered by both genetic and environmental factors, and independent from changes to the underlying DNA sequence-a change in phenotype without a change in genotype-which in turn affects how cells read genes. Epigenetic changes represent a regular and natural occurrence but can be influenced also by factors such as age, environment, and disease state. Epigenetic modifications can manifest themselves not only as the manner in which cells terminally differentiate, but can have also deleterious effects, resulting in diseases such as cancer. At least three systems including DNA methylation, histone modification, and non-coding RNA (ncRNA)-associated gene silencing are thought to initiate and sustain epigenetic change. For example, in Alzheimer's disease (AD), both genetic and non-genetic factors contribute to disease etiopathology. While over 250 gene mutations have been related to familial AD, less than 5% of AD cases are explained by known disease genes. More than likely, non-genetic factors, probably triggered by environmental factors, are causative factors of late-onset AD. AD is associated with dysregulation of DNA methylation, histone modifications, and ncRNAs. Among the classes of ncRNA, microRNAs (miRNAs) have a well-established regulatory relevance. MicroRNAs are highly expressed in CNS neurons, where they play a major role in neuron differentiation, synaptogenesis, and plasticity. MicroRNAs impact higher cognitive functions, as their functional impairment is involved in the etiology of neurological diseases, including AD. Alterations in the miRNA network contribute to AD disease processes, e.g., in the regulation of amyloid peptides, tau, lipid metabolism, and neuroinflammation. MicroRNAs, both as biomarkers for AD and therapeutic targets, are in the early stages of exploration. In addition, emerging data suggest that altered transcription of long ncRNAs, endogenous, ncRNAs longer than 200 nucleotides, may be involved in an elevated risk for AD.

%B J Alzheimers Dis %V 64 %P 671-688 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29991138?dopt=Abstract %R 10.3233/JAD-180259 %0 Journal Article %J J Alzheimers Dis %D 2018 %T NeuroEPO Preserves Neurons from Glutamate-Induced Excitotoxicity. %A Garzón, Fernando %A Coimbra, Débora %A Parcerisas, Antoni %A Rodriguez, Yamila %A García, Julio Cesar %A Soriano, Eduardo %A Rama, Ramón %X

Many experimental studies show that erythropoietin (EPO) has a neuroprotective action in the brain. EPO in acute and chronic neurological disorders, particularly in stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, has neuroprotective effects. We previously reported the neuroprotective effect of NeuroEPO, a low sialic form of EPO, against oxidative stress induced by glutamate excitotoxicity. In this paper, we analyze the effect of NeuroEPO against apoptosis induced by glutamate excitotoxicity in primary neuronal cultures obtained from the forebrains of Wistar rat embryos after 17 days of gestation. Excitotoxicity was induced after nine days of in vitro culture by treatment with a culture medium containing 100μM glutamate for 15 min. To withdraw glutamate, a new medium containing 100 ng NeuroEPO/mL was added. Apoptosis was analyzed after 24 h. Images obtained by phase contrast microscopy show that neurons treated with glutamate exhibit cell body shrinkage, loss of dendrites that do not make contact with neighboring cells, and that NeuroEPO was able to preserve the morphological characteristics of the control. Immunocytochemistry images show that the culture is essentially pure in neurons; that glutamate causes cell mortality, and that this is partially avoided when the culture medium is supplemented with NeuroEPO. Activation of intrinsic apoptotic pathways was analyzed. The decreases in Bcl-2/Bax ratio, increase in the release of cytochrome c, and in the expression and activity of caspase-3 observed in cells treated with glutamate, were restored by NeuroEPO. The results from this study show that NeuroEPO protects cortical neurons from glutamate-induced apoptosis via upregulation of Bcl-2 and inhibit glutamate-induced activation of caspase-3.

%B J Alzheimers Dis %V 65 %P 1469-1483 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30175978?dopt=Abstract %R 10.3233/JAD-180668 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuro-Immuno-Gene- and Genome-Editing-Therapy for Alzheimer's Disease: Are We There Yet? %A Raikwar, Sudhanshu P %A Thangavel, Ramasamy %A Dubova, Iuliia %A Ahmed, Mohammad Ejaz %A Selvakumar, Pushpavathi Govindhasamy %A Kempuraj, Duraisamy %A Zaheer, Smita %A Iyer, Shankar %A Zaheer, Asgar %X

Alzheimer's disease (AD) is a highly complex neurodegenerative disorder and the current treatment strategies are largely ineffective thereby leading to irreversible and progressive cognitive decline in AD patients. AD continues to defy successful treatment despite significant advancements in the field of molecular medicine. Repeatedly, early promising preclinical and clinical results have catapulted into devastating setbacks leading to multi-billion dollar losses not only to the top pharmaceutical companies but also to the AD patients and their families. Thus, it is very timely to review the progress in the emerging fields of gene therapy and stem cell-based precision medicine. Here, we have made sincere efforts to feature the ongoing progress especially in the field of AD gene therapy and stem cell-based regenerative medicine. Further, we also provide highlights in elucidating the molecular mechanisms underlying AD pathogenesis and describe novel AD therapeutic targets and strategies for the new drug discovery. We hope that the quantum leap in the scientific advancements and improved funding will bolster novel concepts that will propel the momentum toward a trajectory leading to a robust AD patient-specific next generation precision medicine with improved cognitive function and excellent life quality.

%B J Alzheimers Dis %V 65 %P 321-344 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040732?dopt=Abstract %R 10.3233/JAD-180422 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuropathologic Correlates of Psychiatric Symptoms in Alzheimer's Disease. %A Ehrenberg, Alexander J %A Suemoto, Claudia K %A França Resende, Elisa de Paula %A Petersen, Cathrine %A Leite, Renata Elaine Paraizo %A Rodriguez, Roberta Diehl %A Ferretti-Rebustini, Renata Eloah de Lucena %A You, Michelle %A Oh, Jun %A Nitrini, Ricardo %A Pasqualucci, Carlos Augusto %A Jacob-Filho, Wilson %A Kramer, Joel H %A Gatchel, Jennifer R %A Grinberg, Lea T %X

Clarifying the relationships between neuropsychiatric symptoms and Alzheimer's disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of São Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes.

%B J Alzheimers Dis %V 66 %P 115-126 %8 2018 Oct 16 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30223398?dopt=Abstract %R 10.3233/JAD-180688 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuroprotective Effects of Amylin Analogues on Alzheimer's Disease Pathogenesis and Cognition. %A Grizzanti, John %A Corrigan, Rachel %A Casadesus, Gemma %X

Type II diabetes (T2D) has been identified as a major risk factor for the development of Alzheimer's disease (AD). Interestingly, both AD and T2D have similar characteristics including amyloid peptide aggregation, decreased metabolism, and increased oxidative stress and inflammation. Despite their prevalence, therapies for these diseases are limited. To date, most therapies for AD have targeted amyloid-β or tau. Unfortunately, most of these clinical trials have been largely unsuccessful, creating a crucial need for novel therapies. A number of studies have shown that metabolic hormone therapies are effective at ameliorating high blood glucose levels in diabetics as well as improving cognitive function in AD and mild cognitive impairment patients. Pramlintide, a synthetic analogue of the pancreatic hormone amylin, has been developed and used for years now as a treatment for both type I diabetes and T2D due to the loss of β-islet cells responsible for producing amylin. Importantly, recent data demonstrates its potential therapeutic role for AD as well. This review aims at addressing parallels between T2D and AD at a pathological and functional level, focusing on amylin signaling as a key, overlapping mediator in both diseases. The potential therapeutic use of this hormone to treat AD will also be explored from a mechanistic viewpoint.

%B J Alzheimers Dis %V 66 %P 11-23 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282360?dopt=Abstract %R 10.3233/JAD-180433 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuroprotective Effects of Ferruginol, Jatrophone, and Junicedric Acid Against Amyloid-β Injury in Hippocampal Neurons. %A Zolezzi, Juan M %A Lindsay, Carolina B %A Serrano, Felipe G %A Ureta, Roxana C %A Theoduloz, Cristina %A Schmeda-Hirschmann, Guillermo %A Inestrosa, Nibaldo C %X

Soluble amyloid-β (Aβ) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer's disease (AD). Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of Aβ oligomers is associated with imbalanced intracellular calcium levels and apoptosis in neurons. In this context, we evaluated the effects of three diterpenes (ferruginol, jatrophone, and junicedric acid) that are found in medicinal plants and have several forms of biological activity. The intracellular calcium levels in hippocampal neurons increased in the presence of ferruginol, jatrophone, and junicedric acid, a result that was consistent with the observed increase in CA1 synaptic transmission in mouse hippocampal slices. Additionally, assays using Aβ peptide demonstrated that diterpenes, particularly ferruginol, restore LTP and reduce apoptosis. Recovery of the Aβ oligomer-induced loss of the synaptic proteins PSD-95, synapsin, VGlut, and NMDA receptor subunit 2A was observed in mouse hippocampal slices treated with junicedric acid. This cascade of events may be associated with the regulation of kinases, e.g., protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), in addition to the activation of the canonical Wnt signaling pathway and could thus provide protection against Aβ oligomers, which trigger synaptic dysfunction. Our results suggest a potential neuroprotective role for diterpenes against the Aβ oligomers-induced neurodegenerative alterations, which make them interesting molecules to be further studied in the context of AD.

%B J Alzheimers Dis %V 63 %P 705-723 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660932?dopt=Abstract %R 10.3233/JAD-170701 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuroprotective Effects of Ginsenoside Rf on Amyloid-β-Induced Neurotoxicity in vitro and in vivo. %A Du, Yehong %A Fu, Min %A Wang, Yu Tian %A Dong, Zhifang %X

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the deposition of amyloid-β peptides (Aβ). Aβ accumulation leads to the formation of neurofibrillary tangles, inflammation, axonal injury, synapse loss, and neuronal apoptosis. Thus, reducing Aβ levels should exert a neuroprotective effect against AD. Ginsenoside Rf, an extract from Panax notoginseng, has potent anti-fatigue, anti-nociception, anti-oxidation, and anti-inflammation properties. However, it is unclear whether ginsenoside Rf is effective in the treatment of AD. Here, we reported that ginsenoside Rf could significantly attenuate Aβ-induced apoptosis in N2A cells, as reflected by a dramatic increase in mitochondrial membrane potential and decrease in Ca2 + concentration, reactive oxygen species, and active caspase-3 expression. Meanwhile, ginsenoside Rf could alleviate the Aβ-induced inflammation reaction, such as the decrease of interferon-gamma (IFN-γ) and active caspase-1 expression and the increase of interleukin-13. Furthermore, we also found that Rf is able to accelerate Aβ clearance and subsequently reduces Aβ level in N2A cells stably transfected with human Swedish mutant APP695 (N2A-APP). More importantly, daily Rf treatment (20 mg/kg, i.p.) throughout the experiment dramatically improved spatial learning and memory in Aβ42-induced mouse model of AD. Taken together, these results indicate that ginsenoside Rf may decrease Aβ-induced neurotoxicity and memory decline via anti-inflammatory response during AD development, suggesting that Rf may be a potential therapeutic agent for treating AD.

%B J Alzheimers Dis %V 64 %P 309-322 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865080?dopt=Abstract %R 10.3233/JAD-180251 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuropsychiatric and Cognitive Subtypes among Community-Dwelling Older Persons and the Association with DSM-5 Mild Neurocognitive Disorder: Latent Class Analysis. %A Liew, Tau Ming %A Yu, Junhong %A Mahendran, Rathi %A Ng, Tze-Pin %A Kua, Ee-Heok %A Feng, Lei %K Aged %K Cognition %K Cognitive Dysfunction %K Diagnostic and Statistical Manual of Mental Disorders %K Female %K Humans %K Latent Class Analysis %K Logistic Models %K Longitudinal Studies %K Male %K Middle Aged %K Neuropsychological Tests %K Sensitivity and Specificity %X

BACKGROUND: Neuropsychiatric symptoms (NPS) have been shown to increase the risk of neurocognitive disorders (NCD), leading to the recently-published criteria of mild behavioral impairment (MBI) to identify pre-dementia using NPS alone. However, MBI drew concerns about over-diagnosing subclinical psychiatric disorders.

OBJECTIVE: We hypothesized that the specificity of NPS in predicting NCD may be improved by considering NPS together with various domains of cognitive deficits. We tested this hypothesis by identifying subtypes based on the combination of NPS and cognitive deficits among community-dwelling older persons, and evaluating how the identified subtypes were associated with mild NCD.

METHODS: Our participants were from a community-based cohort study. They completed assessments such as Geriatric Depression Scale (GDS), Geriatric Anxiety Inventory (GAI), and Montreal Cognitive Assessment (MoCA). Those with possible cognitive impairment underwent further evaluations for mild NCD. Latent class analysis was conducted using GDS, GAI, and MoCA domains. Logistic regression was performed to investigate the association between the latent-classes and mild NCD.

RESULTS: We included 825 participants, and identified four distinct subtypes: Subtype 1 (no NPS or cognitive deficits), Subtype 2 (NPS alone), Subtype 3 (cognitive deficits alone), and Subtype 4 (both NPS and cognitive deficits). Subtype 1 and 2 had low risk of prevalent mild NCD (OR 0.92- 1.00), while Subtype 3 conferred a moderate risk (OR 4.47- 4.85) and Subtype 4 had the highest risk (OR 7.95- 8.63).

CONCLUSION: We demonstrated the benefits of combining NPS and cognitive deficits to predict those at highest risk of prevalent mild NCD. Our findings highlighted the relevance of subclinical psychiatric symptoms in predicting NCD, and indirectly supported the need for longer durations of NPS to improve its specificity.

%B J Alzheimers Dis %V 62 %P 675-686 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480192?dopt=Abstract %R 10.3233/JAD-170947 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuropsychiatric Symptoms and the Diagnostic Stability of Mild Cognitive Impairment. %A Sugarman, Michael A %A Alosco, Michael L %A Tripodis, Yorghos %A Steinberg, Eric G %A Stern, Robert A %X

BACKGROUND: Mild cognitive impairment (MCI) is an intermediate diagnosis between normal cognition (NC) and dementia, including Alzheimer's disease (AD) dementia. However, MCI is heterogeneous; many individuals subsequently revert to NC while others remain stable at MCI for several years. Identifying factors associated with this diagnostic instability could assist in defining clinical populations and determining cognitive prognoses.

OBJECTIVE: The current study examined whether neuropsychiatric symptoms could partially account for the temporal instability in cognitive diagnoses.

METHOD: The sample included 6,763 participants from the National Alzheimer's Coordinating Center Uniform Data Set. All participants had NC at baseline, completed at least two follow-up visits (mean duration: 5.5 years), and had no recent neurological conditions. Generalized linear models estimated by generalized estimating equations examined associations between changes in cognitive diagnoses and symptoms on the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS-15).

RESULTS: 1,121 participants converted from NC to MCI; 324 reverted back to NC and 242 progressed to AD dementia. Higher symptoms on the GDS-15 and circumscribed symptom domains on the NPI-Q were associated with conversion from NC to MCI and a decreased likelihood of reversion from MCI to NC. Individuals with higher symptoms on NPI-Q Hyperactivity and Mood items were more likely to progress to AD dementia.

DISCUSSION: The temporal instability of MCI can be partially explained by neuropsychiatric symptoms. Individuals with higher levels of specific symptoms are more likely to progress to AD dementia and less likely to revert to NC. Identification and treatment of these symptoms might support cognitive functioning in older adults.

%B J Alzheimers Dis %V 62 %P 1841-1855 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614641?dopt=Abstract %R 10.3233/JAD-170527 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuropsychiatric Symptoms Complicating the Diagnosis of Alzheimer's Disease: A Case Report. %A Eikelboom, Willem S %A van Rooij, Jeroen G J %A van den Berg, Esther %A Coesmans, Michiel %A Jiskoot, Lize C %A Singleton, Ellen %A Ossenkoppele, Rik %A van Swieten, John C %A Seelaar, Harro %A Papma, Janne M %X

Neuropsychiatric symptoms (NPS) are increasingly recognized as a core element of Alzheimer's disease (AD); however, clinicians still consider AD primarily as a cognitive disorder. We describe a case in which the underrecognition of NPS as part of AD resulted in substantial delay of an AD diagnosis, a wrong psychiatric diagnosis, and the organization of inappropriate care. The aim of this paper is to acknowledge NPS as an (early) manifestation of AD and to suggest features that may point toward underlying AD in older adults with late-life behavioral changes.

%B J Alzheimers Dis %V 66 %P 1363-1369 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412494?dopt=Abstract %R 10.3233/JAD-180700 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuropsychological Predictors of Long-Term (10 Years) Mild Cognitive Impairment Stability. %A Alves, Luísa %A Cardoso, Sandra %A Maroco, João %A de Mendonça, Alexandre %A Guerreiro, Manuela %A Silva, Dina %X

BACKGROUND: Although the diagnosis of mild cognitive impairment (MCI) corresponds to a condition likely to progress to dementia, essentially Alzheimer's disease, longitudinal studies have shown that some patients may not convert to dementia and maintain the diagnosis of MCI even after many years.

OBJECTIVES: To determine whether patients that maintain the diagnosis of MCI in the long term (10 years) are really stable or just declining slowly, and to identify clinical and neuropsychological characteristics associated with long-term stability.

METHODS: The Cognitive Complaints Cohort (CCC) was searched for MCI cases who maintained that diagnosis for at least 10 years. For each long-term-stable MCI patient, two MCI patients that converted to dementia during follow-up, matched for age and education, were selected from the same database. The baseline and last neuropsychological evaluations for long-term-stable MCI and converter MCI were compared. Baseline neuropsychological predictors of long-term stability were searched for.

RESULTS: Long-term-stable MCI (n = 22) and converter MCI (n = 44) patients did not differ in terms of gender distribution, education, age at first assessment and time between symptom onset and first evaluation. Time of follow-up was on average 11 years for long-term-stable MCI and 3 years for converter MCI. The baseline and follow-up neuropsychological tests were not significantly different in long-term-stable MCI patients, whereas a general decline was observed in converter MCI patients. Higher scores on one memory test, the Word Delayed Total Recall, and on the non-verbal abstraction test, Raven's Progressive Matrices, at the baseline predicted long-term (10 years) clinical stability.

CONCLUSIONS: Some patients with MCI remain clinically and neuropsychologically stable for a decade. Better performances at baseline in memory and non-verbal abstraction tests predict long-term stability.

%B J Alzheimers Dis %V 62 %P 1703-1711 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614683?dopt=Abstract %R 10.3233/JAD-171034 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neurotoxic Effects of Aβ6-42 Peptides Mimicking Putative Products Formed by the Angiotensin Converting Enzyme. %A Medvedev, Alexei E %A Radko, Sergey P %A Yurinskaya, Marina M %A Vinokurov, Maxim G %A Buneeva, Olga A %A Kopylov, Arthur T %A Kozin, Sergey A %A Mitkevich, Vladimir A %A Makarov, Alexander A %X

Angiotensin converting enzyme (ACE) is involved in proteolytic processing of the amyloid-β(Aβ) peptide implicated in the development of Alzheimer's disease (AD) and known products of ACE-based processing of Aβ42 are characterized by reduced aggregability and cytotoxicity. Recently it has been demonstrated that ACE can act as an arginine specific endopeptidase cleaving the N-terminal pentapeptide (Aβ1-5) from synthetic Aβ peptide analogues. In the context of proteolytic processing of full length Aβ42, this suggests possible formation of Aβ6-42 species. The aim of this study was to test a hypothesis that some N-terminally truncated Aβ peptide(s) could retain aggregability and neurotoxic properties typical for Aβ42. We have investigated aggregability of two amyloid-β peptides, Aβ6-42 and isoD7-Aβ6-42, mimicking potential proteolytic products of Aβ42 and isoD7-Aβ42, and evaluated their effects on the repertoire of brain Aβ binding proteins, and cytotoxicity towards neuroblastoma SH-SY5Y cells. Aggregability of isoD7-Aβ6-42 and Aβ6-42 was higher than that of full-length peptides Aβ42 and isoD7-Aβ42, while the repertoire of mouse brain Aβ binding proteins dramatically decreased. Aβ6-42 and isoD7-Aβ6-42 exhibited higher neurotoxicity towards SH-SY5Y cells than Aβ42 and isoD7-Aβ42, respectively. They effectively stimulated production of ROS and NO, and also TNFα secretion by cells. Thus, our results suggest that ACE-dependent processing of full-length Aβs could result in formation of more pathogenic peptides.

%B J Alzheimers Dis %V 66 %P 263-270 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282362?dopt=Abstract %R 10.3233/JAD-180500 %0 Journal Article %J J Alzheimers Dis %D 2018 %T New Beginnings in Alzheimer's Disease: The Most Prevalent Tauopathy. %A Hernández, Félix %A Llorens-Martín, María %A Bolós, Marta %A Pérez, Mar %A Cuadros, Raquel %A Pallas-Bazarra, Noemí %A Zabala, Juan C %A Avila, Jesús %X

Alzheimer's disease (AD) is characterized by the presence of two aberrant structures: namely senile plaques, composed of amyloid-β peptide (Aβ), and neurofibrillary tangles, composed of tau protein. In this regard, Aβ and tau protein have been widely studied in research efforts aiming to find a therapy for AD. Aβ and tau pathologies do not always overlap. The precursor of Aβ is expressed in peripheral tissues and in the central nervous system (CNS), whereas tau is mainly a neuronal protein. Since AD is a disease of the CNS, it has been proposed that Aβ may initiate the disease process, with tau being the executor. In this review, we will focus on future studies of tau pathology, although we will comment on new beginnings for AD, as other molecules other than Aβ and tau may be involved in the onset of dementia.

%B J Alzheimers Dis %V 64 %P S529-S534 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562521?dopt=Abstract %R 10.3233/JAD-179916 %0 Journal Article %J J Alzheimers Dis %D 2018 %T New Insights into the Spontaneous Human Alzheimer's Disease-Like Model Octodon degus: Unraveling Amyloid-β Peptide Aggregation and Age-Related Amyloid Pathology. %A Cisternas, Pedro %A Zolezzi, Juan M %A Lindsay, Carolina %A Rivera, Daniela S %A Martinez, Alexis %A Bozinovic, Francisco %A Inestrosa, Nibaldo C %X

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Despite advances in our understanding of the molecular milieu driving AD pathophysiology, no effective therapy is currently available. Moreover, various clinical trials have continued to fail, suggesting that our approach to AD must be revised. Accordingly, the development and validation of new models are highly desirable. Over the last decade, we have been working with Octodon degus (degu), a Chilean rodent, which spontaneously develops AD-like neuropathology, including increased amyloid-β (Aβ) aggregates, tau hyperphosphorylation, and postsynaptic dysfunction. However, for proper validation of degu as an AD model, the aggregation properties of its Aβ peptide must be analyzed. Thus, in this study, we examined the capacity of the degu Aβ peptide to aggregate in vitro. Then, we analyzed the age-dependent variation in soluble Aβ levels in the hippocampus and cortex of third- to fifth-generation captive-born degu. We also assessed the appearance and spatial distribution of amyloid plaques in O. degus and compared them with the plaques in two AD transgenic mouse models. In agreement with our previous studies, degu Aβ was able to aggregate, forming fibrillar species in vitro. Furthermore, amyloid plaques appeared in the anterior brain structures of O. degus at approximately 32 months of age and in the whole brain at 56 months, along with concomitant increases in Aβ levels and the Aβ42/Aβ40 ratio, indicating that O. degus spontaneously develops AD-like pathology earlier than other spontaneous models. Based on these results, we can confirm that O. degus constitutes a valuable model to improve AD research.

%B J Alzheimers Dis %V 66 %P 1145-1163 %8 2018 %G eng %N 3 %R 10.3233/JAD-180729 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A New Perspective in Utilizing MMP-9 as a Therapeutic Target for Alzheimer's Disease and Type 2 Diabetes Mellitus. %A Kaminari, Archontia %A Tsilibary, Effie C %A Tzinia, Athina %X

Matrix metalloprotease 9 (MMP-9) is a 92 kDa type IV collagenase and a member of the family of endopeptidases. MMP-9 is involved in the degradation of extracellular matrix components, tissue remodeling, cellular receptor stripping, and processing of various signaling molecules. In the CNS, the effects of MMP-9 are quite complex, since it exerts beneficial effects including neurogenesis, angiogenesis, myelogenesis, axonal growth, and inhibition of apoptosis, or destructive effects including apoptosis, blood-brain barrier disorder, and demyelination. Likewise, in the periphery, physiological events, as the involvement of MMP-9 in angiogenesis, for instance in wound healing, can be turned into pathological, such as in tumor metastasis, depending on the state of the organism. Alzheimer's disease is a neurodegenerative disorder, characterized by amyloid accumulation and deposition in the brain. Amyloidogenesis, however, also occurs in diseases of the periphery, such as type II diabetes mellitus, where an analogous type of amyloid, is deposited in the pancreas. Interestingly, both diseases exhibit similar pathology and disease progression, with insulin resistance being a major common denominator. Hence, combinatorial strategies searching new or existing molecules to apply for therapeutic use for both diseases are gaining momentum. MMP-9 is extensively studied due to its association with a variety of physiological and pathological processes. Consequently, meticulous design could render MMP-9 into a potential therapeutic target for Alzheimer's disease and type 2 diabetes mellitus; two seemingly unrelated diseases.

%B J Alzheimers Dis %V 64 %P 1-16 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865065?dopt=Abstract %R 10.3233/JAD-180035 %0 Journal Article %J J Alzheimers Dis %D 2018 %T No Effects of Black Tea on Cognitive Decline Among Older US Men: A Prospective Cohort Study. %A Feng, Lei %A Langsetmo, Lisa %A Yaffe, Kristine %A Sun, Ye %A Fink, Howard A %A Shikany, James M %A Leung, P C %A Lane, Nancy E %A Cauley, Jane A %X

BACKGROUND: Accumulating evidence supports the neuroprotective effects of bioactive compounds from tea leaves. There are limited data from black tea consumption populations.

OBJECTIVE: To determine whether black tea consumption is associated with cognitive decline among older men.

METHODS: We chose to study the association between black tea consumption and cognition using data from the Osteoporotic Fractures in Men (MrOS) cohort, which collected information on tea consumption at baseline and has repeatedly assessed cognitive function in 3,844 men aged 65+ years (mean = 72.4 years). We defined tea drinkers as those who drank black tea at least once per week and further grouped them into weekly drinkers and daily drinkers. Cognitive function was assessed at baseline and approximately 7 years later using the Modified Mini-Mental State Examination (3MSE). Multivariable logistic regression and linear regression models were constructed to assess the association between black tea consumption and risk of fast cognitive decline as a binary variable and change in 3MSE scores as continuous variable. Fast cognitive decline was defined as decline in 3MSE >1.5 standard deviation of mean change score. Models were adjusted for age, education level, and baseline cognitive scores.

RESULTS: Weekly and daily black tea drinkers were 24.8% and 12.4% of the study cohort, respectively. Fast cognitive decline occurred in 243 (6.3%) participants. Tea consumption was not associated with risk of cognitive decline, nor was tea associated with cognitive decline measured by absolute change in 3MSE scores.

CONCLUSIONS: There was no association of black tea consumption and cognitive decline among older men in the US.

%B J Alzheimers Dis %V 65 %P 99-105 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040715?dopt=Abstract %R 10.3233/JAD-180103 %0 Journal Article %J J Alzheimers Dis %D 2018 %T NO-Dependent Akt Inactivation by S-Nitrosylation as a Possible Mechanism of STZ-Induced Neuronal Insulin Resistance. %A Crunfli, Fernanda %A Mazucanti, Caio Henrique %A de Moraes, Ruan Carlos Macêdo %A Costa, Andressa Pereira %A Rodrigues, Alice Cristina %A Scavone, Cristoforo %A Torrão, Andréa da Silva %X

Sporadic Alzheimer's disease (sAD) is associated with energy metabolism deficiency and impairment of insulin receptor (IR) signaling in the brain. In this context, low doses of intracerebroventricular (icv) injection of streptozotocin (STZ) in rodents has been used as an experimental model of sAD which leads to an insulin-resistant brain state and neurodegeneration. However, the STZ effects on brain insulin signaling-related proteins it is not appropriately elucidated. The aim of this study was to evaluate the beginning and progression of alterations in the brain IR pathway of rats after 1, 3, 5, and 7 days of STZ injection and investigate intracellular signaling involved on STZ induced insulin resistance. We observed that STZ injection causes cognitive impairment in the animals, a temporal variation of the insulin signaling-related proteins and apoptosis cell death in the hippocampus. We also have shown that STZ causes insulin resistance and impairment on phosphoinositide 3-kinase (PI3K) activity in the Neuro-2a cells through protein kinase B (Akt) inactivation by S-nitrosylation, which could upregulate GSK3-β activity. STZ ability to cause an insulin-resistant neuron state involves NO production and ROS production which may play an important role in the mechanism linked to STZ-induced neurotoxicity. The icv injection of STZ model and STZ exposed Neuro-2a cells may be potential experimental models for assessing molecules related to the pathogenesis of sAD.

%B J Alzheimers Dis %V 65 %P 1427-1443 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149447?dopt=Abstract %R 10.3233/JAD-180284 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Nomogram for Predicting Amyloid PET Positivity in Amnestic Mild Cognitive Impairment. %A Kim, Si Eun %A Woo, Sookyoung %A Kim, Seon Woo %A Chin, Juhee %A Kim, Hee Jin %A Lee, Byung In %A Park, Jinse %A Park, Kyung Won %A Kang, Do-Young %A Noh, Young %A Ye, Byoung Seok %A Yoo, Han Soo %A Lee, Jin San %A Kim, Yeshin %A Kim, Seung Joo %A Cho, Soo Hyun %A Na, Duk L %A Lockhart, Samuel N %A Jang, Hyemin %A Seo, Sang Won %X

BACKGROUND: Most clinical trials focus on amyloid-β positive (Aβ+) amnestic mild cognitive impairment (aMCI), but screening failures are high because only a half of patients with aMCI are positive on Aβ PET. Therefore, it becomes necessary for clinicians to predict which patients will have Aβ biomarker.

OBJECTIVE: We aimed to compare clinical factors, neuropsychological (NP) profiles, and apolipoprotein E (APOE) genotype between Aβ+ aMCI and Aβ-aMCI and to develop a clinically useful prediction model of Aβ positivity on PET (PET-Aβ+) in aMCI using a nomogram.

METHODS: We recruited 523 aMCI patients who underwent Aβ PET imaging in a nation-wide multicenter cohort. The results of NP measures were divided into following subgroups: 1) Stage (Early and Late-stage), 2) Modality (Visual, Verbal, and Both), 3) Recognition failure, and 4) Multiplicity (Single and Multiple). A nomogram for PET-Aβ+ in aMCI patients was constructed using a logistic regression model.

RESULTS: PET-Aβ+ had significant associations with NP profiles for several items, including high Clinical Dementia Rating Scale Sum of Boxes score (OR 1.47, p = 0.013) and impaired memory modality (impaired both visual and verbal memories compared with visual only, OR 3.25, p = 0.001). Also, presence of APOEɛ4 (OR 4.14, p < 0.001) was associated with PET-Aβ+. These predictors were applied to develop the nomogram, which showed good prediction performance (C-statistics = 0.79). Its prediction performances were 0.77/0.74 in internal/external validation.

CONCLUSIONS: The nomogram consisting of NP profiles, especially memory domain, and APOEɛ4 genotype may provide a useful predictive model of PET-Aβ+ in patients with aMCI.

%B J Alzheimers Dis %V 66 %P 681-691 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320571?dopt=Abstract %R 10.3233/JAD-180048 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Non-Ashkenazi Jewish Origin is Associated with Early Onset Alzheimer's Disease. %A Keret, Ophir %A Shochat, Tzippy %A Steiner, Israel %A Glik, Amir %X

Early-onset Alzheimer's disease (EOAD) accounts for 1-5% of Alzheimer's disease cases and is associated with specific ethnicities. It has been our impression that non-Ashkenazi Jews have a higher rate of EOAD and we therefore explored this hypothesis. We performed a retrospective case control study of EOAD cases referred to our cognitive neurology clinic between January 1999 and December 2016. Patients (n = 129) were compared to age- and geographically-matched controls generated from the Second Israeli National Health Survey (n = 1,811). Data on country of origin, education, dementia family history, depression, and vascular risk factors were compared between the groups. The association of non-Ashkenazi Jewish heritage and country of origin with EOAD was calculated using a logistic multivariate regression model. The EOAD group's mean age was 59.6±4.1 years, with a female predominance (64.3%). The EOAD group had a higher percentage of individuals of non-Ashkenazi Jewish origin (64.3% versus 51.4%, p = 0.003) and of Yemenite descent in particular (16.28% versus 6.24%, p < 0.001). On multiple logistic regression analysis, Yemenite Jewish origin was an independently associated with EOAD (OR 2.54, 95% CI 1.4-4.8). There were no significant differences in parameters between non-Ashkenazi and Ashkenazi Jews. Only 4.6% of EOAD cases had a positive EOAD family history. In conclusion, EOAD is over-represented among non-Ashkenazi Jews. Yemenite origin is independently associated with EOAD and the majority of patients with EOAD have no family history of Alzheimer's disease. Further evaluation with genetic studies is warranted.

%B J Alzheimers Dis %V 65 %P 877-884 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103328?dopt=Abstract %R 10.3233/JAD-180331 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Non-Genetic Risk Factors for Degenerative and Vascular Young Onset Dementia: Results from the INSPIRED and KGOW Studies. %A Cations, Monica %A Draper, Brian %A Low, Lee-Fay %A Radford, Kylie %A Trollor, Julian %A Brodaty, Henry %A Sachdev, Perminder %A Gonski, Peter %A Broe, Gerald Anthony %A Withall, Adrienne %X

BACKGROUND: Several brain reserve, vascular risk, and other modifiable factors have been associated with late-onset dementia, but their association with young onset dementia (YOD) has not been adequately explored.

OBJECTIVE: To examine the association of cognitive reserve enhancing factors, cardiovascular risk factors (including smoking), depression, alcohol use, and traumatic brain injury (TBI) with non-autosomal dominant degenerative and/or vascular YOD.

METHODS: Data for this matched case-control study were taken from two larger studies conducted in NSW, Australia. One comprised all people with YOD within a geographical region, while the other exclusively included Aboriginal and Torres Strait Islander participants. Dementia diagnosis was confirmed by clinical consensus, and risk exposure was retrospectively self- and/or informant-reported.

RESULTS: Participants were 96 people with YOD (58.4% with probable Alzheimer's disease) and 175 age-group, sex, and sample matched control participants. Poor educational attainment, low participation in cognitive leisure activity, stroke, transient ischemic attack, and self-reported very heavy alcohol use were related to the risk of primary degenerative and/or vascular YOD. The effect of hypertension and depression varied depending on when they occurred relative to dementia onset. Current smoking was significantly associated with risk in univariate analyses but did not retain significance in multivariate modelling. There was no association with hypercholesterolemia, diabetes, or TBI of any kind. Some compensation for low educational attainment was possible via a complex occupation later in life.

CONCLUSION: Non-genetic factors have a role in YOD, though the relative importance of each factor may be different to late onset dementia. The timing and severity of exposure, as well as the potential for compensation with later protective exposures, are important considerations for potential prevention strategies.

%B J Alzheimers Dis %V 62 %P 1747-1758 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614682?dopt=Abstract %R 10.3233/JAD-171027 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Non-Phosphorylated Tau in Cerebrospinal Fluid is a Marker of Alzheimer's Disease Continuum in Young Urbanites Exposed to Air Pollution. %A Calderón-Garcidueñas, Lilian %A Mukherjee, Partha S %A Waniek, Katharina %A Holzer, Max %A Chao, Chih-Kai %A Thompson, Charles %A Ruiz-Ramos, Rubén %A Calderón-Garcidueñas, Ana %A Franco-Lira, Maricela %A Reynoso-Robles, Rafael %A González-Maciel, Angelica %A Lachmann, Ingolf %X

Long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards is associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) children exhibit subcortical pretangles in infancy and cortical tau pre-tangles, NFTs, and amyloid phases 1-2 by the 2nd decade. Given their AD continuum, we measured in 507 normal cerebrospinal fluid (CSF) samples (MMC 354, controls 153, 12.82±6.73 y), a high affinity monoclonal non-phosphorylated tau antibody (non-P-Tau), as a potential biomarker of AD and axonal damage. In 81 samples, we also measured total tau (T-Tau), tau phosphorylated at threonine 181 (P-Tau), amyloid-β1-42, BDNF, and vitamin D. We documented by electron microscopy myelinated axonal size and the pathology associated with combustion-derived nanoparticles (CDNPs) in anterior cingulate cortex white matter in 6 young residents (16.25±3.34 y). Non-P-Tau showed a strong increase with age significantly faster among MMC versus controls (p = 0.0055). Aβ1 - 42 and BDNF concentrations were lower in MMC children (p = 0.002 and 0.03, respectively). Anterior cingulate cortex showed a significant decrease (p = <0.0001) in the average axonal size and CDNPs were associated with organelle pathology. Significant age increases in non-P-Tau support tau changes early in a population with axonal pathology and evolving AD hallmarks in the first two decades of life. Non-P-Tau is an early biomarker of axonal damage and potentially valuable to monitor progressive longitudinal changes along with AD multianalyte classical CSF markers. Neuroprotection of young urbanites with PM2.5 and CDNPs exposures ought to be a public health priority to halt the development of AD in the first two decades of life.

%B J Alzheimers Dis %V 66 %P 1437-1451 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412505?dopt=Abstract %R 10.3233/JAD-180853 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Novel Antibody Targeting Tau Phosphorylated at Serine 235 Detects Neurofibrillary Tangles. %A Brici, David %A Götz, Jürgen %A Nisbet, Rebecca M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Animals %K Antibodies, Monoclonal %K Antibody Specificity %K Brain %K Disease Models, Animal %K Humans %K Mice %K Neurofibrillary Tangles %K Phosphorylation %K Plaque, Amyloid %K tau Proteins %X

Alzheimer's disease is characterized by two main pathological hallmarks in the human brain: the extracellular deposition of amyloid-β as plaques and the intracellular accumulation of the hyperphosphorylated protein tau as neurofibrillary tangles (NFTs). Phosphorylated tau (p-tau) specific-antibodies and silver staining have been used to reveal three morphological stages of NFT formation: pre-NFTs, intraneuronal NFTs (iNFTs), and extraneuronal NFTs (eNFTs). Here we characterize a novel monoclonal antibody, RN235, which is specific for tau phosphorylated at serine 235, and detects iNFTs and eNFTs in brain tissue, suggesting that phosphorylation at this site is indicative of late stage changes in tau.

%B J Alzheimers Dis %V 61 %P 899-905 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332046?dopt=Abstract %R 10.3233/JAD-170610 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Novel DA-CH3 Dual Incretin Restores Endoplasmic Reticulum Stress and Autophagy Impairments to Attenuate Alzheimer-Like Pathology and Cognitive Decrements in the APPSWE/PS1ΔE9 Mouse Model. %A Panagaki, Theodora %A Gengler, Simon %A Holscher, Christian %X

Alzheimer's disease (AD) afflicts more than 46.8 million people worldwide, with a newly diagnosed case every 3 seconds and no remission in the disease progression. The discovery of disease-modifying drugs is now on the summit of the neuropharmacological research priorities. The long-lasting derivatives of the insulinotropic incretin hormones-glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-have repeatedly been shown to cross the blood-brain barrier and counteract an array of deleterious effects across a range of experimental models of neuronal degeneration. Clinical trials for the efficacy of GLP-1 agonists in Alzheimer's and Parkinson's diseases have revealed beneficial effects of these anti-diabetic agents in halting neuronal degeneration progression. Herein, we examine whether the chronic treatment with the novel dual GLP-1/GIP receptor agonist DA-CH3 can restore the cognitive decline and AD-like cerebral pathology of the APPSWE/PS1ΔE9 mouse model at the age of 10 months old. We report that once-a-daily, eight-week intraperitoneal administration of 25 nmol/kg of the novel DA-CH3 dual-incretin analog rescues the spatial acquisition and memory impairments of this murine model that corresponds to the attenuation of the excessive plaque deposition, gliosis and synaptic damage in the APPSWE/PS1ΔE9 brain. The amelioration of the AD-related pathology reflects the resolution of the endoplasmic-reticulum stress and derailed autophagy that both lay downstream of the rectified Akt signaling. Collectively, our findings endorse the beneficial effects of the incretin-based therapeutic approaches for the neurotrophic support of the AD brain and for the first time associate the incretin-induced neuroprotection with the proteostasis machinery in vivo.

%B J Alzheimers Dis %V 66 %P 195-218 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282365?dopt=Abstract %R 10.3233/JAD-180584 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Novel GRN Mutations in Alzheimer's Disease and Frontotemporal Lobar Degeneration. %A Piaceri, Irene %A Imperiale, Daniele %A Ghidoni, Enrico %A Atzori, Cristiana %A Bagnoli, Silvia %A Ferrari, Camilla %A Ungari, Silvana %A Ambrogio, Luca %A Sorbi, Sandro %A Nacmias, Benedetta %X

BACKGROUND: During the twentieth century, frontotemporal dementia (FTD) was often misdiagnosed, confused with Alzheimer's disease or psychiatric disorders, jeopardizing care and research.

OBJECTIVE: To analyze the FTD genes in the DNA samples of patients belonging to families clinically classified as probable Alzheimer's disease (FAD) in the early 1990s and not carrying mutation in the three main genes linked to FAD (Presenilin 1, Presenilin 2, and Amyloid precursor protein).

METHODS: The genetic screening was performed on 63 probands diagnosed as FAD before the early 2000s.

RESULTS: Four patients out of the 63 studied (4/63, 6.3%) resulted as carrying four different GRN genetic variations: p.T272SfsX10, p.R110X, p.C149LfsX10, and p.W304C. The first two mutations (p.T272SfsX10, p.R110X) are the most frequent ones in Italy in FTD patients; the latter two (p.C149LfsX10 and p.W304C) are not described in the scientific literature.

CONCLUSION: Our data suggest that it can be important to re-examine FAD patients diagnosed when the FTD spectrum was not well recognized and the causative FTD genes had not yet been identified. Moreover, we propose initially analyzing genes associated with the first form of suspected dementia and, if the results are negative, studying genes implicated in the other form of dementia.

%B J Alzheimers Dis %V 62 %P 1683-1689 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614680?dopt=Abstract %R 10.3233/JAD-170989 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Novel Key Players in the Development of Tau Neuropathology: Focus on the 5-Lipoxygenase. %A Lauretti, Elisabetta %A Praticò, Domenico %X

Tauopathies belong to a large group of neurodegenerative diseases characterized by progressive accumulation of hyperphosphorylated tau. Tau is a microtubule binding protein which is necessary for their assembly and stability. However, tau affinity for microtubules mainly depends on its phosphorylation status, which is the result of a delicate balance between kinases and phosphatases activity. Any significant changes in this equilibrium can promote tau fibrillation, aggregation, neuronal dysfunction, and ultimately neuronal loss. Despite intensive research, the molecular mechanism(s) leading to tau hyperphosphorylation are still unknown and there is no cure for these diseases. Development of an effective strategy that successfully prevents tau excessive phosphorylation and/or tau aggregation may offer a real therapeutic opportunity for these less investigated neurodegenerative conditions. Beside tau, chronic brain inflammation is a common feature of all tauopathies and 5-lipoxygenase, an inflammatory enzyme, is upregulated in brain regions affected by tau pathology. Recently, in vitro studies and preclinical investigations with animal models of tauopathy have implicated 5-lipoxygenase in the regulation of tau phosphorylation through activation of the cyclin-dependent kinase 5 pathway, supporting the novel hypothesis that this protein is a promising therapeutic target for the treatment of tauopathies. In this article, we will discuss the contribution of the 5-lipoxygenase signaling pathway in the development of tau neuropathology, and the promising potential that drugs targeting this enzyme activation hold as a novel disease-modifying therapeutic approach for tauopathies.

%B J Alzheimers Dis %V 64 %P S481-S489 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758943?dopt=Abstract %R 10.3233/JAD-179931 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Novel Lipidized Analog of Prolactin-Releasing Peptide Improves Memory Impairment and Attenuates Hyperphosphorylation of Tau Protein in a Mouse Model of Tauopathy. %A Popelová, Andrea %A Pražienková, Veronika %A Neprašová, Barbora %A Kasperová, Barbora Judita %A Hrubá, Lucie %A Holubová, Martina %A Zemenová, Jana %A Blum, David %A Železná, Blanka %A Galas, Marie-Christine %A Kuneš, Jaroslav %A Maletínská, Lenka %X

Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer's disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11-PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11-PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11-PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11-PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3β, JNK, or MAPK/ERK1/2, remained unchanged by palm11-PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11-PrRP31. Palm11-PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated.

%B J Alzheimers Dis %V 62 %P 1725-1736 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614684?dopt=Abstract %R 10.3233/JAD-171041 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Novel Therapeutic Approach to Treat Alzheimer's Disease by Neurotrophic Support During the Period of Synaptic Compensation. %A Baazaoui, Narjes %A Iqbal, Khalid %X

Alzheimer's disease (AD), at present, is considered an incurable disease and a major dilemma with no drug to stop or slow down its progression. Drugs that are currently available in the market are able to only transiently improve the clinical symptoms. The repeated failures in developing an effective drug has led to the suggestion that the medical intervention was probably too late to be effective since the pathology starts many years before the appearance of the clinical symptoms. Probably, at the time of the appearance of clinical symptoms the brain has undergone major neuronal and synaptic loss. Because of the uncertainty on when to use a prevention therapy, especially targeting amyloid-β (Aβ) and tau pathologies, interventions that rely on the regenerative capacity of the brain such as the modulation of the inherent neurogenesis and neuronal plasticity represent a promising therapeutic strategy. Such an approach can act both at early as well as late stages of the disease and remove the barrier of the time of intervention. In this article, we review studies mainly from our laboratory that show the merit of early intervention during the synaptic and neuronal compensation period where the brain still has the capacity to self-repair by offering neurotrophic support in reversing cognitive impairment, neuronal and synaptic deficits, Aβ, and tau pathologies and decreasing mortality in a transgenic mouse model of AD.

%B J Alzheimers Dis %V 62 %P 1211-1218 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562539?dopt=Abstract %R 10.3233/JAD-170839 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Nutrition: Review on the Possible Treatment for Alzheimer's Disease. %A Botchway, Benson O A %A Moore, Masania K %A Akinleye, Faith O %A Iyer, Ishwari C %A Fang, Marong %K Alzheimer Disease %K Curcumin %K Diet, Mediterranean %K Dietary Supplements %K Humans %K Nutritional Status %K Risk Factors %K Vitamins %X

Since its discovery some hundred years ago, Alzheimer's disease (AD), a neurodegenerative disease and an eminent cause of most dementia, continues to pose problems for affected families and society, especially in developed countries. With the approved medications by the Food and Drugs Administration in the United States, effectual treatment of AD apropos to the complete eradication of the disease continues to be elusive due to complexities relating to the pathophysiology of the disease. Nutrition has and continues to play a salient role in the survival of living organisms with no exception for human beings. Herein, we report the connection between nutrition and AD with particular attention to vitamins, curcumin, and the Mediterranean diet.

%B J Alzheimers Dis %V 61 %P 867-883 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254101?dopt=Abstract %R 10.3233/JAD-170874 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Nutritional Intervention as a Preventive Approach for Cognitive-Related Outcomes in Cognitively Healthy Older Adults: A Systematic Review. %A Solfrizzi, Vincenzo %A Agosti, Pasquale %A Lozupone, Madia %A Custodero, Carlo %A Schilardi, Andrea %A Valiani, Vincenzo %A Sardone, Rodolfo %A Dibello, Vittorio %A Di Lena, Luca %A Lamanna, Angela %A Stallone, Roberta %A Bellomo, Antonello %A Greco, Antonio %A Daniele, Antonio %A Seripa, Davide %A Sabbá, Carlo %A Logroscino, Giancarlo %A Panza, Francesco %X

The link diet-cognitive function/dementia has been largely investigated in observational studies; however, there was a lack of evidence from randomized clinical trials (RCTs) on the prevention of late-life cognitive disorders though dietary intervention in cognitively healthy older adults. In the present article, we systematically reviewed RCTs published in the last four years (2014-2017) exploring nutritional intervention efficacy in preventing the onset of late-life cognitive disorders and dementia in cognitively healthy subjects aged 60 years and older using different levels of investigation (i.e., dietary pattern changes/medical food/nutraceutical supplementation/multidomain approach and dietary macro- and micronutrient approaches) as well as possible underlying mechanisms of nutritional prevention. From the 35 included RCTs, there was moderate evidence that intervention through dietary pattern changes, medical food/nutraceutical supplementation, and multidomain approach improved specific cognitive domains or cognitive-related blood biomarkers. There was high evidence that protein supplementation improved specific cognitive domains or functional status in prefrail older adults without effect.

%B J Alzheimers Dis %V 64 %P S229-S254 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865058?dopt=Abstract %R 10.3233/JAD-179940 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Nutritional Intervention to Prevent Alzheimer's Disease: Potential Benefits of Xanthophyll Carotenoids and Omega-3 Fatty Acids Combined. %A Nolan, John M %A Mulcahy, Riona %A Power, Rebecca %A Moran, Rachel %A Howard, Alan N %X

BACKGROUND: A growing body of scientific evidence suggests that enrichment of certain nutritional compounds in the brain may reduce the risk of Alzheimer's disease (AD).

OBJECTIVE: To investigate the impact of supplemental xanthophyll carotenoids plus omega-3 fatty acids on disease progression in patients with AD.

METHODS: Three trial experiments were performed. In Trials 1 and 2 (performed on patients with AD over an 18-month period), 12 patients (AD status at baseline: 4 mild and 8 moderate) were supplemented with a xanthophyll carotenoid only formulation (Formulation 1; lutein:meso-zeaxanthin:zeaxanthin 10:10:2 mg/day) and 13 patients (AD status at baseline: 2 mild, 10 moderate, and 1 severe) were supplemented with a xanthophyll carotenoid and fish oil combination (Formulation 2; lutein:meso-zeaxanthin:zeaxanthin 10:10:2 mg/day plus 1 g/day of fish oil containing 430 mg docohexaenoic acid [DHA] and 90 mg eicopentaenoic acid [EPA]), respectively. In Trial 3, 15 subjects free of AD (the control group) were supplemented for 6 months with Formulation 1. Blood xanthophyll carotenoid response was measured in all trials by HPLC. Omega-3 fatty acids were profiled by direct infusion mass spectrometry.

RESULTS: Xanthophyll carotenoid concentration increases were significantly greater for Formulation 2 compared to Formulation 1 (p < 0.05), and progression of AD was less for this group (p = 0.003), with carers reporting functional benefits in memory, sight, and mood.

CONCLUSION: This preliminary report suggests positive outcomes for patients with AD who consumed a combination of xanthophyll carotenoids plus fish oil, but further study is required to confirm this important observation.

%B J Alzheimers Dis %V 64 %P 367-378 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29945352?dopt=Abstract %R 10.3233/JAD-180160 %0 Journal Article %J J Alzheimers Dis %D 2018 %T An Objective Method to Accurately Measure Cardiorespiratory Fitness in Older Adults Who Cannot Satisfy Widely Used Oxygen Consumption Criteria. %A Dougherty, Ryan J %A Lindheimer, Jacob B %A Stegner, Aaron J %A Van Riper, Stephanie %A Okonkwo, Ozioma C %A Cook, Dane B %K Aged %K Cardiorespiratory Fitness %K Exercise Test %K Female %K Humans %K Male %K Middle Aged %K Oxygen Consumption %K Reproducibility of Results %K Wisconsin %X

Cardiorespiratory fitness (CRF) is routinely investigated in older adults; however, the most appropriate CRF measure to use for this population has received inadequate attention. This study aimed to 1) evaluate the reliability and validity of the oxygen uptake efficiency slope (OUES) as a sub-maximal measurement of CRF; 2) examine demographic, risk-factor, and exercise testing differences in older adults who satisfied standardized criteria for a peak oxygen consumption (V̇O2peak) test compared to those who did not; and 3) determine the difference between directly measured V̇O2peak values and OUES-predicted V̇O2peak values. One hundred ten enrollees from the Wisconsin Registry for Alzheimer's Prevention participated in this study. Participants performed a graded maximal exercise test and wore an accelerometer for 7 days. For each participant, the OUES was calculated at 75%, 90%, and 100% of exercise duration. V̇O2peak was recorded at peak effort, and one week of physical activity behavior was measured. OUES values calculated at separate relative exercise durations displayed excellent reliability (ICC = 0.995; p < 0.001), and were strongly correlated with V̇O2peak (rrange = 0.801-0.909; p < 0.001). As hypothesized, participants who did not satisfy V̇O2peak criteria were significantly older than those who satisfied criteria (p = 0.049) and attained a directly measured V̇O2peak that was 2.31 mL·kg·min-1 less than the value that was predicted by OUES V̇O2peak (p = 0.003). Older adults are less likely to satisfy V̇O2peak criteria, which results in an underestimation of their CRF. Without adhering to standardized criteria, V̇O2peak measurement error may lead to misinterpretation of CRF and age-related associations. Here, we conclude that OUES is a reliable, valid measurement of CRF which does not require achievement of standardized criteria.

%B J Alzheimers Dis %V 61 %P 601-611 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226867?dopt=Abstract %R 10.3233/JAD-170576 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Observational Study of Clinical and Functional Progression Based on Initial Brain MRI Characteristics in Patients with Alzheimer's Disease. %A Choi, Hojin %A Yang, YoungSoon %A Han, Hyun Jeong %A Jeong, Jee Hyang %A Park, Mee Young %A Kim, Yong Bum %A Jo, Kwang Deog %A Choi, Jin-Yong %A Kang, Kyung-Hun %A Kang, Heeyoung %A Kwon, Do-Young %A Yoo, Bong-Goo %A Lee, Hyun Jin %A Shin, Byoung-Soo %A Jeon, Sung-Man %A Kwon, Oh Dae %A Kim, Jin-Suk %A Lee, Soo-Joo %A Kim, Youngsoo %A Park, Tai-Hwan %A Kim, Young Jin %A Yang, Hui-Jun %A Park, Hyun-Young %A Shin, Hae-Eun %A Lee, Jung Seok %A Jung, Yo Han %A Lee, Ae Young %A Shin, Dong-Ick %A Shin, Kyong Jin %A Park, Kee Hyung %X

BACKGROUND: Magnetic resonance imaging (MRI) is a useful tool to predict the diagnosis and progression of Alzheimer's disease (AD), especially for primary physicians. However, the correlation between baseline MRI findings and AD progression has not been fully established.

OBJECTIVE: To investigate the correlation between hippocampal atrophy (HA) and white matter hyperintensities (WMH) on initial brain MRI images and the degree of cognitive decline and functional changes over 1 year.

METHODS: In this prospective, 12-month observational study, dementia outpatients were recruited from 29 centers across South Korea. Baseline assessments of HA and WMH on baseline brain MRI were derived as well as cognitive function, dementia severity, activities of daily living, and acetylcholinesterase inhibitor (AChEI) use. Follow-up assessments were conducted at 6 and 12 months.

RESULTS: Among 899 enrolled dementia patients, 748 were diagnosed with AD of whom 654 (87%) were taking AChEIs. Baseline WMH showed significant correlations with age, current alcohol consumption, and Clinical Dementia Rating score; baseline HA was correlated with age, family history, physical exercise, and the results of cognitive assessments. Among the AChEI group, changes in the Korean version of the Instrumental Activities of Daily Living (K-IADL) were correlated with the severity of HA on baseline brain MRI, but not with the baseline severity of WMH. In the no AChEI group, changes in K-IADL were correlated with the severity of WMH and HA at baseline.

CONCLUSION: Baseline MRI findings could be a useful tool for predicting future clinical outcomes by primary physicians, especially in relation to patients' functional status.

%B J Alzheimers Dis %V 66 %P 1721-1730 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30452413?dopt=Abstract %R 10.3233/JAD-180565 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Odor Identification Ability Predicts PET Amyloid Status and Memory Decline in Older Adults. %A Kreisl, William Charles %A Jin, Peng %A Lee, Seonjoo %A Dayan, Ezra R %A Vallabhajosula, Shankar %A Pelton, Gregory %A Luchsinger, Jose A %A Pradhaban, Gnanavalli %A Devanand, D P %X

BACKGROUND: Odor identification deficits occur in Alzheimer's disease (AD), as measured by the 40-item University of Pennsylvania Smell Identification Test (UPSIT).

OBJECTIVE: To determine if UPSIT scores predict amyloid-β (Aβ) status, determined by 11C-Pittsburgh Compound B PET. We also compared UPSIT scores to Aβ status in predicting future memory decline.

METHODS: Subjects were recruited into a longitudinal clinical prediction study. We analyzed data from those who had UPSIT, cognitive testing, PIB PET, and at least 12 months' clinical follow-up. Forty-six amnestic mild cognitive impairment patients and 25 cognitively normal controls were included. Amyloid-positivity was defined as composite PIB standardized uptake value ratio >1.5. Logistic regression and Receiver Operating Characteristic Curve analyses tested the predictive utility of impaired olfaction (defined as UPSIT score <35) and amyloid-positivity for memory decline.

RESULTS: High UPSIT scores predicted absence of amyloidosis on PET, with negative predictive value of 100%. Positive predictive value of low UPSIT scores on positive Aβ status was only 41%. Both low UPSIT score (OR = 4.301, 95% CI = 1.248, 14.821, p = 0.021) and positive PET scan (OR = 20.898, 95% CI = 2.222, 196.581, p = 0.008) predicted memory decline.

CONCLUSION: Individuals with high UPSIT scores are less likely to have cerebral amyloidosis or experience memory decline. Therefore, UPSIT has potential as a screening tool to determine utility of Aβ PET in clinical practice or enrollment in clinical trials. Low UPSIT score is a non-specific marker of neurodegeneration that could indicate further workup in patients with memory complaints.

%B J Alzheimers Dis %V 62 %P 1759-1766 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614678?dopt=Abstract %R 10.3233/JAD-170960 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Olfactory Function is Associated with Cognitive Performance: Results of the Heinz Nixdorf Recall Study. %A Tebrügge, Sarah %A Winkler, Angela %A Gerards, Diana %A Weimar, Christian %A Moebus, Susanne %A Jöckel, Karl-Heinz %A Erbel, Raimund %A Jokisch, Martha %X

BACKGROUND: There is strong evidence for an association of olfactory dysfunction and neurodegenerative diseases. Studies on the association of olfaction and cognition in the general population are rare.

OBJECTIVE: To evaluate gender- and age-specific associations of olfactory function and cognitive performance in a well characterized population-based study sample.

METHODS: At the third examination of the Heinz Nixdorf Recall study (n = 3,087), 2,640 participants (48% men; 68.2±7.2 years) underwent Sniffin' Sticks Screening Test measuring olfactory function on a scale of 0-12 points. Olfactory function was rated as anosmic, hyposmic, or normosmic (≤6, 7-10 or ≥11 points, respectively). All participants performed eight validated cognitive subtests. Age- (55-64 years, 65-74 years, 75-86 years) and gender-stratified multivariate analysis of covariance was used to evaluate group differences in cognitive performance.

RESULTS: Women showed better olfactory function than men (p < 0.001). For middle-aged participants, olfactory groups differed in almost all cognitive subtests. The analyses revealed no gender effects, although associations were slightly greater for women than for men. Anosmics showed the worst cognitive performance and normosmics showed the best cognitive performance. In the young- and old-aged groups, a quantitative association was found for anosmics in all subtests and for normosmics and hyposmics in almost all subtests.

CONCLUSION: This is the first study reporting on age-specific associations of olfactory function and cognitive performance in the general population. The association found in middle-aged participants (65-74 years) may serve as a marker to improve identification of persons at high risk for cognitive decline and dementia.

%B J Alzheimers Dis %V 63 %P 319-329 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578482?dopt=Abstract %R 10.3233/JAD-170863 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Optical Depolarization of DCX-Expressing Cells Promoted Cognitive Recovery and Maturation of Newborn Neurons via the Wnt/β-Catenin Pathway. %A Zhao, Ming-Liang %A Chen, Shi-Jin %A Li, Xiao-Hong %A Wang, Li-Na %A Chen, Feng %A Zhong, Shi-Jiang %A Yang, Cheng %A Sun, Sheng-Kai %A Li, Jian-Jun %A Dong, Hua-Jiang %A Dong, Yue-Qing %A Wang, Yi %A Chen, Chong %X

Electrical excitability by membrane depolarization is crucial for survival and maturation of newborn cells in the dentate gyrus of the hippocampus. However, traditional technology for membrane depolarization lacks temporal and spatial precision. Optogenetics can be used to activate channelrhodopsin-2 (ChR2), allowing cationic current to depolarize genetically targeted cells. In this study, we used ChR2-EGFP driven by doublecortin (DCX) to promote survival and maturation of newborn cells in the dentate gyrus after traumatic brain injury (TBI). C57BL/6 mice underwent lateral fluid percussion TBI. TBI mice were transfected with a lentivirus carrying the DCX-ChR2-EGFP gene. We observed that not only immature neurons but also type-2b intermediate progenitor (IPs) and neuroblasts expressed DCX-EGFP, indicating that DCX-expressing newborn cells could provide a long time window for electrical activity regulation. Quantitative results showed that the number of EGFP-expressing cells began to rise at 3 days after TBI and peaked at 9 days after TBI. By optical depolarization of DCX-EGFP-expressing cells between 3 and 12 days, we observed significantly improved cognitive deficits after TBI with enhanced survival and maturation of newborn cells in the dentate gyrus. We also investigated the role of optical depolarization in neural stem cells transfected with a lentivirus carrying the ChR2-DCX-EGFP gene in vitro. By administrating verapamil to block L-type calcium channels, we verified that the up-regulation of MAP2, NeuN, Neurog2, NeuroD1 and GluR2 in newborn cells was mediated by ChR2-elicted depolarization. By using β-catenin inhibitor Dkk1, we demonstrated that optical depolarization of DCX-EGFP-expressing cells facilitated survival and maturation probably through the Wnt/β-catenin signaling cascade.

%B J Alzheimers Dis %V 63 %P 303-318 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614674?dopt=Abstract %R 10.3233/JAD-180002 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Our Tau Tales from Normal to Pathological Behavior. %A Alonso, Alejandra D %A Cohen, Leah S %X

The microtubule associated protein tau in a hyperphosphorylated form was identified as the building block of the filamentous aggregates found in the neurons of Alzheimer's disease (AD) patients. In the abnormal state, hyperphosphorylated tau from AD brains (AD P-tau) was unable to promote microtubule assembly and more importantly, it could inhibit the normal activity of tau and other MAPs. AD P-tau was able to disrupt preformed microtubules and, by binding to normal tau, turn the latter into an AD P-tau like molecule. AD P-tau toxic behavior was prevalent in the soluble form and it was lost upon dephosphorylation. Mutations on tau associated with disease, e.g., R406W in frontotemporal dementia with Parkinsonism linked to chromosome 17, altered its conformation to make it a better substrate for kinases. Using phospho-mimetics, it was found that the minimum phospho-sites necessary to acquire such a toxic behavior of tau were at 199, 212, 231 and 262, and tau pseudophosphorylated at those sites in combination with R406W was named Pathological Human Tau (PH-Tau). PH-Tau expressed in cells had similar behavior to AD P-tau: disruption of the microtubule system, change in the normal subcellular localization, and gain of toxic function for cells. In animal models expressing PH-Tau, it was found that two putative mechanisms of neurodegeneration exist depending on the concentration of the toxic protein, both involving cognitive decline, due to synaptic dysfunction at lower concentration and neuronal death at higher. Studies investigating the mechanism of tau pathology and its transmission from neuron to neuron are currently ongoing.

%B J Alzheimers Dis %V 64 %P S507-S516 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614672?dopt=Abstract %R 10.3233/JAD-179906 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Our Working Point of View of Tau Protein. %A Avila, Jesús %X

Tau protein, which was discovered in Prof. Kirschner's laboratory in 1975, has been the focus of my research over the last 40 years. In this issue of the Journal of Alzheimer's Disease commemorating its 20th year of publication, I will provide a short review of some of the features of my relationship with tau.

%B J Alzheimers Dis %V 62 %P 1277-1285 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036830?dopt=Abstract %R 10.3233/JAD-170600 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Outcomes for Hospitalized Older Adults with Down Syndrome in the United States. %A Mendiratta, Priya %A Wei, Jeanne Y %A Dayama, Neeraj %A Li, Xiaocong %X

BACKGROUND: Patients with Down syndrome (DS) often survive into adulthood. Relatively little information is currently available regarding hospitalization outcomes among mature, older adults with DS.

OBJECTIVE: To identify risk factors associated with hospital mortality rates and increased costs for hospitalized older adults with DS.

METHODS: Data on hospitalized older adults with DS (≥65 years) were identified from the Nationwide Inpatient Sample database (6) from 2002 through 2012. Multivariate analyses were performed to evaluate risk factors associated with hospital mortality and hospitalization cost in these patients.

RESULTS: A total of 2,134 older adults with DS were identified. A temporal increase over the 11-year period was observed in the number of older adults with DS who were hospitalized (trend p < 0.0001). However, the hospital mortality rate and post-hospital discharge to skilled nursing facilities have decreased during the same time period. Risk factors associated with increased hospital mortality included advanced age (70-79 years), female gender, admissions in the western United States, and presence of comorbid conditions (ischemic heart disease, Alzheimer's disease, and cerebrovascular accident). The mean cost was $18,241 (SD $56,105) over the 11-year period. However, no significant temporal changes in costs were noted (trend p = 0.14).

CONCLUSIONS: The number of hospitalized elderly Americans with DS has increased over the 11-year period. However, hospital mortality and discharge to skilled nursing facilities have decreased during the same time period. Several demographic and co-morbid factors are associated with increased mortality. No significant differences in temporal trends in costs were noted.

%B J Alzheimers Dis %V 66 %P 377-386 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320569?dopt=Abstract %R 10.3233/JAD-171067 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease. %A Wezyk, Michalina %A Szybinska, Aleksandra %A Wojsiat, Joanna %A Szczerba, Marcelina %A Day, Kelly %A Ronnholm, Harriet %A Kele, Malin %A Berdynski, Mariusz %A Peplonska, Beata %A Fichna, Jakub Piotr %A Ilkowski, Jan %A Styczyńska, Maria %A Barczak, Anna %A Zboch, Marzena %A Filipek-Gliszczyńska, Anna %A Bojakowski, Krzysztof %A Skrzypczak, Magdalena %A Ginalski, Krzysztof %A Kabza, Michal %A Makalowska, Izabela %A Barcikowska-Kotowicz, Maria %A Wojda, Urszula %A Falk, Anna %A Zekanowski, Cezary %X

 The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-β. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-β pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD.

%B J Alzheimers Dis %V 62 %P 175-202 %8 2018 %G eng %N 1 %R 10.3233/JAD-170830 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Oxidative Stress, Amyloid-β Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer's Disease. %A Butterfield, D Allan %A Boyd-Kimball, Debra %X

Oxidative stress is implicated in the pathogenesis and progression of Alzheimer's disease (AD) and its earlier stage, amnestic mild cognitive impairment (aMCI). One source of oxidative stress in AD and aMCI brains is that associated with amyloid-β peptide, Aβ1-42 oligomers. Our laboratory first showed in AD elevated oxidative stress occurred in brain regions rich in Aβ1-42, but not in Aβ1-42-poor regions, and was among the first to demonstrate Aβ peptides led to lipid peroxidation (indexed by HNE) in AD and aMCI brains. Oxidatively modified proteins have decreased function and contribute to damaged key biochemical and metabolic pathways in which these proteins normally play a role. Identification of oxidatively modified brain proteins by the methods of redox proteomics was pioneered in the Butterfield laboratory. Four recurring altered pathways secondary to oxidative damage in brain from persons with AD, aMCI, or Down syndrome with AD are interrelated and contribute to neuronal death. This "Quadrilateral of Neuronal Death" includes altered: glucose metabolism, mTOR activation, proteostasis network, and protein phosphorylation. Some of these pathways are altered even in brains of persons with preclinical AD. We opine that targeting these pathways pharmacologically and with lifestyle changes potentially may provide strategies to slow or perhaps one day, prevent, progression or development of this devastating dementing disorder. This invited review outlines both in vitro and in vivo studies from the Butterfield laboratory related to Aβ1-42 and AD and discusses the importance and implications of some of the major achievements of the Butterfield laboratory in AD research.

%B J Alzheimers Dis %V 62 %P 1345-1367 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562527?dopt=Abstract %R 10.3233/JAD-170543 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Oxidative Stress in Elderly with Different Cognitive Status: My Mind Project. %A Fattoretti, Patrizia %A Malavolta, Marco %A Fabbietti, Paolo %A Papa, Roberta %A Giacconi, Robertina %A Costarelli, Laura %A Galeazzi, Roberta %A Paoloni, Cristina %A Postacchini, Demetrio %A Lattanzio, Fabrizia %A Giuli, Cinzia %X

BACKGROUND: Biomarkers of oxidative stress have been associated with cognitive status in humans and have been proposed to guide prognosis/treatment in Alzheimer's disease (AD) and mild cognitive impairment (MCI).

OBJECTIVE: The aim of this study was to compare oxidative stress status in the plasma of mild-moderate AD, MCI, and healthy elderly with normal cognition (HE) undergoing a non-pharmacological intervention including multi-modal cognitive training ("My Mind Project").

METHODS: A prospective randomized trial involving 321 elderly people enrolled in Marche Region, Italy. Each subject was randomly assigned to an experimental (cognitive training) or to a control group. Cognitive performances and biomarkers have been analyzed before intervention (baseline), immediately after termination (follow-up 1), after 6 months (follow-up 2), and after 2 years (follow-up 3). The biological antioxidant potential (BAP) to Diacron reactive oxygen metabolites (d-ROM) ratio has been used as an indicator of oxidative stress status and as outcome variable.

RESULTS: We have found no differences in the oxidative status among AD, MCI, and HE. Neither did we find a significant effect of the intervention within experimental groups. Gender was the sole factor with a strong significant effect on BAP/d-ROM.

CONCLUSIONS: Based on these results, the utility of biomarkers of oxidative stress to guide prognosis/treatment in AD or MCI seems to be limited by lack of specificity, large interindividual variability, and gender bias.

%B J Alzheimers Dis %V 63 %P 1405-1414 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843238?dopt=Abstract %R 10.3233/JAD-171117 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Ozone Atmospheric Pollution and Alzheimer's Disease: From Epidemiological Facts to Molecular Mechanisms. %A Croze, Marine L %A Zimmer, Luc %K Air Pollution %K Alzheimer Disease %K Animals %K Central Nervous System %K Humans %K Incidence %K Inhalation Exposure %K Ozone %K Particulate Matter %X

Atmospheric pollution is a well-known environmental hazard, especially in developing countries where millions of people are exposed to airborne pollutant levels above safety standards. Accordingly, several epidemiological and animal studies confirmed its role in respiratory and cardiovascular pathologies and identified a strong link between ambient air pollution exposure and adverse health outcomes such as hospitalization and mortality. More recently, the potential deleterious effect of air pollution inhalation on the central nervous system was also investigated and mounting evidence supports a link between air pollution exposure and neurodegenerative pathologies, especially Alzheimer's disease (AD). The focus of this review is to highlight the possible link between ozone air pollution exposure and AD incidence. This review's approach will go from observational and epidemiological facts to the proposal of molecular mechanisms. First, epidemiological and postmortem human study data concerning residents of ozone-severely polluted megacities will be presented and discussed. Then, the more particular role of ozone air pollution in AD pathology will be described and evidenced by toxicological studies in rat or mouse with ozone pollution exposure only. The experimental paradigms used to reproduce in rodent the human exposure to ozone air pollution will be described. Finally, current insights into the molecular mechanisms through which ozone inhalation can affect the brain and play a role in AD development or progression will be recapitulated.

%B J Alzheimers Dis %V 62 %P 503-522 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480184?dopt=Abstract %R 10.3233/JAD-170857 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Palmitoylethanolamide Blunts Amyloid-β42-Induced Astrocyte Activation and Improves Neuronal Survival in Primary Mouse Cortical Astrocyte-Neuron Co-Cultures. %A Beggiato, Sarah %A Borelli, Andrea Celeste %A Ferraro, Luca %A Tanganelli, Sergio %A Antonelli, Tiziana %A Tomasini, Maria Cristina %K Amyloid beta-Peptides %K Analysis of Variance %K Animals %K Animals, Newborn %K Anti-Inflammatory Agents, Non-Steroidal %K Astrocytes %K Cell Survival %K Cells, Cultured %K Cerebral Cortex %K Coculture Techniques %K Ethanolamines %K Mice %K Mice, Inbred C57BL %K Microtubule-Associated Proteins %K Neurons %K Palmitic Acids %K Peptide Fragments %K Time Factors %X

BACKGROUND: Based on the pivotal role of astrocytes in brain homeostasis and the strong metabolic cooperation existing between neurons and astrocytes, it has been suggested that astrocytic dysfunctions might cause and/or contribute to neuroinflammation and neurodegenerative processes. Therapeutic approaches aimed at both neuroprotection and neuroinflammation reduction may prove particularly effective in slowing the progression of these diseases. The endogenous lipid mediator palmitoylethanolamide (PEA) displayed neuroprotective and anti(neuro)inflammatory properties, and demonstrated interesting potential as a novel treatment for Alzheimer's disease.

OBJECTIVE AND METHODS: We firstly evaluated whether astrocytes could participate in regulating the Aβ42-induced neuronal damage, by using primary mouse astrocytes cell cultures and mixed astrocytes-neurons cultures. Furthermore, the possible protective effects of PEA against Aβ42-induced neuronal toxicity have also been investigated by evaluating neuronal viability, apoptosis, and morphometric parameters.

RESULTS: The presence of astrocytes pre-exposed to Aβ42 (0.5μM; 24 h) induced a reduction of neuronal viability in primary mouse astrocytes-neurons co-cultures. Furthermore, under these experimental conditions, an increase in the number of neuronal apoptotic nuclei and a decrease in the number of MAP-2 positive neurons were observed. Finally, astrocytic Aβ42 pre-exposure induced an increase in the number of neurite aggregations/100μm as compared to control (i.e., untreated) astrocytes-neurons co-cultures. These effects were not observed in neurons cultured in the presence of astrocytes pre-exposed to PEA (0.1μM), applied 1 h before and maintained during Aβ42 treatment.

CONCLUSION: Astrocytes contribute to Aβ42-induced neurotoxicity and PEA, by blunting Aβ42-induced astrocyte activation, improved neuronal survival in mouse astrocyte-neuron co-cultures.

%B J Alzheimers Dis %V 61 %P 389-399 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154284?dopt=Abstract %R 10.3233/JAD-170699 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Parietal Involvement in the Semantic Variant of Primary Progressive Aphasia with Alzheimer's Disease Cerebrospinal Fluid Profile. %A Bera, Géraldine %A Migliaccio, Raffaella %A Michelin, Thibaut %A Lamari, Foudil %A Ferrieux, Sophie %A Nogues, Marie %A Bertin, Hugo %A Habert, Marie Odile %A Dubois, Bruno %A Teichmann, Marc %A Kas, Aurélie %X

Semantic variant of primary progressive aphasia (svPPA) is typically associated with non-Alzheimer's disease (AD) pathology. However, some anatomopathological studies have found AD lesions in those patients. We compared brain perfusion SPECT of 18 svPPA patients with cerebrospinal fluid (CSF) biomarkers indicative of non-AD pathology (svPPA-nonAD) and three svPPA patients with CSF biomarkers indicative of underlying AD (svPPA-AD). All svPPA patients had severe left temporopolar hypoperfusion. SvPPA-nonAD had additional anterior cingulate and mediofrontal hypoperfusion, whereas svPPA-AD had greater left parietal and posterior cingulate involvement. Parietal damage in svPPA constitutes a biomarker for underlying Alzheimer pathology thus refining the classification of this PPA variant.

%B J Alzheimers Dis %V 66 %P 271-280 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282352?dopt=Abstract %R 10.3233/JAD-180087 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Parkinsonism is a Phenotypical Signature of Amyloidopathy in Patients with Gait Disorders. %A Allali, Gilles %A Kern, Ilse %A Laidet, Magali %A Armand, Stéphane %A Assal, Frèdèric %X

BACKGROUND: Central neurological gait abnormalities (CNGA) are frequently associated with parkinsonism in older adults. However, the neuropathological substrates and the clinical impact of parkinsonism have been not described in CNGA.

OBJECTIVE: This cross-sectional study aims to compare the CSF total tau, Aβ1-42, and phosphorylated tau levels in non-Parkinson's disease (PD) patients with CNGA with and without parkinsonism and to study the clinical impact of parkinsonism on gait and cognition.

METHODS: CSF biomarkers were measured by ELISA in 49 non-PD patients with CNGA (77.7±6.6 years; 32.7% women). Gait was quantified with an optoelectronic system and cognition with a comprehensive neuropsychological assessment. Parkinsonism was defined by presence of bradykinesia and at least one of the following signs among muscular rigidity, rest tremor, or postural instability.

RESULTS: Parkinsonism was identified in 14 CNGA patients (28.6% ). CSF Aβ1-42 level was decreased in CNGA patients with parkinsonism (β: - 189.4; 95% CI [- 352.3; - 26.6]; p = 0.024) even after adjusting for age, gender, comorbidities, and total white matter burden; while CSF total tau and phosphorylated tau levels were similar between CNGA patients with and without parkinsonism. CNGA patients with parkinsonism presented decreased attentional and executive performances but similar gait parameters than those without parkinsonism.

CONCLUSION: Parkinsonism represents a phenotype related with amyloidopathy-decreased CSF Aβ1-42 level-in non-PD patients with CNGA. This phenotype is clinically associated with impaired cognition, but similar quantitative gait parameters in comparison to CNGA patients without parkinsonism.

%B J Alzheimers Dis %V 63 %P 1373-1381 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843235?dopt=Abstract %R 10.3233/JAD-171055 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Past and the Future of Alzheimer's Disease Fluid Biomarkers. %A Blennow, Kaj %A Zetterberg, Henrik %K Alzheimer Disease %K Animals %K Biomarkers %K Humans %X

Following the development of the first methods to measure the core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers total-tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of amyloid-β (Aβ42), there has been an enormous expansion of this scientific research area. Today, it is generally acknowledged that these biochemical tests reflect several central pathophysiological features of AD and contribute diagnostically relevant information, also for prodromal AD. In this article in the 20th anniversary issue of the Journal of Alzheimer's Disease, we review the AD biomarkers, from early assay development to their entrance into diagnostic criteria. We also summarize the long journey of standardization and the development of assays on fully automated instruments, where we now have high precision and stable assays that will serve as the basis for common cut-off levels and a more general introduction of these diagnostic tests in clinical routine practice. We also discuss the latest expansion of the AD CSF biomarker toolbox that now also contains synaptic proteins such as neurogranin, which seemingly is specific for AD and predicts rate of future cognitive deterioration. Last, we are at the brink of having blood biomarkers that may be implemented as screening tools in the early clinical management of patients with cognitive problems and suspected AD. Whether this will become true, and whether it will be plasma Aβ42, the Aβ42/40 ratio, or neurofilament light, or a combination of these, remains to be established in future clinical neurochemical studies.

%B J Alzheimers Dis %V 62 %P 1125-1140 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170773?id=journal-of-alzheimers-disease%2Fjad170773 %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562534?dopt=Abstract %R 10.3233/JAD-170773 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Past to Future: What Animal Models Have Taught Us About Alzheimer's Disease. %A Martini, Alessandra C %A Forner, Stefania %A Trujillo-Estrada, Laura %A Baglietto-Vargas, David %A LaFerla, Frank M %X

Alzheimer's disease (AD) impairs memory and causes significant cognitive deficits. The disease course is prolonged, with a poor prognosis, and thus exacts an enormous economic and social burden. Over the past two decades, genetically engineered mouse models have proven indispensable for understanding AD pathogenesis, as well as for discovering new therapeutic targets. Here we highlight significant studies from our laboratory that have helped advance the AD field by elucidating key pathogenic processes operative in AD and exploring a variety of aspects of the disease which may yield novel therapeutic strategies for combatting this burdensome disease.

%B J Alzheimers Dis %V 64 %P S365-S378 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504540?dopt=Abstract %R 10.3233/JAD-179917 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Pathological Correlates of Cognitive Impairment in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. %A Robinson, Andrew C %A Davidson, Yvonne S %A Horan, Michael A %A Pendleton, Neil %A Mann, David M A %X

The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation. Alzheimer-type pathology was common throughout the cohort and generally correlated well with cognitive status. However, there was some overlap between cognitive status and measures of Alzheimer pathology with 26% of cognitively intact participants reaching either CERAD B or C, 11% reaching Thal phase 4 or 5, and 29% reaching Braak stage III- VI. Cerebral amyloid angiopathy(CAA), α-synuclein, and TDP-43 pathology was less common, but when present correlated well with cognitive status. Possession of APOEɛ4 allele(s) was associated with more severe Alzheimer-type and CAA pathology and earlier death, whereas possession of APOEɛ2 allele(s) had no effect on pathology but was more common in cognitively intact individuals. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort is pathologically representative when compared with similar studies. Cognitive impairment in life correlates strongly with all pathologies examined and the APOE status of an individual can affect pathology severity and longevity.

%B J Alzheimers Dis %8 2018 May 28 %G eng %R 10.3233/JAD-180171 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Pathologically Confirmed Alzheimer's Disease in APOE ɛ2 Homozygotes is Rare but Does Occur. %A Stipho, Faissal %A Jackson, Robert %A Sabbagh, Marwan N %X

BACKGROUND: Homozygous APOEɛ4 status is a well-known risk factor in the development of Alzheimer's disease (AD). However, other genotypes of APOE have not yet been found to have equal clinical significance. There is a paucity of reports regarding clinically or pathologically described AD in APOEɛ2 homozygotes compared to the other alleles.

OBJECTIVE: To notify clinicians that patients with homozygous APOEɛ2 are also at risk of developing AD based on results from the largest prospectively gathered registry of brain samples to date.

METHODS: We queried the National Alzheimer's Coordinating Center (NACC) database for autopsy-confirmed AD cases. Of the Uniform Data Set (UDS) participants who are deceased, 5,779 were diagnosed with dementia at their last UDS visit prior to death, and autopsy data is available for 3,518.

RESULTS: Of the brains in the NACC database with pathologically confirmed dementia, seven were found to be homozygous for APOEɛ2, which represents only 0.2% of the autopsy-confirmed sample. Furthermore, pathology-confirmed AD represents 29% (2/7) of the APOEɛ2/ɛ2 patients diagnosed with dementia.

CONCLUSIONS: Although rare, autopsy-confirmed AD can be present in APOEɛ2/ɛ2 carriers.

%B J Alzheimers Dis %V 62 %P 1527-1530 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562509?dopt=Abstract %R 10.3233/JAD-171060 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. %A Kirson, Noam Y %A Scott Andrews, J %A Desai, Urvi %A King, Sarah B %A Schonfeld, Sophie %A Birnbaum, Howard G %A Ball, Daniel E %A Kahle-Wrobleski, Kristin %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition Disorders %K Cohort Studies %K Datasets as Topic %K Disease Progression %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Statistics, Nonparametric %K Time Factors %X

BACKGROUND: Effectiveness of Alzheimer's disease (AD) treatments may depend critically on the timeliness of intervention.

OBJECTIVE: To compare characteristics and outcomes of patients diagnosed with probable AD (prAD) based on time elapsed from first onset of cognitive decline.

METHODS: Patients with ≥1 prAD diagnosis and ≥1 follow-up visit were selected from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS; 9/2005-6/2015) and stratified based on the time between the perceived onset of cognitive decline at baseline and first prAD diagnosis (i.e., earlier versus later diagnosis). Characteristics at baseline and prAD diagnosis, clinically meaningful progression, and medication use following prAD diagnosis were compared.

RESULTS: Median time from perceived onset of cognitive decline to prAD diagnosis was 4.5 years (earlier diagnosis: ≤3.46; later diagnosis: >5.71). Earlier-diagnosed patients (n = 1,476) were younger at baseline (74.3 versus 76.3 years) and had better cognitive and functional scores than later-diagnosed patients (n = 1,474). At first prAD diagnosis, earlier-diagnosed patients had lower mean global Clinical Dementia Rating (CDR) score (0.8 versus 1.1), higher mean Mini-Mental State Examination (MMSE) (22.6 versus 20.0), and lower mean Functional Activities Questionnaire (11.6 versus 17.3). Earlier- and later-diagnosed patients experienced similar time to a decrease of ≥3 points in MMSE (median 23.2 versus 23.1 months, p = 0.83), but earlier-diagnosed patients had longer time to a CDR score of ≥2 points, and longer times to initiation of AD medication and antipsychotic agents (all p < 0.01).

CONCLUSION: Earlier prAD diagnosis in NACC data is associated with higher cognitive function and lower functional impairment at diagnosis.

%B J Alzheimers Dis %V 61 %P 295-307 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154268?dopt=Abstract %R 10.3233/JAD-170078 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Patient Engagement: The Fundació ACE Framework for Improving Recruitment and Retention in Alzheimer's Disease Research. %A Boada, Merce %A Santos-Santos, Miguel A %A Rodríguez-Gómez, Octavio %A Alegret, Montserrat %A Cañabate, Pilar %A Lafuente, Asunción %A Abdelnour, Carla %A Buendia, Mar %A de Dios, Maria José %A Morera, Amèrica %A Sanabria, Ángela %A Campo, Laura %A Ruiz, Agustin %A Tárraga, Lluís %X

Alzheimer's disease (AD) research is at a critical time. The global society is increasingly aware of the frightening rate of growth of the human and financial burden caused by this condition and of the urgent need to halt its progression. Consequently, the scientific community holds great responsibility to quickly put in place and optimize the machinery necessary for testing new treatments or interventions. In this context demand for participants for AD research is at an all-time high. In this review, we will focus on a methodological factor that is increasingly recognized as a key factor that shapes trial populations and affects validity of results in clinical trials: patient engagement, recruitment, and retention. We outline specific problems relevant to patient engagement in AD including recruiting enough participants, difficulties in participant retention, ensuring the recruited sample is representative of the general AD population, the burden of screening failures, and new challenges related to recruiting in preclinical disease. To address the urgent need for more research studying the applicability and cost-effectiveness of different recruitment strategies across different settings and nationalities, we describe the Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project, a public-private partnership promoted by the Innovative Medicine Initiative (IMI), which will provide a large multinational quantitative analysis comparing different innovative recruitment models. We also discuss strategies that address each problem and draw on the experience of Fundació ACE to argue that focusing resources on comprehensive AD centers that offer coordinated clinical and social care and participate in basic and clinical research, is an effective and efficient way of implementing many of the discussed strategies.

%B J Alzheimers Dis %V 62 %P 1079-1090 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562541?dopt=Abstract %R 10.3233/JAD-170866 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Patients with Dementia in Primary Care: Who Is Referred to a Neurologist/Psychiatrist and What Patient-Oriented Factors Are Associated with the Visit? %A Strohmaier, Urs %A Keller, Felix %A Kilimann, Ingo %A Michalowsky, Bernhard %A Wucherer, Diana %A Zwingmann, Ina %A Teipel, Stefan %A Hoffmann, Wolfgang %A Thyrian, Jochen René %X

BACKGROUND: The current guidelines imply that basic medical diagnostics for dementia should be provided by general practitioners in cooperation with other specialists such as neurologists and psychiatrists.

OBJECTIVES: The aims of this paper were to 1) compare the dementia patients of general practice residents whose care is co-managed by neurology/psychiatry residents with those whose care is not; 2) identify the patient variables associated with the utilization of neurological and psychiatric specialists; and 3) describe the frequency of imaging used for dementia patients in primary care.

METHODS: The analyses utilized data from 485 individuals who screened positive for dementia in primary care (PWD). Clinical variables and the utilization of specialists were assessed via medical records and face-to-face interviews. The factors associated with the utilization of specialists were assessed using multivariate linear regression and included age, sex, relationship status, cognitive impairment, depression, activities of daily living, and formal diagnosis of dementia.

RESULTS: Our results show that 89 out of 485 study participants (18.4%) were referred to specialists 12 months prior to assessment. Of these 89 individuals, 14.6% (n = 13) did not receive imaging diagnostics, while 39.3% (n = 35) received brain imaging by CT scan and 46.1% (n = 41) by MRI. PWD referred to specialists differed from those not referred, in age, relationship status, and the presence of a formal diagnosis. Our multivariate analysis revealed that younger age (OR = 0.95; 95% -confidence interval 0.90-0.99; p = 0.04) and higher functional impairment (OR = 1.15; 95% -confidence interval 1.02-1.30; p = 0.02) were associated with a visit to a specialist.

DISCUSSION: Only 1 out of every 4 to 5 individuals who have screened positive for dementia have visited a specialist in psychiatry or neurology. While in general, women utilized specialists less often than men, younger and more functionally impaired patients were more likely to be sent to a specialist by their treating general practitioner. Almost 90% of the patients sent to a specialist received cranial neuroimaging, suggesting high adherence to diagnostic guidelines in specialized care.

%B J Alzheimers Dis %V 64 %P 925-932 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889067?dopt=Abstract %R 10.3233/JAD-180196 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Patterns of Neuropsychological Dysfunction and Cortical Volume Changes in Logopenic Aphasia. %A Owens, Tyler E %A Machulda, Mary M %A Duffy, Joseph R %A Strand, Edythe A %A Clark, Heather M %A Boland, Sarah %A Martin, Peter R %A Lowe, Val J %A Jack, Clifford R %A Whitwell, Jennifer L %A Josephs, Keith A %X

BACKGROUND: Neuropsychological assessment can add essential information to the characterization of individuals presenting with the logopenic variant of primary progressive aphasia (lvPPA).

OBJECTIVE: This study examined the neuropsychological characteristics of lvPPA patients. We also examined differences in regional and whole brain atrophy based on neuropsychological profiles.

METHODS: We conducted a hierarchical cluster analysis on memory, executive functioning, and visuospatial neuropsychological test data for 56 individuals with lvPPA. We then compared resultant clusters to left middle temporal, inferior parietal, and superior parietal regions-of-interest using multivariate analysis of covariance. We also performed voxel-level analyses.

RESULTS: We identified three clusters characterized as lvPPA with no neurocognitive impairment (n = 5), lvPPA with mild neurocognitive deficits (n = 23), and lvPPA with marked cognitive deficits (n = 28). WAB-AQ was associated with left middle temporal volume. Superior parietal volumes were smaller for the lvPPA group with marked cognitive symptoms compared to the less severe groups. Voxel-level analyses showed greater atrophy in temporal, parietal, lateral occipital, and frontal regions, left worse than right. Age, disease duration, gender, WAB-AQ, and PiB-PET did not account for differences between groups.

CONCLUSIONS: LvPPA patients without cognitive deficits in other domains were relatively uncommon while 50% of our sample exhibited pronounced neurocognitive deficits outside the language domain. Pronounced cognitive deficits in lvPPA are associated with widespread atrophy, left worse than right. Our study underscores the importance of examining neuropsychological function in addition to language in patients with lvPPA.

%B J Alzheimers Dis %V 66 %P 1015-1025 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30372673?dopt=Abstract %R 10.3233/JAD-171175 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Patterns of Physical Activity and Sedentary Behavior for Older Adults with Alzheimer's Disease, Mild Cognitive Impairment, and Cognitively Normal in Hong Kong. %A Lu, Zhihui %A Harris, Tamara B %A Shiroma, Eric J %A Leung, Jason %A Kwok, Timothy %X

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, and mild cognitive impairment (MCI) is a transitional phase between healthy cognition and dementia. Physical activity (PA) has protective effects on cognitive decline. However, few studies have examined how PA and sedentary behavior is structured throughout the day in older adults across varied cognitive status in Hong Kong.

OBJECTIVE: This study aimed to compare patterns of PA and sedentary behavior among individuals with AD, MCI, or normal cognition living in Hong Kong.

METHODS: Participants in the MrOs and MsOs Hong Kong cohort study and the Hong Kong AD biomarker study (n = 810) wore a wrist-worn accelerometer for 7 days in free-living environment. Patterns of PA in wake time and in-bed time, and detailed analysis of sedentary bouts were compared between groups using analysis of covariance adjusting for covariates.

RESULTS: Participants with MCI and low MoCA only did not differ from their cognitively normal peers in PA and sedentary behavior. Nevertheless, when comparing to the others, participants with AD exhibited significantly lower average daily counts per minute during the day (p < 0.05), and tended to start their activity later in the morning. AD participants spent a larger proportion of time in sedentary behavior (p < 0.05) and had more sedentary bouts≥30 minutes (p < 0.05).

CONCLUSIONS: The pattern of PA and sedentary behavior was different between individuals with AD and the others. Cognitive status may alter the purpose and type of PA intervention for AD individuals.

%B J Alzheimers Dis %V 66 %P 1453-1462 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412502?dopt=Abstract %R 10.3233/JAD-180805 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Patterns of Regional Cerebral Blood Flow as a Function of Age Throughout the Lifespan. %A Amen, Daniel G %A Egan, Sachit %A Meysami, Somayeh %A Raji, Cyrus A %A George, Noble %X

BACKGROUND: Understanding the influence of aging on the brain remains a challenge in determining its role as a risk factor for Alzheimer's disease.

OBJECTIVE: To identify patterns of aging in a large neuroimaging cohort.

METHODS: A large psychiatric cohort of 31,227 individuals received brain SPECT at rest and during a concentration task for a total of 62,454 scans. ANOVA was done to identify the mean age trends over the course of the age range in this group, 0- 105 years. A regression model in which brain SPECT regions of interest was used to predict chronological age (CA) was then utilized to derive brain estimated age (BEA). The difference between CA and BEA was calculated to determine increased brain aging in common disorders in our sample such as depression, dementia, substance use, and anxiety.

RESULTS: Throughout the lifespan, variations in perfusion were observed in childhood, adolescence, and late life. Increased brain aging was seen in alcohol use, cannabis use, anxiety, bipolar, schizophrenia, attention-deficit/hyperactivity disorder, and in men.

CONCLUSION: Brain SPECT can predict chronological age and this feature varies as a function of common psychiatric disorders.

%B J Alzheimers Dis %8 2018 Aug 03 %G eng %R 10.3233/JAD-180598 %0 Journal Article %J J Alzheimers Dis %D 2018 %T PCSK9 Concentrations in Cerebrospinal Fluid Are Not Specifically Increased in Alzheimer's Disease. %A Courtemanche, Hélène %A Bigot, Edith %A Pichelin, Matthieu %A Guyomarch, Béatrice %A Boutoleau-Bretonnière, Claire %A Le May, Cédric %A Derkinderen, Pascal %A Cariou, Bertrand %X

The role of PCSK9 in Alzheimer's disease (AD) is controversial. We compared cerebrospinal fluid (CSF) PCSK9 concentrations in 36 AD and 31 non-AD patients. CSF PCSK9 levels did not differ between AD and non-AD groups (2.80 versus 2.62 ng/mL). However, PCSK9 CSF levels were increased in AD and non-AD patients with other neurodegenerative process (non-AD ND, n = 20) compared to patients without neurodegenerative disorders (non-ND, n = 11): 2.80 versus 2.30 (p < 0.005) and 2.83 versus 2.30 ng/mL (p = NS), respectively. CSF PCSK9 were positively correlated with AD biomarkers (Aβ1-42, T-tau, and P-tau). PCSK9 concentrations in CSF are increased in neurodegenerative disorders rather than specifically in AD.

%B J Alzheimers Dis %V 62 %P 1519-1525 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562508?dopt=Abstract %R 10.3233/JAD-170993 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Periodontal Pathogens and Associated Intrathecal Antibodies in Early Stages of Alzheimer's Disease. %A Laugisch, Oliver %A Johnen, Andreas %A Maldonado, Alejandra %A Ehmke, Benjamin %A Bürgin, Walter %A Olsen, Ingar %A Potempa, Jan %A Sculean, Anton %A Duning, Thomas %A Eick, Sigrun %X

BACKGROUND: Recent studies suggest a link between periodontitis and Alzheimer's disease (AD).

OBJECTIVE: Verification of the presence of periodontal pathogens and the intrathecal generation of pathogen-specific antibodies in 20 patients with AD and 20 with other forms of dementia (DEM-noAD).

METHODS: Clinical periodontal indices were recorded. Cerebrospinal fluid (CSF) was analyzed for total tau protein (T-tau) and amyloid-β (Aβ1-42). In serum and CSF, antibody levels against Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Treponema species were quantified. The presence of selected bacteria and inflammatory biomarkers were determined in periodontium, serum, and CSF.

RESULTS: In line with diagnoses, CSF-levels of Aβ1-42 were significantly lower in AD than DEM-noAD patients. Periodontal destruction and inflammation were omnipresent with no difference between groups. P. gingivalis, T. forsythia, and Treponema species were detected in more than 50% of subgingival biofilm samples, but neither in serum nor in the CSF. Elevated levels of anti-pathogen antibodies in CSF of 16 patients (7 AD; 9 DEM-noAD) compared to serum highlight a possibility of the intrathecal immune response to pathogens. There was no significant difference in antibodies levels against selected bacteria in CSF and serum between groups. Multivariate regression analysis and general linear models revealed an association of the T-tau level in AD group with both serum levels of anti-P. gingivalis antibodies and MCP-1/CCL-2.

CONCLUSION: Periodontal pathogens may enter the brain and stimulate a local immune response. However, in patients with dementia at the age up to 70 years, periodontal pathogens do not act as a trigger for developing AD.

%B J Alzheimers Dis %V 66 %P 105-114 %8 2018 Oct 16 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30223397?dopt=Abstract %R 10.3233/JAD-180620 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Personality Modulates the Efficacy of Art Intervention on Chronic Pain in a Population of Patients with Alzheimer's Disease. %A Rouch, Isabelle %A Pongan, Elodie %A Leveque, Yohana %A Tillmann, Barbara %A Trombert, Béatrice %A Getenet, Jean Claude %A Auguste, Nicolas %A Krolak-Salmon, Pierre %A Laurent, Bernard %A Dorey, Jean-Michel %X

BACKGROUND: Alzheimer's disease (AD) mainly occurs in elderly individuals. Comorbidities and chronic pain are frequent in this population. Previous studies revealed that personality modulates both chronic pain (CP) andADoccurrence and evolution. Moreover, as pain treatments can induce side-effects, non-drugs treatments, such as art interventions, are interesting alternative therapies for decreasing CP in these patients.

OBJECTIVE: Our aim was to assess the potential role of personality traits on art intervention efficacy for reducing CP in a population of patients with mild AD.

METHODS: Design: multicenter randomized controlled trial. Fifty mild AD patients underwent a 12-week art intervention including singing and painting groups. Personality was assessed with the Big Five Inventory before the sessions. CP was measured with Numeric Rating Scale (NRS) [Usual pain (NRS-U) and most Intense pain (NRS-I)], Simple Visual Scale [Usual pain (SVS-U) and most Intense pain (SVS-I)] and Brief Pain Inventory (BPI) before and after the sessions. The influence of personality traits on CP evolution before and after art intervention was assessed with multiple linear regression models.

RESULTS: A positive association was observed between neuroticism and the evolution of three CP measures including NRS-U (B = 0.34, p = 0.01), SVS-U (B = 0.20, p = 0.04), and BPI-U (B = 0.46, p = 0.02) evolution. No significant relationship was observed between neuroticism and NRS-I, SVS-I and BPI-R evolution.

CONCLUSIONS: Our findings suggest that neuroticism can decrease the efficacy of group art intervention on pain in patients with mild AD. Individual therapies could be more appropriate for these patients. These results emphasize the interest of taking into account patients' personality before proposing them to participate to a group therapy.

%B J Alzheimers Dis %V 63 %P 617-624 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660937?dopt=Abstract %R 10.3233/JAD-170990 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Perspectives on Communicating Biomarker-Based Assessments of Alzheimer's Disease to Cognitively Healthy Individuals. %A Milne, Richard %A Bunnik, Eline %A Diaz, Ana %A Richard, Edo %A Badger, Shirlene %A Gove, Dianne %A Georges, Jean %A Fauria, Karine %A Molinuevo, Jose-Luis %A Wells, Katie %A Ritchie, Craig %A Brayne, Carol %K Adult %K Aged %K Alzheimer Disease %K Biomarkers %K Caregivers %K Disclosure %K Female %K Focus Groups %K Humans %K Male %K Middle Aged %K Qualitative Research %K Risk Factors %K Spain %K United Kingdom %X

In clinical trials which target pathophysiological mechanisms associated with Alzheimer's disease, research participants who are recruited based on biomarker test results should be informed about their increased risk of developing Alzheimer's dementia. This paper presents the results of a qualitative focus group study of attitudes and concerns toward learning information about biomarker-based risk status among healthy research participants in the United Kingdom and Spain and people with dementia and their supporters/caregivers from countries represented in the European Working Group of People with Dementia of Alzheimer Europe. The study identified expectations related to learning risk status and preferences related to the content, quality, and follow-up of the disclosure process. The latter emphasize distinctions between risk and diagnoses, the importance of clear information about risk, and suggestions for risk reduction, as well as expectations for follow up and support. The implications of these preferences for practice are discussed. Providing details of research participants' experience and views may serve as a guide for the development of processes for the responsible disclosure of Alzheimer's disease biomarkers.

%B J Alzheimers Dis %V 62 %P 487-498 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170813?id=journal-of-alzheimers-disease%2Fjad170813 %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480179?dopt=Abstract %R 10.3233/JAD-170813 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Perspectives on Oxidative Stress in Alzheimer's Disease and Predictions of Future Research Emphases. %A Butterfield, D Allan %X

Oxidative stress, an overproduction of free radicals or a diminution of free radical scavenging ability relative to those of cognitively aged-matched controls, is widely recognized as a critical component of the pathogenesis and progression of Alzheimer's disease (AD). This recognition arose in significant part from the work in the author's laboratory, complemented by research from others' laboratories. The Butterfield laboratory discovered the oxidative stress associated with oligomeric amyloid-β peptide manifested primarily as elevated oxidative modification of proteins and peroxidation of lipids. Such oxidative damage caused neuronal death, which undoubtedly underlies the progressive loss of cognition in AD. Identification of specific oxidatively modified brain proteins in subjects with AD or amnestic mild cognitive impairment was achieved by the methods of redox proteomics, pioneered in the author's laboratory. The importance and significance of the research emanating from the Butterfield laboratory rest on the paradigm shift of thinking regarding the roles of oxidative stress and resulting damage to key proteins and biochemical pathways in the pathogenesis and progression of AD. Predictions of future research directions also are presented. Given the enormous financial and personal burden placed upon citizens (and governments) of the US from AD, and the surety that the number of AD patients will greatly increase over the next 20-30 years, greater understanding of the molecular basis of pathogenesis and progression of AD is essential. Our laboratory is privileged to have contributed to better understanding of AD and provided rationales to identify effective therapeutic targets for this devastating dementing disorder.

%B J Alzheimers Dis %V 64 %P S469-S479 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504538?dopt=Abstract %R 10.3233/JAD-179912 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Phenomenological Characteristics of Future Thinking in Alzheimer's Disease. %A Moustafa, Ahmed A %A El Haj, Mohamad %X

This study investigates phenomenological reliving of future thinking in Alzheimer's disease (AD) patients and matched controls. All participants were asked to imagine in detail a future event, and afterward, were asked to rate phenomenological characteristics of their future thinking. As compared to controls, AD participants showed poor rating for reliving, travel in time, visual imagery, auditory imagery, language, and spatiotemporal specificity. However, no significant differences were observed between both groups in emotion and importance of future thinking. Results also showed lower rating for visual imagery relative to remaining phenomenological features in AD participants compared to controls; conversely, these participants showed higher ratings for emotion and importance of future thinking. AD seems to compromise some phenomenological characteristics of future thinking, especially, visual imagery; however, other phenomenological characteristics, such as emotion, seem to be relatively preserved in these populations. By highlighting the phenomenological experience of future thinking in AD, our paper opens a unique window into the conscious experience of the future in AD patients.

%B J Alzheimers Dis %V 63 %P 1279-1287 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758947?dopt=Abstract %R 10.3233/JAD-180182 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Physical Activity and Hippocampal Sub-Region Structure in Older Adults with Memory Complaints. %A Siddarth, Prabha %A Rahi, Berna %A Emerson, Natacha D %A Burggren, Alison C %A Miller, Karen J %A Bookheimer, Susan %A Lavretsky, Helen %A Dobkin, Bruce %A Small, Gary %A Merrill, David A %K Aged %K Aged, 80 and over %K Cognition %K Cross-Sectional Studies %K Executive Function %K Exercise %K Female %K Geriatric Assessment %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Memory %K Memory Disorders %K Middle Aged %K Neuropsychological Tests %X

BACKGROUND: Physical activity (PA) plays a major role in maintaining cognition in older adults. PA has been shown to be correlated with total hippocampal volume, a memory-critical region within the medial temporal lobe (MTL). However, research on associations between PA and MTL sub-region integrity is limited.

OBJECTIVE: To examine the relationship between PA, MTL thickness, and its sub-regions, and cognitive function in non-demented older adults with memory complaints.

METHODS: Twenty-nine subjects aged ≥60 years, with memory complaints were recruited for this cross-sectional study. PA was tracked for 7 days using accelerometers, and average number of steps/day determined. Subjects were categorized into two groups: those who walked ≤4000 steps/day (lower PA) and those with >4000 steps/day (higher PA). Subjects received neuropsychological testing and 3T MRI scans. Nonparametric ANCOVAs controlling for age examined differences between the two groups.

RESULTS: Twenty-six subjects aged 72.7(8.1) years completed the study. The higher PA group (n = 13) had thicker fusiform gyrus (median difference = 0.11 mm, effect size (ES) = 1.43, p = 0.001) and parahippocampal cortex (median difference = 0.12 mm, ES = 0.93, p = 0.04) compared to the lower PA group. The higher PA group also exhibited superior performance in attention and information-processing speed (median difference = 0.90, ES = 1.61, p = 0.003) and executive functioning (median difference = 0.97, ES = 1.24, p = 0.05). Memory recall was not significantly different between the two groups.

CONCLUSION: Older non-demented individuals complaining of memory loss who walked >4000 steps each day had thicker MTL sub-regions and better cognitive functioning than those who walked ≤4000 steps. Future studies should include longitudinal analyses and explore mechanisms mediating hippocampal related atrophy.

%B J Alzheimers Dis %V 61 %P 1089-1096 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254088?dopt=Abstract %R 10.3233/JAD-170586 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Physical Fitness and Aortic Stiffness Explain the Reduced Cognitive Performance Associated with Increasing Age in Older People. %A Kennedy, Greg %A Meyer, Denny %A Hardman, Roy J %A Macpherson, Helen %A Scholey, Andrew B %A Pipingas, Andrew %X

BACKGROUND: Greater physical fitness is associated with reduced rates of cognitive decline in older people; however, the mechanisms by which this occurs are still unclear. One potential mechanism is aortic stiffness, with increased stiffness resulting in higher pulsatile pressures reaching the brain and possibly causing progressive micro-damage. There is limited evidence that those who regularly exercise may have lower aortic stiffness.

OBJECTIVE: To investigate whether greater fitness and lower aortic stiffness predict better cognitive performance in older people and, if so, whether aortic stiffness mediates the relationship between fitness and cognition.

METHODS: Residents of independent living facilities, aged 60-90, participated in the study (N = 102). Primary measures included a computerized cognitive assessment battery, pulse wave velocity analysis to measure aortic stiffness, and the Six-Minute Walk test to assess fitness. Based on hierarchical regression analyses, structural equation modelling was used to test the mediation hypothesis.

RESULTS: Both fitness and aortic stiffness independently predicted Spatial Working Memory (SWM) performance, however no mediating relationship was found. Additionally, the derived structural equation model shows that, in conjunction with BMI and sex, fitness and aortic stiffness explain 33% of the overall variation in SWM, with age no longer directly predicting any variation.

CONCLUSIONS: Greater fitness and lower aortic stiffness both independently predict better SWM in older people. The strong effect of age on cognitive performance is totally mediated by fitness and aortic stiffness. This suggests that addressing both physical fitness and aortic stiffness may be important to reduce the rate of age associated cognitive decline.

%B J Alzheimers Dis %V 63 %P 1307-1316 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865082?dopt=Abstract %R 10.3233/JAD-171107 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Phytochemicals from Achillea fragrantissima are Modulators of AβPP Metabolism. %A Bartolotti, Nancy %A Disouky, Ahmed %A Kalinski, Arthur %A Elmann, Anat %A Lazarov, Orly %X

Plant derivatives offer a novel and natural source of therapeutics. The desert plant Achillea fragrantissima (Forssk) Sch. Bip (Af) is characterized by protective antioxidative and anti-inflammatory properties. Here, we examined the effect of two Af-derived phytochemicals on learning and memory, amyloid-β protein precursor (AβPP) metabolism, and tau phosphorylation in the familial Alzheimer's disease-linked APPswe/PS1ΔE9 mouse model. We observed that mice that were injected with the phytochemicals showed a trend of improvement, albeit statistically insignificant, in the Novel Object Recognition task. However, we did not observe improvement in contextual fear conditioning, suggesting that the benefits of treatment may be either indirect or task-specific. In addition, we observed an increase in the full-length form of AβPP in the brains of mice treated with Af-derived phytochemicals. Interestingly, both in vivo and in vitro, there was no change in levels of soluble Aβ, oligomeric Aβ, or the carboxyl terminus fragments of AβPP (APP-CTFs), suggesting that the increase in full length AβPP does not exacerbate AβPP pathology, but may stabilize the full-length form of the molecule. Together, our data suggest that phytochemicals present in Af may have a modest positive impact on the progression of Alzheimer's disease.

%B J Alzheimers Dis %V 66 %P 1425-1435 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400087?dopt=Abstract %R 10.3233/JAD-180068 %0 Journal Article %J J Alzheimers Dis %D 2018 %T PICALM Gene Methylation in Blood of Alzheimer's Disease Patients Is Associated with Cognitive Decline. %A Mercorio, Roberta %A Pergoli, Laura %A Galimberti, Daniela %A Favero, Chiara %A Carugno, Michele %A Dalla Valle, Elisabetta %A Barretta, Francesco %A Cortini, Francesca %A Scarpini, Elio %A Valentina, Valentina Bollati %A Pesatori, Angela Cecilia %X

Epigenetic mechanisms might be involved in Alzheimer's disease (AD). Genetic polymorphisms in several genes, including APOE (Apolipoprotein E), PSEN1 (Presenilin 1), CR1 (Complement receptor 1), and PICALM (Phosphatidylinositol binding clathrin assembly protein), have been associated to an increased AD risk. However, data regarding methylation of these specific genes are lacking. We evaluated DNA methylation measured by quantitative bisulfite-PCR pyrosequencing in 43 AD patients and 38 healthy subjects (HS). In a multivariate age- and gender-adjusted model, PICALM methylation was decreased in AD compared to HS (mean = 3.54 and 4.63, respectively, p = 0.007). In AD, PICALM methylation level was also positively associated to Mini-Mental Scale Examination (MMSE) score (percent change 3.48%, p = 0.008). Moreover, a negative association between PICALM methylation and age was observed only in HS (percent change - 2.29%, p = 0.002). In conclusion, our data suggest a possible role of PICALM methylation in AD, particularly related to cognitive function. Given the small study sample and the associative nature of our study, further prospective investigations are required to assess the dynamics of DNA methylation in the early stages of AD development.

%B J Alzheimers Dis %V 65 %P 283-292 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040717?dopt=Abstract %R 10.3233/JAD-180242 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Pink1 Regulates Tyrosine Hydroxylase Expression and Dopamine Synthesis. %A Lu, Lingling %A Jia, Huanzhen %A Gao, Ge %A Duan, Chunli %A Ren, Jing %A Li, Yi %A Yang, Hui %X

PTEN induced putative kinase 1 (PINK1), also known as PARK6, is causally linked to familial Parkinsonism, and heterozygous loss of PINK1 is a risk factor for sporadic Parkinson's disease. However, little is known about its physiological function. Its deficiency was shown to decrease dopamine without significant loss of dopaminergic neurons. We investigated the mechanistic basis for this observation in the present study using dopaminergic MN9D cells. We found that PINK1 knockdown resulted in dopamine content to decrease with suppressed tyrosine hydroxylase expression in cells. Conversely, PINK1 overexpression increased tyrosine hydroxylase protein level. We also found that PINK1 deficiency blocked the nuclear translocation and activity of nuclear receptor-related 1, a transcription factor regulating tyrosine hydroxylase gene expression. These data suggest that PINK1 regulates tyrosine hydroxylase gene expression and dopamine content by modulating the transcriptional activity of nuclear receptor-related 1. Taken together, our results reveal a novel function of PINK1 in dopamine homeostasis.

%B J Alzheimers Dis %V 63 %P 1361-1371 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843233?dopt=Abstract %R 10.3233/JAD-170832 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Plasma Amyloid-β (Aβ42) Correlates with Cerebrospinal Fluid Aβ42 in Alzheimer's Disease. %A Teunissen, Charlotte E %A Chiu, Ming-Jang %A Yang, Che-Chuan %A Yang, Shieh-Yueh %A Scheltens, Philip %A Zetterberg, Henrik %A Blennow, Kaj %X

The 42 amino acid form of amyloid-β (Aβ42) plays a key role in the pathogenesis of Alzheimer's disease (AD) and is a core biomarker for the diagnosis of AD. Numerous studies have shown that cerebrospinal fluid (CSF) Aβ42 concentrations are decreased in AD, when measured by enzyme-linked immunosorbent assay (ELISA) and other conventional immunoassays. While most studies report no change in plasma Aβ42, independent studies using the immunomagnetic reduction (IMR) technique report an increase in plasma Aβ42 levels in AD. To confirm the opposite changes of Aβ42 levels in CSF and plasma for AD, we assayed the levels of Aβ42 in plasma of subjects with known CSF Aβ42 levels. In total 43 controls and 63 AD patients were selected at two sites: the VU University Medical Center (n = 55) and Sahlgrenska University Hospital (n = 51). IMR and ELISA were applied to assay Aβ42 in plasma and CSF, respectively. We found a moderately negative correlation between plasma and CSF Aβ42 levels in AD patients (r = -0.352), and a weakly positive correlation in controls (r = 0.186). These findings further corroborate that there are opposite changes of Aβ42 levels in CSF and plasma in AD. The possible causes for the negative correlation are discussed by taken assay technologies, Aβ42 transport from brain to peripheral blood, and sample matrix into account.

%B J Alzheimers Dis %V 62 %P 1857-1863 %8 2018 Mar 27 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614646?dopt=Abstract %R 10.3233/JAD-170784 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Plasma Antioxidant Status in Patients with Alzheimer's Disease and Cognitively Intact Elderly: A Meta-Analysis of Case-Control Studies. %A Mullan, Kathryn %A Cardwell, Chris R %A McGuinness, Bernadette %A Woodside, Jayne V %A McKay, Gareth J %X

Serum antioxidants may afford neuroprotection against Alzheimer's disease (AD) via correction of the pro-oxidative imbalance but findings reported have been inconsistent. We compared the pooled mean difference in serum levels of ten dietary antioxidants between patients with AD and cognitively intact controls from 52 studies in meta-analyses using random-effects models. Patients with AD had significantly lower plasma levels of α-carotene, β-carotene, lycopene, lutein, vitamin A, C, and E, and uric acid. No significant difference was observed for plasma levels of β-cryptoxanthin and zeaxanthin. Considerable heterogeneity was detected across studies. The lower serum levels of dietary antioxidants from the carotene and vitamin subclasses observed in individuals with AD suggest reduced systemic availability of these subclasses in this prevalent form of dementia. To our knowledge, these are the first meta-analyses to demonstrate lower serum lycopene and to evaluate β-cryptoxanthin, lutein, and zeaxanthin levels in AD. In light of the significant heterogeneity detected across studies, caution should be exercised in the interpretation of the data and therapeutic intervention approaches considered through supplementation measures. Our data may better inform interventions to improve antioxidant status in a condition of major public health importance.

%B J Alzheimers Dis %V 62 %P 305-317 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439339?dopt=Abstract %R 10.3233/JAD-170758 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Platelets: Peripheral Biomarkers of Dementia? %A Akingbade, Oluwatomi E S %A Gibson, Claire %A Kalaria, Raj N %A Mukaetova-Ladinska, Elizabeta B %X

Dementia continues to be the most burdening neurocognitive disorder, having a negative impact on the lives of millions. The search for biomarkers to improve the clinical diagnosis of dementia is ongoing, with the focus on effective use of readily accessible peripheral markers. In this review, we concentrate on platelets as biomarkers of dementia and analyze their potential as easily-accessible clinical biomarkers for various subtypes of dementia. Current platelet protein biomarkers that have been investigated for their clinical utility in the diagnosis of dementia, in particular Alzheimer's disease, include amyloid-β protein precursor (AβPP), the AβPP secretases (BACE1 and ADAM10), α-synuclein, tau protein, serotonin, cholesterol, phospholipases, clusterin, IgG, surface receptors, MAO-B, and coated platelets. Few of them, i.e., platelet tau, AβPP (particularly with regards to coated platelets) and secreted ADAM10 and BACE1 show the most promise to be taken forward into clinical setting to diagnose dementia. Aside from protein biomarkers, changes in factors such as mean platelet volume have the potential to play a very specific role in both the dementia diagnosis and prognosis. This review raises a number of research questions for consideration before application of the above biomarkers to routine clinical setting. It is without doubt that there is a need for more clarification on the effects of dementia on platelet morphology and protein content before these changes can be clinically applied as dementia biomarkers and explored further in differentiating distinct dementia subtypes.

%B J Alzheimers Dis %V 63 %P 1235-1259 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843245?dopt=Abstract %R 10.3233/JAD-180181 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Polypharmacy and Potentially Inappropriate Medication in People with Dementia: A Nationwide Study. %A Kristensen, Rachel Underlien %A Nørgaard, Ane %A Jensen-Dahm, Christina %A Gasse, Christiane %A Wimberley, Theresa %A Waldemar, Gunhild %X

BACKGROUND: Polypharmacy (use of ≥5 different medications) and potentially inappropriate medication (PIM) are well-known risk factors for numerous negative health outcomes. However, the use of polypharmacy and PIM in people with dementia is not well-described.

OBJECTIVE: To examine the prevalence of polypharmacy and PIM in older people with and without dementia in a nationwide population.

METHODS: Cross-sectional study of the Danish population aged ≥65 in 2014 (n = 1,032,120) based on register data, including information on diagnoses and dispensed prescriptions. Polypharmacy and PIM use among people with (n = 35,476) and without dementia (n = 994,231) were compared, stratified by living situation and adjusted for age, sex, and comorbidity. The red-yellow-green list from the Danish Institute for Rational Pharmacotherapy and the German PRISCUS list were used to define PIM.

RESULTS: People with dementia were more frequently exposed to polypharmacy (dementia: 62.6% versus no-dementia: 35.1%, p < 0.001) and likewise PIM (red-yellow-green: 45.0% versus 29.7%, p < 0.001; PRISCUS: 24.4% versus 13.2%, p < 0.001). After adjustments for age, sex, and comorbidity, the likelihood of polypharmacy and PIM was higher for community-dwelling people with dementia than without dementia (odds ratio (OR); [95% confidence interval (CI)] polypharmacy: 1.50 [1.45-1.55]; red-yellow-green: 1.27 [1.23-1.31]; PRISCUS: 1.25 [1.20-1.30]). In contrast, dementia slightly decreased the odds of polypharmacy and PIM in nursing home residents.

CONCLUSION: Use of polypharmacy and PIM were widespread in the older population and more so in people with dementia. This could have negative implications for patient-safety and demonstrates the need for interventions to improve drug therapy in people with dementia.

%B J Alzheimers Dis %V 63 %P 383-394 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578483?dopt=Abstract %R 10.3233/JAD-170905 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Positive Effects of Viewing Gardens for Persons with Dementia. %A Goto, Seiko %A Shen, Xuting %A Sun, Minkai %A Hamano, Yutaka %A Herrup, Karl %X

Dementia is highly prevalent among the worldwide elderly population. Only a small number of the currently marketed drugs are effective in controlling its symptoms, and none has any effect on its progression. Further, as the condition advances, even these pharmaceuticals lose their efficiency, and new research into interventions that might improve the life quality of patients at the end stage of dementia and their families is increasingly rare. In our previous studies, we explored the benefits of exposure to nature, in the form of a Japanese garden, for persons with advanced dementia. In the current work, we extended our observations to two new locations and a new set of subjects with a different ethnic composition with the goal of identifying interventions that might improve their quality of life. We found that, even in these new settings, garden observation not only relieved physiological stress, it improved qualitative measures such as verbalization and memory retrieval. We present data that viewing the garden is a holistic experience rather a solely visual stimulus. Our new data further support the conclusion that garden observation is worth including in the care planning schedule of advanced dementia patients. Its low cost and easy availability make it an economical adjunct to current pharmacological methods that has the potential to improve the quality of life of people with dementia.

%B J Alzheimers Dis %V 66 %P 1705-1720 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30507568?dopt=Abstract %R 10.3233/JAD-170510 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Positive Feedback Loops in Alzheimer's Disease: The Alzheimer's Feedback Hypothesis. %A Doig, Andrew J %X

The dominant model for Alzheimer's disease (AD) is the amyloid cascade hypothesis, in which the accumulation of excess amyloid-β (Aβ) leads to inflammation, excess glutamate and intracellular calcium, oxidative stress, tau hyperphosphorylation and tangle formation, neuronal loss, and ultimately dementia. In a cascade, AD proceeds in a unidirectional fashion, with events only affecting downstream processes. Compelling evidence now exists for the presence of positive feedback loops in AD, however, involving oxidative stress, inflammation, glutamate, calcium, and tau. The pathological state of AD is thus a system of positive feedback loops, leading to amplification of the initial perturbation, rather than a linear cascade. Drugs may therefore be effective by targeting numerous points within the loops, rather than concentrating on upstream processes. Anti-inflammatories and anti-oxidants may be especially valuable, since these processes are involved in many loops and hence would affect numerous processes in AD.

%B J Alzheimers Dis %V 66 %P 25-36 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282364?dopt=Abstract %R 10.3233/JAD-180583 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Possible Role of Chitin-Like Proteins in the Etiology of Alzheimer's Disease. %A Lomiguen, Christine %A Vidal, Luis %A Kozlowski, Piotr %A Prancan, Arthur %A Stern, Robert %X

Chitin is a β-linked straight chain carbohydrate matrix monopolymer prominent in invertebrates, from fungi to arthropods. Surprisingly, chitin is now documented in vertebrates, including humans, a component of vertebrate physiology that has been neglected until now. Chitin levels are elevated in Alzheimer's disease (AD) patients, not only in the central nervous system but also in the cerebrospinal fluid and plasma. Elevated levels of chitin lectin have been reported in patients with AD. Chitinase activity varies widely in the human population. Chitin levels can increase in individuals with intrinsically low chitinase activity. Elevated amounts of chitin can reflect accumulation of the small chitin fragments that remain wherever rapid hyaluronan synthesis occurs. Another source of chitin may be from remote fungal infections. Chitin can be toxic for neurons, and its accumulation may lead to the development of AD. We present new suggestions for animal models and treatment modalities that could prove useful in future research endeavors. An unexpected connection with Gaucher's disease patients and their heterozygote relatives is also identified. These chitin-related mechanisms are novel approaches to AD whose etiology until now has defied explication.

%B J Alzheimers Dis %V 66 %P 439-444 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282354?dopt=Abstract %R 10.3233/JAD-180326 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Post Traumatic Stress Disorder Heralding the Onset of Semantic Frontotemporal Dementia. %A Bonanni, Laura %A Franciotti, Raffaella %A Martinotti, Giovanni %A Vellante, Federica %A Flacco, Maria Elena %A Di Giannantonio, Massimo %A Thomas, Astrid %A Onofrj, Marco %X

BACKGROUND: Post traumatic stress disorder (PTSD) is associated with cognitive decline. The dementia type following PTSD is unclear.

OBJECTIVE: To assess whether PTSD is associated with a specific dementia.

METHODS: Prospective study: 46 PTSD patients (DSM-IV-TR) were followed for 6-10 years with clinical, neuropsychological, imaging evaluations for possible development of dementia.Retrospective study:849 dementia patients followed during 1999-2014 (509 Alzheimer's disease, AD; 207 dementia with Lewy bodies, DLB; 90 vascular dementia, VaD; 43 frontotemporal dementia, FTD) and 287 patients with any neurological condition (including patients with/without dementia) were evaluated for the presence of PTSD in their history.

RESULTS: Prospective study: 8 patients developed dementia; 1 AD, 1 DLB, 6 semantic FTD (13.0% of the PTSD population). Retrospective study: 38 patients (4.5%) had a history of PTSD; 3.5% of AD, 4.3% of DLB, 14.0% of FTD, 5.6% of VaD. The percentage was higher in FTD than in AD or DLB (χ2 = 10, p = 0.001, and χ2 = 6, p = 0.02). At difference with AD, DLB, or VaD, FTD incidence among dementia patients with PTSD history (38 patients) was higher than in the dementia population overall (16% versus 5%, χ2 = 8, p = 0.005). The impact of possible demographical/clinical confounders (age, gender, MMSE) was excluded by Poisson regression. PTSD prevalence in the comparative group without dementia matched the prevalence in the Italian general population (1.1%). PTSD prevalence in the demented comparative group matched the prevalence in our dementia retrospective cohort, 3.7%).

DISCUSSION: PTSD was associated with the development of semantic FTD.

%B J Alzheimers Dis %V 63 %P 203-215 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614666?dopt=Abstract %R 10.3233/JAD-171134 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Postmortem T2*- Weighted MRI Imaging of Cortical Iron Reflects Severity of Alzheimer's Disease. %A Bulk, Marjolein %A Kenkhuis, Boyd %A Graaf, Linda M van der %A Goeman, Jelle J %A Natté, Remco %A Weerd, Louise van der %X

The value of iron-based MRI changes for the diagnosis and staging of Alzheimer's disease (AD) depends on an association between cortical iron accumulation and AD pathology. Therefore, this study determined the cortical distribution pattern of MRI contrast changes in cortical regions selected based on the known distribution pattern of tau pathology and investigated whether MRI contrast changes reflect the underlying AD pathology in the different lobes. T2*-weighted MRI was performed on postmortem cortical tissue of controls, late-onset AD (LOAD), and early-onset AD (EOAD) followed by histology and correlation analyses. Combining ex vivo high-resolution MRI and histopathology revealed that: 1) LOAD and EOAD have a different distribution pattern of AD pathological hallmarks and MRI contrast changes over the cortex, with EOAD showing more severe MRI changes; 2) per lobe, severity of AD pathological hallmarks correlates with iron accumulation, and hence with MRI. Therefore, iron-sensitive MRI sequences allow detection of the cortical distribution pattern of AD pathology ex vivo.

%B J Alzheimers Dis %8 2018 Aug 07 %G eng %R 10.3233/JAD-180317 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Postsynaptic Proteome of Non-Demented Individuals with Alzheimer's Disease Neuropathology. %A Zolochevska, Olga %A Bjorklund, Nicole %A Woltjer, Randall %A Wiktorowicz, John E %A Taglialatela, Giulio %X

Some individuals, here referred to as Non-Demented with Alzheimer's Neuropathology (NDAN), retain their cognitive function despite the presence of amyloid plaques and tau tangles typical of symptomatic Alzheimer's disease (AD). In NDAN, unlike AD, toxic amyloid-β oligomers do not localize to the postsynaptic densities (PSDs). Synaptic resistance to amyloid-β in NDAN may thus enable these individuals to remain cognitively intact despite the AD-like pathology. The mechanism(s) responsible for this resistance remains unresolved and understanding such protective biological processes could reveal novel targets for the development of effective treatments for AD. The present study uses a proteomic approach to compare the hippocampal postsynaptic densities of NDAN, AD, and healthy age-matched persons to identify protein signatures characteristic for these groups. Subcellular fractionation followed by 2D gel electrophoresis and mass spectrometry were used to analyze the PSDs. We describe fifteen proteins which comprise the unique proteomic signature of NDAN PSDs, thus setting them apart from control subjects and AD patients.

%B J Alzheimers Dis %8 2018 Jul 30 %G eng %R 10.3233/JAD-180179 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Potential Factors Associated with Cognitive Improvement of Individuals Diagnosed with Mild Cognitive Impairment or Dementia in Longitudinal Studies. %A Hadjichrysanthou, Christoforos %A McRae-McKee, Kevin %A Evans, Stephanie %A De Wolf, Frank %A Anderson, Roy M %X

Despite the progressive nature of Alzheimer's disease and other dementias, it is observed that many individuals that are diagnosed with mild cognitive impairment (MCI) in one clinical assessment, may return back to normal cognition (CN) in a subsequent assessment. Less frequently, such 'back-transitions' are also observed in people that had already been diagnosed with later stages of dementia. In this study, an analysis was performed on two longitudinal cohort datasets provided by 1) the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 2) the National Alzheimer's Coordinating Centre (NACC). The focus is on the observed improvement of individuals' clinical condition recorded in these datasets to explore potential associations with different factors. It is shown that, in both datasets, transitions from MCI to CN are significantly associated with younger age, better cognitive function, and the absence of ApoE ɛ4 alleles. Better cognitive function and in some cases the absence of ApoE ɛ4 alleles are also significantly associated with transitions from types of dementia to less severe clinical states. The effect of gender and education is not clear-cut in these datasets, although highly educated people who reach MCI tend to be more likely to show an improvement in their clinical state. The potential effect of other factors such as changes in symptoms of depression is also discussed. Although improved clinical outcomes can be associated with many factors, better diagnostic tools are required to provide insight into whether such improvements are a result of misdiagnosis, and if they are not, whether they are linked to improvements in the underlying neuropathological condition.

%B J Alzheimers Dis %V 66 %P 587-600 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320573?dopt=Abstract %R 10.3233/JAD-180101 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Potential Novel Approaches to Understand the Pathogenesis and Treat Alzheimer's Disease. %A Drummond, Eleanor %A Goñi, Fernando %A Liu, Shan %A Prelli, Frances %A Scholtzova, Henrieta %A Wisniewski, Thomas %X

There is growing genetic and proteomic data highlighting the complexity of Alzheimer's disease (AD) pathogenesis. Greater use of unbiased "omics" approaches is being increasingly recognized as essential for the future development of effective AD research, that need to better reflect the multiple distinct pathway abnormalities that can drive AD pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans. We highlight our recent efforts to increase use of human tissue to gain a better understanding of the AD pathogenesis subtype variety and to develop several distinct therapeutic approaches tailored to address this diversity. These therapeutic approaches include the blocking of the Aβ/apoE interaction, stimulation of innate immunity, and the simultaneous blocking of Aβ/tau oligomer toxicity. We believe that future successful therapeutic approaches will need to be combined to better reflect the complexity of the abnormal pathways triggered in AD pathogenesis.

%B J Alzheimers Dis %V 64 %P S299-S312 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562516?dopt=Abstract %R 10.3233/JAD-179909 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial. %A Wilcock, Gordon K %A Gauthier, Serge %A Frisoni, Giovanni B %A Jia, Jianping %A Hardlund, Jiri H %A Moebius, Hans J %A Bentham, Peter %A Kook, Karin A %A Schelter, Bjoern O %A Wischik, Damon J %A Davis, Charles S %A Staff, Roger T %A Vuksanovic, Vesna %A Ahearn, Trevor %A Bracoud, Luc %A Shamsi, Kohkan %A Marek, Ken %A Seibyl, John %A Riedel, Gernot %A Storey, John M D %A Harrington, Charles R %A Wischik, Claude M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Antipsychotic Agents %K Cohort Studies %K Double-Blind Method %K Female %K Humans %K International Cooperation %K Male %K Mental Status and Dementia Tests %K Methylene Blue %K Middle Aged %K Treatment Outcome %X

BACKGROUND: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation.

OBJECTIVES: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD.

METHODS: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error.

RESULTS: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy.

CONCLUSIONS: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.

%B J Alzheimers Dis %V 61 %P 435-457 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154277?dopt=Abstract %R 10.3233/JAD-170560 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Pramlintide: The Effects of a Single Drug Injection on Blood Phosphatidylcholine Profile for Alzheimer's Disease. %A Tao, Qiushan %A Zhu, Haihao %A Chen, Xi %A Stern, Robert A %A Kowall, Neil %A Au, Rhoda %A Blusztajn, Jan Krzysztof %A Qiu, Wei Qiao %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Female %K Humans %K Islet Amyloid Polypeptide %K Logistic Models %K Male %K Middle Aged %K Phosphatidylcholines %K ROC Curve %K tau Proteins %X

Studies suggest that a single injection of pramlintide, an amylin analog, induces changes in Alzheimer's disease (AD) biomarkers in the blood of AD mouse models and AD patients. The aim of this study was to examine whether a pramlintide challenge combined with a phosphatidylcholine (PC) profile diagnoses of AD and mild cognitive impairment (MCI) better than PC alone. Non-diabetic subjects with cognitive status were administered a single subcutaneous injection of 60 mcg of pramlintide under fasting condition. A total of 71 PCs, amyloid-β peptide (Aβ), and total tau (t-tau) in plasma at different time points were measured and treated as individual variables. A single injection of pramlintide altered the levels of 7 PCs in the blood, while a pramlintide injection plus food modulated the levels of 10 PCs in the blood (p < 0.05). The levels of 2 PCs in MCI and 12 PCs in AD in the pramlintide challenge were significantly lower than the ones in controls. We found that while some PCs were associated with only Aβ levels, other PCs were associated with both Aβ and t-tau levels. A receiver operating characteristic analysis of the PCs was combined with the Aβ and t-tau data to produce an area under the curve predictive value of 0.9799 between MCI subjects and controls, 0.9794 between AD subjects and controls, and 0.9490 between AD and MCI subjects. A combination of AD biomarkers and a group of PCs post a pramlintide challenge may provide a valuable diagnostic and prognostic test for AD and MCI.

%B J Alzheimers Dis %V 62 %P 597-609 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480193?dopt=Abstract %R 10.3233/JAD-170948 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Precision Medicine Model for Targeted NSAID Therapy in Alzheimer's Disease. %A O'Bryant, Sid E %A Zhang, Fan %A Johnson, Leigh A %A Hall, James %A Edwards, Melissa %A Grammas, Paula %A Oh, Esther %A Lyketsos, Constantine G %A Rissman, Robert A %X

BACKGROUND: To date, the therapeutic paradigm for Alzheimer's disease (AD) has focused on a single intervention for all patients. However, a large literature in oncology supports the therapeutic benefits of a precision medicine approach to therapy. Here we test a precision-medicine approach to AD therapy.

OBJECTIVE: To determine if a baseline, blood-based proteomic companion diagnostic predicts response to NSAID therapy.

METHODS: Proteomic assays of plasma from a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to rofecoxib (25 mg once daily), naproxen (220 mg twice-daily) or placebo.

RESULTS: 474 participants with mild-to-moderate AD were screened with 351 enrolled into the trial. Using support vector machine (SVM) analyses, 89% of the subjects randomized to either NSAID treatment arms were correctly classified using a general NSAID companion diagnostic. Drug-specific companion diagnostics yielded 98% theragnostic accuracy in the rofecoxib arm and 97% accuracy in the naproxen arm.

CONCLUSION: Inflammatory-based companion diagnostics have significant potential to identify select patients with AD who have a high likelihood of responding to NSAID therapy. This work provides empirical support for a precision medicine model approach to treating AD.

%B J Alzheimers Dis %V 66 %P 97-104 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30198872?dopt=Abstract %R 10.3233/JAD-180619 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Preclinical Alzheimer's Disease: Implications for Refinement of the Concept. %A Vos, Stephanie J B %A Visser, Pieter Jelle %X

Increasing interest in clinical trials and clinical research settings to identify Alzheimer's disease (AD) in the earliest stages of the disease has led to the concept of preclinical AD. Individuals with preclinical AD have AD pathology without clinical symptoms yet. Accumulating evidence has shown that biomarkers can identify preclinical AD and that preclinical AD is associated with a poor clinical outcome. Little is known yet about the role of vascular and lifestyle risk factors in the development of preclinical AD. In order to better understand preclinical AD pathology and clinical progression rates, there is a need to refine the concept of preclinical AD. This will be of great value for advancements in future research, clinical trials, and eventually clinical practice.

%B J Alzheimers Dis %V 64 %P S213-S227 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865060?dopt=Abstract %R 10.3233/JAD-179943 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease: Structural Brain Biomarkers. %A Marizzoni, Moira %A Ferrari, Clarissa %A Jovicich, Jorge %A Albani, Diego %A Babiloni, Claudio %A Cavaliere, Libera %A Didic, Mira %A Forloni, Gianluigi %A Galluzzi, Samantha %A Hoffmann, Karl-Titus %A Molinuevo, José Luis %A Nobili, Flavio %A Parnetti, Lucilla %A Payoux, Pierre %A Ribaldi, Federica %A Rossini, Paolo Maria %A Schönknecht, Peter %A Soricelli, Andrea %A Hensch, Tilman %A Tsolaki, Magda %A Visser, Pieter Jelle %A Wiltfang, Jens %A Richardson, Jill C %A Bordet, Régis %A Blin, Olivier %A Frisoni, Giovanni B %X

BACKGROUND: Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients.

OBJECTIVE: To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression.

METHODS: APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers.

RESULTS: Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction).

CONCLUSION: MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs.

%B J Alzheimers Dis %8 2018 Jun 09 %G eng %R 10.3233/JAD-180152 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Predicting Imminent Progression to Clinically Significant Memory Decline Using Volumetric MRI and FDG PET. %A Stonnington, Cynthia M %A Chen, Yinghua %A Savage, Cary R %A Lee, Wendy %A Bauer Iii, Robert J %A Sharieff, Sameen %A Thiyyagura, Pradeep %A Alexander, Gene E %A Caselli, Richard J %A Locke, Dona E C %A Reiman, Eric M %A Chen, Kewei %X

BACKGROUND: Brain imaging measurements can provide evidence of possible preclinical Alzheimer's disease (AD). Their ability to predict individual imminent clinical conversion remains unclear.

OBJECTIVE: To investigate the ability of pre-specified volumetric magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) measurements to predict which cognitively unimpaired older participants would subsequently progress to amnestic mild cognitive impairment (aMCI) within 2 years.

METHODS: From an apolipoprotein E4 (APOE4) enriched prospective cohort study, 18 participants subsequently progressed to the clinical diagnosis of aMCI or probable AD dementia within 1.8±0.8 years (progressors); 20 participants matched for sex, age, education, and APOE allele dose remained cognitively unimpaired for at least 4 years (nonprogressors). A complementary control group not matched for APOE allele dose included 35 nonprogressors. Groups were compared on baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD and by voxel-wise differences in regional gray matter volume and glucose metabolism. Receiver Operating Characteristic, binary logistic regression, and leave-one-out procedures were used to predict clinical outcome for the a priori measures.

RESULTS: Compared to non-progressors and regardless of APOE-matching, progressors had significantly reduced baseline MRI and PET measurements in brain regions preferentially affected by AD and reduced hippocampal volume was the strongest predictor of an individual's imminent progression to clinically significant memory decline (79% sensitivity/78% specificity among APOE-matched cohorts).

CONCLUSION: Regional MRI and FDG-PET measurements may be useful in predicting imminent progression to clinically significant memory decline.

%B J Alzheimers Dis %8 2018 Apr 04 %G eng %R 10.3233/JAD-170852 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prediction and Early Detection of Alzheimer's Dementia: Professional Disclosure Practices and Ethical Attitudes. %A Schweda, Mark %A Kögel, Anna %A Bartels, Claudia %A Wiltfang, Jens %A Schneider, Anja %A Schicktanz, Silke %X

BACKGROUND: Biomarker-supported testing for preclinical and prodromal Alzheimer's disease (AD) finds its way into clinical practice. Professional attitudes and practices regarding disclosure and ethical issues are controversial in many countries.

OBJECTIVES: Against this background, the objective was to survey the actual practice and the attitudes of physicians in German hospitals and memory clinics in order to explore possible practical insecurities and ethical concerns.

METHODS: A detailed survey with 37 items was conducted among medical professionals at German hospitals and memory clinics (n = 108). Analyses were performed using SPSS 21.0 (IBM). Findings were based on frequency and percentage distribution.

RESULTS: Nearly half of the respondents stated that persons with mild cognitive impairment and pathological cerebrospinal fluid biomarkers were informed they had or would soon develop AD. While 81% acknowledged a 'right not to know', 75% said that results were always communicated. A majority agreed there was a benefit of prediction or later life planning [end-of-life, financial, family, housing (73-75%)] but also expected high psychological stress (82%) and self-stigmatization (70%) for those tested.

CONCLUSIONS: There is considerable heterogeneity and insecurity regarding prediction and early detection in the context of AD in Germany. Information of professionals and standardization of professional testing and disclosure practices are needed.

%B J Alzheimers Dis %V 62 %P 145-155 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439325?dopt=Abstract %R 10.3233/JAD-170443 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prediction of Alzheimer's Dementia in Patients with Amnestic Mild Cognitive Impairment in Clinical Routine: Incremental Value of Biomarkers of Neurodegeneration and Brain Amyloidosis Added Stepwise to Cognitive Status. %A Lange, Catharina %A Suppa, Per %A Pietrzyk, Uwe %A Makowski, Marcus R %A Spies, Lothar %A Peters, Oliver %A Buchert, Ralph %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloidosis %K Brain %K Cognitive Dysfunction %K Female %K Fluorodeoxyglucose F18 %K Humans %K Imaging, Three-Dimensional %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %K Survival Analysis %K tau Proteins %X

The aim of this study was to evaluate the incremental benefit of biomarkers for prediction of Alzheimer's disease dementia (ADD) in patients with mild cognitive impairment (MCI) when added stepwise in the order of their collection in clinical routine. The model started with cognitive status characterized by the ADAS-13 score. Hippocampus volume (HV), cerebrospinal fluid (CSF) phospho-tau (pTau), and the FDG t-sum score in an AD meta-region-of-interest were compared as neurodegeneration markers. CSF-Aβ1-42 was used as amyloidosis marker. The incremental prognostic benefit from these markers was assessed by stepwise Kaplan-Meier survival analysis in 402 ADNI MCI subjects. Predefined cutoffs were used to dichotomize patients as 'negative' or 'positive' for AD characteristic alteration with respect to each marker. Among the neurodegeneration markers, CSF-pTau provided the best incremental risk stratification when added to ADAS-13. FDG PET outperformed HV only in MCI subjects with relatively preserved cognition. Adding CSF-Aβ provided further risk stratification in pTau-positive subjects, independent of their cognitive status. Stepwise integration of biomarkers allows stepwise refinement of risk estimates for MCI-to-ADD progression. Incremental benefit strongly depends on the patient's status according to the preceding diagnostic steps. The stepwise Kaplan-Meier curves might be useful to optimize diagnostic workflow in individual patients.

%B J Alzheimers Dis %V 61 %P 373-388 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154285?dopt=Abstract %R 10.3233/JAD-170705 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Predictors of Age of Diagnosis and Survival of Alzheimer's Disease in Down Syndrome. %A Sinai, Amanda %A Mokrysz, Claire %A Bernal, Jane %A Bohnen, Ingrid %A Bonell, Simon %A Courtenay, Ken %A Dodd, Karen %A Gazizova, Dina %A Hassiotis, Angela %A Hillier, Richard %A McBrien, Judith %A McCarthy, Jane %A Mukherji, Kamalika %A Naeem, Asim %A Perez-Achiaga, Natalia %A Rantell, Khadija %A Sharma, Vijaya %A Thomas, David %A Walker, Zuzana %A Whitham, Sarah %A Strydom, Andre %K Age of Onset %K Alzheimer Disease %K Down Syndrome %K England %K Female %K Humans %K Male %K Middle Aged %K Risk Factors %K Survival Analysis %X

BACKGROUND: People with Down syndrome (DS) are an ultra-high risk population for Alzheimer's disease (AD). Understanding the factors associated with age of onset and survival in this population could highlight factors associated with modulation of the amyloid cascade.

OBJECTIVE: This study aimed to establish the typical age at diagnosis and survival associated with AD in DS and the risk factors associated with these.

METHODS: Data was obtained from the Aging with Down Syndrome and Intellectual Disabilities (ADSID) research database, consisting of data extracted from clinical records of patients seen by Community Intellectual Disability Services (CIDS) in England. Survival times when considering different risk factors were calculated.

RESULTS: The mean age of diagnosis was 55.80 years, SD 6.29. Median survival time after diagnosis was 3.78 years, and median age at death was approximately 60 years. Survival time was associated with age of diagnosis, severity of intellectual disability, living status, anti-dementia medication status, and history of epilepsy. Age at diagnosis and treatment status remained predictive of survival time following adjustment.

CONCLUSION: This study provides the best estimate of survival in dementia within the DS population to date, and is in keeping with previous estimates from smaller studies in the DS population. This study provides important estimates and insights into possible predictors of survival and age of diagnosis of AD in adults with DS, which will inform selection of participants for treatment trials in the future.

%B J Alzheimers Dis %V 61 %P 717-728 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226868?dopt=Abstract %R 10.3233/JAD-170624 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Predictors of Delirium Development in Older Medical Inpatients: Readily Identifiable Factors at Admission. %A O'Regan, Niamh A %A Fitzgerald, James %A Adamis, Dimitrios %A Molloy, David William %A Meagher, David %A Timmons, Suzanne %X

BACKGROUND: Identifying patients at high risk of delirium is crucial to facilitate prevention. Although dementia is the most consistent risk factor across populations, it remains under-diagnosed. Hence understanding other markers of delirium vulnerability on admission is important.

OBJECTIVE: We aimed to identify predictors of incident delirium development in older medical inpatients that were readily identifiable at presentation to the emergency department.

METHODS: Medical inpatients of ≥70 years were assessed on admission for delirium using the Revised Delirium Rating Scale (DRS-R98) and those with prevalent delirium were excluded. Consenting non-delirious patients were then assessed daily using the DRS-R98. Data pertaining to multiple baseline delirium risk factors were collected, including pre-morbid dementia. Multivariable logistic regression was used to examine which factors predicted the development of incident delirium.

RESULTS: Of 555 patients approached, 184 (33.1%) had prevalent delirium. Following other exclusions, 191 were included in the study and 61 developed incident delirium. Predictors of incident delirium on multivariable analysis, controlling for confounders, were dementia (OR 2.54, 95% CI 1.01-6.43, p = 0.048); Barthel Index score (OR 1.15 for each unit decrease in score, 95% CI 1.06-1.25, p = 0.001), and Modified Cumulative Illness Rating Scale score (OR 1.13 for each unit increase in score, 95% CI 1.05-1.22, p = 0.001).

CONCLUSION: Dementia is a well-known risk factor for delirium; however, it too is under-recognized and on admission can be missed. Conversely, the Barthel Index is a simple and widely used measure of functional ability that may prove useful in stratifying those at risk of in-hospital delirium on admission.

%B J Alzheimers Dis %V 64 %P 775-785 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966197?dopt=Abstract %R 10.3233/JAD-180178 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Preoperative Phosphorylated Tau Concentration in the Cerebrospinal Fluid Can Predict Cognitive Function Three Years after Shunt Surgery in Patients with Idiopathic Normal Pressure Hydrocephalus. %A Nakajima, Madoka %A Miyajima, Masakazu %A Ogino, Ikuko %A Akiba, Chihiro %A Kawamura, Kaito %A Kamohara, Chihiro %A Fusegi, Keiko %A Harada, Yoshinao %A Hara, Takeshi %A Sugano, Hidenori %A Tange, Yuichi %A Karagiozov, Kostadin %A Kasuga, Kensaku %A Ikeuchi, Takeshi %A Tokuda, Takahiko %A Arai, Hajime %X

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is commonly treated by cerebrospinal fluid (CSF) shunting. However, the long-term efficacy of shunt intervention in the presence of comorbid Alzheimer's disease (AD) pathology is debated.

OBJECTIVE: To identify AD-associated CSF biomarkers predictive of shunting surgery outcomes in patients with iNPH.

METHODS: Preoperative levels of total and phosphorylated Tau (p-Tau) were measured in 40 patients with iNPH divided into low (<30 pg/mL) and high (≥30 pg/mL) p-Tau groups and followed up for three years after lumboperitoneal shunting. The modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), Frontal Assessment Battery, and iNPH Grading Scale scores were compared between the age-adjusted low (n = 24; mean age 75.7 years [SD 5.3]) and high (n = 11; mean age 76.0 years [SD 5.6]) p-Tau groups.

RESULTS: Cognitive function improved early in the low p-Tau group and was maintained thereafter (p = 0.005). In contrast, the high p-Tau group showed a gradual decline to baseline levels by the third postoperative year (p = 0.040). Although the p-Tau concentration did not correlate with the preoperative MMSE score, a negative correlation appeared and strengthened during follow-up (R2 = 0.352, p < 0.001). Furthermore, the low p-Tau group showed rapid and sustained mRS grade improvement, whereas mRS performance gradually declined in the high p-Tau group.

CONCLUSIONS: Preoperative CSF p-Tau concentration predicted some aspects of cognitive function after shunt intervention in patients with iNPH. The therapeutic effects of shunt treatment were shorter-lasting in patients with coexisting AD pathology.

%B J Alzheimers Dis %V 66 %P 319-331 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30248058?dopt=Abstract %R 10.3233/JAD-180557 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Preserved Structural Network Organization Mediates Pathology Spread in Alzheimer's Disease Spectrum Despite Loss of White Matter Tract Integrity. %A Powell, Fon %A Tosun, Duygu %A Sadeghi, Roksana %A Weiner, Michael %A Raj, Ashish %X

Models of Alzheimer's disease (AD) hypothesize stereotyped progression via white matter (WM) fiber connections, most likely via trans-synaptic transmission of toxic proteins along neuronal pathways. An important question in the field is whether and how organization of fiber pathways is affected by disease. It remains unknown whether fibers act as conduits of degenerative pathologies, or if they also degenerate with the gray matter network. This work uses graph theoretic modeling in a longitudinal design to investigate the impact of WM network organization on AD pathology spread. We hypothesize if altered WM network organization mediates disease progression, then a previously published network diffusion model will yield higher prediction accuracy using subject-specific connectomes in place of a healthy template connectome. Neuroimaging data in 124 subjects from ADNI were assessed. Graph topology metrics show preserved network organization in patients compared to controls. Using a published diffusion model, we further probe the effect of network alterations on degeneration spread in AD. We show that choice of connectome does not significantly impact the model's predictive ability. These results suggest that, despite measurable changes in integrity of specific fiber tracts, WM network organization in AD is preserved. Further, there is no difference in the mediation of putative pathology spread between healthy and AD-impaired networks. This conclusion is somewhat at variance with previous results, which report global topological disturbances in AD. Our data indicates the combined effect of edge thresholding, binarization, and inclusion of subcortical regions to network graphs may be responsible for previously reported effects.

%B J Alzheimers Dis %V 65 %P 747-764 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578480?dopt=Abstract %R 10.3233/JAD-170798 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prevalence and Determinants of Agonistic Autoantibodies Against α1-Adrenergic Receptors in Patients Screened Positive for Dementia: Results from the Population-Based DelpHi-Study. %A Thyrian, Jochen René %A Hertel, Johannes %A Schulze, Lara N %A Dörr, Marcus %A Prüss, Harald %A Hempel, Petra %A Bimmler, Marion %A Kunze, Rudolf %A Grabe, Hans Jörgen %A Teipel, Stefan %A Hoffmann, Wolfgang %X

BACKGROUND: There is a need to assess promising biomarkers for diagnosis and treatment response in real-life settings. Despite the important role of vascular risk factors, cardiovascular biomarkers have played a minor role in dementia research. Agonistic autoantibodies (agAAB) directed against G-protein-coupled receptors (GPCR) are discussed as modulators of pathology and clinical manifestation.

OBJECTIVE: 1) Describe prevalence of agAAB directed against GPCR, especially agABB against α1-adrenergic receptors (α1-AR-agAAB) and agABB directed against β2-adrenergic receptors (β2-AR-agAAB) and 2) identify factors associated with agAAB in people with dementia during routine care.

METHODS: Blood samples and data from 95 subjects who screened positive for dementia from a primary care cohort, analyzed using an enzyme-linked immunosorbent assay (ELISA) for detecting agAAB. Sociodemographic and clinical data were assessed, and medical records checked.

RESULTS: In 40 (42%) samples, agAAB was detected, with n = 29 (31%) representing α1-AR-agAAB and n = 21 (22%) β2-AR-agAAB. There was no association between the presence of any antibody and a formal diagnosis of dementia. However, patients with coronary heart disease were more likely (OR = 4.23) to have α1-AR-agAAB than those without coronary heart disease. There were no associations between agAAB and age, sex, education, or cognitive impairment.

DISCUSSION: For the first time, we show that autoantibodies have a significant prevalence in people with dementia in a routine care setting. Previous findings were restricted to highly selective samples. We replicated the association between α1-AR-agAAB in patients with coronary heart diseases but were not able to find other factors associated with the presence of agAAB.

%B J Alzheimers Dis %V 64 %P 1091-1097 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010118?dopt=Abstract %R 10.3233/JAD-171096 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prevalence of Delirium in a Population of Elderly Outpatients with Dementia: A Retrospective Study. %A Addesi, Desirée %A Maio, Raffaele %A Smirne, Nicoletta %A Laganà, Valentina %A Altomari, Natalia %A Puccio, Gianfranco %A Colao, Rosanna %A Cupidi, Chiara %A Perticone, Francesco %A Bruni, Amalia Cecilia %K Aged %K Aged, 80 and over %K Antipsychotic Agents %K Cohort Studies %K Delirium %K Dementia %K Female %K Geriatric Assessment %K Humans %K Male %K Outpatients %K Prevalence %K Severity of Illness Index %X

BACKGROUND: Delirium is a multifactorial geriatric syndrome and often occurs in patients with cognitive impairment. It also remains under-recognized, specifically in elderly outpatients, because signs of delirium might overlap with symptoms of dementia.

OBJECTIVE: The aim of the present study is to retrospectively apply the chart-based delirium instrument on a cohort of elderly outpatients with dementia, to assess prevalence and features of delirium in this population.

METHODS: We randomly selected 650 medical records of outpatients referred to the "Neurogenetic Regional Centre" (CRN) of Lamezia Terme. Each evaluation included demographics, medical history, drugs, type and severity of dementia, and cognitive and functional status. Delirium was identified by the application of the chart-based delirium instrument.

RESULTS: The prevalence of delirium was 13.3%. The study population was divided, according to the presence of delirium, into two subgroups. Compared to the no delirium group, the delirium group was significantly older and had greater cognitive impairment with lower MMSE scores both at baseline and at the end of the follow up. They also had a significant lower score on the ADL and IADL. In this group, a higher intake of antihypertensive and antipsychotic drugs, together with a lower intake of cholinesterase inhibitors and memantine, was observed.

CONCLUSIONS: In this study, the chart-based delirium instrument was applied to an outpatient population affected by dementia and followed for a long time. Our data confirm the importance that age and frailty play on the genesis of delirium and suggest attention should be paid to the pharmacological treatment of these patients.

%B J Alzheimers Dis %V 61 %P 251-257 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171993?dopt=Abstract %R 10.3233/JAD-170339 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prevalence of Dementia and Associated Risk Factors: A Population-Based Study in the Philippines. %A Dominguez, Jacqueline %A Fe de Guzman, Ma %A Reandelar, Macario %A Thi Phung, Thien Kieu %X

BACKGROUND: The Philippines is experiencing rapid demographic aging and with it, the dementia epidemic. Prevalence of dementia and associated risk factors have not been studied in the Philippines.

OBJECTIVES: The study aimed to provide a reliable estimate of dementia prevalence and identify associated risk factors in the Filipino population.

METHODS: 1460 participants 60 years and older were randomly selected from the Marikina City's senior registry. A multidisciplinary team (nurse, psychologist, and neurologist) administered a comprehensive assessment to the study population: health history, neurological examination, Geriatric Depression Scale, Neuropsychiatric Inventory, Disability Assessment for Dementia, Alzheimer's Disease 8, and Clinical Dementia Rating Scale. The neurologist analyzed all clinical data to diagnose dementia based on the DSM-IV criteria, Alzheimer's Disease (AD) on the NINCDS-ADRDA criteria, vascular dementia (VaD) on the Hachinski Ischemic Scale, cognitive impairment no dementia (CIND) on a CDR score of 0.5 and not fulfilling DSM-IV criteria for dementia. Risk factors were correlated with dementia prevalence using multivariate binary logistic regression.

RESULTS: 1460 persons were randomly selected. 1367 agreed to participate and underwent all assessments. The response rate was 93.6%. Dementia prevalence was found to be 10.6% (95% CI 9.0 to 12.4) with the breakdown 85.5% AD, 11.7% VaD, and 2.7% other dementias. In this population, 82.0% of men and 70.4% of women had at least one cardiovascular risk factor (hypertension, diabetes, dyslipidemia, smoking), which was associated with VaD prevalence but not AD.

CONCLUSION: The prevalence of dementia, CIND, and cardiovascular risk factors are high in the Philippines.

%B J Alzheimers Dis %V 63 %P 1065-1073 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710725?dopt=Abstract %R 10.3233/JAD-180095 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prevalence of Potentially Inappropriate Medication Use in Older Inpatients with and without Cognitive Impairment: A Systematic Review. %A Redston, Mitchell R %A Hilmer, Sarah N %A McLachlan, Andrew J %A Clough, Alexander J %A Gnjidic, Danijela %K Aged %K Cognitive Dysfunction %K Dementia %K Humans %K Inpatients %K Polypharmacy %K Potentially Inappropriate Medication List %K Prevalence %K Quality of Life %X

BACKGROUND: Older people with cognitive impairment, including dementia and delirium, are high users of acute care services internationally. Potentially inappropriate medication (PIM) use may be associated with adverse outcomes, including hospital re-admission, functional disability, and mortality.

OBJECTIVE: This systematic review aimed to quantify and compare the prevalence of PIMs in older inpatients with and without cognitive impairment.

METHODS: A systematic search of observational studies was performed independently assessed by two reviewers in Embase, Medline, PsycINFO, International Pharmaceutical Abstracts, Scopus, and Informit. Articles published in English during the period January 2007-June 2017 that reported PIM prevalence in hospital inpatients ≥ 65 years were included. PIMs were defined as the presence of polypharmacy (multiple medication use) and using implicit or explicit tools, such as the Beers criteria, and 'Screening Tool of Older Person's Prescriptions' (STOPP).

RESULTS: 47 articles were included. In studies measuring polypharmacy (n = 15), the prevalence of PIMs ranged from 53.2% to 89.8% and 30.4% to 97.1% for inpatients with and without cognitive impairment, respectively, and 24.0% to 80.0% when cognitive status was unreported. In studies employing explicit and implicit tools (n = 35), the prevalence of PIMs when cognitive impairment was reported ranged from 20.6% to 80.5% using the Beers criteria, and 39.3% to 88.5% using STOPP. When cognitive status was unreported, the prevalence of PIMs ranged from 7.0% to 79.2% using the Beers criteria, and 20.0% to 63.4% using STOPP.

CONCLUSION: Our findings suggest a high prevalence of PIMs in older inpatients with and without cognitive impairment. Future studies should investigate the impact of PIM use on patient-centered outcomes, such as functional status and quality of life, to inform enhanced acute care services.

%B J Alzheimers Dis %V 61 %P 1639-1652 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29278890?dopt=Abstract %R 10.3233/JAD-170842 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prevalence, Safety, and Effectiveness of Oral Anticoagulant Use in People with and without Dementia or Cognitive Impairment: A Systematic Review and Meta-Analysis. %A Fanning, Laura %A Ryan-Atwood, Taliesin E %A Bell, J Simon %A Meretoja, Atte %A McNamara, Kevin P %A Dārziņš, Pēteris %A Wong, Ian C K %A Ilomäki, Jenni %X

BACKGROUND: Differences in management and outcomes of oral anticoagulant (OAC) use may exist for people with and without dementia or cognitive impairment (CI).

OBJECTIVE: To systematically review the prevalence and safety and effectiveness outcomes of OAC use in people with and without dementia or CI.

METHODS: MEDLINE, EMBASE, and CINAHL were searched for studies reporting prevalence or safety and effectiveness outcomes of OAC use for people with and without dementia, published between 2000 to September 2017. Study selection, data extraction, and quality assessment were performed by two reviewers.

RESULTS: studies met pre-specified inclusion criteria (21 prevalence studies, 6 outcomes studies). People with dementia had 52% lower odds of receiving OAC compared to people without dementia. Mean OAC prevalence was 32% for people with dementia, compared to 48% without dementia. There was no difference in the composite outcome of embolic events, myocardial infarction, and all-cause death between dementia and non-dementia groups (adjusted hazard ratio (HR) 0.72, 95% CI, 0.45-1.14, p = 0.155). Bleeding rate was lower for people without dementia (HR 0.56, 95% CI, 0.37-0.85). Adverse warfarin events were more common for residents of long-term care with dementia (adjusted incidence rate ratio 1.48, 95% CI, 1.20-1.82). Community-dwelling people with dementia treated with warfarin had poorer anticoagulation control than those without dementia (mean time in therapeutic range (TTR) % ±SD, 38±26 (dementia), 61±27 (no dementia), p < 0.0001).

CONCLUSION: A lower proportion of people with dementia received oral anticoagulation compared with people without dementia. People with dementia had higher bleeding risk and poorer anticoagulation control when treated with warfarin.

%B J Alzheimers Dis %V 65 %P 489-517 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056420?dopt=Abstract %R 10.3233/JAD-180219 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prevalence, Semiology, and Risk Factors of Epilepsy in Alzheimer's Disease: An Ambulatory EEG Study. %A Horváth, András %A Szűcs, Anna %A Hidasi, Zoltán %A Csukly, Gábor %A Barcs, Gábor %A Kamondi, Anita %X

BACKGROUND: Alzheimer's disease (AD) is the primary cause of cognitive decline. A growing body of evidence suggests that AD patients have a higher risk to develop epileptic seizures; however, results are contradictory due to different methodological approaches of previous studies.

OBJECTIVE: We aimed to identify the prevalence, semiology, and risk factors of epilepsy in AD using long-term EEG.

METHODS: We selected forty-two AD patients and examined them using 24-hour ambulatory EEG. Neurological and epileptological data were collected with retro- and prospective methods. We analyzed the semiology of the identified seizures and the possible risk factors using logistic regression analysis.

RESULTS: We identified seizures confirmed by EEG in 24%. The majority of the seizures were aware focal (72%) without any motor activity (55%). We found epileptiform discharges without seizures in 28%. Patients with seizures and only with epileptic EEG activity showed similar clinical and demographical features. Higher education (OR:1.8) and lower Addenbrooke Examination Score (OR: 0.9) were identified as risk factors of epilepsy. Increase of 0.1 point in the Verbal-Language/Orientation-Memory ratio (VLOM) was associated with higher epilepsy risk as well (OR:2.9).

CONCLUSION: Epilepsy is a frequent comorbidity of AD. Since most of the seizures are aware non-motor focal seizures, sensitive EEG techniques are required for precise diagnosis of epilepsy. Long-term ambulatory EEG is a safe and well-tolerated option. Epileptiform EEG in AD signals the presence of concomitant epilepsy. Clinicians have to pay attention to comorbid epilepsy in dementia patients with high education, with high VLOM ratio and severe stage.

%B J Alzheimers Dis %V 63 %P 1045-1054 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710705?dopt=Abstract %R 10.3233/JAD-170925 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Price of Stress: High Bedtime Salivary Cortisol Levels Are Associated with Brain Atrophy and Cognitive Decline in Stroke Survivors. Results from the TABASCO Prospective Cohort Study. %A Tene, Oren %A Hallevi, Hen %A Korczyn, Amos D %A Shopin, Ludmila %A Molad, Jeremy %A Kirschbaum, Clemens %A Bornstein, Natan M %A Shenhar-Tsarfaty, Shani %A Kliper, Efrat %A Auriel, Eitan %A Usher, Sali %A Stalder, Tobias %A Ben Assayag, Einor %X

BACKGROUND AND OBJECTIVE: Previous studies suggest that excessive cortisol levels after stroke are associated with cognitive dysfunction. However, limited data exist regarding associations between post-stroke cortisol levels, brain abnormalities, genetic factors, and cognitive outcome. We sought to study these issues in a longitudinal stroke survivors cohort.

METHODS: Data from 182 cognitively intact ischemic stroke patients from the TABASCO study were available. Saliva cortisol levels (bedtime and post-awakening) and cognitive assessments were obtained on admission, and 6, 12, and 24 months thereafter. During hospitalization, patients underwent 3T MRI scans and APOE genotyping.

RESULTS: Higher bedtime cortisol levels immediately post-stroke were associated with larger neurological deficits (p < 0.001), brain atrophy (p = 0.025), worse white matter integrity (p = 0.003), and worse cognitive results up to 24 months post-stroke. These findings remained significant when adjusted for age, gender, education, smoking, stroke severity, apolipoprotein E4 (ApoE4) status, and body mass index. ApoE4 negatively modified the relation between cortisol and memory. As a group, participants who presented with high admission bedtime cortisol levels continued to present relatively elevated bedtime levels across all examined time-points, and this group had inferior memory and executive functioning scores compared to the lower cortisol group 24 months post-stroke (p = 0.05, p = 0.035, respectively). Post-awakening cortisol levels were not associated with neuroimaging findings or cognitive scores.

CONCLUSIONS: High bedtime salivary cortisol levels post-stroke may provide information about dysregulation of diurnal HPA-axis activity under acute challenge conditions, and predict worse cognitive outcome. ApoE4 genotype might modify this association. These findings call for specific stress management interventions in stroke survivors.

%B J Alzheimers Dis %V 65 %P 1365-1375 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149451?dopt=Abstract %R 10.3233/JAD-180486 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prodromal Alzheimer's Disease Demonstrates Increased Errors at a Simple and Automated Anti-Saccade Task. %A Holden, John G %A Cosnard, Alexandre %A Laurens, Brice %A Asselineau, Julien %A Biotti, Damien %A Cubizolle, Stéphanie %A Dupouy, Sandrine %A Formaglio, Maıté %A Koric, Lejla %A Seassau, Magali %A Tilikete, Caroline %A Vighetto, Alain %A Tison, François %X

Saccade alterations are potential early signs of Alzheimer's disease. However, uncertainty persists in how early and reliably automated saccade recording systems detect impairments. This multicenter pathophysiological case-control transversal study explored saccade execution in carefully diagnosed amnestic mild cognitive impairment patients fulfilling research criteria for prodromal Alzheimer's disease (n = 29), as compared to both aged-matched mild Alzheimer's disease patients (n = 23) and controls (n = 27). Auto-coded saccades from horizontal (gap) vertical (step) stimulus elicited pro-saccades, and anti-saccade (gap) tasks were compared across the 3 groups. Mild cognitive impairment patients committed significantly more anti-saccade errors compared to controls (46.9 versus 24.3%, p < 0.001). Conventional analyses of the auto-coded stimulus elicited saccades parameters did not distinguish the amnestic mild cognitive impairment from controls or the mild Alzheimer's disease group. However, an offline analysis of manually coded saccade latencies, using resampling statistics did reveal subtle differences among the groups. Analysis of the manually coded data revealed that the mild Alzheimer's disease group had a reliably larger self-corrected error-rate than in amnestic mild cognitive impairment and controls (p = 0.003). Analysis of the manually coded saccade latencies, using more sensitive lognormal bootstrap analysis revealed a continuum, from amnestic mild cognitive impairment to mild Alzheimer's disease, of an increased severity of impaired inhibition of stimulus elicited saccades and correct voluntary saccade initiation. Anti-saccade error rates and psychometric measures of executive and several other cognitive functions were moderately and negatively correlated. Overall, inhibitory impairments in stimulus elicited saccades, characteristic of Alzheimer's disease, may be detected early in presumed prodromal patients using a simple, automated anti-saccade task.

%B J Alzheimers Dis %V 65 %P 1209-1223 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149445?dopt=Abstract %R 10.3233/JAD-180082 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Profiling of Specific Gene Expression Pathways in Peripheral Cells from Prodromal Alzheimer's Disease Patients. %A Serpente, Maria %A Fenoglio, Chiara %A Cioffi, Sara Maria Giulia %A Oldoni, Emanuela %A Arcaro, Marina %A Arighi, Andrea %A Fumagalli, Giorgio Giulio %A Ghezzi, Laura %A Scarpini, Elio %A Galimberti, Daniela %K Aged %K Alzheimer Disease %K Antigens, CD %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Gene Expression Profiling %K Humans %K Insulin %K Male %K Middle Aged %K Receptor, Insulin %X

Herein, we performed a gene expression profiling in a cohort of 10 mild cognitive impairment (MCI), subdivided, according to the analysis of cerebrospinal fluid biomarkers, in prodromal Alzheimer's disease (AD) and non-AD MCI, as compared with 27 AD patients and 24 controls, in order to detect early gene expression alterations. We observed a significant upregulation of insulin (INS) and INS Receptor (INSR) expression levels in AD both prodromal and fully symptomatic, as compared with controls, but not in MCI subjects. Our results suggest an early dysregulation of INS and INSR in AD pathogenesis and pave the way to a possible utility of these transcripts as peripheral biomarkers.

%B J Alzheimers Dis %V 61 %P 1289-1294 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376874?dopt=Abstract %R 10.3233/JAD-170861 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Progress and Challenges in Frontotemporal Dementia Research: A 20-Year Review. %A Hodges, John R %A Piguet, Olivier %X

The landscape of frontotemporal dementia (FTD) has evolved remarkably in recent years and is barely recognizable from two decades ago. Knowledge of the clinical phenomenology, cognition, neuroimaging, genetics, pathology of the different subtypes of FTD, and their relations to other neurodegenerative conditions, has increased rapidly, due in part, to the growing interests into these neurodegenerative brain conditions. This article reviews the major advances in the field of FTD over the past 20 years, focusing primarily on the work of Frontier, the frontotemporal dementia clinical research group, based in Sydney, Australia. Topics covered include clinical presentations (cognition, behavior, neuroimaging), pathology, genetics, and disease progression, as well as interventions and carer directed research. This review demonstrates the improvement in diagnostic accuracy and capacity to provide advice on genetic risks, prognosis, and outcome. The next major challenge will be to capitalize on these research findings to develop effective disease modifying drugs, which are currently lacking.

%B J Alzheimers Dis %V 62 %P 1467-1480 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504536?dopt=Abstract %R 10.3233/JAD-171087 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Progress of Brain Amyloid Deposition in Familial Alzheimer's Disease with Taiwan D678H APP Mutation. %A Weng, Yi-Ching %A Hsiao, Ing-Tsung %A Huang, Chu-Yun %A Huang, Kuo-Lun %A Liu, Chi-Hung %A Chang, Ting-Yu %A Yen, Tzu-Chen %A Lin, Kun-Ju %A Huang, Chin-Chang %X

BACKGROUND: The amyloid AV-45 (florbetapir) positron emission tomography (PET) has been used in the study of the familial Alzheimer's disease (FAD) with the D678H amyloid precursor protein (APP) mutation. In addition, the progress of the disease remains unknown.

OBJECTIVE: We aim to investigate the progression rate of amyloid accumulation in FAD patients with this mutation by neuroimages analysis.

METHODS: The clinical course, changes in cognitive function, brain magnetic resonance imaging (MRI) and 18F-AV-45 PET scan were investigated in FAD patients and sporadic AD (sAD) patients. We compared the amyloid deposition pattern in serial brain 18F-AV-45 PET scan among the FAD, familial mild cognitive impairment (FMCI), and sMCI and sAD patients.

RESULTS: Seven familial patients received a follow-up survey. The follow up duration for brain AV-45 PET was from 1.54 to 3.61 years. In 4 FMCI patients, an increased regional SUVR was noted, and the annual change rates were increased from 1.03% to 18.82%. However, a decreased regional SUVR was noted in 3 FAD patients and the annual change rates were from -2.62% to -16.03%. As compared with the sAD and sMCI patients, the annual change rate is statistically significant in FAD and FMCI patients respectively.

CONCLUSIONS: The data indicate a biphasic course with an initial increase and then a decrease of SUVR in brain amyloid PET scan in familial APP mutation patients. The data also reveal that the novel Taiwan APP (D678H) mutation has a more amyloid burden than the sAD patients, particularly in an MCI stage.

%B J Alzheimers Dis %V 66 %P 775-787 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320594?dopt=Abstract %R 10.3233/JAD-180824 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Progression of Alzheimer's Disease: A Longitudinal Study in Norwegian Memory Clinics. %A Eldholm, Rannveig Sakshaug %A Barca, Maria Lage %A Persson, Karin %A Knapskog, Anne-Brita %A Kersten, Hege %A Engedal, Knut %A Selbæk, Geir %A Brækhus, Anne %A Skovlund, Eva %A Saltvedt, Ingvild %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Disease Progression %K Female %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Memory %K Neuropsychological Tests %K Norway %X

BACKGROUND: The course of Alzheimer's disease (AD) varies considerably between individuals. There is limited evidence on factors important for disease progression.

OBJECTIVE: The primary aim was to study the progression of AD, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Secondary aims were to investigate whether baseline characteristics are important for differences in progression, and to examine the correlation between progression assessed using three different instruments: CDR-SB (0-18), the cognitive test Mini-Mental State Examination (MMSE, 0-30), and the functional measure Instrumental Activities of Daily Living (IADL, 0-1).

METHODS: The Progression of AD and Resource use (PADR) study is a longitudinal observational study in three Norwegian memory clinics.

RESULTS: In total, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16-37) months. The mean annual increase in CDR-SB was 1.6 (SD 1.8), the mean decrease in MMSE score 1.9 (SD 2.6), and the mean decrease in IADL score 0.13 (SD 0.14). Of the 282 patients, 132 (46.8%) progressed slowly, with less than 1 point yearly increase in CDR-SB. Cognitive test results at baseline predicted progression rate, and together with age, ApoE, history of hypertension, and drug use could explain 17% of the variance in progression rate. The strongest correlation of change was found between CDR-SB and IADL scores, the weakest between MMSE and IADL scores.

CONCLUSION: Progression rate varied considerably among AD patients; about half of the patients progressed slowly. Cognitive test results at baseline were predictors of progression rate.

%B J Alzheimers Dis %V 61 %P 1221-1232 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254085?dopt=Abstract %R 10.3233/JAD-170436 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Progression of Alzheimer's Disease-Related Pathology and Cell Counts in a Patient with Idiopathic Normal Pressure Hydrocephalus. %A Libard, Sylwia %A Laurell, Katarina %A Cesarini, Kristina Giuliana %A Alafuzoff, Irina %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Biopsy %K Brain %K Cell Count %K Disease Progression %K Female %K Glial Fibrillary Acidic Protein %K Humans %K Hydrocephalus, Normal Pressure %K Microglia %K tau Proteins %X

We had an opportunity to assess the change observed in the brain regarding Alzheimer's disease (AD)-related alterations, cell count, and inflammation that took place during a period of 21 months in a subject with a definite diagnosis of AD and idiopathic Normal Pressure Hydrocephalus (iNPH). Four neuronal markers, i.e., synaptophysin, microtubule associated protein 2, non-phosphorylated neurofilament H (SMI32), and embryonic lethal abnormal visual system proteins 3/4 HuC/HuD (HuC/HuD); three microglial markers CD68, Human Leucocytic Antigen DR, ionized calcium-binding adaptor molecule 1, glial fibrillary acidic protein (GFAP); and AD-related markers, hyperphosphorylated τ (HPτ) and amyloid-β (Aβ, Aβ40, Aβ42) were assessed. Morphometrically assessed immunoreactivity of all neuronal and all microglial markers and Aβ42 decreased parallel with an increase in the HPτ in the frontal cortex. The expression of GFAP was stable with time. The first sample was obtained during the therapeutic shunting procedure for iNPH, and the second sample was obtained postmortem. Negligible reactive changes were observed surrounding the shunt channel. In conclusion, in the late stage of AD with time, a neuronal loss, increase in the HPτ, and decrease in Aβ42 and microglia was observed, whereas the expression of GFAP was rather stable. The observations described here suggest that when a brain biopsy has been obtained from an adult subject with iNPH, the assessment of postmortem brain is of major significance.

%B J Alzheimers Dis %V 61 %P 1451-1462 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376849?dopt=Abstract %R 10.3233/JAD-170446 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Progression of Dementia and Cognitive Decline in a Dutch 2-Year Cohort Study of People with Young-Onset Dementia. %A Gerritsen, Adrie A J %A Bakker, Christian %A Verhey, Frans R J %A Bor, Hans %A Pijnenburg, Yolande A L %A de Vugt, Marjolein E %A Koopmans, Raymond T C M %X

BACKGROUND: The progression of dementia in people with young-onset dementia (YOD) is relatively unknown.

OBJECTIVE: To investigate the progression of dementia and cognitive decline in the three most common subtypes in YOD and to explore which factors are associated with this course.

METHODS: The course of dementia was examined in 198 people with YOD. The primary outcomes were cognitive function, as assessed by the Mini-Mental State Examination (MMSE) and dementia severity, as assessed by the Global Deterioration Scale (GDS). Mixed-model analyses were used to explore factors associated with the course of dementia of the diagnostic sub-types.

RESULTS: The mean overall two-year progression of dementia severity was 0.9 GDS points, this was a statistically significant change (p = 0.012) and was not significant different for the three dementia subtypes. The mean overall two-year decline in cognitive function was 1.6 points on the MMSE. The differences in cognitive decline were statistically significant (p = 0.046) among the three diagnosis groups, AD participants showed the greatest decline, of 2.3 points. In addition to lower education (p = 0.010), higher scores on the Neuropsychiatric Inventory (NPI) sub-syndromes psychosis (p < 0.001) and hyperactivity (p = 0.002) were associated with higher rates of cognitive decline. In contrast, higher scores on the NPI affect cluster were associated with lower levels of cognitive decline (p < 0.001).

CONCLUSION: Different YOD subtypes show different rates of decline in cognitive functioning, and this decline seems less progressive compared to those observed in studies in late-onset AD. Further research is needed to evaluate whether managing neuropsychiatric symptoms can positively influence the decline of cognitive function.

%B J Alzheimers Dis %V 63 %P 343-351 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614650?dopt=Abstract %R 10.3233/JAD-170859 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Progression of Neuropsychiatric Symptoms in Alzheimer's Disease During a Five-Year Follow-Up: Kuopio ALSOVA Study. %A Hallikainen, Ilona %A Hongisto, Kristiina %A Välimäki, Tarja %A Hänninen, Tuomo %A Martikainen, Janne %A Koivisto, Anne M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Anxiety %K Caregivers %K Delusions %K Disease Progression %K Female %K Finland %K Hallucinations %K Humans %K Linear Models %K Male %K Motor Activity %K Multivariate Analysis %K Neuropsychological Tests %K Severity of Illness Index %X

BACKGROUND: An improved understanding of the role of neuropsychiatric symptoms (NPS) in the course of Alzheimer's disease (AD) has recently emerged. NPS lead to hospitalization and caregiver stress, but are more variable during the course of the disease than other symptoms. Knowledge about the role of specific NPS in disease progression and prognosis is especially limited.

OBJECTIVES: To examine the relationship between specific NPS and AD severity during a 5-year follow-up period, and to determine which baseline NPS predict AD progression.

METHODS: 236 persons with very mild (CDR 0.5) or mild (CDR 1) AD at baseline and their caregivers were followed up for five years as part of the ALSOVA study. The Neuropsychiatric Inventory was used to assess NPS, and AD severity progression was measured with the Clinical Dementia Rating Sum of Boxes. Data was analyzed with Generalized Estimated Equations and Linear Mixed Models.

RESULTS: The baseline NPS that best predicted AD progression were delusions, agitation, and aberrant motor behavior, while AD severity during follow-up was associated with hallucinations, delusions, agitation, apathy, aberrant motor behavior, and sleep and appetite disturbances.

CONCLUSIONS: Persons with mild AD presenting delusions, agitation, and aberrant motor behavior at the time of diagnosis could have a more rapidly progressing disease, and some NPS are associated with AD severity. These results highlight the importance of evaluating NPS at the time of AD diagnosis, and the need to offer additional support to persons presenting delusions, agitation and aberrant motor behavior, and their caregivers.

%B J Alzheimers Dis %V 61 %P 1367-1376 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376861?dopt=Abstract %R 10.3233/JAD-170697 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Progressive Acalculia Presentation of Parietal Variant Alzheimer's Disease. %A Mendez, Mario F %A Moheb, Negar %A Desarzant, Randy E %A Teng, Edmond H %X

BACKGROUND: Many patients with early-onset Alzheimer's disease (EOAD; age of onset <65 years) have non-amnestic presentations involving language (logopenic primary progressive aphasia, lvPPA), visuospatial abilities (posterior cortical atrophy, PCA), and even asymmetric symptoms consistent with corticobasal syndrome (CBS). An inferior parietal lobule variant of EOAD commonly presents with progressive difficulty with calculations.

METHODS: We reviewed 276 EOAD patients for presentations with predominant acalculia. These patients were diagnosed with clinically probable Alzheimer's disease (AD) verified by positron emission tomography (PET) or cerebrospinal fluid amyloid-β or tau biomarkers.

RESULTS: We identified 18 (9M/9F) (6.5%) EOAD patients with progressive acalculia that did not meet most criteria for lvPPA, visual PCA, or CBS. Their ages of onset and presentation were 56.6 (5.0) and 59.4 (6.5), respectively. Their acalculia was consistent with a primary acalculia ("anarithmetia") not explained by language or visuospatial impairments. Many also had anomia (14/18), ideomotor apraxia (13/18), and the complete Gerstmann's syndrome (7/18). Visual analysis of their diverse magnetic resonance imaging disclosed biparietal atrophy, disproportionately worse on the left.

CONCLUSIONS: Primary acalculia may be the most common manifestation of an inferior parietal presentation of EOAD affecting the left intraparietal sulcus. This parietal variant also commonly involves progressive anomia, ideomotor apraxia, and other elements of Gerstmann's syndrome. The early recognition of patients with this variant, which is distinguishable from lvPPA, visual PCA, or CBS, would be facilitated by its recognition as a unique subtype of EOAD.

%B J Alzheimers Dis %V 63 %P 941-948 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710718?dopt=Abstract %R 10.3233/JAD-180024 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression. %A Scheltens, Nienke M E %A Tijms, Betty M %A Heymans, Martijn W %A Rabinovici, Gil D %A Cohn-Sheehy, Brendan I %A Miller, Bruce L %A Kramer, Joel H %A Wolfsgruber, Steffen %A Wagner, Michael %A Kornhuber, Johannes %A Peters, Oliver %A Scheltens, Philip %A van der Flier, Wiesje M %X

BACKGROUND: Alzheimer's disease (AD) is a heterogeneous disorder.

OBJECTIVE: To investigate whether cognitive AD subtypes are associated with different rates of disease progression.

METHODS: We included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n = 290), Alzheimer's Disease Neuroimaging Initiative (n = 268), Dementia Competence Network (n = 226), and University of California, San Francisco (n = 282) with available follow-up data. Patients were previously clustered into two subtypes based on their neuropsychological test results: one with most prominent memory impairment (n = 663) and one with most prominent non-memory impairment (n = 403). We examined associations between cognitive subtype and disease progression, as measured with repeated Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale sum of boxes (CDR sob), using linear mixed models. Furthermore, we investigated mortality risk associated with subtypes using Cox proportional hazard analyses.

RESULTS: Patients were 71±9 years old; 541 (51%) were female. At baseline, pooled non-memory patients had worse MMSE scores (23.1±0.1) and slightly worse CDR sob (4.4±0.1) than memory patients (MMSE 24.0±0.1; p < 0.001; CDR sob 4.1±0.1; p < 0.001). During follow-up, pooled non-memory patients showed steeper annual decline in MMSE (-2.8±0.1) and steeper annual increase in CDR sob (1.8±0.1) than memory patients (MMSE - 1.9±0.1; pinteraction<0.001; CDR sob 1.3±0.1; pinteraction<0.001). Furthermore, the non-memory subtype was associated with an increased risk of mortality compared with the memory subtype at trend level (HR = 1.36, CI = 1.00-1.85, p = 0.05).

CONCLUSIONS: AD patients with most prominently non-memory impairment show faster disease progression and higher risk of mortality than patients with most prominently memory impairment.

%B J Alzheimers Dis %8 2018 Aug 03 %G eng %R 10.3233/JAD-171088 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer's Disease. %A Reddy, P Hemachandra %A Manczak, Maria %A Yin, XiangLing %A Grady, Mary Catherine %A Mitchell, Andrew %A Tonk, Sahil %A Kuruva, Chandra Sekhar %A Bhatti, Jasvinder Singh %A Kandimalla, Ramesh %A Vijayan, Murali %A Kumar, Subodh %A Wang, Rui %A Pradeepkiran, Jangampalli Adi %A Ogunmokun, Gilbert %A Thamarai, Kavya %A Quesada, Kandi %A Boles, Annette %A Reddy, Arubala P %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Blood-Brain Barrier %K Curcumin %K Disease Models, Animal %K Humans %K Mice %K Neuroprotective Agents %K Randomized Controlled Trials as Topic %K Spices %X

The purpose of our article is to assess the current understanding of Indian spice, curcumin, against amyloid-β (Aβ)-induced toxicity in Alzheimer's disease (AD) pathogenesis. Natural products, such as ginger, curcumin, and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes, and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on Aβ and curcumin has revealed that curcumin prevents Aβ aggregation and crosses the blood-brain barrier, reach brain cells, and protect neurons from various toxic insults of aging and Aβ in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin's bioavailability and urgent need for new formulations to increase its brain levels to treat patients with AD.

%B J Alzheimers Dis %V 61 %P 843-866 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332042?dopt=Abstract %R 10.3233/JAD-170512 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau. %A Chen, Mei %A Song, Hailong %A Cui, Jiankun %A Johnson, Catherine E %A Hubler, Graham K %A DePalma, Ralph G %A Gu, Zezong %A Xia, Weiming %X

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ)-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development.

%B J Alzheimers Dis %V 66 %P 751-773 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30347620?dopt=Abstract %R 10.3233/JAD-180726 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Protofibrillar and Fibrillar Amyloid-β Binding Proteins in Cerebrospinal Fluid. %A Rahman, M Mahafuzur %A Westermark, Gunilla T %A Zetterberg, Henrik %A Härd, Torleif %A Sandgren, Mats %X

Aggregation and deposition of misfolded amyloid-β (Aβ) peptide in the brain is central to Alzheimer's disease (AD). Oligomeric, protofibrillar, and fibrillar forms of Aβ are believed to be neurotoxic and cause neurodegeneration in AD, but the toxicity mechanisms are not well understood and may involve Aβ-interacting molecular partners. In a previous study, we identified potential Aβ42 protofibrillar-binding proteins in serum and cerebrospinal fluid (CSF) using an engineered version of Aβ42 (Aβ42CC) that forms protofibrils, but not fibrils. Here we studied binding of proteins to Aβ42 fibrils in AD and non-AD CSF and compared these with protofibrillar Aβ42CC-binding partners. Aβ42 fibrils sequestered 2.4-fold more proteins than Aβ42CC protofibrils. Proteins with selective binding to fibrillar aggregates with low nanomolar affinity were identified. We also found that protofibrillar and fibrillar Aβ-binding proteins represent distinct functional categories. Aβ42CC protofibrils triggered interactions with proteins involved in catalytic activities, like transferases and oxidoreductases, while Aβ42 fibrils were more likely involved in binding to proteoglycans, growth factors and neuron-associated proteins, e.g., neurexin-1, -2, and -3. Interestingly, 10 brain-enriched proteins were identified among the fibril-binding proteins, while protofibril-extracted proteins had more general expression patterns. Both types of Aβ aggregates bound several extracellular proteins. Additionally, we list a set of CSF proteins that might have potential to discriminate between AD and non-AD CSF samples. The results may be of relevance both for biomarker studies and for studies of Aβ-related toxicity mechanisms.

%B J Alzheimers Dis %V 66 %P 1053-1064 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30372682?dopt=Abstract %R 10.3233/JAD-180596 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Prototype for the Voice Analysis Diagnosis of Alzheimer's Disease. %A Martínez-Sánchez, Francisco %A Meilán, Juan José G %A Carro, Juan %A Ivanova, Olga %X

BACKGROUND: Speech variations enable us to map the performance of cognitive processes of syntactic, semantic, phonological, and articulatory planning and execution. Speaking is one of the first functions to be affected by neurodegenerative complaints such as Alzheimer's disease (AD), which makes the speech a highly promising biomarker for detecting the illness before the first preclinical symptoms appear.

OBJECTIVE: This paper has sought to develop and validate a technological prototype that adopts an automated approach to speech analysis among older people.

METHODS: It uses a mathematical algorithm based on certain discriminatory variables to estimate the probability of developing AD.

RESULTS AND CONCLUSION: This device may be used at a preclinical stage by non-expert health professionals to determine the likelihood of the onset of AD.

%B J Alzheimers Dis %V 64 %P 473-481 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914025?dopt=Abstract %R 10.3233/JAD-180037 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Psychological and Mnemonic Benefits of Nostalgia for People with Dementia. %A Ismail, Sanda %A Christopher, Gary %A Dodd, Emily %A Wildschut, Tim %A Sedikides, Constantine %A Ingram, Tom A %A Jones, Roy W %A Noonan, Krist A %A Tingley, Danielle %A Cheston, Richard %X

BACKGROUND: Studies with non-clinical populations show that nostalgia increases psychological resources, such as self-esteem and social connectedness.

OBJECTIVES: Our objectives were to find out if the benefits of nostalgia in non-clinical populations generalize to people with dementia and if nostalgia facilitates recall of dementia-related information.

METHODS: All three experiments recruited participants with mild or moderate levels of dementia. Experiment 1 tested whether nostalgia (compared to control) enhances psychological resources among 27 participants. Experiment 2 used music to induce nostalgia (compared to control) in 29 participants. Experiment 3 compared recall for self-referent dementia statements among 50 participants randomized to either a nostalgia or control condition. Findings across experiments were synthesized with integrative data analysis.

RESULTS: Nostalgia (compared to control) significantly increased self-reported social connectedness, meaning in life, self-continuity, optimism, self-esteem, and positive (but not negative) affect (Experiments 1-3). Compared to controls, nostalgic participants also recalled significantly more self-referent dementia-related information (Experiment 3).

CONCLUSION: This series of experiments extends social psychological research with non-clinical populations into dementia care, providing evidence that nostalgia significantly enhances psychological resources. The finding that nostalgia increased recall of self-referent statements about dementia suggests that this emotion lends participants the fortitude to face the threat posed by their illness. The finding has potentially important clinical implications both for the development of reminiscence therapy and for facilitating adjustment to a diagnosis of dementia.

%B J Alzheimers Dis %V 65 %P 1327-1344 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149444?dopt=Abstract %R 10.3233/JAD-180075 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Psychological Distress, Self-Beliefs, and Risk of Cognitive Impairment and Dementia. %A Sutin, Angelina R %A Stephan, Yannick %A Terracciano, Antonio %X

Depressive symptoms and a history of mental disorders are associated with increased risk for dementia. Less is known about whether other aspects of psychological distress and negative self-beliefs also increase risk. The purpose of this research is to examine 1) whether eight aspects of psychological distress and self-beliefs (anxiety, negative affect, hostility, anger-in, anger-out, hopelessness, pessimism, perceived constraints) are associated with risk of incident dementia and cognitive impairment not dementia (CIND), 2) whether the associations are independent of depressive symptoms and history of a mental health diagnosis, and 3) whether the associations are also independent of behavioral, clinical, and genetic risk factors. A total of 9,913 participants (60% female) from the Health and Retirement Study completed the baseline measures, scored in the non-impaired range of cognition at baseline, and had cognitive status assessed across the 6-8-year follow-up. Baseline measures included eight aspects of psychological distress and self-beliefs, cognitive performance, depressive symptoms, and genetic, clinical, and behavioral risk factors. Participants who scored higher on anxiety, negative affect, hostility, pessimism, hopelessness, and perceived constraints were at a 20-30% increased risk of dementia and a 10-20% increased risk of CIND. The associations held controlling for baseline depressive symptoms, history of a mental health diagnosis, clinical and behavioral risk factors, and genetic risk. Anger-in and anger-out were unrelated to risk of either dementia or CIND. Independent of the core experience of depressed affect, other aspects of negative emotionality and self-beliefs increase risk of mild and severe cognitive impairment, which suggests additional targets of intervention.

%B J Alzheimers Dis %V 65 %P 1041-1050 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103318?dopt=Abstract %R 10.3233/JAD-180119 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Psychometric Properties of Apathy Scales in Dementia: A Systematic Review. %A Mohammad, Dana %A Ellis, Courtney %A Rau, Allison %A Rosenberg, Paul B %A Mintzer, Jacobo %A Ruthirakuhan, Myuri %A Herrmann, Nathan %A Lanctôt, Krista L %X

Apathy is a prevalent and problematic neuropsychiatric symptom in those with dementia that is emerging as a treatment target, necessitating accurate assessment. While many apathy scales are available, not all have been developed for use exclusively in dementia, and psychometric properties may vary across different populations. This systematic review aimed to provide an overview of the psychometric properties of apathy scales used in Alzheimer's disease (AD) and related dementias, as well as rate the methodological quality of supporting studies. In addition, for those scales identified, performance in clinical trials was reviewed. A search was conducted through Medline, Psychinfo, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Articles that reported psychometric properties of an apathy scale in an AD or mixed dementia population were included. Of 15 articles, the methodological quality ratings of the studies ranged from adequate to excellent. Three clinical trials and two pooled analyses of clinical trials were included that used apathy scales evaluated in this review. Three scales emerged. The Neuropsychiatric Inventory apathy subscale (NPI-apathy) and the Apathy Evaluation Scale (AES) had the greatest number of studies evaluating psychometric properties and were also used in the clinical trials and have shown sensitivity to change. The Dementia Apathy Interview and Rating demonstrated excellent values of internal consistency, validity, and reliability for use in an AD population. Future research should address comparative scale performance and assess ability to distinguish subtypes of apathy. Validation may include evaluation of performance against specific imaging defined deficits.

%B J Alzheimers Dis %V 66 %P 1065-1082 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400094?dopt=Abstract %R 10.3233/JAD-180485 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Putative Dementia Cases Fluctuate as a Function of Mini-Mental State Examination Cut-Off Points. %A Rosa, Ilka M %A Henriques, Ana G %A Wiltfang, Jens %A da Cruz E Silva, Odete A B %K Age Factors %K Aged %K Aged, 80 and over %K Cohort Studies %K Community Health Planning %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Neuropsychological Tests %K ROC Curve %X

As the population ages, there is a growing need to quickly and accurately identify putative dementia cases. Many cognitive tests are available; among those commonly used are the Cognitive Dementia Rating (CDR) and the Mini-Mental Status Examination (MMSE). The aim of this work was to compare the validity and reliability of these cognitive tests in a primary care based cohort (pcb-Cohort). The MMSE and the CDR were applied to 568 volunteers in the pcb-Cohort. Distinct cut-off points for the MMSE were considered, namely MMSE 27, MMSE 24, and MMSE PT (adapted for the Portuguese population). The MMSE 27 identified the greatest number of putative dementia cases, and, as determined by the ROC curve, it was the most sensitive and specific of the MMSE cut-offs considered. Putative predictive or risk factors identified included age, literacy, depression, and diabetes mellitus (DM). DM has previously been indicated as a risk factor for dementia and Alzheimer's disease. Comparatively, the MMSE 27 cut-off has the greatest sensibility (94.9%) and specificity (66.3%) when compared to MMSE PT and MMSE 24. Upon comparing MMSE and CDR scores, the latter identified a further 146 putative dementia cases, thus permitting one to propose that in an ideal situation, both tests should be employed. This increases the likelihood of identifying putative dementia cases for subsequent follow up work, thus these cognitive tests represent important tools in patient care. Further, this is a significant study for Portuguese populations, where few of these studies have been carried out.

%B J Alzheimers Dis %V 61 %P 157-167 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125486?dopt=Abstract %R 10.3233/JAD-170501 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Putative Gonadotropin-Releasing Hormone Agonist Therapy and Dementia: An Application of Medicare Hospitalization Claims Data. %A Smith, Mark A %A Bowen, Richard L %A Nguyen, Richard Q %A Perry, George %A Atwood, Craig S %A Rimm, Alfred A %X

BACKGROUND: Estrogen and hormone replacement therapies to reduce Alzheimer's disease (AD) have yielded conflicting results. However, this study proposes that the well-characterized increase in serum gonadotropins following menopause or andropause are accountable for the increased risk of developing AD among the elderly population.

OBJECTIVE: To determine the role of gonadotropins in the development of AD and investigate gonadotropin-releasing hormone (GnRH) agonist therapy as a potential preventative and/or disease-modifying approach to AD management.

METHODS: Male Medicare beneficiaries aged 67 to 75 and hospitalized with prostate cancer (n = 115,789) were compared to three control groups: men of the same demographics undergoing a cholecystectomy (n = 97,267), herniorrhaphy (n = 68,778), or transurethral prostatectomy (n = 267,691). A proportion of the patients hospitalized with prostate cancer were assumed to have low concentrations of serum gonadotropins and sex steroids as a result of GnRH agonist therapy, while those in the control groups were assumed to have elevated gonadotropin but lowered sex steroid levels that are associated with andropause in this age group.

RESULTS: The rates of development of select diagnoses of dementia, including AD, over a twelve-year follow-up period following surgery. When compared to control patients, men hospitalized with prostate cancer have a protection against dementia after twelve years of follow-up, with relative risks ranging from 0.48 to 0.83.

CONCLUSION: Patients with prostate cancer are treated with the GnRH analogue leuprolide acetate, our data suggest that leuprolide acetate may be therapeutic for AD via its downregulation of serum gonadotropins.

%B J Alzheimers Dis %V 63 %P 1269-1277 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782310?dopt=Abstract %R 10.3233/JAD-170847 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Pyk2 is a Novel Tau Tyrosine Kinase that is Regulated by the Tyrosine Kinase Fyn. %A Li, Chuanzhou %A Götz, Jürgen %X

The protein tyrosine kinase Pyk2 is encoded by PTK2B, a novel Alzheimer's disease (AD) susceptibility variant, with the PTK2B risk allele being associated with increased mRNA levels, suggestive of increased Pyk2 levels. However, the role of Pyk2, a member of the focal adhesion kinase (FAK) family, in AD pathology and its regulation are largely unknown. To address this, we generated mice with neuronal expression of human Pyk2. Because we had previously reported an association of Pyk2 and hyperphosphorylated tau (a hallmark feature of AD) in human tau transgenic pR5 mice, we also generated Pyk2/tau double-transgenic mice, which exhibit increased tyrosine phosphorylation and accumulation of tau. We further demonstrated that Pyk2 colocalizes, interacts with, and phosphorylates tau in vivo and in vitro. Importantly, although Pyk2 interacts with the established tyrosine-directed tau kinase Fyn, we identified an increased Pyk2 activity in mice which constitutively overexpress Fyn (FynCA), and a decreased activity in mice lacking Fyn (FynKO). Together, our study reveals a novel role for Pyk2 as a direct tyrosine kinase of tau that is active downstream of Fyn. Our analysis may enhance the understanding of how the PTK2B risk allele contributes to tauopathy.

%B J Alzheimers Dis %V 64 %P 205-221 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782321?dopt=Abstract %R 10.3233/JAD-180054 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quality of Life, Care Resource Use, and Costs of Dementia in 8 European Countries in a Cross-Sectional Cohort of the Actifcare Study. %A Handels, Ron L H %A Sköldunger, Anders %A Bieber, Anja %A Edwards, Rhiannon Tudor %A Gonçalves-Pereira, Manuel %A Hopper, Louise %A Irving, Kate %A Jelley, Hannah %A Kerpershoek, Liselot %A Marques, Maria J %A Meyer, Gabriele %A Michelet, Mona %A Portolani, Elisa %A Røsvik, Janne %A Selbaek, Geir %A Stephan, Astrid %A de Vugt, Marjolein %A Wolfs, Claire %A Woods, Bob %A Zanetti, Orazio %A Verhey, Frans %A Wimo, Anders %X

BACKGROUND: With 10.5 million people with dementia in Europe and $301 billion associated costs, governments face challenges organizing access to care.

OBJECTIVE: To examine the costs related to formal and informal care use and quality of life for people with dementia in eight European countries, and explore the association with unmet needs.

METHODS: Cross-sectional data from 451 persons with dementia and their informal caregivers of the Actifcare cohort study were obtained. Formal and informal care use was multiplied by country specific unit prices of services. Needs were measured using the CANE and health-related quality of life (HRQOL) of the person with dementia (both self- and proxy-rated) and informal caregiver's quality of life using EQ-5D-5L, ICECAP-O, DEMQOL-U, and CarerQol utility scores. The association between costs and country, European region, and unmet needs was assessed using multi-level linear regression.

RESULTS: Self-rated EQ-5D-5L utility score was higher than proxy-rated (0.84 and 0.71, respectively). Informal caregivers' utility score was 0.84. Across eight countries annual mean costs of formal and informal care were approximately € 17,000. Unmet needs were not associated with annual costs of care, nor with proxy-rated HRQOL, but were associated with self-rated HRQOL.

CONCLUSION: We found varying relationships between unmet needs and quality of life, and no association between unmet needs and care costs, although the results were sensitive to various factors. Future research should further investigate the relation between unmet needs, quality of life and costs to generate a better understanding of the effects of (un)timely access to care.

%B J Alzheimers Dis %V 66 %P 1027-1040 %8 2018 %G eng %N 3 %R 10.3233/JAD-180275 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantifying the Diagnostic Pathway for Patients with Cognitive Impairment: Real-World Data from Seven European and North American Countries. %A Ritchie, Craig W %A Black, Christopher M %A Khandker, Rezaul K %A Wood, Robert %A Jones, Eddie %A Hu, Xiaohan %A Ambegaonkar, Baishali M %X

To ensure that patients with dementia and their caregivers receive appropriate treatment and support, early diagnosis is essential but remains challenging. Real-world data from a multi-national, cross-sectional survey of physicians and their patients were analyzed to quantify the diagnostic pathway for dementia, including a focus on severity of patients' cognitive impairment (CI) at the time of symptom onset, referral and subsequent diagnosis. Data were collected for 7,620 patients with CI. Most patients saw a healthcare professional within 1 year of first symptoms and received a diagnosis within 3-7 months of initial consultation. However, only 20% of patients received a diagnosis before their disease progressed beyond the prodromal stage and 23.5% already had moderate CI at diagnosis. These findings show that the goal of identifying and diagnosing CI at the earliest stages of disease is, for many patients, not achieved. Efforts toward public awareness and proactive, earlier detection and intervention, must be maintained-indeed where possible invigorated.

%B J Alzheimers Dis %V 62 %P 457-466 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439347?dopt=Abstract %R 10.3233/JAD-170864 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers. %A Ramos de Matos, Mafalda %A Ferreira, Catarina %A Herukka, Sanna-Kaisa %A Soininen, Hilkka %A Janeiro, André %A Santana, Isabel %A Baldeiras, Ines %A Almeida, Maria Rosário %A Lleo, Alberto %A Dols-Icardo, Oriol %A Alcolea, Daniel %A Benussi, Luisa %A Binetti, Giuliano %A Paterlini, Anna %A Ghidoni, Roberta %A Nacmias, Benedetta %A Meulenbroek, Olga %A van Waalwijk van Doorn, Linda J C %A Kuiperi, H Bea J %A Hausner, Lucrezia %A Waldemar, Gunhild %A Simonsen, Anja Hviid %A Tsolaki, Magda %A Gkatzima, Olymbia %A Resende de Oliveira, Catarina %A Verbeek, Marcel M %A Clarimón, Jordi %A Hiltunen, Mikko %A de Mendonça, Alexandre %A Martins, Madalena %X

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

%B J Alzheimers Dis %V 66 %P 639-652 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320580?dopt=Abstract %R 10.3233/JAD-180512 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantitative Magnetization Transfer of White Matter Tracts Correlates with Diffusion Tensor Imaging Indices in Predicting the Conversion from Mild Cognitive Impairment to Alzheimer's Disease. %A Makovac, Elena %A Serra, Laura %A Di Domenico, Carlotta %A Marra, Camillo %A Caltagirone, Carlo %A Cercignani, Mara %A Bozzali, Marco %X

Patients with amnestic mild cognitive impairment (aMCI) have higher probability to develop Alzheimer's disease (AD) than elderly controls. The detection of subtle changes in brain structure associated with disease progression and the development of tools to identify patients at high risk for dementia in a short time is crucial. Here, we used probabilistic white matter (WM) tractography to explore microstructural alterations within the main association, limbic, and commissural pathways in aMCI patients who converted to AD after 1 year follow-up (MCIconverters) and those who remained stable (MCIstable). Both diffusion tensor imaging (DTI) and quantitative magnetization transfer (qMT) parameters have been considered for a comprehensive pathophysiological characterization of the WM damage. Overall, tract-specific parameters derived from qMT and DTI at baseline were able to differentiate aMCI patients who converted to AD from those who remained stable in time. In particular, the qMT exchange rate, RMB0, of the right uncinate fasciculus was significantly decreased in MCIconverters, whereas fractional anisotropy was significantly decreased in the bilateral superior cingulum in MCIconverters compared to MCIstable. These results confirm the involvement of WM and particularly of association fibers in the progression of AD, highlighting disconnection as a potential mechanism.

%B J Alzheimers Dis %V 63 %P 561-575 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689722?dopt=Abstract %R 10.3233/JAD-170995 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantitative PET and Histology of Brain Biopsy Reveal Lack of Selective Pittsburgh Compound-B Binding to Intracerebral Amyloidoma. %A Groot, Colin %A Tolboom, Nelleke %A Ikonomovic, Milos D %A Lammertsma, Adriaan A %A Boon, Baayla D C %A Barkhof, Frederik %A Scheltens, Philip %A Klunk, William E %A Rozemuller, Annemieke J M %A Ossenkoppele, Rik %A van Berckel, Bart N M %X

This single case study examines selective Pittsburgh compound-B (PiB) binding to an intracerebral light-chain amyloidoma using a 90-minute dynamic [11C]PiB-PET scan and brain biopsy tissue. Parametric non-displaceable binding potential (BPND) images showed low specific binding in the amyloidoma (BPND = 0.23), while relative tracer delivery was adequate (R1 = 0.44). Histology of the tissue revealed strong coloring with Congo-red, thioflavin-S, and X-34, indicating presence of amyloid. However, immunological staining with 6F/3D revealed absence of amyloid-β and histofluorescence of 6-CN-PiB, a highly fluorescent derivative of PiB, was at background levels. Our results suggest that PiB does not detect the atypical amyloid pathology associated with an intracerebral light-chain amyloidoma. These findings are of interest to clinicians and researchers applying [11C]PiB-PET to detect atypical forms of amyloid pathology.

%B J Alzheimers Dis %8 2018 Jul 18 %G eng %R 10.3233/JAD-180316 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantitative Susceptibility Mapping of Amyloid-β Aggregates in Alzheimer's Disease with 7T MR. %A Tiepolt, Solveig %A Schäfer, Andreas %A Rullmann, Michael %A Roggenhofer, Elisabeth %A Gertz, Hermann-Josef %A Schroeter, Matthias L %A Patt, Marianne %A Bazin, Pierre-Louis %A Jochimsen, Thies H %A Turner, Robert %A Sabri, Osama %A Barthel, Henryk %X

BACKGROUND: PET imaging is an established technique to detect cerebral amyloid-β (Aβ) plaques in vivo. Some preclinical and postmortem data report an accumulation of redox-active iron near Aβ plaques. Quantitative susceptibility mapping (QSM) at high-field MRI enables iron deposits to be depicted with high spatial resolution.

OBJECTIVE: Aim of this study was to examine whether iron and Aβ plaque accumulation is related and thus, whether 7T MRI might be an additive diagnostic tool to Aβ PET imaging.

METHODS: Postmortem human Alzheimer's disease (AD) and healthy control (HC) frontal gray matter (GM) was imaged with 7T MRI which resulted in T1 maps and QSM. Aβ plaque load was determined by histopathology. In vivo, 10 Aβ PET-positive AD patients (74.1±6.0a) and 10 Aβ PET-negative HCs (67.1±4.4a) underwent 7T MR examination and QSM maps were analyzed. Severity of cognitive deficits was determined by MMSE.

RESULTS: Postmortem, the susceptibility of Aβ plaque-containing GM were higher than those of Aβ plaque-free GM (0.011±0.002 versus - 0.008±0.003 ppm, p < 0.001). In vivo, only the bilateral globus pallidus showed significantly higher susceptibility in AD patients compared to HCs (right: 0.277±0.018 versus - 0.009±0.009 ppm; left: 0.293±0.014 versus - 0.007±0.012 ppm, p < 0.0001). The pallidal QSM values were negatively correlated with those of the MMSE (r = - 0.69, p = 0.001).

CONCLUSION: The postmortem study revealed significant susceptibility differences between the Aβ plaque-containing and Aβ plaque-free GM, whereas in vivo only the QSM values of the globus pallidus differed significantly between AD and HC group. The pallidal QSM values correlated with the severity of cognitive deficits. These findings encourage efforts to optimize the 7T-QSM methodology.

%B J Alzheimers Dis %V 64 %P 393-404 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865069?dopt=Abstract %R 10.3233/JAD-180118 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Rab10 Phosphorylation is a Prominent Pathological Feature in Alzheimer's Disease. %A Yan, Tingxiang %A Wang, Luwen %A Gao, Ju %A Siedlak, Sandra L %A Huntley, Mikayla L %A Termsarasab, Pichet %A Perry, George %A Chen, Shu G %A Wang, Xinglong %X

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles (NFTs), senile plaques (SPs), and a progressive loss of neuronal cells in selective brain regions. Rab10, a small Rab GTPase involved in vesicular trafficking, has recently been identified as a novel protein associated with AD. Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson's disease. However, the phosphorylation state of Rab10 has not yet been investigated in AD. Here, using a specific antibody recognizing LRRK2-mediated Rab10 phosphorylation at the amino acid residue threonine 73 (pRab10-T73), we performed immunocytochemical analysis of pRab10-T73 in hippocampal tissues of patients with AD. pRab10-T73 was prominent in NFTs in neurons within the hippocampus in all cases of AD examined, whereas immunoreactivity was very faint in control cases. Other characteristic AD pathological structures including granulovacuolar degeneration, dystrophic neurites and neuropil threads also contained pRab10-T73. The pRab10-T73 immunoreactivity was diminished greatly following dephosphorylation with alkaline phosphatase. pRab10-T73 was further found to be highly co-localized with hyperphosphorylated tau (pTau) in AD, and demonstrated similar pathological patterns as pTau in Down syndrome and progressive supranuclear palsy. Although pRab10-T73 immunoreactivity could be noted in dystrophic neurites surrounding SPs, SPs were largely negative for pRab10-T73. These findings indicate that Rab10 phosphorylation could be responsible for aberrations in the vesicle trafficking observed in AD leading to neurodegeneration.

%B J Alzheimers Dis %V 63 %P 157-165 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562525?dopt=Abstract %R 10.3233/JAD-180023 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Rapidly Progressive Alzheimer's Disease: Contributions to Clinical-Pathological Definition and Diagnosis. %A Abu-Rumeileh, Samir %A Capellari, Sabina %A Parchi, Piero %X

Rapidly progressive Alzheimer's disease (rpAD) has recently been recognized as a clinical disease subtype characterized by rapidly progressive cognitive decline and/or short disease duration, and the possible occurrence of early focal neurological signs. Consistently, rpAD represents a relatively frequent alternative diagnosis among cases referred as possible or probable Creutzfeldt-Jakob disease (CJD) to surveillance centers for prion disease worldwide. Indeed, the early clinical differential diagnosis between the two disorders can be challenging given the partial overlap in clinical features and cerebrospinal fluid (CSF) levels of the protein surrogate markers 14-3-3 and total-tau. Although typical AD and rpAD seem to share the neuropathological core features, recent evidence suggests that a distinctive molecular signature involving the structure of amyloid-β aggregates and the proteomic landscape of amyloid plaques may distinguish rpAD from typical AD. Here we review clinical, neuropathologic, and molecular features and diagnostic findings, including CSF biomarker data, reported to date in rpAD. Furthermore, we summarize the main clinic-pathological and laboratory features of 27 autopsy confirmed cases of rpAD referred to our center. The results of this retrospective analysis, while largely confirming previously published genetic, clinical, and neuropathologic data, suggest a higher prevalence of moderate to severe cerebral amyloid angiopathy in rpAD compared to typical AD, a finding to explore further and validate in a larger patient group.

%B J Alzheimers Dis %8 2018 Apr 25 %G eng %R 10.3233/JAD-171181 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Rapidly Progressive Alzheimer's Disease in Two Distinct Autopsy Cohorts. %A Pillai, Jagan A %A Appleby, Brian S %A Safar, Jiri %A Leverenz, James B %X

BACKGROUND: A rapidly progressive phenotype of Alzheimer's disease (AD) has been described in some prion disease cohorts. Limited information regarding rapidly progressive AD (rpAD) is available from longitudinal national cohorts.

OBJECTIVE: To compare the clinical characteristics of rpAD in two different national cohorts.

METHODS: A retrospective analysis was performed on AD subjects with available neuropathology in the National Alzheimer's Coordinating Center (NACC) database and among neuropathologically characterized AD cases from the National Prion Disease Pathology Surveillance Center (NPDPSC) that were evaluated for suspected prion disease. In the NACC cohort, rpAD was delineated by the lower 10th percentile of follow up duration from pre-dementia to death duration among subjects meeting pathological diagnosis of AD.

RESULTS: rpAD from the NPDPSC had a shorter mean symptom duration than the NACC identified rpAD cases (11.6 months versus 62.4 months) and were also younger at the time of their death (60.0 versus 81.8 years). NACC identified rpAD subjects, beginning from a predementia stage, had slower rate of MMSE change per year than NPDPSC cases (2.5 versus 6.0 points).

CONCLUSIONS: rpAD constitute an important subset of AD subjects in whom a rapid course of symptomatic clinical decline is noted, as confirmed in both national cohorts. rpAD was best characterized by survival time (≤3 years), as there were clear differences between the rpAD cohorts in terms of symptom duration, age at death, and MMSE change per year, likely due to the strong selection biases. rpAD could shed light on the biology of rate of progression in AD.

%B J Alzheimers Dis %V 64 %P 973-980 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966195?dopt=Abstract %R 10.3233/JAD-180155 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Rare Variants in PLD3 Increase Risk for Alzheimer's Disease in Han Chinese. %A Tan, Meng-Shan %A Zhu, Jun-Xia %A Cao, Xi-Peng %A Yu, Jin-Tai %A Tan, Lan %X

Next-generation sequencing studies had reported that a rare coding variant p.V232M in PLD3 was associated with Alzheimer's disease (AD) and a two-fold increased AD risk in European cohorts. To test whether coding region variants of PLD3 were associated with AD in a large Han Chinese cohort, we performed sequencing to analyze all exons of PLD3, and demonstrated that rare variants p.I163M and c.1020-8G>A conferred considerable risk of late-onset AD (LOAD) in our cohort. Meanwhile, the previously reported p.V232M variant was identified in our AD group. These findings indicate that rare variants of PLD3 may play an important role in LOAD in northern Han Chinese.

%B J Alzheimers Dis %V 64 %P 55-59 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865074?dopt=Abstract %R 10.3233/JAD-180205 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Rationale and Design of the Mechanistic Potential of Antihypertensives in Preclinical Alzheimer's (HEART) Trial. %A Wharton, Whitney %A Goldstein, Felicia C %A Tansey, Malú G %A Brown, Alexandra L %A Tharwani, Sonum D %A Verble, Danielle D %A Cintron, Amarallys %A Kehoe, Patrick G %K African Americans %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Antihypertensive Agents %K Biomarkers %K Blood Pressure %K Brain %K Clinical Trials, Phase I as Topic %K Female %K Georgia %K Humans %K Linear Models %K Male %K Middle Aged %K Randomized Controlled Trials as Topic %K Renin-Angiotensin System %K Telmisartan %X

Research indicates that certain antihypertensive medications alter Alzheimer's disease (AD) biomarkers in Caucasians. The renin angiotensin system (RAS) regulates blood pressure (BP) in the body and the brain and may directly influence AD biomarkers, including amyloid-β (Aβ) neuropathology, cerebral blood flow (CBF), and inflammatory markers. This hypothesis is supported by studies, including ours, showing that antihypertensives targeting the RAS reduce the risk and slow the progression of AD in Caucasians. While mounting evidence supports a protective role of RAS medications in Caucasians, this mechanism has not been explored in African Americans. To assess the mechanism by which RAS medications modify the brain RAS, cerebrospinal fluid (CSF) Aβ, CBF, and inflammatory markers in African Americans, we are conducting an eight month, Phase Ib randomized, placebo controlled trial, enrolling 60 middle-aged (45-70 years), non-demented individuals, at risk for AD by virtue of a parental history. Participants include normotensive and treated hypertensives that have never been exposed to a RAS medication. Participants are randomized (1 : 1:1) by gender and BP medication use (yes/no) to one of three groups: placebo, or 20 mg, or 40 mg telmisartan (Micardis), to determine the dose required to penetrate the CNS. Our overarching hypothesis is that, compared to placebo, both doses of telmisartan will penetrate the CNS and produce salutary, dose dependent effects on the brain RAS as well as CSF Aβ, CBF, and CSF inflammatory markers in African Americans, over eight months. This manuscript describes the trial rationale and design.

%B J Alzheimers Dis %V 61 %P 815-824 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254080?dopt=Abstract %R 10.3233/JAD-161198 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Rationale and Design of the Reducing Pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR) Trial. %A Kehoe, Patrick G %A Blair, Peter S %A Howden, Beth %A Thomas, David L %A Malone, Ian B %A Horwood, Jeremy %A Clement, Clare %A Selman, Lucy E %A Baber, Hannah %A Lane, Athene %A Coulthard, Elizabeth %A Passmore, Anthony Peter %A Fox, Nick C %A Wilkinson, Ian B %A Ben-Shlomo, Yoav %K Activities of Daily Living %K Alzheimer Disease %K Antihypertensive Agents %K Atrophy %K Blood Pressure Monitors %K Brain %K Clinical Trials, Phase II as Topic %K Disease Progression %K Double-Blind Method %K Female %K Humans %K Losartan %K Magnetic Resonance Imaging %K Male %K Multivariate Analysis %K Quality of Life %K Randomized Controlled Trials as Topic %K Regression Analysis %K Renin-Angiotensin System %X

BACKGROUND: Anti-hypertensives that modify the renin angiotensin system may reduce Alzheimer's disease (AD) pathology and reduce the rate of disease progression.

OBJECTIVE: To conduct a phase II, two arm, double-blind, placebo-controlled, randomized trial of losartan to test the efficacy of Reducing pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR).

METHODS: Men and women aged at least 55 years with mild-to-moderate AD will be randomly allocated 100 mg encapsulated generic losartan or placebo once daily for 12 months after successful completion of a 2-week open-label phase and 2-week placebo washout to establish drug tolerability. 228 participants will provide at least 182 subjects with final assessments to provide 84% power to detect a 25% difference in atrophy rate (therapeutic benefit) change over 12 months at an alpha level of 0.05. We will use intention-to-treat analysis, estimating between-group differences in outcomes derived from appropriate (linear or logistic) multivariable regression models adjusting for minimization variables.

RESULTS: The primary outcome will be rate of whole brain atrophy as a surrogate measure of disease progression. Secondary outcomes will include changes to 1) white matter hyperintensity volume and cerebral blood flow; 2) performance on a standard series of assessments of memory, cognitive function, activities of daily living, and quality of life. Major assessments (for all outcomes) and relevant safety monitoring of blood pressure and bloods will be at baseline and 12 months. Additional cognitive assessment will also be conducted at 6 months along with safety blood pressure and blood monitoring. Monitoring of blood pressure, bloods, and self-reported side effects will occur during the open-label phase and during the majority of the post-randomization dispensing visits.

CONCLUSION: This study will identify whether losartan is efficacious in the treatment of AD and whether definitive Phase III trials are warranted.

%B J Alzheimers Dis %V 61 %P 803-814 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226862?dopt=Abstract %R 10.3233/JAD-170101 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Rationale Behind the New Alzheimer's Disease Conceptualization: Lessons Learned During the Last Decades. %A Molinuevo, José Luis %A Minguillon, Carolina %A Rami, Lorena %A Gispert, Juan Domingo %X

In the last decades, progress in neuroimaging techniques and cerebrospinal fluid assays has enabled the characterization of several Alzheimer's disease (AD) biomarkers. This knowledge has shifted the conceptualization of AD from a clinical-pathological construct, where its diagnosis required the presence of dementia with distinct pathologic features, toward a clinical-biological one that recognizes AD as a pathological continuum with a clinical picture that ranges from normal cognition to a dementia stage. Specifically, AD is now divided into three stages: preclinical (abnormal biomarkers and no or only subtle cognitive impairment), mild cognitive impairment or prodromal AD (abnormal pathophysiological biomarkers and episodic memory impairment), and dementia (abnormal biomarkers and clear cognitive and functional impairment). The possibility of assessing AD pathophysiology in vivo before the onset of clinical symptoms in the preclinical stage provides the unprecedented opportunity to intervene at earlier stages of the continuum in secondary prevention trials. Currently, large cohort studies of cognitively healthy participants are undergoing with the main aim of disentangling the natural history of AD to identify individuals with an increased risk of developing AD in the near future to be recruited in these clinical trials. In this paper, we review how the concept of AD has changed over the years as well as discuss the implications of this conceptual change.

%B J Alzheimers Dis %V 62 %P 1067-1077 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562531?dopt=Abstract %R 10.3233/JAD-170698 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Rbfox3/NeuN Regulates Alternative Splicing of Tau Exon 10. %A Gu, Jianlan %A Chen, Feng %A Chu, Dandan %A Lu, Ying %A Iqbal, Khalid %A Gong, Cheng-Xin %A Liu, Fei %X

Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau or 4R-tau, which are under developmental regulation. Dysregulation of tau exon 10 splicing is sufficient to cause neurodegenerative disorders. The RNA-binding Fox3 (Rbfox3), identified as NeuN, regulates RNA processing. However, whether Rbfox3/NeuN regulates tau exon 10 splicing is unknown. In the present study, we found that the developmental expression of 4R-tau coincided with the expression of Rbfox3 in rat brains. Rbfox3 enhanced tau exon 10 inclusion. Tau intron 10 contains UGCAUG, the conservative binding sequence of Rbfox3. Intron 10 of tau pre-mRNA was co-immunoprecipitated by Rbfox3/NeuN. Deletion mutants of the RNA recognition motif (RRM) or three RNA-binding sites of the RRM in Rbfox3/NeuN failed to enhance tau exon 10 inclusion. Rbfox3, specifically expressed in the fetal brain, did not affect tau exon 10 splicing. The level of Rbfox3/NeuN was reduced and was associated with the ratio of 4R-tau/3R-tau in the excitotoxic mouse brains induced by kainic acid. These findings suggest that Rbfox3/NeuN regulates the alternative splicing of tau exon 10 and that decreased Rbfox3/NeuN may lower the ratio of 4R-tau/3R-tau.

%B J Alzheimers Dis %V 66 %P 1695-1704 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30475774?dopt=Abstract %R 10.3233/JAD-180882 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Reaction of Amyloid-β Peptide Antibody with Different Infectious Agents Involved in Alzheimer's Disease. %A Vojdani, Aristo %A Vojdani, Elroy %A Saidara, Evan %A Kharrazian, Datis %X

As early as the 1980s, molecular virologist Ruth Itzhaki began to investigate if there was a causal connection between infections and neurodegenerative disorder. Although the theory has yet to be universally embraced, in 2016 Itzhaki and 33 other scientists from all over the world published a review article in this very journal presenting evidence for the causal role of pathogens in Alzheimer's disease (AD). Exactly how and in what way pathogens affect the induction of AD has yet to be determined, but one possible answer may involve the cross-reactivity of different pathogens with amyloid-β (Aβ). Aβ autoantibodies have been detected in the serum and cerebrospinal fluid of AD patients and in some healthy individuals. In the present study our major goal was to investigate whether antibodies made against Aβ would react both with other brain proteins as well as pathogens associated with AD as a result of molecular mimicry or the binding of bacterial toxins to Aβ42. Our study used a specific monoclonal antibody made against Aβ42, which not only reacted strongly with Aβ42, tau protein, and α-synuclein, but also had from weak to strong reactions with 25 different pathogens or their molecules, some of which have been associated with AD. The homology between peptide stretches of microbial origin and proteins involved in AD could be a mechanism by which antibodies to homologous peptides mount attacks against autoantigens in AD. We concluded that bacterial molecules bind to Aβ protein, forming small oligomers, then encasing pathogens and their molecules to form amyloid plaques, the tell-tale markers of AD. Conversely, these same Aβ peptides induce the production of antibodies to both Aβ42 and bacterial molecules, which may inhibit bacterial pathogenesis, but in the process may promote amyloid plaque formation.

%B J Alzheimers Dis %V 63 %P 847-860 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689721?dopt=Abstract %R 10.3233/JAD-170961 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Real World Recruiting of Older Subjects with Mild Cognitive Impairment for Exercise Trials: Community Readiness is Pivotal. %A Sanders, Marit L %A Stuckenschneider, Tim %A Devenney, Kate E %A Lawlor, Brian %A Schneider, Stefan %A Olde Rikkert, Marcel G M %K Aged %K Cognitive Dysfunction %K Europe %K Exercise %K Female %K Humans %K Life Style %K Male %K Middle Aged %K Patient Selection %X

Prevention trials in subjects with mild cognitive impairment (MCI), especially lifestyle interventions, can be difficult to carry out, particularly the recruitment and retention of subjects. We experienced these challenges in our multi-site one-year exercise trial in MCI, NeuroExercise. Trial recruitment rates differed significantly across sites; the non-medical sport university site, providing free access to a range of group exercise in a sports environment, proved far more successful than memory clinics linked to hospitals. This suggests that non-medical settings and a non-medical research community facilitating physical activities may be important factors in recruitment of subjects with MCI for large prevention trials.

%B J Alzheimers Dis %V 62 %P 579-581 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480202?dopt=Abstract %R 10.3233/JAD-171083 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Real-World, Multinational, Retrospective Observational Survey of the ADAS-Cog and Associations with Healthcare Resource Utilization in Patients with Alzheimer's Disease. %A Ritchie, Craig W %A Khandker, Rezaul K %A Pike, James %A Black, Christopher M %A Jones, Eddie %A Ambegaonkar, Baishali M %X

BACKGROUND: Alzheimer's disease (AD) is one of the most costly conditions, both economically and regarding patient disability and dependency. The huge costs coupled with the predicted increase in prevalence worldwide are likely to challenge healthcare systems in the future. The classic version of the Alzheimer's Disease Assessment Scale-Cognition subscale (ADAS-Cog) is generally seen as the current gold standard primary outcome measure of cognitive symptom progression in dementia clinical trials.

OBJECTIVE: This study evaluated the relationship between ADAS-Cog scores as a measure of clinical progression and the healthcare resource utilization (HCRU)-measured burden of cognitive impairment in patients with mild cognitive impairment, AD, or suspected AD in the real world.

METHODS: A retrospective observational survey of physicians and their consulting patients with multiple ADAS-Cog scores. Regression models were constructed for HCRU variables (e.g., consultations, hospitalizations, caregiving requirements) with ADAS-Cog rate of change, baseline ADAS-Cog, and their interaction included as exposure variables.

RESULTS: 651 patient records were completed by 154 physicians. Approximately 70% of patients had mild to moderate dementia. In 56.7% of patients, clinical progression was maintained/stable from baseline. Mean change in ADAS-Cog (adjusted to 12 months) was 2.8 points and change scores increased with increasing dementia severity. Most HCRU variables increased significantly (p < 0.05; joint test) with increasing ADAS-Cog scores (indexing clinical deterioration).

CONCLUSION: The results suggest that further understanding the relationship between HCRU and ADAS-Cog changes in real-world clinical practice could potentially provide a baseline upon which the success of disease-modifying, as well as newer symptomatic, dementia therapies can be judged.

%B J Alzheimers Dis %V 64 %P 899-910 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966202?dopt=Abstract %R 10.3233/JAD-180306 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Reappraisal of Aβ40 and Aβ42 Peptides Measurements in Cerebrospinal Fluid of Patients with Alzheimer's Disease. %A Fiorini, Michele %A Bongianni, Matilde %A Benedetti, Maria Donata %A Monaco, Salvatore %A Zanusso, Gianluigi %X

Cerebrospinal fluid (CSF) biomarkers are currently included in the diagnostic criteria for Alzheimer's disease (AD), in particular, decreased concentrations of amyloid-β peptide 1-42 (Aβ42) in the CSF, coupled with increased levels of tau and phosphorylated tau proteins, are supportive of AD diagnosis. To date, the quantification of Aβ42 levels with antibody-dependent immunoassay shows a marked variability among different laboratories and is also affected by different pre-analytical factors, suggesting that part of Aβ42 peptides might be aggregated and thus undetected by antibodies. To bypass an antibody-dependent measurement, we determined the Aβ40 and Aβ42 levels by immunoblot. We analyzed CSF samples from 35 patients with clinical diagnosis of probable AD and from 15 age-matched normal controls; CSF Aβ levels were determined by two different ELISA kits and by immunoblot analysis. Aβ40 levels measured by ELISA were comparable to those obtained by immunoblot, whereas CSF concentrations of Aβ42 measured by ELISA were significantly lower compared to values obtained by immunoblot quantification. Biochemical analysis, following 1D- and 2D-PAGE analysis, showed that the qualitative composition of Aβ peptides in the CSF is similar in AD and controls but different from that of AD brain tissues. Moreover, sedimentation velocity in sucrose gradient of CSF and brain homogenate from AD demonstrated that Aβ42 in CSF is different from Aβ42 in brain in terms of solubility and aggregation state.

%B J Alzheimers Dis %V 66 %P 219-227 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282368?dopt=Abstract %R 10.3233/JAD-180616 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Reduced Cerebrovascular Reserve Capacity as a Biomarker of Microangiopathy in Alzheimer's Disease and Mild Cognitive Impairment. %A Urbanova, Barbora Soukupova %A Schwabova, Jaroslava Paulasova %A Magerova, Hana %A Jansky, Petr %A Marková, Hana %A Vyhnálek, Martin %A Laczó, Jan %A Hort, Jakub %A Tomek, Ales %X

BACKGROUND: Cerebral microangiopathy in Alzheimer's disease (AD) causes chronic hypoperfusion and probably accelerates neurodegenerative changes.

OBJECTIVE: We hypothesize microvascular impairment could be present already in mild cognitive impairment (MCI) and can be revealed using transcranial color-coded sonography (TCCS) and the breath-holding maneuver.

METHODS: Three groups of subjects (AD in the stage of dementia, MCI, and cognitively normal controls) with detailed neuropsychological testing and low cerebrovascular burden (no history of stroke, no intra- or extracranial artery stenoses, and no severe vascular lesions on brain MRI), underwent a TCCS assessment of peak systolic (PSV), mean flow (MFV), and end diastolic velocities (EDV) and resistance and pulsatility indices (RI, PI) in large intracranial vessels bilaterally. Cerebrovascular reserve capacity was assessed using the breath-holding index (BHI) in middle cerebral artery (MCA) bilaterally. The ultrasound parameters were compared between the groups, correlated with neuropsychological tests, and compared between amnestic and non-amnestic MCI subtypes.

RESULTS: Fourteen AD (3 males, 67.9±11.1 years, MMSE 18.0±4.6), 24 MCI (13 males, 71.9±7.3 years, MMSE 28.0±1.6), and 24 risk factor-matched controls (14 males, 67.8±6.4 years, MMSE 29.1±1.2) were enrolled. Significant differences were found between AD and controls in MFV, EDV, RI, PI in right MCA after breath holding, in PSV, MFV, EDV in left MCA after breath holding, and in BHI on the left side. The left BHI correlated positively with verbal memory test.

CONCLUSION: Results show decreased cerebrovascular reserve capacity in AD as a sign of impaired cerebral hemodynamic status without severe underlying atherosclerosis. This can be identified using TCCS and BHI.

%B J Alzheimers Dis %V 63 %P 465-477 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614647?dopt=Abstract %R 10.3233/JAD-170815 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Reduced Gray Matter Volume of the Thalamus and Hippocampal Region in Elderly Healthy Adults with no Impact of APOE ɛ4: A Longitudinal Voxel-Based Morphometry Study. %A Squarzoni, Paula %A Duran, Fabio Luis Souza %A Busatto, Geraldo F %A Alves, Tania Correa Toledo de Ferraz %K Aged %K Aging %K Apolipoprotein E4 %K Atrophy %K Cross-Sectional Studies %K Female %K Gray Matter %K Healthy Volunteers %K Hippocampus %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Organ Size %K Thalamus %X

BACKGROUND: Many cross-sectional voxel-based morphometry (VBM) investigations have shown significant inverse correlations between chronological age and gray matter (GM) volume in several brain regions in healthy humans. However, few VBM studies have documented GM decrements in the healthy elderly with repeated MRI measurements obtained in the same subjects. Also, the extent to which the APOE ɛ4 allele influences longitudinal findings of GM reduction in the healthy elderly is unclear.

OBJECTIVE: Verify whether regional GM changes are associated with significant decrements in cognitive performance taking in account the presence of the APOE ɛ4 allele.

METHODS: Using structural MRI datasets acquired in 55 cognitively intact elderly subjects at two time-points separated by approximately three years, we searched for voxels showing significant GM reductions taking into account differences in APOE genotype.

RESULTS: We found global GM reductions as well as regional GM decrements in the right thalamus and left parahippocampal gyrus (p < 0.05, family-wise error corrected for multiple comparisons over the whole brain). These findings were not affected by APOE ɛ4.

CONCLUSIONS: Irrespective of APOE ɛ4, longitudinal VBM analyses show that the hippocampal region and thalamus are critical sites where GM shrinkage is greater than the degree of global volume reduction in healthy elderly subjects.

%B J Alzheimers Dis %V 62 %P 757-771 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480170?dopt=Abstract %R 10.3233/JAD-161036 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Regional Distribution, Asymmetry, and Clinical Correlates of Tau Uptake on [18F]AV-1451 PET in Atypical Alzheimer's Disease. %A Tetzloff, Katerina A %A Graff-Radford, Jonathan %A Martin, Peter R %A Tosakulwong, Nirubol %A Machulda, Mary M %A Duffy, Joseph R %A Clark, Heather M %A Senjem, Matthew L %A Schwarz, Christopher G %A Spychalla, Anthony J %A Drubach, Daniel A %A Jack, Clifford R %A Lowe, Val J %A Josephs, Keith A %A Whitwell, Jennifer L %X

BACKGROUND: Despite common pathology, Alzheimer's disease (AD) can have multiple clinical presentations which pathological studies suggest result from differences in the regional distribution of tau pathology. Positron emission tomography (PET) ligands are now available that can detect tau proteins in vivo and hence can be used to investigate the biological mechanisms underlying atypical AD.

OBJECTIVE: To assess regional patterns of tau uptake on PET imaging in two atypical AD variants, posterior cortical atrophy (PCA) and logopenic progressive aphasia (lvPPA).

METHODS: Eighteen PCA and 19 lvPPA subjects that showed amyloid-β deposition on PET underwent tau-PET imaging with [18F]AV-1451. Group comparisons of tau uptake in PCA and lvPPA were performed using voxel-level and regional-level analyses. We also assessed the degree of lobar tau asymmetry and correlated regional tau uptake to age and performance on clinical evaluations.

RESULTS: Both syndromes showed diffuse tau uptake throughout all cortical regions, although PCA showed greater uptake in occipital regions compared to lvPPA, and lvPPA showed greater uptake in left frontal and temporal regions compared to PCA. While lvPPA showed predominant left-asymmetric tau deposition, PCA was more bilateral. Younger subjects showed greater tau uptake bilaterally in frontal and parietal lobes than older subjects, and sentence repetition, Boston naming test, simultanagnosia, and visuoperceptual function showed specific regional tau correlates.

CONCLUSION: Tau deposition is closely related to clinical presentation in atypical AD with age playing a role in determining the degree of cortical tau deposition.

%B J Alzheimers Dis %V 62 %P 1713-1724 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614676?dopt=Abstract %R 10.3233/JAD-170740 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Regional White Matter Hyperintensity Influences Grey Matter Atrophy in Mild Cognitive Impairment. %A Vipin, Ashwati %A Foo, Heidi Jing Ling %A Lim, Joseph Kai Wei %A Chander, Russell Jude %A Yong, Ting Ting %A Ng, Adeline Su Lyn %A Hameed, Shahul %A Ting, Simon Kang Seng %A Zhou, Juan %A Kandiah, Nagaendran %X

The association between cerebrovascular disease pathology (measured by white matter hyperintensities, WMH) and brain atrophy in early Alzheimer's disease (AD) remain to be elucidated. Thus, we investigated how WMH influence neurodegeneration and cognition in prodromal and clinical AD. We examined 51 healthy controls, 35 subjects with mild cognitive impairment (MCI), and 30 AD patients. We tested how total and regional WMH is related to specific grey matter volume (GMV) reductions in MCI and AD compared to controls. Stepwise regression analysis was further performed to investigate the association of GMV and regional WMH volume with global cognition. We found that total WMH volume was highest in AD but showed the strongest association with lower GMV in MCI. Frontal and parietal WMH had the most extensive influence on GMV loss in MCI. Additionally, parietal lobe WMH volume (but not hippocampal atrophy) was significantly associated with global cognition in MCI while smaller hippocampal volume (but not WMH volume) was associated with lower global cognition in AD. Thus, although WMH volume was highest in AD subjects, it had a more pervasive influence on brain structure and cognitive impairment in MCI. Our study thus highlights the importance of early detection of cerebrovascular disease, as its intervention at the MCI stage might potentially slow down neurodegeneration.

%B J Alzheimers Dis %V 66 %P 533-549 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320575?dopt=Abstract %R 10.3233/JAD-180280 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Relationship Between Amyloid-β Positivity and Progression to Mild Cognitive Impairment or Dementia over 8 Years in Cognitively Normal Older Adults. %A Dang, Christa %A Harrington, Karra D %A Lim, Yen Ying %A Ames, David %A Hassenstab, Jason %A Laws, Simon M %A Yassi, Nawaf %A Hickey, Martha %A Rainey-Smith, Stephanie %A Robertson, Joanne %A Sohrabi, Hamid R %A Salvado, Olivier %A Weinborn, Michael %A Villemagne, Victor L %A Rowe, Christopher C %A Masters, Colin L %A Maruff, Paul %X

BACKGROUND: Preclinical Alzheimer's disease (AD) is defined by cerebral amyloid-β positivity (Aβ+) in cognitively normal (CN) older adults.

OBJECTIVE: To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study.

METHODS: Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to Aβ+, APOEɛ4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n = 599) over 8 years.

RESULTS: 17.7% Aβ+ and 8.1% Aβ-progressed over 8 years (OR: 2.43). Risk of progression for Aβ+ was 65-104% greater than Aβ-. Aβ+ APOEɛ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aβ+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ɛ4 carriage (HR: 2.63); only age was a significant risk factor in Aβ-(HR: 1.09). Aβ-progressors were not near the threshold for Aβ+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA.

CONCLUSION: Aβ+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOEɛ4 carriage provides further predictive value in the presence of Aβ+. These data suggest that Aβ-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aβ deposition may be the result of neuropathological processes other than AD that accumulate with age.

%B J Alzheimers Dis %V 65 %P 1313-1325 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149452?dopt=Abstract %R 10.3233/JAD-180507 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Relationship Between Body Mass Index, ApoE4 Status, and PET-Based Amyloid and Neurodegeneration Markers in Amyloid-Positive Subjects with Normal Cognition or Mild Cognitive Impairment. %A Blautzik, Janusch %A Kotz, Sebastian %A Brendel, Matthias %A Sauerbeck, Julia %A Vettermann, Franziska %A Winter, Yaroslav %A Bartenstein, Peter %A Ishii, Kazunari %A Rominger, Axel %X

Body weight loss in late-life is known to occur at a very early stage of Alzheimer's disease (AD). Apolipoprotein E4 (ApoE4) represents a major genetic risk factor for AD and is linked to an increased cortical amyloid-β (Aβ) accumulation. Since the relationship between body weight, ApoE4, and AD pathology is poorly investigated, we aimed to evaluate whether ApoE4 allelic status modifies the association of body mass index (BMI) with markers of AD pathology. A total of 368 Aβ-positive cognitively healthy or mild cognitive impaired subjects had undergone [18F]-AV45-PET, [18F]-FDG-PET, and T1w-MRI examinations. Composite cortical [18F]-AV45 uptake and [18F]-FDG uptake in posterior cingulate cortex were calculated as surrogates of cortical Aβ load and glucose metabolism, respectively. Multiple linear regressions were performed to assess the relationships between these PET biomarkers with BMI, present cognitive performance, and cognitive changes over time. Multivariate analysis of covariance was conducted to test for statistical differences between ApoE4/BMI categories on the PET markers and cognitive scores. In carriers of the ApoE4 allele only, BMI was inversely associated with cortical amlyoid load (β= -0.193, p < 0.005) and recent cognitive decline (β= -0.209, p < 0.05), and positively associated with cortical glucose metabolism in an AD-vulnerable region (β= 0.145, p < 0.05). ApoE4/BMI category analyses demonstrated lower Aβ load, higher posterior cingulate glucose metabolism, improved cognitive performance, and lower progression of cognitive decline in obese ApoE4 carriers. The effect of ApoE4 in promoting the accumulation of cortical amyoid, which may itself be a driver for weight loss, may be moderated by altering leptin signaling in the hypothalamus.

%B J Alzheimers Dis %V 65 %P 781-791 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697560?dopt=Abstract %R 10.3233/JAD-170064 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Relationship between Obstructive Sleep Apnea and Alzheimer's Disease. %A Andrade, Andreia G %A Bubu, Omonigho M %A Varga, Andrew W %A Osorio, Ricardo S %X

Obstructive sleep apnea (OSA) and Alzheimer's disease (AD) are highly prevalent conditions with growing impact on our aging society. While the causes of OSA are now better characterized, the mechanisms underlying AD are still largely unknown, challenging the development of effective treatments. Cognitive impairment, especially affecting attention and executive functions, is a recognized clinical consequence of OSA. A deeper contribution of OSA to AD pathogenesis is now gaining support from several lines of research. OSA is intrinsically associated with disruptions of sleep architecture, intermittent hypoxia and oxidative stress, intrathoracic and hemodynamic changes as well as cardiovascular comorbidities. All of these could increase the risk for AD, rendering OSA as a potential modifiable target for AD prevention. Evidence supporting the relevance of each of these mechanisms for AD risk, as well as a possible effect of AD in OSA expression, will be explored in this review.

%B J Alzheimers Dis %V 64 %P S255-S270 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782319?dopt=Abstract %R 10.3233/JAD-179936 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Relationship of Area of Soft Drusen in Retina with Cerebral Amyloid-β Accumulation and Blood Amyloid-β Level in the Elderly. %A Shoda, Chiho %A Kitagawa, Yorihisa %A Shimada, Hiroyuki %A Yuzawa, Mitsuko %A Tateno, Amane %A Okubo, Yoshiro %X

BACKGROUND: Histopathological studies have confirmed that soft drusen contains amyloid-β (Aβ).

OBJECTIVE: To examine the relationship between the area of soft drusen in the macular area and cerebral Aβ accumulation or plasma Aβ level in elderly persons without dementia.

METHODS: Fourteen consecutive patients (18 eyes) aged ≥50 years with macular soft drusen were studied prospectively. From color fundus photographs, the area of soft drusen (pixel) within a 6,000 μm diameter with the macula as center was measured. Standard uptake value ratio (SUVR) was obtained from positron emission tomography using florbetapir, which indicates the ratio of cerebral cortical-to-cerebellar Aβ accumulation. Ratio of plasma Aβ1-42 to Aβ1-40 level was calculated.

RESULTS: Mean age was 73.3±7.6 years. The soft drusen area was 4.32±2.42 mm2. The SUVR was 1.08±0.15. Plasma Aβ1-42/Aβ1-40 ratio was 0.17±0.08. When SUVR ≥1.10 was defined as positive and <1.10 as negative, the soft drusen area in SUVR-positive patients (6.19±1.14 mm2) was significantly (p = 0.0043) larger than that in SUVR-negative patients (3.13±2.27 mm2). Multivariate regression analysis showed that SUVR positivity correlated with soft drusen area (p = 0.0484) and with Voxel-based Specific Regional Analysis System for Alzheimer's Disease score (p = 0.0360). However, there was no correlation with gender (p = 0.1921), age (p = 0.2361), Alzheimer's Disease Assessment Scale score (p = 0.6310), Mini-Mental State Examination score (p = 0.4246), or plasma Aβ1-42/Aβ1-40 ratio (p = 0.8398).

CONCLUSION: Among elderly persons without dementia, the area of soft drusen was larger in those with more extensive cerebral Aβ accumulation. The area of soft drusen may be a biomarker of cerebral Aβ accumulation.

%B J Alzheimers Dis %V 62 %P 239-245 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439351?dopt=Abstract %R 10.3233/JAD-170956 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Relationships between Cognition and Activities of Daily Living in Alzheimer's Disease During a 5-Year Follow-Up: ALSOVA Study. %A Saari, Toni %A Hallikainen, Ilona %A Hänninen, Tuomo %A Räty, Hannu %A Koivisto, Anne %X

BACKGROUND: Impaired cognition and activities of daily living (ADL) are core symptoms of Alzheimer's disease (AD), but their relationship is unclear.

OBJECTIVES: To explore relationships between cognitive domains and functional ability during 5-year follow-up in persons with AD.

METHODS: We analyzed ALSOVA study data from 236 individuals with very mild or mild AD at baseline. The CERAD Neuropsychological Battery (CERAD-NB) was used as a cognitive measure and Alzheimer's Disease Cooperative Study ADL (ADCS-ADL) as a functional measure, analyzing the IADL and BADL sub-scores separately. Annual regression models and linear mixed-effect models (LMMs) covering a 5-year follow-up period were used.

RESULTS: Annually, the CERAD-NB total and especially Verbal Fluency, Clock Drawing, and Constructional Praxis were associated with the total ADCS-ADL and IADL scores increasingly yet modestly, and to a lesser extent the BADL score. In the LMMs, the same measures and MMSE were associated with ADL.

CONCLUSION: Measures of executive function and visuoconstructive skills appear to be associated with caregiver-interview based ADL measure during the progression of AD.

%B J Alzheimers Dis %V 64 %P 269-279 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889073?dopt=Abstract %R 10.3233/JAD-171059 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Relationships Between Lower Olfaction and Brain White Matter Lesions in Elderly Subjects with Mild Cognitive Impairment. %A Heinrich, Juliette %A Vidal, Jean-Sébastien %A Simon, Axelle %A Rigaud, Anne-Sophie %A Hanon, Olivier %A Epelbaum, Jacques %A Viollet, Cécile %A Duron, Emmanuelle %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Atrophy %K Cognitive Dysfunction %K Cross-Sectional Studies %K Disease Progression %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Multivariate Analysis %K Neuropsychological Tests %K Olfaction Disorders %K Severity of Illness Index %K White Matter %X

BACKGROUND: Olfactory impairment is reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD) and is associated with hippocampal atrophy. In elderly people, dementia with AD neuropathology and white matter lesions (WML) is common. In this context, olfactory impairment could also depend on the presence of WML.

OBJECTIVE: To assess the cross-sectional relationship between olfaction and WML in elderly subjects with MCI.

METHODS: Consecutive subjects, >65 years old, diagnosed as MCI after a comprehensive neuropsychological assessment in an expert memory center, with a brain MRI performed within a year and without major depressive state, were included. Olfaction was assessed by the Brief Smell Identification Test (BSIT). Two trained neuroradiologists, blind to cognitive and olfaction status, visually assessed hippocampal atrophy according to Scheltens' scale and WML according to Fazekas criteria.

RESULTS: Seventy-five MCI subjects (mean age (SD) = 77.1 (6.2) years, 74.7% of women) were included. After adjustment for age and sex, factors associated with low BSIT scores were older age (p = 0.007), lower BMI (p = 0.08), lower MMSE score (p = 0.05), lower FCRST (p = 0.008), hippocampal atrophy (p = 0.04), periventricular WML (p = 0.007), and deep WML burden (p = 0.005). In multivariate analysis, severe deep WML (OR (95% CI) = 6.29 (1.4-35.13), p = 0.02) remained associated with low BSIT score independently from hippocampal atrophy.

CONCLUSION: In elderly MCI subjects, low olfactory performances are associated with WML, whose progression may be slowed by vascular treatments. A longitudinal study to evaluate whether the progression of WML, hippocampal atrophy and low olfactory function, can predict accurately conversion from MCI to dementia is ongoing.

%B J Alzheimers Dis %V 61 %P 1133-1141 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332036?dopt=Abstract %R 10.3233/JAD-170378 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Relevance of Coded Prodromal Mild Cognitive Impairment in the Routine Treatment of Patients with Dementia in Germany. %A Bohlken, Jens %A Kostev, Karel %X

Little is known about the impact of prior mild cognitive impairment (MCI, ICD-10: F06.7) diagnosis on the time to dementia diagnosis, anti-dementia drug therapy, and treatment persistence in patients with dementia (PWD). Patients with dementia diagnoses who started anti-dementia therapy between January 2010 and December 2016 were selected from 203 neurological/psychiatric practices in the Disease Analyzer databank (IQVIA). Patients with a history of MCI were compared to non-MCI controls in terms of demographic characteristics, anti-dementia therapy, and the rate of persistence with anti-dementia drugs. For persistence analyses, a 1:1 matching procedure was used based on age, gender, type of residence, and depression and dementia diagnosis. Persistence was represented using Kaplan-Meier curves. A Cox regression analysis was used to determine the influence of MCI diagnosis on persistence with anti-dementia drugs. 339 PWD with MCI diagnoses and 339 controls were available for analysis. PWD with MCI were younger (78.9 versus 80.4 years), less likely to live in a nursing home (8.5% versus 22.5%), more frequently received donepezil (40.1% versus 33.7%), and more likely to exhibit comorbid depression (29.6% versus 16.9%). There was no association between the risk of treatment discontinuation and prior MCI diagnosis. After 24 months, 40% versus 41.1% of patients had discontinued treatment. The prior MCI diagnosis presumably led to an earlier diagnosis of dementia and earlier anti-dementia treatment. Treatment continuity did not differ, which would suggest that it does not depend on prior MCI diagnosis but on the behavior of patients and their caregiving relatives.

%B J Alzheimers Dis %V 65 %P 393-399 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056428?dopt=Abstract %R 10.3233/JAD-180567 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Relevance of Iron in the Pathogenesis of Multiple System Atrophy: A Viewpoint. %A Kaindlstorfer, Christine %A Jellinger, Kurt A %A Eschlböck, Sabine %A Stefanova, Nadia %A Weiss, Günter %A Wenning, Gregor K %K alpha-Synuclein %K Brain %K Humans %K Inclusion Bodies %K Iron %K Magnetic Resonance Imaging %K Multiple System Atrophy %K Oligodendroglia %K Parkinsonian Disorders %X

Iron is essential for cellular development and maintenance of multiple physiological processes in the central nervous system. The disturbance of its homeostasis leads to abnormal iron deposition in the brain and causes neurotoxicity via generation of free radicals and oxidative stress. Iron toxicity has been established in the pathogenesis of Parkinson's disease; however, its contribution to multiple system atrophy (MSA) remains elusive. MSA is characterized by cytoplasmic inclusions of misfolded α-synuclein (α-SYN) in oligodendrocytes referred to as glial cytoplasmic inclusions (GCIs). Remarkably, the oligodendrocytes possess high amounts of iron, which together with GCI pathology make a contribution toward MSA pathogenesis likely. Consistent with this observation, the GCI density is associated with neurodegeneration in central autonomic networks as well as olivopontocerebellar and striatonigral pathways. Iron converts native α-SYN into a β-sheet conformation and promotes its aggregation either directly or via increasing levels of oxidative stress. Interestingly, α-SYN possesses ferrireductase activity and α-SYN expression underlies iron mediated translational control via RNA stem loop structures. Despite a correlation between progressive putaminal atrophy and iron accumulation as well as clinical decline, it remains unclear whether pathologic iron accumulation in MSA is a secondary event in the cascade of neuronal degeneration rather than a primary cause. This review summarizes the current knowledge of iron in MSA and gives evidence for perturbed iron homeostasis as a potential pathogenic factor in MSA-associated neurodegeneration.

%B J Alzheimers Dis %V 61 %P 1253-1273 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376857?dopt=Abstract %R 10.3233/JAD-170601 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Religious Orders Study and Rush Memory and Aging Project. %A Bennett, David A %A Buchman, Aron S %A Boyle, Patricia A %A Barnes, Lisa L %A Wilson, Robert S %A Schneider, Julie A %X

BACKGROUND: The Religious Orders Study and Rush Memory and Aging Project are both ongoing longitudinal clinical-pathologic cohort studies of aging and Alzheimer's disease (AD).

OBJECTIVES: To summarize progress over the past five years and its implications for understanding neurodegenerative diseases.

METHODS: Participants in both studies are older adults who enroll without dementia and agree to detailed longitudinal clinical evaluations and organ donation. The last review summarized findings through the end of 2011. Here we summarize progress and study findings over the past five years and discuss new directions for how these studies can inform on aging and AD in the future.

RESULTS: We summarize 1) findings on the relation of neurobiology to clinical AD; 2) neurobiologic pathways linking risk factors to clinical AD; 3) non-cognitive AD phenotypes including motor function and decision making; 4) the development of a novel drug discovery platform.

CONCLUSION: Complexity at multiple levels needs to be understood and overcome to develop effective treatments and preventions for cognitive decline and AD dementia.

%B J Alzheimers Dis %V 64 %P S161-S189 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865057?dopt=Abstract %R 10.3233/JAD-179939 %0 Journal Article %J J Alzheimers Dis %D 2018 %T REM Sleep Behavior Disorder and Alzheimer's Disease: Definitely No Relationship? %A Galbiati, Andrea %A Carli, Giulia %A Hensley, Michael %A Ferini-Strambi, Luigi %X

Rapid eye movement (REM) sleep behavior disorder (RBD) is a REM sleep parasomnia characterized by the loss of the typical muscular atonia present during healthy REM sleep. RBD can occur in the absence of other neurological conditions or in association with a neurodegenerative disorder. It is now well established that RBD is a strong predictor of neurodegeneration, in particular synucleinopathies, such as Parkinson's disease, Lewy body dementia (LBD), or multiple system atrophy. However, some longitudinal studies report that a minority of patients develop either overlapping form of dementia or Alzheimer disease's (AD). Although AD is reported as a possible development in patients with RBD, it is in a limited number of cases and there are concerns about the accuracy of the diagnostic criteria. Neuropsychological impairments identified in cross-sectional studies of RBD patients describe a profile similar to that observed in dementia related to synucleinopathies. However, only deficits in executive function predict the development of neurodegeneration. Longitudinal studies reported the development of AD in RBD patients in about 7% of cases with variability ranging from 3% and 11%. Since the majority of longitudinal investigations do not report AD as a possible development for RBD patients the proportion may be overestimated. The study of the relationship between RBD and AD may be confounded by two factors that lead to misdiagnosis: the use of clinical criteria alone and the overlap between the clinical features and neuropathology of AD and LBD. Future studies to investigate this association must use updated diagnostic criteria incorporating ancillary investigations.

%B J Alzheimers Dis %V 63 %P 1-11 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578489?dopt=Abstract %R 10.3233/JAD-171164 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Reproducibility of Alzheimer's Disease Cerebrospinal Fluid-Biomarker Measurements under Clinical Routine Conditions. %A Vogelgsang, Jonathan %A Wedekind, Dirk %A Bouter, Caroline %A Klafki, Hans-W %A Wiltfang, Jens %X

Analysis of cerebrospinal fluid (CSF) is one of the key tools for the state-of-the-art differential diagnosis of dementias. Dementia due to Alzheimer's disease (AD) is characterized by elevated CSF levels of total Tau (tTau) and phospho-181-Tau (pTau) and low CSF amyloid-β42 (Aβ42). Discrepancies in the laboratory analysis of human materials are well known and much effort has been put into harmonization procedures. In this study, we measured CSF biomarkers of more than 100 patients obtained under clinical routine conditions in two different clinical laboratories. The CSF biomarker levels obtained from the two different sites were significantly correlated: R2 = 0.7129 (tTau, p < 0.001), 0.7914 (pTau, p < 0.001), 0.5078 (Aβ42, p < 0.001), 0.5739 (Aβ40, p < 0.001), and 0.4308 (Aβ42/40, p < 0.001). However, the diagnostic classifications of the Aβ42, tTau, and pTau levels of identical subjects into normal versus pathological range made by the two different sites showed substantial discrepancies (31.5%, 29.6%, and 25.0% discordant cases, respectively). Applying Aβ42/40, instead of CSF Aβ42 alone, lead to a reduction of the discordant cases to 16.8%. Our findings suggest that CSF Aβ42/40 can outperform Aβ42 as a biomarker for AD neuropathology, not only under well-controlled study conditions but also in real life clinical routine. Thus, we recommend the inclusion of Aβ42/40 as a CSF biomarker in the diagnostic procedure.

%B J Alzheimers Dis %V 62 %P 203-212 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439341?dopt=Abstract %R 10.3233/JAD-170793 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Rethinking the Reserve with a Translational Approach: Novel Ideas on the Construct and the Interventions. %A Serra, Laura %A Gelfo, Francesca %A Petrosini, Laura %A Di Domenico, Carlotta %A Bozzali, Marco %A Caltagirone, Carlo %X

The concept of brain, cognitive, and neural reserves has been introduced to account for the apparent discrepancies between neurological damage and clinical manifestations. However, these ideas are yet theoretical suggestions that are not completely assimilated in the clinical routine. The mechanisms of the reserves have been extensively studied in neurodegenerative pathologies, in particular in Alzheimer's disease. Both human and animal studies addressed this topic by following two parallel pathways. The specific aim of the present review is to attempt to combine the suggestions derived from the two different research fields to deepen the knowledge about reserves. In fact, the achievement of a comprehensive theoretical framework on reserve mechanisms is an essential step to propose well-timed interventions tailored to the clinical characteristics of patients. The present review highlights the importance of addressing three main aspects: the definition of reserve proxy measures, the interaction between reserve level and therapeutic interventions, and the specific time-window of reserve efficacy.

%B J Alzheimers Dis %V 65 %P 1065-1078 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149458?dopt=Abstract %R 10.3233/JAD-180609 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Retinoic Acid Enhances Apolipoprotein E Synthesis in Human Macrophages. %A Clemens, Vera %A Regen, Francesca %A Le Bret, Nathalie %A Heuser, Isabella %A Hellmann-Regen, Julian %K Alzheimer Disease %K Apolipoproteins E %K Cells, Cultured %K Humans %K Macrophages %K Signal Transduction %K Tretinoin %X

Apolipoprotein E (ApoE) represents a pivotal target in Alzheimer's disease (AD) and is modulated through retinoic acid (RA), an endogenous neuroprotective and anti-inflammatory compound. A major source of ApoE are microglia, which are pathologically activated in AD. Activated microglia are known to block RA signaling. This suggests a vicious cycle between inflammation, RA signaling, and ApoE homeostasis in AD pathogenesis. To test this hypothesis, we investigated effects of RA and proinflammatory activation on ApoE synthesis in primary human macrophage-derived microglial-like cells. Our results indicate that proinflammatory activation attenuates ApoE synthesis, an effect blocked by RA.

%B J Alzheimers Dis %V 61 %P 1295-1300 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376871?dopt=Abstract %R 10.3233/JAD-170823 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Retrospective Belgian Multi-Center MRI Biomarker Study in Alzheimer's Disease (REMEMBER). %A Niemantsverdriet, Ellis %A Ribbens, Annemie %A Bastin, Christine %A Benoit, Florence %A Bergmans, Bruno %A Bier, Jean-Christophe %A Bladt, Roxanne %A Claes, Lene %A De Deyn, Peter Paul %A Deryck, Olivier %A Hanseeuw, Bernard %A Ivanoiu, Adrian %A Lemper, Jean-Claude %A Mormont, Eric %A Picard, Gaëtane %A Salmon, Eric %A Segers, Kurt %A Sieben, Anne %A Smeets, Dirk %A Struyfs, Hanne %A Thiery, Evert %A Tournoy, Jos %A Triau, Eric %A Vanbinst, Anne-Marie %A Versijpt, Jan %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

BACKGROUND: Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer's disease (AD).

OBJECTIVE: We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression.

METHODS: The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n = 887) and follow-up (FU, n = 95) T1-weighted brain MRIs and time-linked neuropsychological data were available.

RESULTS: The cohort consisted of cognitively healthy controls (HC, n = 93), subjective cognitive decline (n = 102), mild cognitive impairment (MCI, n = 379), and AD dementia (n = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n = 95) compared to HC (FU>24months, p = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment.

CONCLUSION: WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials.

%B J Alzheimers Dis %V 63 %P 1509-1522 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782314?dopt=Abstract %R 10.3233/JAD-171140 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Review of the Familial Alzheimer's Disease Locus PRESENILIN 2 and Its Relationship to PRESENILIN 1. %A Jiang, Haowei %A Jayadev, Suman %A Lardelli, Michael %A Newman, Morgan %X

PRESENILIN 1 (PSEN1) and PRESENILIN 2 (PSEN2) genes are loci for mutations causing familial Alzheimer's disease (fAD). However, the function of these genes and how they contribute to fAD pathogenesis has not been fully determined. This review provides a summary of the overlapping and independent functions of the PRESENILINS with a focus on the lesser studied PSEN2. As a core component of the γ-secretase complex, the PSEN2 protein is involved in many γ-secretase-related physiological activities, including innate immunity, Notch signaling, autophagy, and mitochondrial function. These physiological activities have all been associated with AD progression, indicating that PSEN2 plays a particular role in AD pathogenesis.

%B J Alzheimers Dis %V 66 %P 1323-1339 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412492?dopt=Abstract %R 10.3233/JAD-180656 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology. %A Hampel, Harald %A Toschi, Nicola %A Babiloni, Claudio %A Baldacci, Filippo %A Black, Keith L %A Bokde, Arun L W %A Bun, René S %A Cacciola, Francesco %A Cavedo, Enrica %A Chiesa, Patrizia A %A Colliot, Olivier %A Coman, Cristina-Maria %A Dubois, Bruno %A Duggento, Andrea %A Durrleman, Stanley %A Ferretti, Maria-Teresa %A George, Nathalie %A Genthon, Remy %A Habert, Marie-Odile %A Herholz, Karl %A Koronyo, Yosef %A Koronyo-Hamaoui, Maya %A Lamari, Foudil %A Langevin, Todd %A Lehéricy, Stéphane %A Lorenceau, Jean %A Neri, Christian %A Nisticò, Robert %A Nyasse-Messene, Francis %A Ritchie, Craig %A Rossi, Simone %A Santarnecchi, Emiliano %A Sporns, Olaf %A Verdooner, Steven R %A Vergallo, Andrea %A Villain, Nicolas %A Younesi, Erfan %A Garaci, Francesco %A Lista, Simone %K Alzheimer Disease %K Animals %K Brain %K Humans %K Neurology %K Neurophysiology %K Precision Medicine %K Systems Biology %K Translational Medical Research %X

The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular, and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an "omics"-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical, and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer's disease. The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group "Alzheimer Precision Medicine" (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development toward breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND.

%B J Alzheimers Dis %V 64 %P S47-S105 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad179932?id=journal-of-alzheimers-disease%2Fjad179932 %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562524?dopt=Abstract %R 10.3233/JAD-179932 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Risk Factors Associated with Cortical Thickness and White Matter Hyperintensities in Dementia Free Okinawan Elderly. %A Silbert, Lisa C %A Lahna, David %A Promjunyakul, Nutta-On %A Boespflug, Erin %A Ohya, Yusuke %A Higashiuesato, Yasushi %A Nishihira, Junko %A Katsumata, Yuriko %A Tokashiki, Takashi %A Dodge, Hiroko H %X

BACKGROUND: Cortical gray matter (GM) and white matter (WM) deterioration are signals of neurodegeneration and increased dementia risk; however, their specific etiologies in dementia-free aging is unclear.

OBJECTIVE: The objective of this study was to examine potentially modifiable risk factors of GM and WM degeneration in a well-characterized cohort of dementia-free elderly.

METHODS: 96 Okinawan elderly participants (age 83.6) from the Keys to Optimal Cognitive Aging Project (KOCOA) underwent MRI and cognitive evaluation. Serum markers of inflammation (interleukin-6 (IL-6), high sensitivity C-reactive protein), cerebrovascular disease (systolic blood pressure (SBP) 140+, hemoglobin A1C (HgbA1C), total cholesterol), and essential minerals (copper (Cu), magnesium, and calcium) were examined in relation to mean cortical thickness (MCT) and white matter hyperintensities (WMH), adjusting for age and gender. Voxel-based morphometry (VBM) analyses identified relationships between regional GM density and the above markers.

RESULTS: Decreased MCT was associated with SBP 140 + (p = 0.029) and increased serum IL-6 (p = 0.036), HgbA1C (p = 0.002), and Cu (p = 0.025). In VBM analyses, increased IL-6, HgbA1C, and Cu were associated with decreased GM density in temporal lobe regions. HgbA1C (p = 0.004) was associated with greater WMH volume.

CONCLUSIONS: Peripheral markers of Cu, CVD risk, and inflammation are associated with MRI-markers of decreased brain health in dementia-free Okinawan elderly, with regional cortical thinning in areas involved in early accumulation of Alzheimer's disease pathology. Results identify potentially modifiable biomarkers as targets in the prevention of dementia in older individuals.

%B J Alzheimers Dis %V 63 %P 365-372 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578488?dopt=Abstract %R 10.3233/JAD-171153 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Risk Factors of Rapid Cognitive Decline in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. %A Song, Ya-Nan %A Wang, Ping %A Xu, Wei %A Li, Jie-Qiong %A Cao, Xi-Peng %A Yu, Jin-Tai %A Tan, Lan %X

BACKGROUND: The conclusions about risk factors for rapid cognitive decline (RCD) in Alzheimer's disease (AD) and mild cognitive impairment (MCI) remain contradictory.

OBJECTIVE: To explore the factors predicting RCD in AD and MCI.

METHODS: We searched the PubMed, EMBASE, and the Cochrane Library from inception to May 27, 2017 for studies investigating factors associated with faster cognitive progression in AD and MCI. Effect sizes were meta-analyzed using fixed-effects and random-effects models.

RESULTS: Fifty-three studies with 14,330 patients (12,396 AD and 1,934 MCI) were included in the systematic review. The following factors were identified to increase the risk of RCD in AD: Apolipoprotein E4 (ApoE4) (SMD [95% CI]: 0.52 [0.06,0.98]), early age at onset (SMD [95% CI]: -0.42 [-0.71, -0.13]), high level of education (RR = 2.05, 95% CI = 1.26 to 3.33), early appearance of extrapyramidal signs (RR = 2.18; 95% CI = 1.30 to 3.67), and neuropsychiatric conditions including hallucination (RR = 2.01, 95% CI = 1.40 to 2.87), strolling (RR = 1.99, 95% CI = 1.38 to 2.86), agitation (RR = 1.66, 95% CI = 1.23 to 2.24), and psychosis (RR = 1.42, 95% CI = 1.07 to 1.89). Instead, advanced age (≥75 years) (RR = 0.96, 95% CI = 0.93 to 0.99), diabetes (RR = 0.57; 95% CI = 0.35 to 0.93), and multidrug therapy (RR = 0.61, 95% CI = 0.60 to 0.62) would lower the risk of RCD. Furthermore, systematic research also reviewed seven risk factors associated with RCD in MCI.

CONCLUSION: ApoE4, early onset, early appearance of extrapyramidal signs, high education level, and neuropsychiatric conditions might increase the risk of RCD while older age, diabetes, and multidrug therapy were the protective factors for AD.

%B J Alzheimers Dis %V 66 %P 497-515 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320579?dopt=Abstract %R 10.3233/JAD-180476 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Risk of Alzheimer's Disease in Obstructive Sleep Apnea Syndrome: Amyloid-β and Tau Imaging. %A Elias, Alby %A Cummins, Tia %A Tyrrell, Regan %A Lamb, Fiona %A Doré, Vincent %A Williams, Robert %A Rosenfeld, J V %A Hopwood, Malcolm %A Villemagne, Victor L %A Rowe, Christopher C %X

BACKGROUND: An association between obstructive sleep apnea (OSA) and Alzheimer's disease has been suggested but little is known about amyloid-β and tau deposition in this syndrome.

OBJECTIVE: To determine amyloid and tau burden and cognitive function in OSA in comparison with those without a diagnosis of OSA.

METHODS: The status of OSA was determined by asking participants about history of polysomnographic diagnosis of OSA and the use of Continuous Positive Airway Pressure (CPAP). A comprehensive neuropsychological battery measured cognitive function. Positron emission tomography (PET) was used to measure standardized uptake value ratio (SUVR) of 18F-florbetaben and 18F-AV1451, to quantify amyloid and tau burden.

RESULTS: 119 male Vietnam veterans completed assessment. Impairment in visual attention and processing speed and increased body mass index (BMI) were seen in subjects with OSA compared with those without a diagnosis OSA. The cortical uptake of 18F-florbetaben was higher in the OSA group than in the control group (SUVR: 1.35±0.21 versus 1.27±0.16, p = 0.04). There were more apolipoprotein E ɛ4 allele (APOE ɛ4) carriers in the OSA group than in the control group. In multilinear regression analysis, the significance of OSA in predicting 18F-florbetaben uptake remained independent of age and vascular risk factors but not when BMI or APOE ɛ4 was adjusted. The reported use of CPAP (n = 14) had no effect on cognitive or amyloid PET findings. There was no significant difference in 18F-AV1451 uptake between the two groups.

CONCLUSIONS: Obstructive sleep apnea is associated with Alzheimer's disease pathology, but this relationship is moderated by APOE ɛ4 and BMI.

%B J Alzheimers Dis %V 66 %P 733-741 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320587?dopt=Abstract %R 10.3233/JAD-180640 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Risk of Conversion to Dementia in a Mild Behavioral Impairment Group Compared to a Psychiatric Group and to a Mild Cognitive Impairment Group. %A Taragano, Fernando E %A Allegri, Ricardo F %A Heisecke, Silvina L %A Martelli, María I %A Feldman, Mónica L %A Sánchez, Viviana %A García, Virginia A %A Tufro, Graciela %A Castro, Diego M %A Leguizamón, Patricio Perez %A Guelar, Verónica %A Ruotolo, Eva %A Zegarra, Cecilia %A Dillon, Carol %X

BACKGROUND: There is insufficient available information on behavioral changes in the absence of cognitive impairment as factors increasing the risk of conversion to dementia.

OBJECTIVE: To observe and analyze patients with mild behavioral impairment (MBI), mild cognitive impairment (MCI), and a psychiatry group (PG) to compare the risk of progression to dementia.

METHODS: From 677 initially assessed ≥60-year-old patients, a series of 348 patients was studied for a five-year period until censoring or conversion to dementia: 96 with MBI, 87 with MCI, and 165 with general psychiatry disorders, including 4 subgroups: Anxiety, Depression, Psychosis and Others. All patients were assessed with clinical, psychiatric, neurological, neuropsychological, and neuroimaging studies.

RESULTS: From 348 patients, 126 evolved to dementia (36.2%). Conversion was significantly higher in MBI (71.5%), followed by the MCI-MBI overlap (59.6%) and MCI (37.8%) groups, compared to PG (13.9%) (Log-rank p < 0.001). MCI patients mostly converted to Alzheimer's dementia, while MBI converted to frontotemporal dementia and Lewy body dementia. Patients in PG converted to Lewy body dementia and frontotemporal dementia.

CONCLUSION: Conversion to dementia is significantly higher in patients with neuropsychiatric symptoms. The MBI concept generates a new milestone in the refining of diagnosis of neurodegenerative diseases and the possibility of creating neuropsychiatric profiles. Its earlier identification will allow new possibilities for therapeutic intervention.

%B J Alzheimers Dis %V 62 %P 227-238 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439333?dopt=Abstract %R 10.3233/JAD-170632 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Role of Amyloid-β and Tau Proteins in Alzheimer's Disease: Confuting the Amyloid Cascade. %A Gulisano, Walter %A Maugeri, Daniele %A Baltrons, Marian A %A Fà, Mauro %A Amato, Arianna %A Palmeri, Agostino %A D'Adamio, Luciano %A Grassi, Claudio %A Devanand, D P %A Honig, Lawrence S %A Puzzo, Daniela %A Arancio, Ottavio %X

The "Amyloid Cascade Hypothesis" has dominated the Alzheimer's disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies.

%B J Alzheimers Dis %V 64 %P S611-S631 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865055?dopt=Abstract %R 10.3233/JAD-179935 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Role of ASK1/p38 Cascade in a Mouse Model of Alzheimer's Disease and Brain Aging. %A Hasegawa, Yu %A Toyama, Kensuke %A Uekawa, Ken %A Ichijo, Hidenori %A Kim-Mitsuyama, Shokei %K Aging %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Aspartic Acid Endopeptidases %K Avoidance Learning %K Disease Models, Animal %K Gene Expression Regulation %K MAP Kinase Kinase Kinase 5 %K MAP Kinase Signaling System %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Presenilin-1 %K Reaction Time %X

To examine the role of ASK1 in Alzheimer's disease (AD), we generated 5XFAD mice deficient in ASK1 and investigated the characteristics of old 5XFAD and wild-type mice with ASK1 deficiency. ASK1 deficiency improved cognitive function in 24-month-old 5XFAD mice, which was associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade seems to play some role in the pathogenesis of AD in mice. In 24-month-old wild-type mice, ASK1 deficiency increased cerebral vasoreactivity to acetazolamide and significantly reduced brain soluble Aβ, which were also associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade may contribute to brain aging of wild-type mice. Collectively, our present results provided the evidence suggesting the involvement of ASK1/p38 cascade in AD and brain aging.

%B J Alzheimers Dis %V 61 %P 259-263 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154282?dopt=Abstract %R 10.3233/JAD-170645 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Role of Blood-Brain Barrier in Alzheimer's Disease. %A Cai, Zhiyou %A Qiao, Pei-Feng %A Wan, Cheng-Qun %A Cai, Min %A Zhou, Nan-Kai %A Li, Qin %X

The blood-brain barrier (BBB) is involved in the pathogenesis of Alzheimer's disease (AD). BBB is a highly selective semipermeable structural and chemical barrier which ensures a stable internal environment of the brain and prevents foreign objects invading the brain tissue. BBB dysfunction induces the failure of Aβ transport from brain to the peripheral circulation across the BBB. Especially, decreased levels of LRP-1 (low density lipoprotein receptor-related protein 1) and increased levels of RAGE (receptor for advanced glycation endproducts) at the BBB can cause the failure of Aβ transport. The pathogenesis of AD is related to the BBB structural components, including pericytes, astrocytes, vascular endothelial cells, and tight junctions. BBB dysfunction will trigger neuroinflammation and oxidative stress, then enhance the activity of β-secretase and γ-secretase, and finally promote Aβ generation. A progressive accumulation of Aβ in brain and BBB dysfunction may become a feedback loop that gives rise to cognitive impairment and the onset of dementia. The correlation between BBB dysfunction and tau pathology has been well-reported. Therefore, regulating BBB function may be a new therapeutic target for treating AD.

%B J Alzheimers Dis %V 63 %P 1223-1234 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782323?dopt=Abstract %R 10.3233/JAD-180098 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Role of Cognitive Reserve in Alzheimer's Disease and Aging: A Multi-Modal Imaging Review. %A Menardi, Arianna %A Pascual-Leone, Alvaro %A Fried, Peter J %A Santarnecchi, Emiliano %X

Comforts in modern society have generally been associated with longer survival rates, enabling individuals to reach advanced age as never before in history. With the increase in longevity, however, the incidence of neurodegenerative diseases, especially Alzheimer's disease, has also doubled. Nevertheless, most of the observed variance, in terms of time of clinical diagnosis and progression, often remains striking. Only recently, differences in the social, educational and occupational background of the individual, as proxies of cognitive reserve (CR), have been hypothesized to play a role in accounting for such discrepancies. CR is a well-established concept in literature; lots of studies have been conducted in trying to better understand its underlying neural substrates and associated biomarkers, resulting in an incredible amount of data being produced. Here, we aimed to summarize recent relevant published work addressing the issue, gathering evidence for the existence of a common path across research efforts that might ease future investigations by providing a general perspective on the actual state of the arts. An innovative model is hereby proposed, addressing the role of CR across structural and functional evidences, as well as the potential implementation of non-invasive brain stimulation techniques in the causal validation of such theoretical frame.

%B J Alzheimers Dis %V 66 %P 1341-1362 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30507572?dopt=Abstract %R 10.3233/JAD-180549 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Role of Genetics and Epigenetics in the Pathogenesis of Alzheimer's Disease and Frontotemporal Dementia. %A Fenoglio, Chiara %A Scarpini, Elio %A Serpente, Maria %A Galimberti, Daniela %K Alzheimer Disease %K Animals %K Epigenesis, Genetic %K Frontotemporal Dementia %K Genetic Predisposition to Disease %K Humans %X

Alzheimer's disease (AD) and frontotemporal dementia (FTD) represent the first cause of dementia in senile and pre-senile population, respectively. A percentage of cases have a genetic cause, inherited with an autosomal dominant pattern of transmission. The majority of cases, however, derive from complex interactions between a number of genetic and environmental factors. Gene variants may act as risk or protective factors. Their combination with a variety of environmental exposures may result in increased susceptibility to these diseases or may influence their course. The scenario is even more complicated considering the effect of epigenetics, which encompasses mechanisms able to alter the expression of genes without altering the DNA sequence. In this review, an overview of the current genetic and epigenetic progresses in AD and FTD will be provided, with particular focus on 1) causative genes, 2) genetic risk factors and disease modifiers, and 3) epigenetics, including methylation, non-coding RNAs and chromatin remodeling.

%B J Alzheimers Dis %V 62 %P 913-932 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170702?id=journal-of-alzheimers-disease%2Fjad170702 %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562532?dopt=Abstract %R 10.3233/JAD-170702 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Role of Lifestyle Factors and Sleep Duration for Late-Onset Dementia: A Cohort Study. %A Larsson, Susanna C %A Wolk, Alicja %X

BACKGROUND: The role of lifestyle factors and sleep for dementia is uncertain.

OBJECTIVE: To examine the associations of major lifestyle factors and sleep duration with risk of late-onset dementia.

METHODS: We used data from a population-based cohort of 28,775 Swedish adults who were ≥65 years of age and completed a questionnaire about lifestyle and other modifiable factors in the autumn of 1997. Dementia cases were ascertained by linkage with the Swedish National Patient Register.

RESULTS: During a mean follow-up of 12.6 years, dementia was diagnosed among 3,755 participants (mean age at diagnosis 83.2±5.1 years). There were no associations of an overall healthy diet (defined by a modified Dietary Approaches to Stop Hypertension Diet score or a Mediterranean diet score), alcohol and coffee consumption, or physical activity with dementia incidence. Compared with never smokers, dementia risk was increased in former and current smokers (hazard ratio [95% confidence interval] = 1.13 [1.04-1.23] and 1.10 [1.00-1.21], respectively). Extended time of sleep (>9 h per night) was associated with an increased risk of dementia. However, this association appeared to be related to a reverse causation effect since the association did not remain after exclusion of cases diagnosed within the first five or ten years of follow-up.

CONCLUSIONS: This study found no evidence that major lifestyle factors, aside from smoking, or sleep duration influence the risk of dementia.

%B J Alzheimers Dis %V 66 %P 579-586 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320581?dopt=Abstract %R 10.3233/JAD-180529 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Role of Neuroinflammation in the Trajectory of Alzheimer's Disease and in vivo Quantification Using PET. %A Edison, Paul %A Brooks, David J %X

Recent evidence suggests that neuroinflammation and immunity play a significant role in Alzheimer's disease and other neurodegenerative diseases. It has also been observed that, independent of the presence of aggregated proteins, neuroinflammation could be present in different neurodegenerative diseases. It has also been suggested that neuroinflammation could occur well ahead of amyloid deposition in AD. Recent genetic studies and other preclinical studies specifically point to a role of neuroinflammation and, in this review, we evaluate the evidence of neuroinflammation in the Alzheimer's disease trajectory and the different imaging modalities by which we could monitor neuroinflammation in vivo in humans.

%B J Alzheimers Dis %V 64 %P S339-S351 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865053?dopt=Abstract %R 10.3233/JAD-179929 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Role of Noradrenergic Brain Nuclei in the Regulation of Carotid Artery Blood Flow: Pharmacological Evidence from Anesthetized Pigs with Alpha-2 Adrenergic Receptor Modulator Drugs. %A Wirth, Klaus J %X

BACKGROUND: Cerebral hypoperfusion and degeneration of the noradrenergic locus coeruleus (LC) occur early in Alzheimer's disease (AD). Cerebral blood vessels are densely innervated by noradrenergic projections from the LC suggesting a functional role for the regulation of cerebral blood flow (CBF). Experimental LC stimulation, however, has provided no clarity as decreases or increases in CBF were reported from different experimental settings and investigators.

OBJECTIVE: To find out with pharmacological methods whether endogenously released norepinephrine (NE) increases or decreases carotid artery blood flow (CABF) in anesthetized pigs by investigating the effect of centrally acting alpha-2 adrenergic drugs, which increase (atipamezole) or decrease (xylazine) NE in the brain.

METHODS: CABF was measured by a Doppler-flow probe placed around the left carotid artery in pentobarbital anesthetized young pigs.

RESULTS: Neither current antihypertensive drugs nor pharmacological stimulation of dopamine, histamine, serotonin or acetylcholine receptors changed CABF. The alpha-2 adrenergic-receptor agonist xylazine decreased, while the antagonist atipamezole raised CABF. This rise was abolished by a combined treatment with endothelial NO-synthase inhibitor Nω-Nitro-L-arginine methyl ester (L-NAME) and the non-selective β-receptor antagonist propranolol. Propranolol alone did not decrease CABF in contrast to L-NAME but decreased CABF after L-NAME, surprisingly.

CONCLUSION: Pharmacological evidence suggests that NE released in the brain of anesthetized pigs raises CABF involving β-adrenergic mechanisms and nitric oxide. If in awake humans NE released from the LC had vasodilator effects early LC degeneration could be involved in early cerebral hypoperfusion of AD. Moreover, a cerebral adrenergic vascular innervation deficit, possibly resulting from LC degeneration, and systemic endothelial dysfunction together may act synergistically to reduce CBF.

%B J Alzheimers Dis %V 66 %P 407-419 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30248055?dopt=Abstract %R 10.3233/JAD-180340 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Role of the Glyoxalase System in Alzheimer's Disease. %A Jiang, Lianying %A Wang, Jiafeng %A Wang, Zhigang %A Huang, Wenhui %A Yang, Yixia %A Cai, Zhiyou %A Li, Keshen %X

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disease. The main pathological features of AD are the formation of amyloid-β deposits in the anterior cerebral cortex and hippocampus as well as the formation of intracellular neurofibrillary tangles. Thus far, accumulating evidence shows that glycation is closely related to AD. As a final product resulting from the crosslinking of a reducing sugar or other reactive carbonyls and a protein, the advanced glycation end products have been found to be associated with the formation of amyloid-β and neurofibrillary tangles in AD. As a saccharification inhibitor, the glyoxalase system and its substrate methylglyoxal (MG) were certified to be associated with AD onset and development. As an active substance of AGEs, MG could cause direct or indirect damage to nerve cells and tissues. MG is converted to D-lactic acid after decomposition by the glyoxalase system. Under normal circumstances, MG metabolism is in a dynamic equilibrium, whereas MG accumulates in cells in the case of aging or pathological states. Studies have shown that increasing glyoxalase activity and reducing the MG level can inhibit the generation of oxidative stress and AGEs, thereby alleviating the symptoms and signs of AD to some extent. This paper focuses on the relevant mechanisms of action of the glyoxalase system and MG in the pathogenesis of AD, as well as the potential of inhibiting the production of advanced glycation end products in the treatment of AD.

%B J Alzheimers Dis %V 66 %P 887-899 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400091?dopt=Abstract %R 10.3233/JAD-180413 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Role of the Gut Microbiota in the Metabolism of Polyphenols as Characterized by Gnotobiotic Mice. %A Pasinetti, Giulio Maria %A Singh, Risham %A Westfall, Susan %A Herman, Francis %A Faith, Jeremiah %A Ho, Lap %X

A growing body of experimental data suggests that microbes in the gut influence behavior and can alter brain physiology and neurochemistry. Although promising, researchers are only starting to understand the potential of the gut microbiota for use in neurological disease. Recent evidence demonstrated that gastrointestinal activities are linked to mood disorders such as anxiety, depression, and most recently, cognitive functions in age-related neurodegenerative disorders. Studies from our group and others are uncovering new evidence suggesting that the gut microbiota plays a crucial role in the metabolism and bioavailability of certain dietary compounds and synthetic drugs. Based on this evidence, this review article will discuss the implications of the gut microbiota in mechanisms of bioavailability and biotransformation with an emphasis on dietary polyphenol compounds. This will be followed by a survey of ongoing innovative research identifying the ability of individual gut bacteria to enhance the bioavailability of gut-derived, brain-penetrating, bioactive polyphenol metabolites that ultimately influence mechanisms associated with the promotion of resilience against psychological and cognitive impairment in response to stress. Lastly, current research initiatives aimed at promoting the generation of brain bioactive polyphenol metabolites by specialized gut microbes will be discussed, specifically the use of gnotobiotic mice to develop bioengineered second generation probiotics. We propose that leveraging the gut microbial ecosystem to generate brain targeted bioactive metabolites from dietary polyphenols can attenuate lifestyle risk factors and promote resilience against age-related cognitive decline.

%B J Alzheimers Dis %V 63 %P 409-421 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660942?dopt=Abstract %R 10.3233/JAD-171151 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Role of Verb Fluency in the Detection of Early Cognitive Impairment in Alzheimer's Disease. %A Alegret, Montserrat %A Peretó, Mar %A Pérez, Alba %A Valero, Sergi %A Espinosa, Ana %A Ortega, Gemma %A Hernandez, Isabel %A Mauleón, Ana %A Rosende-Roca, Maitee %A Vargas, Liliana %A Rodríguez-Gómez, Octavio %A Abdelnour, Carla %A Berthier, Marcelo L %A Bak, Thomas H %A Ruiz, Agustin %A Tárraga, Lluís %A Boada, Merce %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cognitive Dysfunction %K Cross-Sectional Studies %K Early Diagnosis %K Executive Function %K Female %K Humans %K Language Tests %K Logistic Models %K Longitudinal Studies %K Male %K Middle Aged %K Proportional Hazards Models %K Sensitivity and Specificity %K Spain %X

BACKGROUND: Verb fluency (VF) is the less commonly used fluency test, despite several studies suggesting its potential as a neuropsychological assessment tool.

OBJECTIVE: To investigate the presence of VF deficits in mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia; to assess the usefulness of VF in the detection of cognitively healthy (CH) people who will convert to MCI, and from MCI to dementia; and to establish the VF cut-offs useful in the cognitive assessment of Spanish population.

METHODS: 568 CH, 885 MCI, and 367 mild AD dementia individuals were administered the VF test and a complete neuropsychological battery. Longitudinal analyses were performed in 231 CH and 667 MCI subjects to search for VF predictors of diagnosis conversion.

RESULTS: A worsening on VF performance from CH, MCI to AD dementia groups was found. Lower performances on VF were significantly related to conversion from CH to MCI/MCI to dementia. When the effect of time to conversion was analyzed, a significant effect of VF was found on the faster conversion from CH to MCI, but not from MCI to dementia. Moreover, VF cut-off scores and sensitivity/specificity values were calculated for 6 conditions (3 age ranges by 2 educational levels).

CONCLUSION: The VF test may be a useful tool for the differential diagnosis of cognitive failure in the elderly. Since VF deficits seem to take place in early stages of the disease, it is a suitable neuropsychological tool for the detection not only of CH people who will convert to MCI, but also from MCI to dementia.

%B J Alzheimers Dis %V 62 %P 611-619 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480180?dopt=Abstract %R 10.3233/JAD-170826 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Roles of Mitochondrial 17β-Hydroxysteroid Dehydrogenase Type 10 in Alzheimer's Disease. %A He, Xue-Ying %A Isaacs, Charles %A Yang, Song-Yu %K 3-Hydroxyacyl CoA Dehydrogenases %K Alzheimer Disease %K Amyloid beta-Peptides %K Brain %K Endoplasmic Reticulum %K Humans %K Mitochondria %K Neurotransmitter Agents %K Oxidation-Reduction %X

17β-Hydroxysteroid dehydrogenase type 10 is a multifunctional, homotetrameric, mitochondrial protein encoded by the HSD17B10 gene at Xp 11.2. This protein, 17β-HSD10, is overexpressed in brain cells of Alzheimer's disease (AD) patients. It was reported to be involved in AD pathogenesis as the endoplasmic reticulum-associated amyloid-β binding protein (ERAB) and as amyloid-β binding alcohol dehydrogenase (ABAD). However, the exaggerated catalytic efficiencies for ERAB/ABAD in these reports necessitated the re-characterization of the catalytic functions of this brain enzyme. In addition to isoleucine metabolism, 17β-HSD10 is also responsible for the mitochondrial metabolism of neurosteroids such as 5α-androstane-3α,17β-diol and 17β-estradiol. These neurosteroids are inactivated by the oxidation catalyzed by 17β-HSD10. Since neurosteroid homeostasis is presumably essential for cognitive function, analysis of the impact of 17β-HSD10 and its inhibitor, amyloid-β peptide (Aβ), on the metabolism of neuroactive steroids offers a new approach to AD pathogenesis.

%B J Alzheimers Dis %V 62 %P 665-673 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480196?dopt=Abstract %R 10.3233/JAD-170974 %0 Journal Article %J J Alzheimers Dis %D 2018 %T S-[18F]THK-5117-PET and [11C]PIB-PET Imaging in Idiopathic Normal Pressure Hydrocephalus in Relation to Confirmed Amyloid-β Plaques and Tau in Brain Biopsies. %A Leinonen, Ville %A Rauramaa, Tuomas %A Johansson, Jarkko %A Bottelbergs, Astrid %A Tesseur, Ina %A van der Ark, Peter %A Pemberton, Darrel %A Koivisto, Anne M %A Jääskeläinen, Juha E %A Hiltunen, Mikko %A Herukka, Sanna-Kaisa %A Blennow, Kaj %A Zetterberg, Henrik %A Jokinen, Pekka %A Rokka, Johanna %A Helin, Semi %A Haaparanta-Solin, Merja %A Solin, Olof %A Okamura, Nobuyuki %A Kolb, Hartmuth C %A Rinne, Juha O %X

BACKGROUND: Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer's disease (AD) and monitor drug effects in clinical trials. S-[18F]THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S-[18F]THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo.

OBJECTIVE: Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S-[18F]THK-5117, and [11C]PIB PET against tau and amyloid lesions in brain biopsy.

METHODS: Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with previous shunt surgery including right frontal cortical brain biopsy and CSF Aβ1 - 42, total tau, and P-tau181 measures, underwent brain MRI, [11C]PIB PET, and S-[18F]THK-5117 PET imaging.

RESULTS: Seven patients had amyloid-β (Aβ, 4G8) plaques, two both Aβ and phosphorylated tau (Pτ, AT8) and one only Pτ in biopsy. As expected, increased brain biopsy Aβ was well associated with higher [11C]PIB uptake in PET. However, S-[18F]THK-5117 uptake did not show any statistically significant correlation with either brain biopsy Pτ or CSF P-tau181 or total tau.

CONCLUSIONS: S-[18F]THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous Aβ and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology.

%B J Alzheimers Dis %V 64 %P 171-179 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865068?dopt=Abstract %R 10.3233/JAD-180071 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Sally-Anne Test in Patients with Alzheimer's Disease Dementia. %A Takenoshita, Shintaro %A Terada, Seishi %A Yokota, Osamu %A Kutoku, Yumiko %A Wakutani, Yosuke %A Nakashima, Makoto %A Maki, Yohko %A Hattori, Hideyuki %A Yamada, Norihito %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition Disorders %K Disease Progression %K Female %K Humans %K Logistic Models %K Male %K Neuropsychological Tests %K Social Behavior Disorders %K Theory of Mind %X

Social cognition has recently been recognized as one of the essential cognitive domains. Some reports suggested that patients with Alzheimer's disease dementia (ADD) presented significant theory of mind deficits even in the mild condition. However, most previous studies included only small numbers of patients with ADD. The present study administered the first-order false belief (Sally-Anne) test to 116 consecutive patients with ADD from the outpatient units of the Memory Clinic and compared the characteristics of the two groups with correct and incorrect answers on the test. Then various clinical characteristics were evaluated. Only 37.1% of patients with ADD correctly answered the Sally-Anne test with the right explanation. Comparison between the two groups of correct and incorrect answers revealed a significant association between the frontal assessment battery score and the result of the Sally-Anne test in the multiple logistic regression analyses. Thus, patients with ADD presented a significant deficit in social cognition even in the mild condition. Frontal dysfunction was thought to be related to the deficits in mild ADD.

%B J Alzheimers Dis %V 61 %P 1029-1036 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332047?dopt=Abstract %R 10.3233/JAD-170621 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Secular Trends in Dementia Prevalence and Incidence Worldwide: A Systematic Review. %A Stephan, Blossom C M %A Birdi, Ratika %A Tang, Eugene Yee Hing %A Cosco, Theodore D %A Donini, Lorenzo M %A Licher, Silvan %A Ikram, M Arfan %A Siervo, Mario %A Robinson, Louise %X

BACKGROUND: Time trends for dementia prevalence and incidence rates have been reported over the past seven decades in different countries and some have reported a decline.

OBJECTIVE: To undertake a systematic review to critically appraise and provide an evidence-based summary of the magnitude and direction of the global changes in dementia prevalence and incidence across time.

METHODS: Medline, EMBASE, and PsychINFO were searched for studies focused on secular trends in dementia prevalence and/or incidence until 18 December 2017. In total, 10,992 articles were identified and 43 retained.

RESULTS: Overall, prevalence rates are largely increasing (evidence primarily from record-based surveys and cohort studies in Japan, Canada, and France) or have remained stable (evidence primarily from cohort studies in Sweden, Spain and China). A significant decline in prevalence has however been reported in more recent studies (i.e., from 2010 onwards) from Europe (e.g., UK and Sweden) and the USA. Incidence rates have generally remained stable or decreased in China, Canada, France, Germany, Denmark, Sweden, the Netherlands, UK, and USA. An increase has only been reported in five countries: Italy, Japan, Wales, Germany, and the Netherlands. Only one study reported findings (stability in incidence) from a low and middle-income country using data from Nigeria.

CONCLUSIONS: The evidence on secular trends in the prevalence and incidence of dementia is mixed including contradictory findings using different (and in some cases the same) datasets in some countries (e.g., the USA, UK, and Sweden). This making it difficult to draw concrete conclusions. However, declining trends recently observed in some high-income Western countries in the most recent two decades including the UK, USA, and Sweden are encouraging. Updated dementia prevalence and incidence estimates will inform public health and financial planning as well as development of prevention strategies.

%B J Alzheimers Dis %V 66 %P 653-680 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30347617?dopt=Abstract %R 10.3233/JAD-180375 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Selection of Important Genes and Their Correlated Behavior in Alzheimer's Disease. %A Cruz-Rivera, Yazeli E %A Perez-Morales, Jaileene %A Santiago, Yaritza M %A Gonzalez, Valerie M %A Morales, Luisa %A Cabrera-Rios, Mauricio %A Isaza, Clara E %X

In 2017, approximately 5 million Americans were living with Alzheimer's disease (AD), and it is estimated that by 2050 this number could increase to 16 million. In this study, we apply mathematical optimization to approach microarray analysis to detect differentially expressed genes and determine the most correlated structure among their expression changes. The analysis of GSE4757 microarray dataset, which compares expression between AD neurons without neurofibrillary tangles (controls) and with neurofibrillary tangles (cases), was casted as a multiple criteria optimization (MCO) problem. Through the analysis it was possible to determine a series of Pareto efficient frontiers to find the most differentially expressed genes, which are here proposed as potential AD biomarkers. The Traveling Sales Problem (TSP) model was used to find the cyclical path of maximal correlation between the expression changes among the genes deemed important from the previous stage. This leads to a structure capable of guiding biological exploration with enhanced precision and repeatability. Ten genes were selected (FTL, GFAP, HNRNPA3, COX1, ND2, ND3, ND4, NUCKS1, RPL41, and RPS10) and their most correlated cyclic structure was found in our analyses. The biological functions of their products were found to be linked to inflammation and neurodegenerative diseases and some of them had not been reported for AD before. The TSP path connects genes coding for mitochondrial electron transfer proteins. Some of these proteins are closely related to other electron transport proteins already reported as important for AD.

%B J Alzheimers Dis %V 65 %P 193-205 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040709?dopt=Abstract %R 10.3233/JAD-170799 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Self- and Informant-Reported Memory Complaints: Frequency and Severity in Cognitively Intact Individuals and those with Mild Cognitive Impairment and Neurodegenerative Dementias. %A Rahman-Filipiak, Annalise M %A Giordani, Bruno %A Heidebrink, Judith %A Bhaumik, Arijit %A Hampstead, Benjamin M %X

BACKGROUND: Subjective memory complaints (SMCs) are incorporated into the diagnosis of mild cognitive impairment (MCI) and neurodegenerative dementias; however, the relative frequency of SMCs in cognitively intact older adults and those with different types of dementia is poorly understood. Similarly, the concordance between self- versus informant-reported SMCs has not been compared across different diagnostic groups.

OBJECTIVE: This study aimed to evaluate the frequency of self-reported (Objective 1) and informant-reported (Objective 2) SMCs in cognitively intact adults or those diagnosed with MCI or a neurodegenerative dementia. Agreement between participant and informant complaints was also evaluated (Objective 3).

METHODS: Baseline evaluation data were drawn from 488 participants (Mage = 70.49 years; Medu = 15.62 years) diagnosed as cognitively intact, non-amnestic MCI, amnestic single domain MCI, amnestic multi-domain MCI, possible/probable Alzheimer's disease, dementia with Lewy bodies, or frontotemporal dementia. Participants and their informants completed the Memory Assessment Clinic Questionnaire.

RESULTS: One-way ANCOVAs controlling for age, education, and depression revealed no group differences in severity of self-reported SMCs. In contrast, informant memory ratings followed the expected clinical pattern, with comparable and most impaired ratings given to participants with any dementia diagnosis, followed by those with any MCI diagnosis, followed by cognitively intact participants. There was inconsistent agreement between self- and informant-reported SMC ratings in any of the impaired groups.

CONCLUSIONS: Given greater diagnostic specificity and internal consistency of informant report, clinicians should weigh this information more heavily than self-report in the diagnostic process.

%B J Alzheimers Dis %V 65 %P 1011-1027 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30124444?dopt=Abstract %R 10.3233/JAD-180083 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Self-Reported Physical Activity is Associated with Tau Burden Measured by Positron Emission Tomography. %A Brown, Belinda M %A Rainey-Smith, Stephanie R %A Doré, Vincent %A Peiffer, Jeremiah J %A Burnham, Samantha C %A Laws, Simon M %A Taddei, Kevin %A Ames, David %A Masters, Colin L %A Rowe, Christopher C %A Martins, Ralph N %A Villemagne, Victor L %X

Numerous animal studies have reported exercise reduces the accumulation of Alzheimer's disease pathology, including amyloid-β (Aβ) and tau. Furthermore, we previously reported a relationship between higher levels of physical activity (PA) and lower brain Aβ burden in a human population. The recent advent of tau positron emission tomography (PET) tracers enables us to extend our investigations into the evaluation of the relationship between PA and brain tau burden. Utilizing data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we have examined the cross-sectional relationship between habitual PA and PET-quantified tau burden. Forty-three cognitively healthy older adults were categorized into low-moderate PA (LMPA; n = 16) or high PA (HPA; n = 27), based on self-reported PA levels. Tau PET imaging with the AV1451 tracer was conducted on all participants. The LMPA group had significantly higher neocortical tau burden (presented as a z-score; 1.22±1.98), compared to the HPA group (z-score: - 0.28±1.18). The difference between the LMPA and HPA groups was also evident when examining regional tau burden in the temporoparietal cortex and the prefrontal cortex. Our results suggest an association between self-reported PA level and brain tau burden. Future longitudinal and interventional studies utilizing larger samples sizes are vital to further investigate the nature of the relationship between tau and PA.

%B J Alzheimers Dis %V 63 %P 1299-1305 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758940?dopt=Abstract %R 10.3233/JAD-170998 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Separating Symptomatic Alzheimer's Disease from Depression based on Structural MRI. %A Klöppel, Stefan %A Kotschi, Maria %A Peter, Jessica %A Egger, Karl %A Hausner, Lucrezia %A Frölich, Lutz %A Förster, Alex %A Heimbach, Bernhard %A Normann, Claus %A Vach, Werner %A Urbach, Horst %A Abdulkadir, Ahmed %X

Older patients with depression or Alzheimer's disease (AD) at the stage of early dementia or mild cognitive impairment may present with objective cognitive impairment, although the pathology and thus therapy and prognosis differ substantially. In this study, we assessed the potential of an automated algorithm to categorize a test set of 65 T1-weighted structural magnetic resonance images (MRI). A convenience sample of elderly individuals fulfilling clinical criteria of either AD (n = 28) or moderate and severe depression (n = 37) was recruited from different settings to assess the potential of the pattern recognition method to assist in the differential diagnosis of AD versus depression. We found that our algorithm learned discriminative patterns in the subject's grey matter distribution reflected by an area under the receiver operator characteristics curve of up to 0.83 (confidence interval ranged from 0.67 to 0.92) and a balanced accuracy of 0.79 for the separation of depression from AD, evaluated by leave-one-out cross validation. The algorithm also identified consistent structural differences in a clinically more relevant scenario where the data used during training were independent from the data used for evaluation and, critically, which included five possible diagnoses (specifically AD, frontotemporal dementia, Lewy body dementia, depression, and healthy aging). While the output was insufficiently accurate to use it directly as a means for classification when multiple classes are possible, the continuous output computed by the machine learning algorithm differed between the two groups that were investigated. The automated analysis thus could complement, but not replace clinical assessments.

%B J Alzheimers Dis %V 63 %P 353-363 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614658?dopt=Abstract %R 10.3233/JAD-170964 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Serotonin Selective Reuptake Inhibitor Treatment Improves Cognition and Grey Matter Atrophy but not Amyloid Burden During Two-Year Follow-Up in Mild Cognitive Impairment and Alzheimer's Disease Patients with Depressive Symptoms. %A Brendel, Matthias %A Sauerbeck, Julia %A Greven, Sonja %A Kotz, Sebastian %A Scheiwein, Franziska %A Blautzik, Janusch %A Delker, Andreas %A Pogarell, Oliver %A Ishii, Kazunari %A Bartenstein, Peter %A Rominger, Axel %X

Late-life depression, even when of subsyndromal severity, has shown strong associations with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Preclinical studies have suggested that serotonin selective reuptake inhibitors (SSRIs) can attenuate amyloidogenesis. Therefore, we aimed to investigate the effect of SSRI medication on amyloidosis and grey matter volume in subsyndromal depressed subjects with MCI and AD during an interval of two years. 256 cognitively affected subjects (225 MCI/ 31 AD) undergoing [18F]-AV45-PET and MRI at baseline and 2-year follow-up were selected from the ADNI database. Subjects with a positive depression item (DEP(+); n = 73) in the Neuropsychiatric Inventory Questionnaire were subdivided to those receiving SSRI medication (SSRI(+); n = 24) and those without SSRI treatment (SSRI(-); n = 49). Longitudinal cognition (Δ-ADAS), amyloid deposition rate (standardized uptake value, using white matter as reference region (SUVRWM), and changes in grey matter volume were compared using common covariates. Analyses were performed separately in all subjects and in the subgroup of amyloid-positive subjects. Cognitive performance in DEP(+)/SSRI(+) subjects (Δ-ADAS: -5.0%) showed less deterioration with 2-year follow-up when compared to DEP(+)/SSRI(-) subjects (Δ-ADAS: +18.6%, p < 0.05), independent of amyloid SUVRWM at baseline. With SSRI treatment, the progression of grey matter atrophy was reduced (-0.9% versus -2.7%, p < 0.05), notably in fronto-temporal cortex. A slight trend towards lower amyloid deposition rate was observed in DEP(+)/SSRI(+) subjects versus DEP(+)/SSRI(-). Despite the lack of effect to amyloid PET, SSRI medication distinctly rescued the declining cognitive performance in cognitively affected patients with depressive symptoms, and likewise attenuated grey matter atrophy.

%B J Alzheimers Dis %V 65 %P 793-806 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010116?dopt=Abstract %R 10.3233/JAD-170387 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Serum Copper is not Altered in Frontotemporal Lobar Degeneration. %A Squitti, Rosanna %A Fostinelli, Silvia %A Siotto, Mariacristina %A Ferrari, Clarissa %A Binetti, Giuliano %A Benussi, Luisa %A Rongioletti, Mauro %A Ghidoni, Roberta %X

Meta-analyses show copper dyshomeostasis in Alzheimer's disease. However, a study evaluating copper changes in other neurodegenerative forms of dementia has not yet been performed. In this study, we assessed copper, ceruloplasmin, copper not bound to ceruloplasmin, and copper to ceruloplasmin ratio in 85 patients affected by frontotemporal lobar degeneration (FTLD) and 55 healthy controls. Data were analyzed through multivariate ANOVA models taking into account age and sex as covariates and the stratification for FTLD variants, after calculating power analysis to ensure the reliability of the conclusions drawn. The study revealed no difference between the groups.

%B J Alzheimers Dis %V 63 %P 1427-1432 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843237?dopt=Abstract %R 10.3233/JAD-171074 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Serum C-Peptide, Visfatin, Resistin, and Ghrelin are Altered in Sporadic and GRN-Associated Frontotemporal Lobar Degeneration. %A Zanardini, Roberta %A Benussi, Luisa %A Fostinelli, Silvia %A Saraceno, Claudia %A Ciani, Miriam %A Borroni, Barbara %A Padovani, Alessandro %A Binetti, Giuliano %A Ghidoni, Roberta %K Aged %K Biomarkers %K C-Peptide %K Female %K Frontotemporal Lobar Degeneration %K Ghrelin %K Humans %K Kaplan-Meier Estimate %K Male %K Middle Aged %K Mutation %K Nicotinamide Phosphoribosyltransferase %K Progranulins %K Resistin %X

Frontotemporal lobar degeneration (FTLD) is a group of complex neurodegenerative disease characterized by progressive deterioration of the frontal and anterior temporal lobes of the brain resulting in different heterogeneous conditions, mainly characterized by personality changes, behavioral disturbances, such as binge eating, and deficits in language and executive functions. Null mutations in progranulin gene (GRN) are one of the most frequent genetic determinants in familial frontotemporal dementia. Recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance revealing its metabolic function. Increasing evidence suggests that neurodegenerative dementias are associated with a higher prevalence of metabolic changes than in the general population. According to these findings, the aim of this study is to investigate putative alterations in markers linked to metabolic functions (i.e., C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon, insulin, resistin, and three adipokines as visfatin, leptin, and plasminogen activator inhibitor-1 total) in sporadic and GRN-related FTLD. We found that 1) C-peptide is increased in sporadic and GRN-mutated FTLD patients; in addition, we demonstrated an anticipation of the disease in patients with the highest C-peptide concentrations; 2) visfatin is slightly reduced in the whole FTLD group; 3) resistin, an adipokine involved in inflammatory-related diseases, is specifically increased in FTLD due to GRN null mutations; 4) ghrelin concentration is specifically increased in pre-symptomatic subjects and FTLD patients with GRN mutations. These findings support the hypothesis that alterations in metabolic pattern are involved in FTLD progression highlighting novel putative targets for the development of preventive and personalized therapies.

%B J Alzheimers Dis %V 61 %P 1053-1060 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226876?dopt=Abstract %R 10.3233/JAD-170747 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Serum Non-Ceruloplasmin Non-Albumin Copper Elevation in Mild Cognitive Impairment and Dementia due to Alzheimer's Disease: A Case Control Study. %A Rozzini, Luca %A Lanfranchi, Francesco %A Pilotto, Andrea %A Catalani, Simona %A Gilberti, Maria Enrica %A Paganelli, Matteo %A Apostoli, Pietro %A Padovani, Alessandro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cognitive Dysfunction %K Copper %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Psychiatric Status Rating Scales %X

Several studies showed high serum copper levels in Alzheimer's disease (AD). The present study applied a newly developed method to detect serum copper free from proteins (free-Cu). Forty-four patients affected by dementia due to AD, thirty-six patients affected by mild cognitive impairment (MCI) due to AD, and twenty-eight healthy controls underwent clinical, cognitive, and MRI assessment. The new method showed higher free-Cu concentrations in MCI and dementia due to AD compared to controls (p < 0.0001). No correlation between copper levels, cognitive or MRI measures were found.

%B J Alzheimers Dis %V 61 %P 907-912 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332043?dopt=Abstract %R 10.3233/JAD-170552 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Severe Agitation in Dementia: An Explorative Secondary Data Analysis on the Prevalence and Associated Factors in Nursing Home Residents. %A Palm, Rebecca %A Sorg, Christian G G %A Ströbel, Armin %A Gerritsen, Debby L %A Holle, Bernhard %X

BACKGROUND: The phenomena of severe agitation is not well understood and often not adequately treated.

OBJECTIVE: This article determines the prevalence and associated factors of severe agitation in nursing home residents with dementia.

METHODS: Secondary data analysis within an observational study in German nursing homes with n = 1,967 participants. We assessed severity of agitation with the Neuropsychiatric Inventory Questionnaire (NPI-Q) and defined the construct of agitation as a composite score of the NPI-Q items agitation/aggression, disinhibition, and irritability/lability; the dependent variable of severe agitation was considered as being present in residents who scored 'severe' in at least one of these symptoms. A binary logistic regression model was calculated to estimate associations.

RESULTS: The prevalence of severe agitation was 6.3% (n = 124). The strongest associations were found for elation/euphoria (OR 7.6, CI 3.1-18.5), delusions (OR 7.3, CI 4.0-13.2), apathy/indifference (OR 2.8, CI 1.7-4.7), anxiety (OR 2.2, CI 1.2-3.8), nighttime behaviors (OR 2.4, CI 1.4-4.2), motor disturbances (OR 2.4, CI 1.4-4.1), and male sex (OR 2.4. CI 1.3-4.2).

CONCLUSION: Severe agitation in nursing home residents with dementia is a relevant clinical issue as approximately 70% of residents have a dementia. Residents with elation/euphoria and delusions may have a stronger risk of showing severe agitation. We consider delusions as a possible cause of agitation and therefore a prelude to agitation. Although it might be possible that elation/euphoria follows from agitation, we hypothesize that the residents first experience elation/ euphoria and exhibit agitation afterwards.

%B J Alzheimers Dis %V 66 %P 1463-1470 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412491?dopt=Abstract %R 10.3233/JAD-180647 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Severity-Related Increase and Cognitive Correlates of Serum VEGF Levels in Alzheimer's Disease ApoE4 Carriers. %A Alvarez, X Anton %A Alvarez, Irene %A Aleixandre, Manuel %A Linares, Carlos %A Muresanu, Dafin %A Winter, Stefan %A Moessler, Herbert %X

Vascular endothelial growth factor (VEGF) is an angioneurin involved in the regulation of vascular and neural functions relevant for the pathophysiology of Alzheimer's disease (AD), but the influence of AD severity and ApoE4 status on circulating VEGF and its relationship with cognition has not been investigated. We assessed serum VEGF levels and cognitive performance in AD, amnestic mild cognitive impairment (MCI), and control subjects. VEGF levels were higher in AD patients than in MCI cases and controls (p < 0.05) and showed a progressive increase with clinical severity in the whole study population (p < 0.01). Among AD patients, severity-related VEGF elevations were significant in ApoE4 carriers (p < 0.05), but not in non-carriers. Increased VEGF levels were associated with disease severity and showed mild correlations with cognitive impairment that were only consistent for the ADAS-cog+ items remembering test instructions (memory) and maze task (executive functions) in the group of AD patients (p < 0.05). On the other hand, higher VEGF values were related to better memory and language performance in ApoE4 carriers with moderately-severe AD. According to these results showing severity- and ApoE4-related differences in serum VEGF and its cognitive correlates, it is suggested that increases in VEGF levels might represent an endogenous response driven by pathological factors and could entail cognitive benefits in AD patients, particularly in ApoE4 carriers. Our findings support the notion that VEGF constitutes a relevant molecular target to be further explored in AD pathology and therapy.

%B J Alzheimers Dis %V 63 %P 1003-1013 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710700?dopt=Abstract %R 10.3233/JAD-160477 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Sex Influences the Accuracy of Subjective Memory Complaint Reporting in Older Adults. %A Sundermann, Erin E %A Edmonds, Emily C %A Delano-Wood, Lisa %A Galasko, Douglas R %A Salmon, David P %A Rubin, Leah H %A Bondi, Mark W %K Aged %K Cognitive Dysfunction %K Female %K Humans %K Logistic Models %K Male %K Memory Disorders %K Mental Recall %K Neuropsychological Tests %K Self Report %K Sex Factors %X

Subjective memory complaints (SMC) are required when diagnosing amnestic mild cognitive impairment (aMCI), although their relationship with objective memory performance and Alzheimer's disease (AD) pathology remains unclear. We investigated whether the sex of the patient/participant moderates these associations. Participants were 940 normal control (NC) and aMCI participants from the Alzheimer's Disease Neuroimaging Initiative. SMC were assessed via the memory scale of the Everyday Cognition questionnaire. Discrepancy scores were calculated between self- and informant-reports and categorized into "overestimates," "comparable estimates", and "underestimates" of SMC. We conducted linear and logistic regressions to examine the interaction of sex with self- and informant-reported SMC and discrepancy group on the Rey Auditory Verbal Learning Test (RAVLT) Immediate and Delayed Recall and on PET measures of amyloid-β (Aβ) positivity. Diagnosis-stratified analyses were also conducted. Overall, there were sex by self- and informant-reported SMC interactions for Immediate and Delayed Recall. Despite a higher proportion of "overestimates" in women, greater self- and informant-reported SMC showed a stronger relationship to poorer RAVLT scores in women versus men. Diagnosis-stratified analyses revealed that results were driven by aMCI participants. Conversely, overall, greater self- and informant-reported SMC related to greater odds of Aβ positivity regardless of sex. In diagnosis-stratified analyses, only informant-reported SMC related to Aβ positivity in aMCI. Relative to "comparable estimates," "underestimates" of SMC were associated with poorer RAVLT scores across sexes in the overall sample and in aMCI. The predictive utility of self-report SMC may be limited to women in aMCI. Sex differences should be considered when evaluating SMC.

%B J Alzheimers Dis %V 61 %P 1163-1178 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332038?dopt=Abstract %R 10.3233/JAD-170425 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Sex Moderates the Impact of Diagnosis and Amyloid PET Positivity on Hippocampal Subfield Volume. %A Caldwell, Jessica Z K %A Berg, Jody-Lynn %A Shan, Guogen %A Cummings, Jeffrey L %A Banks, Sarah J %X

We examined moderation effects of sex and diagnosis on the effect of positive florbetapir positron emission tomography (PET) amyloid-β (Aβ) scan (A+) on hippocampus subfield volumes in 526 normal control (NC) and early mild cognitive impairment (eMCI) participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI2; ADNI-GO). Regression moderation models showed that women- but not men- with NC designation did not show reduced subiculum volumes despite A+. At the eMCI stage, A+ was detrimental across sexes. Findings were significant while accounting for the effects of age, cognition at screening, education, and APOE4 carrier status. These findings suggest that women with A+ have early neural resistance to Alzheimer's disease-related amyloid burden.

%B J Alzheimers Dis %V 64 %P 79-89 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865063?dopt=Abstract %R 10.3233/JAD-180028 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Sex-Dependent Differences in Spontaneous Autoimmunity in Adult 3xTg-AD Mice. %A Kapadia, Minesh %A Mian, M Firoz %A Michalski, Bernadeta %A Azam, Amber B %A Ma, Donglai %A Salwierz, Patrick %A Christopher, Adam %A Rosa, Elyse %A Zovkic, Iva B %A Forsythe, Paul %A Fahnestock, Margaret %A Sakic, Boris %X

The triple-transgenic (3xTg-AD) mouse strain is a valuable model of Alzheimer's disease (AD) because it develops both amyloid-β (Aβ) and tau brain pathology. However, 1-year-old 3xTg-AD males no longer show plaques and tangles, yet early in life they exhibit diverse signs of systemic autoimmunity. The current study aimed to address whether females, which exhibit more severe plaque/tangle pathology at 1 year of age, show similar autoimmune phenomena and if so, whether these immunological changes coincide with prodromal markers of AD pathology, markers of learning and memory formation, and epigenetic markers of neurodegenerative disease. Six-month-old 3xTg-AD and wild-type mice of both sexes were examined for T-cell phenotype (CD3+, CD8+, and CD4+ populations), serological measures (autoantibodies, hematocrit), soluble tau/phospho-tau and Aβ levels, brain-derived neurotrophic factor (BDNF) expression, and expression of histone H2A variants. Although no significant group differences were seen in tau/phospho-tau levels, 3xTg-AD mice had lower brain mass and showed increased levels of soluble Aβ and downregulation of BDNF expression in the cortex. Splenomegaly, depleted CD+ T-splenocytes, increased autoantibody levels and low hematocrit were more pronounced in 3xTg-AD males than in females. Diseased mice also failed to exhibit sex-specific changes in histone H2A variant expression shown by wild-type mice, implicating altered nucleosome composition in these immune differences. Our study reveals that the current 3xTg-AD model is characterized by systemic autoimmunity that is worse in males, as well as transcriptional changes in epigenetic factors of unknown origin. Given the previously observed lack of plaque/tangle pathology in 1-year-old males, an early, sex-dependent autoimmune mechanism that interferes with the formation and/or deposition of aggregated protein species is hypothesized. These results suggest that more attention should be given to studying sex-dependent differences in the immunological profiles of human patients.

%B J Alzheimers Dis %V 63 %P 1191-1205 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710702?dopt=Abstract %R 10.3233/JAD-170779 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Sex-Related Reserve Hypothesis in Alzheimer's Disease: Changes in Cortical Thickness with a Five-Year Longitudinal Follow-Up. %A Lee, Juyoun %A Cho, Hanna %A Jeon, Seun %A Kim, Hee Jin %A Kim, Yeo Jin %A Lee, Jeongmin %A Kim, Sung Tae %A Lee, Jong-Min %A Chin, Juhee %A Lockhart, Samuel N %A Lee, Ae Young %A Na, Duk L %A Seo, Sang Won %X

BACKGROUND: Sex effects on the progression of Alzheimer's disease (AD) have received less attention than other demographic factors, including onset age and education.

OBJECTIVE: The aim of this study was to investigate whether sex affected cortical thinning in the disease progression of AD.

METHODS: We prospectively recruited 36 patients with early-stage AD and 14 people with normal cognition. All subjects were assessed with magnetic resonance imaging at baseline, Year 1, Year 3, and Year 5. We performed cortical thickness analyses using surface-based morphometry on magnetic resonance imaging.

RESULTS: Women with AD showed more rapid cortical thinning in the left dorsolateral frontal cortex, left superior temporal gyrus, bilateral temporo-parietal association cortices, bilateral anterior cingulate gyri, bilateral medial frontal cortices, and bilateral occipital cortices over 5 years than men with AD, even though there was no difference in cortical thickness at baseline. In contrast, there were no regions of significantly more rapid atrophy in men with AD.

CONCLUSIONS: Our findings suggest that women deteriorate faster than men in the progression of AD.

%B J Alzheimers Dis %V 65 %P 641-649 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056418?dopt=Abstract %R 10.3233/JAD-180049 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Shear-Induced Amyloid Formation in the Brain: III. The Roles of Shear Energy and Seeding in a Proposed Shear Model. %A Trumbore, Conrad N %X

If cerebrospinal and interstitial fluids move through very narrow brain flow channels, these restrictive surroundings generate varying levels of fluid shear and different shear rates, and dissolved amyloid monomers absorb different shear energies. It is proposed that dissolved amyloid-β protein (Aβ) and other amyloid monomers undergo shear-induced conformational changes that ultimately lead to amyloid monomer aggregation even at very low brain flow and shear rates. Soluble Aβ oligomers taken from diseased brains initiate in vivo amyloid formation in non-diseased brains. The brain environment is apparently responsible for this result. A mechanism involving extensional shear is proposed for the formation of a seed Aβ monomer molecule that ultimately promotes templated conformational change of other Aβ molecules. Under non-quiescent, non-equilibrium conditions, gentle extensional shear within the brain parenchyma, and perhaps even during laboratory preparation of Aβ samples, may be sufficient to cause subtle conformational changes in these monomers. These result from brain processes that significantly lower the high activation energy predicted for the quiescent Aβ dimerization process. It is further suggested that changes in brain location and changes brought about by aging expose Aβ molecules to different shear rates, total shear, and types of shear, resulting in different conformational changes in these molecules. The consequences of such changes caused by variable shear energy are proposed to underlie formation of amyloid strains causing different amyloid diseases. Amyloid researchers are urged to undertake studies with amyloids, anti-amyloid drugs, and antibodies while all of these are under shear conditions similar to those in the brain.

%B J Alzheimers Dis %V 65 %P 47-70 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040710?dopt=Abstract %R 10.3233/JAD-171003 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Shear-Induced Amyloid Formation in the Brain: IV. Effects on Synapses Surrounding Senile Plaque and in Plaque-Free Regions. %A Trumbore, Conrad N %X

Amyloid-β oligomers (AβO) have been proposed as neurotoxins in the synaptic dysfunction that precedes Alzheimer's disease symptoms. Human and animal model studies report that senile plaques contain a halo of AβO molecules surrounding these plaques. A far smaller number of oligomers are distributed widely in plaque-free regions. It has been suggested that oligomers migrate from halos to nearby synapses and are incorporated into both pre- and postsynaptic terminals. These two types of oligomers have two different toxicities when extracted and injected in animal models. This paper proposes a shear-energy based explanation for the data in these studies. Shear hypotheses in the preceding three papers in this series are applied to suggest how the hydrodynamics and resulting shear patterns explain the spatial distribution of both AβO types, the apparent synapse loss in the vicinity of plaque particles, and possible reasons for the differing toxicities. A shear-based mechanism is proposed for the preferential migration of locally shear-excited Aβ molecules into the synaptic cleft. It is proposed that high energy laminar shear generated by the forced diversion of interstitial fluid around the flow-impeding plaque particle is responsible for the formation of AβOs around the plaque. It is suggested that in plaque-free regions, a different type of AβO with different toxicity is generated by lower energy shear flow around synapses, depositing AβO within the synapse from either the neuron membrane surface or by prion-like seeding within the synaptic cleft by locally-sheared Aβ molecules near the synapse entry.

%B J Alzheimers Dis %V 66 %P 57-73 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30223395?dopt=Abstract %R 10.3233/JAD-171080 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Short-Term Effects of Microglia-Specific Mitochondrial Dysfunction on Amyloidosis in Transgenic Models of Alzheimer's Disease. %A Steffen, Johannes %A Stenzel, Jan %A Ibrahim, Saleh %A Pahnke, Jens %X

Reduction of mitochondrial activity is a subtle and early event in the pathogenesis of Alzheimer's disease. Mitochondrial damage and consequentially enhanced production of reactive oxygen species is particularly occurring in the vicinity of amyloid plaques. Since all cells are affected by mitochondrial damage, analyses of cell type-specific effects are challenging. To study the impact of mitochondrial alterations on microglial activity in a homogeneous genetic background, we generated bone marrow chimeras of irradiated 46-days-old APP-transgenic mice. For reconstitution, bone marrow from CX3CR1-eGFP mice with mitochondria of either non-obese diabetic or C57BL/6J animals was utilized. Successful reconstitution was evident in 100-day-old animals, by the presence of eGFP-positive cells in liver and spleen. In the brain, one-third of IBA1-positive microglia cells were newly recruited eGFP-expressing cells. Although donor-derived microglia were equally located in the proximity of amyloid plaques, no difference was observed in either the amyloid level, total number, or microglial coverage of plaques. These results indicate that during this brief and early phase of amyloid deposition, beneficial mitochondrial alterations in the newly recruited third of microglial cells were not sufficient to affect the amyloidosis in APP-transgenic mice.

%B J Alzheimers Dis %V 65 %P 465-474 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040730?dopt=Abstract %R 10.3233/JAD-180395 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Simultaneous Aerobic Exercise and Memory Training Program in Older Adults with Subjective Memory Impairments. %A McEwen, Sarah C %A Siddarth, Prabha %A Abedelsater, Berna %A Kim, Yena %A Mui, Wenli %A Wu, Pauline %A Emerson, Natacha D %A Lee, Jacob %A Greenberg, Shayna %A Shelton, Tiffany %A Kaiser, Scott %A Small, Gary W %A Merrill, David A %K Aged %K Attention %K California %K Cognition %K Executive Function %K Exercise %K Female %K Humans %K Learning %K Male %K Memory %K Memory Disorders %K Middle Aged %K Treatment Outcome %X

BACKGROUND: Several modifiable lifestyle factors have been shown to have potential beneficial effects in slowing cognitive decline. Two such factors that may affect cognitive performance and slow the progression of memory loss into dementia in older adults are cognitive training and physical activity. There are currently no effective treatments for dementia; therefore, preventative strategies to delay or prevent the onset of dementia are of critical importance.

OBJECTIVE: The aim of this study was to determine the relative effectiveness of simultaneous performance of memory training and aerobic exercise to a sequential performance intervention on memory functioning in older adults.

METHODS: 55 older adults (aged 60- 75) with subjective memory impairments (non-demented and non-MCI) completed the intervention that consisted of 90-minute small group classes held twice weekly. Participants were randomized to either 4-weeks of supervised strategy-based memory training done simultaneously while stationary cycling (SIM) or sequentially after the stationary cycling (SEQ). Standardized neurocognitive measures of memory, executive functioning, speed of processing, attention, and cognitive flexibility were assessed at baseline and post-intervention.

RESULTS: The SIM group, but not the SEQ group, had a significant improvement on composite memory following the intervention (t(51) = 2.7, p = 0.01, effect size (ES) = 0.42) and transfer to non-trained reasoning abilities (t(51) = 6.0, ES = 0.49) and complex attention (t(51) = 3.1, p = 0.003, ES = 0.70). Conversely, the SEQ group, but not the SIM, showed significant improvement in executive functioning (t(51) = 5.0, p = 0.0001, ES = 0.96).

CONCLUSION: These findings indicate that a 4-week simultaneous memory training and aerobic exercise program is sufficient to improve memory, attention, and reasoning abilities in older adults.

%B J Alzheimers Dis %V 62 %P 795-806 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480182?dopt=Abstract %R 10.3233/JAD-170846 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Single Subject Classification of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Using Anatomical, Diffusion Tensor, and Resting-State Functional Magnetic Resonance Imaging. %A Bouts, Mark J R J %A Möller, Christiane %A Hafkemeijer, Anne %A van Swieten, John C %A Dopper, Elise %A van der Flier, Wiesje M %A Vrenken, Hugo %A Wink, Alle Meije %A Pijnenburg, Yolande A L %A Scheltens, Philip %A Barkhof, Frederik %A Schouten, Tijn M %A de Vos, Frank %A Feis, Rogier A %A van der Grond, Jeroen %A de Rooij, Mark %A Rombouts, Serge A R B %X

BACKGROUND/OBJECTIVE: Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to-on a subject-basis-differentiate these dementia-types is not yet known.

METHODS: Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier's ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC).

RESULTS: Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p = 0.41).

CONCLUSION: Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI.

%B J Alzheimers Dis %V 62 %P 1827-1839 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614652?dopt=Abstract %R 10.3233/JAD-170893 %0 Journal Article %J J Alzheimers Dis %D 2018 %T SIRT1 Deacetylates SC35 and Suppresses Its Function in Tau Exon 10 Inclusion. %A Yin, Xiaomin %A Jiang, Xiaosu %A Wang, Jia %A Qian, Shuo %A Liu, Fei %A Qian, Wei %K Alternative Splicing %K Alzheimer Disease %K Exons %K HEK293 Cells %K HeLa Cells %K Humans %K Phosphorylation %K Ribonucleoproteins %K Serine-Arginine Splicing Factors %K Sirtuin 1 %K tau Proteins %K Tauopathies %X

Approximately equal amounts of 3R-tau and 4R-tau resulting from alternative splicing of tau exon 10 is necessary to maintain normal brain function. Dysregulation of alternative splicing of tau exon 10 and the imbalance of 3R-tau/4R-tau have been seen in inherited and sporadic tauopathies. Splicing factor SC35 (also name as SRSF2) plays an important role in promoting tau exon 10 inclusion. SC35 is post-translationally modified by phosphorylation and acetylation, but the role of acetylation in SC35-medicated tau exon 10 inclusion is unknown. Sirtuin type 1 (SIRT1) is an enzyme that deacetylates proteins and associates with age-related disease such as Alzheimer's disease. In the present study, we determined the role of SIRT1 in SC35 acetylation and in the alternative splicing of tau exon 10. We found that SIRT1 interacts with and deacetylates SC35, and inhibits SC35-promoted tau exon 10 inclusion. Substituting K52 residue of SC35 by arginine impairs the role of SC35 in tau exon 10 inclusion. These results suggest that SIRT1 may serve as a therapeutic target for tauopathy by regulating SC35-mediated tau exon 10 splicing.

%B J Alzheimers Dis %V 61 %P 561-570 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226865?dopt=Abstract %R 10.3233/JAD-170418 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Sleep and EEG Power Spectral Analysis in Three Transgenic Mouse Models of Alzheimer's Disease: APP/PS1, 3xTgAD, and Tg2576. %A Kent, Brianne A %A Strittmatter, Stephen M %A Nygaard, Haakon B %X

BACKGROUND: Sleep disturbances have long been associated with Alzheimer's disease (AD), and there is a growing interest in how these disturbances might impact AD pathophysiology. Despite this growing interest, surprisingly little is known about how sleep architecture and the broader neuronal network are affected in widely used transgenic mouse models of AD.

OBJECTIVE: We analyzed sleep and electroencephalography (EEG) power in three transgenic mouse models of AD, using identical and commercially available hardware and analytical software. The goal was to assess the suitability of these mouse lines to model sleep and the broader neuronal network dysfunction measured by EEG in AD.

METHODS: Tg2576, APP/PS1, and 3xTgAD transgenic AD mice were studied using in vivo EEG recordings for sleep/wake time and power spectral analysis.

RESULTS: Both the APP/PS1 model at 8- 10 months and the Tg2576 model at 12 months of age exhibited stage-dependent decreases in theta and delta power, and shifts in the power spectra toward higher frequencies. Stage-dependent power spectral analyses showed no changes in the 3xTgAD model at 18 months of age. The percentage of time spent awake, in non-rapid eye movement sleep (NREM), or in rapid-eye-movement sleep (REM) was not different between genotypes in any of the transgenic lines.

CONCLUSION: Our findings are consistent with data from several other transgenic AD models as well as certain studies in patients with mild cognitive impairment. Further studies will be needed to better understand the correlation between EEG spectra and AD pathophysiology, both in AD models and the human condition.

%B J Alzheimers Dis %V 64 %P 1325-1336 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29991134?dopt=Abstract %R 10.3233/JAD-180260 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Small Molecule Inhibitor of Plasminogen Activator Inhibitor-1 Reduces Brain Amyloid-β Load and Improves Memory in an Animal Model of Alzheimer's Disease. %A Akhter, Hasina %A Huang, Wen-Tan %A van Groen, Thomas %A Kuo, Hui-Chien %A Miyata, Toshio %A Liu, Rui-Ming %X

Alzheimer's disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain is a pathological hallmark of AD and is believed to be a central disease-causing and disease-promoting event. In a previous study, we showed that deletion of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), significantly reduced brain Aβ load in APP/PS1 mice, an animal model of familial AD. In this study, we further show that oral administration of TM5275, a small molecule inhibitor of PAI-1, for a period of 6 weeks, inhibits the activity of PAI-1 and increases the activities of tPA and uPA as well as plasmin, which is associated with a reduction of Aβ load in the hippocampus and cortex and improvement of learning/memory function in APP/PS1 mice. Protein abundance of low density lipoprotein related protein-1 (LRP-1), a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, as well as plasma Aβ42 are increased, whereas the expression and processing of full-length amyloid-β protein precursor is not affected by TM5275 treatment in APP/PS1 mice. In vitro studies further show that PAI-1 increases, whereas TM5275 reduces, Aβ40 level in the culture medium of SHSY5Y-APP neuroblastoma cells. Collectively, our data suggest that TM5275 improves memory function of APP/PS1 mice, probably by reducing brain Aβ accumulation through increasing plasmin-mediated degradation and LRP-1-mediated efflux of Aβ in the brain.

%B J Alzheimers Dis %V 64 %P 447-457 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914038?dopt=Abstract %R 10.3233/JAD-180241 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Small Vessel Cerebrovascular Pathology Identified by Magnetic Resonance Imaging Is Prevalent in Alzheimer's Disease and Mild Cognitive Impairment: A Potential Target for Intervention. %A Scott, Tammy M %A Bhadelia, Rafeeque A %A Qiu, Wei Qiao %A Folstein, Marshal F %A Rosenberg, Irwin H %X

BACKGROUND: There is evidence that Alzheimer's disease (AD) has significant cerebrovascular etiopathogenesis. Understanding potentially modifiable risk factors for vascular disease can help design long-term intervention strategies for controlling or preventing cognitive dysfunction attributable to cerebrovascular disease.

OBJECTIVE: To evaluate the presence and severity of markers of cerebrovascular pathology, its relationship to diagnostic categories of dementia, including AD, and association with the metabolic biomarker homocysteine.

METHODS: In a cross-sectional observational study, 340 community-dwelling elders received a clinical evaluation including brain MRI and neuropsychological tests. Dementia and mild cognitive impairment (MCI) were diagnosed by consensus committee. Fasting total plasma homocysteine was measured. Statistical analyses were adjusted for demographics and cerebrovascular risk factors.

RESULTS: Nearly 25% of those diagnosed with AD had small vessel infarcts (SVI). Periventricular white matter hyperintensity (pvWMHI) was prevalent in participants with AD (61%) or MCI (amnesic 61% and non-amnesic 54%, respectively). Participants with SVI and/or pvWMHI also had greater brain atrophy. Homocysteine concentrations were higher in individuals with cerebrovascular findings than in those without. In individuals with cerebrovascular disease, homocysteine was inversely related to executive function (p = 0.022) and directly related to degree of brain atrophy (p = 0.009).

CONCLUSIONS: We demonstrated a significant prevalence of small vessel markers of cerebrovascular pathology in individuals diagnosed with AD, with a significant concurrence between cerebrovascular disease and brain and ventricular atrophy. While current research on AD has focused on amyloid-βpeptide deposition, tau-pathology, and microglial activation and inflammation, greater attention to the cerebrovascular contribution to this neurodegenerative disease presents an additional target for therapeutic prevention and intervention.

%B J Alzheimers Dis %V 65 %P 293-302 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040728?dopt=Abstract %R 10.3233/JAD-180366 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Social Dysfunction in Older Age and Relationships with Cognition, Depression, and Apathy: The GreatAGE Study. %A Lozupone, Madia %A Panza, Francesco %A Piccininni, Marco %A Copetti, Massimiliano %A Sardone, Rodolfo %A Imbimbo, Bruno P %A Stella, Eleonora %A D'Urso, Francesca %A Barulli, Maria Rosaria %A Battista, Petronilla %A Grasso, Alessandra %A Tortelli, Rosanna %A Capozzo, Rosa %A Coppola, Francesco %A Abbrescia, Daniela Isabel %A Bellomo, Antonello %A Giannelli, Gianluigi %A Quaranta, Nicola %A Seripa, Davide %A Logroscino, Giancarlo %X

BACKGROUND: Most studies focused on only one measure of social dysfunction in older age, without proper validation and distinction across different dimensions including subjectivity, structural, and functional aspects.

OBJECTIVE: We sought to validate the Social Dysfunction Rating Scale (SDRS) and its factorial structure, also determining the association of SDRS with cognitive functions, global psychopathology, and social deprivation.

METHODS: The SDRS was administered to 484 Italian community-dwelling elderly, recruited in the GreatAGE study, a population-based study on aging conducted in Castellana Grotte, Bari, Southern Italy. We determined objective and subjective psychometric properties of SDRS against the gold standard evaluation of social dysfunction according to the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders (SCID-I) criterion.

RESULTS: The SDRS showed a moderate accuracy with an optimal cut-off of 26 maximized with higher sensitivity (0.74,95% CI:0.63-0.84) than specificity (0.57,95% CI:0.50-0.64). A five-factor structure was carried out and five dimensions of SDRS were identified (loneliness; social isolation; feeling of contribution/uselessness; lack of leisure activities; anxiety for the health). Education and global cognitive functions were inversely correlated to SDRS, while a direct association with global psychopathology, depression, and apathy was found. The prevalence of higher SDRS scores was major in subjects with current psychiatric disorders versus other subjects.∥Conclusion: The SDRS could be a valid instrument to capture both size and quality of social dysfunction, both in subjects with psychiatric disorders and in normal subjects. Several categories of social dysfunction differed only in the degree of health deprivation, not in social or material deprivation.

%B J Alzheimers Dis %V 65 %P 989-1000 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103335?dopt=Abstract %R 10.3233/JAD-180466 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Some Methodological Characteristics of Alzheimer-Associated Urine Neuronal Thread Protein Detected by Enzyme-Linked Immunosorbent Assay. %A Jin, He %A Wang, Rong %A Liu, Zhaohui %A Jia, Qiang %A Wu, Yanchuan %A Zhao, Zhiwei %A Wang, Yulan %A Zhang, Xu %X

BACKGROUND: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been found to be a candidate biomarker of Alzheimer's disease (AD).

OBJECTIVE: To investigate the effects of urine collected time, different preservatives addition, and storage condition on the measurement of urine AD7c-NTP by enzyme-linked immunosorbent assay (ELISA).

METHODS: Three hundred urine samples were collected from 20 participants at three time points on five consecutive days. These samples were immediately placed at 4°C and detected within 2 h. The single spot samples of the first day morning were split into eleven duplicate aliquots (a-k) of 1 ml each, (a) without any preservative (untreated), (b) containing boric acid (2 g/L), (c) containing NaHCO3 (5 g/L), (a-c) were detected at six different time points. For the other eight preservative-free samples, (d-g) were stored at -20°C and (h-k) were stored at -70°C, respectively, detected at different time points. All of the results were compared with the baseline urine.

RESULTS: The urine AD7c-NTP levels at different time points behaved stably (p > 0.05). Urine samples without any preservative increased over time, and compared with the NaHCO3 addition group, boric acid addition group behaved stably. Samples stored at -20°C and -70°C led to an obviously false positive.

CONCLUSIONS: AD7c-NTP can be tested using random urine instead of the first morning urine. If the specimen cannot be tested in time, boric acid appears to be an acceptable preservative with storage at 4°C, freezing is not recommended.

%B J Alzheimers Dis %V 63 %P 255-262 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614662?dopt=Abstract %R 10.3233/JAD-171109 %0 Journal Article %J J Alzheimers Dis %D 2018 %T SORL1 Variants in Familial Alzheimer's Disease. %A Gómez-Tortosa, Estrella %A Ruggiero, María %A Sainz, Ma José %A Villarejo-Galende, Alberto %A Prieto-Jurczynska, Cristina %A Venegas Pérez, Begoña %A Ordás, Carlos %A Agüero, Pablo %A Guerrero-López, Rosa %A Pérez-Pérez, Julián %K Aged %K Alzheimer Disease %K Case-Control Studies %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Humans %K LDL-Receptor Related Proteins %K Male %K Membrane Transport Proteins %K Middle Aged %K Mutation %K Polymorphism, Single Nucleotide %K Siblings %K Spain %X

The SORL1 gene encodes a protein involved in the amyloidogenic process, and its variants have been associated with Alzheimer's disease (AD) physiopathology. We screened for SORL1 variants in 124 familial (44 early- and 80 late-onset) dementia of Alzheimer type (DAT) cases. Nine potentially pathogenic changes (three not previously reported and six rare variants) were found in nine probands (7%). After screening the control population and siblings (presence in at least 1/200 controls and/or absence of segregation pattern), a causal relationship with the disease was considered unlikely in six variants and uncertain in one. The change Trp848Ter and a splice-site variant remained likely correlated with the disease. SORL1 mutations are present in 7% of our familial DAT cohort, though in most cases cannot be considered the direct cause of the disease.

%B J Alzheimers Dis %V 61 %P 1275-1281 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376855?dopt=Abstract %R 10.3233/JAD-170590 %0 Journal Article %J J Alzheimers Dis %D 2018 %T SPARCL1 Accelerates Symptom Onset in Alzheimer's Disease and Influences Brain Structure and Function During Aging. %A Seddighi, Sahba %A Varma, Vijay R %A An, Yang %A Varma, Sudhir %A Beason-Held, Lori L %A Tanaka, Toshiko %A Kitner-Triolo, Melissa H %A Kraut, Michael A %A Davatzikos, Christos %A Thambisetty, Madhav %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Brain %K Calcium-Binding Proteins %K Cerebrovascular Circulation %K Cognition Disorders %K Extracellular Matrix Proteins %K Female %K Humans %K Independent Living %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Polymorphism, Single Nucleotide %K Positron-Emission Tomography %X

We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging.

%B J Alzheimers Dis %V 61 %P 401-414 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154276?dopt=Abstract %R 10.3233/JAD-170557 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Spatial Navigation in the Elderly with Alzheimer's Disease: A Cross-Sectional Study. %A Zanco, Marcos %A Plácido, Jessica %A Marinho, Valeska %A Ferreira, José Vinicius %A de Oliveira, Felipe %A Monteiro-Junior, Renato %A Barca, Maria %A Engedal, Knut %A Laks, Jerson %A Deslandes, Andrea %X

BACKGROUND: Spatial navigation is a fundamental cognitive ability that allows an individual to maintain independence by facilitating the safe movement from one place to another. It emerges as one of the first deficits in patients with Alzheimer's disease (AD).

OBJECTIVE: To compare spatial navigation performance in the healthy elderly and AD patients through use of the Floor Maze Test (FMT)- an easy-to-apply two-dimensional (2D) maze- and determine which cognitive and functional capacities were associated with performance in this task.

METHODS: The FMT was administered to 24 AD patients and 36 healthy controls. Spatial navigation was evaluated through the FMT. Functional capacity was evaluated through the Senior Fitness Test battery of tests. Cognitive functions were evaluated through the Mini-Mental State Examination (MMSE), verbal fluency, digit span test, and the Rey Auditory Verbal Learning Test (RAVLT).

RESULTS: The group with AD was significantly slower and presented more errors at all stages of the FMT. Planning Time (PT) performance was associated with cardiorespiratory resistance (Step test) and delayed memory according to the RAVLT (R2 = 0.395, p < 0.001). Performance in the Immediate Maze Time (IMT) and Delayed Maze Time (DMT) was associated with global cognitive status (MMSE) (R2 = 0.509) and delayed memory (R2 = 0.540).

CONCLUSION: Patients with AD present significant spatial navigation deficits. Their performance on the FMT is influenced by cardiorespiratory capacity, memory, and global cognitive function. As exercise helps to improve executive function and functional capacity, future intervention studies should be carried out to analyze the possible effects of physical exercise on spatial navigation.

%B J Alzheimers Dis %V 66 %P 1683-1694 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30507580?dopt=Abstract %R 10.3233/JAD-180819 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Stabilized Low-n Amyloid-β Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat. %A Watremez, William %A Jackson, Joshua %A Almari, Bushra %A McLean, Samantha L %A Grayson, Ben %A Neill, Joanna C %A Fischer, Nicolas %A Allouche, Ahmad %A Koziel, Violette %A Pillot, Thierry %A Harte, Michael K %X

BACKGROUND: With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies.

OBJECTIVE: The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat.

METHODS: Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus).

RESULTS: Acute ICV administration of Aβo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss.

CONCLUSION: Taken together the results suggest that acute administration of soluble low-n Aβo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology.

%B J Alzheimers Dis %V 62 %P 213-226 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439327?dopt=Abstract %R 10.3233/JAD-170489 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Statins and Brain Health: Alzheimer's Disease and Cerebrovascular Disease Biomarkers in Older Adults. %A Ramanan, Vijay K %A Przybelski, Scott A %A Graff-Radford, Jonathan %A Castillo, Anna M %A Lowe, Val J %A Mielke, Michelle M %A Roberts, Rosebud O %A Reid, Robert I %A Knopman, David S %A Jack, Clifford R %A Petersen, Ronald C %A Vemuri, Prashanthi %X

BACKGROUND: Statins have been proposed to reduce the risk of Alzheimer's disease (AD).

OBJECTIVE: Assess whether long-term statin use was associated with neuroimaging biomarkers of aging and dementia.

METHODS: Methods: We analyzed neuroimaging biomarkers in 1,160 individuals aged 65+ from the Mayo Clinic Study of Aging, a population-based prospective longitudinal study of cognitive aging.

RESULTS: Statin-treated (5+ years of therapy) individuals had greater burden of mid-and late-life cardiovascular disease (p < 0.001) than statin-untreated (≤3 months) individuals. Lower fractional anisotropy in the genu of the corpus callosum, an early marker of cerebrovascular disease, was associated with long-term statin exposure (p < 0.035). No significant associations were identified between long-term statin exposure and cerebral amyloid or tau burden, AD pattern neurodegeneration, or white matter hyperintensity burden.

CONCLUSIONS: Long-term statin therapy was not associated with differences in AD biomarkers. Individuals with long-term statin exposure had worse white matter integrity in the genu of the corpus callosum, consistent with the coexistence of higher cerebrovascular risk factor burden in this group.

%B J Alzheimers Dis %V 65 %P 1345-1352 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149450?dopt=Abstract %R 10.3233/JAD-180446 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Stereological Investigation of the Effects of Treadmill Running Exercise on the Hippocampal Neurons in Middle-Aged APP/PS1 Transgenic Mice. %A Chao, Fenglei %A Jiang, Lin %A Zhang, Yi %A Zhou, Chunni %A Zhang, Lei %A Tang, Jing %A Liang, Xin %A Qi, Yingqiang %A Zhu, Yanqing %A Ma, Jing %A Tang, Yong %X

The risk of cognitive decline during Alzheimer's disease (AD) can be reduced if physical activity is maintained; however, the specific neural events underlying this beneficial effect are still uncertain. To quantitatively investigate the neural events underlying the effect of running exercise on middle-aged AD subjects, 12-month-old male APP/PS1 mice were randomly assigned to a control group or running group, and age-matched non-transgenic littermates were used as a wild-type group. AD running group mice were subjected to a treadmill running protocol (regular and moderate intensity) for four months. Spatial learning and memory abilities were assessed using the Morris water maze. Hippocampal amyloid plaques were observed using Thioflavin S staining and immunohistochemistry. Hippocampal volume, number of neurons, and number of newborn cells (BrdU+ cells) in the hippocampus were estimated using stereological techniques, and newborn neurons were observed using double-labelling immunofluorescence. Marked neuronal loss in both the CA1 field and dentate gyrus (DG) and deficits in both the neurogenesis and survival of new neurons in the DG of middle-aged APP/PS1 mice were observed. Running exercise could improve the spatial learning and memory abilities, reduce amyloid plaques in the hippocampi, delay neuronal loss, induce neurogenesis, and promote the survival of newborn neurons in the DG of middle-aged APP/PS1 mice. Exercise-induced protection of neurons and adult neurogenesis within the DG might be part of the important structural basis of the improved spatial learning and memory abilities observed in AD mice.

%B J Alzheimers Dis %V 63 %P 689-703 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689723?dopt=Abstract %R 10.3233/JAD-171017 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Stereological Quantification of Plaques and Tangles in Neocortex from Alzheimer's Disease Patients. %A Madsen, Jes Buster %A Folke, Jonas %A Pakkenberg, Bente %X

We estimated by stereological methods the neocortical volume occupied by plaques and tangles in females dying with severe Alzheimer's disease (AD), age-matched female subjects with severe vascular dementia (VaD), and normal control brains. Stereological investigations include a uniform sampling of the tissue in the whole of neocortex and its subdivisions. Resultant volume estimates provide information about the overall burden of these two pathological changes and their volume fractions and allow for correlational studies between the pathological changes and factors such as the total neocortical neuronal cell numbers, dementia test scores, and age. We estimated the volume of plaques and tangles in the entire neocortex and frontal-, temporal-, parietal-, and occipital cortex in nine female AD brains, four female patients dying with VaD, and six neurologically normal female control brains using point-counting in uniform samples of neocortex. The volume occupied by plaques comprised approximately 1% of neocortex, while the neocortical tangles made up approximately 0.1% of neocortex of AD patients but were scarcely present in the other study groups. The individual tangle and plaque volumes did not correlate to the ultimate dementia score of the AD subjects, despite correlating with reduced neocortical volume. In neocortex of AD patients, the burden of plaques and tangles is much higher than that in patients with severe vascular dementia or normal older women but only occupy a small fraction of the neocortical volume.

%B J Alzheimers Dis %V 64 %P 723-734 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914026?dopt=Abstract %R 10.3233/JAD-180105 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Stimulation of SIRT1 Attenuates the Level of Oxidative Stress in the Brains of APP/PS1 Double Transgenic Mice and in Primary Neurons Exposed to Oligomers of the Amyloid-β Peptide. %A Dong, Yang-Ting %A Cao, Kun %A Tan, Long-Chun %A Wang, Xiao-Ling %A Qi, Xiao-Lan %A Xiao, Yan %A Guan, Zhi-Zhong %X

In the study, we examined whether the silent information regulator 1 (SIRT1) can attenuate oxidative stress in the brains of mice carrying the APP/PS1 double mutation and/or in primary neonatal rat neurons exposed to oligomers of amyloid-β peptide (AβOs). Starting at 4 or 8 months of age, the transgenic mice were treated with resveratrol (RSV, a stimulator of SIRT1) or suramin (an inhibitor) (each 20 mg/kg BW/day) for two months. The primary neurons were exposed to AβOs (0.5 μM) for 48 h and thereafter RSV (20 μM) or suramin (300 mg/ml) for 24 h. Cell viability was assessed by the CCK-8 assay; SIRT1 protein and mRNA determined by western blotting and real-time PCR, respectively; senile plaques examined immunohistochemically; ROS monitored by flow cytometry; and the contents of OH-, H2O2, O2·-, and MDA, and the activities of SOD and GSH-Px measured by standard biochemical procedures. In comparison to wild-type mice or untreated primary neurons, the expression of SIRT1 was significantly lower in the brains of APP/PS1 mice or neurons exposed to AβOs. In these same systems, increased numbers of senile plaques and a high level of oxidative stress were apparent. Interestingly, these two latter changes were attenuated by treatment with RSV, but enhanced by suramin. These findings indicate that SIRT1 may be neuroprotective.

%B J Alzheimers Dis %V 63 %P 283-301 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614660?dopt=Abstract %R 10.3233/JAD-171020 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Structural Anatomical Investigation of Long-Term Memory Deficit in Behavioral Frontotemporal Dementia. %A Bertoux, Maxime %A Flanagan, Emma C %A Hobbs, Matthew %A Ruiz-Tagle, Amparo %A Delgado, Carolina %A Miranda, Marcelo %A Ibáñez, Agustín %A Slachevsky, Andrea %A Hornberger, Michael %X

Although a growing body of work has shown that behavioral variant frontotemporal dementia (bvFTD) could present with severe amnesia in approximately half of cases, memory assessment is currently the clinical standard to distinguish bvFTD from Alzheimer's disease (AD). Thus, the concept of "relatively preserved episodic memory" in bvFTD remains the basis of its clinical distinction from AD and a criterion for bvFTD's diagnosis. This view is supported by the idea that bvFTD is not characterized by genuine amnesia and hippocampal degeneration, by contrast to AD. In this multicenter study, we aimed to investigate the neural correlates of memory performance in bvFTD as assessed by the Free and Cued Selective Reminding Test (FCSRT). Imaging explorations followed a two-step procedure, first relying on a visual rating of atrophy of 35 bvFTD and 34 AD patients' MRI, contrasted with 29 controls; and then using voxel-based morphometry (VBM) in a subset of bvFTD patients. Results showed that 43% of bvFTD patients presented with a genuine amnesia. Data-driven analysis on visual rating data showed that, in bvFTD, memory recall & storage performances were significantly predicted by atrophy in rostral prefrontal and hippocampal/perihippocampal regions, similar to mild AD. VBM results in bvFTD (pFWE<0.05) showed similar prefrontal and hippocampal regions in addition to striatal and lateral temporal involvement. Our findings showed the involvement of prefrontal as well as medial/lateral temporal atrophy in memory deficits of bvFTD patients. This contradicts the common view that only frontal deficits explain memory impairment in this disease and plead for an updated view on memory dysfunctions in bvFTD.

%B J Alzheimers Dis %V 62 %P 1887-1900 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614645?dopt=Abstract %R 10.3233/JAD-170771 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Structural Connectivity Alterations Along the Alzheimer's Disease Continuum: Reproducibility Across Two Independent Samples and Correlation with Cerebrospinal Fluid Amyloid-β and Tau. %A Tucholka, Alan %A Grau-Rivera, Oriol %A Falcon, Carles %A Rami, Lorena %A Sánchez-Valle, Raquel %A Lladó, Albert %A Gispert, Juan Domingo %A Molinuevo, José Luis %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Atrophy %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Cohort Studies %K Disease Progression %K Female %K Gray Matter %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Reproducibility of Results %K Spain %K tau Proteins %K White Matter %X

BACKGROUND: Gray matter changes associated with the progression of Alzheimer's disease (AD) have been thoroughly studied. However, alterations in white matter tracts have received less attention, particularly during early or preclinical stages of the disease.

OBJECTIVE: To identify the structural connectivity changes across the AD continuum.

METHODS: We performed probabilistic tractography in a total of 183 subjects on two independent samples that include control (n = 68) and preclinical AD individuals (n = 28), patients diagnosed with mild cognitive impairment (MCI) due to AD (n = 44), and AD patients (n = 43). We compared the connectivity between groups, and with CSF Aβ42 and tau biomarkers.

RESULTS: We observed disconnections in preclinical individuals, mainly located in the temporal lobe. This pattern of disconnection spread to the parietal and frontal lobes at the MCI stage and involved almost all the brain in AD. These findings were not driven by gray matter atrophy.

DISCUSSION: Using tractography, we were able to identify white matter changes between subsequent disease stages and, notably, also in preclinical AD. Therefore, this method may be useful for detecting early and specific brain structural changes during preclinical AD stage.

%B J Alzheimers Dis %V 61 %P 1575-1587 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376852?dopt=Abstract %R 10.3233/JAD-170553 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Study of a Supplement Containing Huperzine A and Curcumin in Dementia Patients and Individuals with Mild Cognitive Impairment. %A Tabira, Takeshi %A Kawamura, Nobutoshi %X

Extracts from Huperzia serrata (HS) function as a cholinesterase inhibitor and a glutamic acid receptor antagonist. We tested a supplement containing HS extracts, curcumin, and others in dementia patients and individuals with mild cognitive impairment (MCI) in an open label study. Most patients with Alzheimer's disease, dementia with Lewy bodies, and MCI individuals exhibited improvements in cognitive functions, as assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale Japanese version. The scores were significantly improved at 6-12 weeks compared with baseline scores (p = 0.007) and at 22-28 weeks (p = 0.004). Thus, this supplement may be administered to dementia patients as well as MCI individuals.

%B J Alzheimers Dis %V 63 %P 75-78 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614668?dopt=Abstract %R 10.3233/JAD-171154 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Study of Amyloid-β and Phosphotau in Plaques and Neurons in the Hippocampus of Alzheimer's Disease Patients. %A Furcila, Diana %A DeFelipe, Javier %A Alonso-Nanclares, Lidia %X

The main pathological hallmarks in Alzheimer's disease (AD) are the presence of extracellular amyloid plaques, primarily consisting of amyloid-β (Aβ) peptide, and the accumulation of paired helical filaments of hyperphosphorylated tau protein (PHF-Tau) within neurons. Since CA1 is one of the most affected regions in AD, mainly at early stages, we have performed a detailed analysis of the CA1 region from 11 AD patients (demented and clinically similar; Braak stages IV-VI) to better understand the possible relationship between the presence and distribution of different neurochemical types of Aβ plaques and PHF-Tau immunoreactive  (- ir)  neurons. Hence, we have examined hippocampal sections in confocal microscopy images from double and triple-immunostained sections, to study labeled plaques and PHF-Tau-ir neurons using specific software tools. There are four main findings in the present study. First, the pyramidal layer of proximal CA1 (close to CA2) contains the smallest number of both plaques and PHF-Tau-ir neurons. Second, a large proportion of Aβ-ir plaques were also characterized by the presence of PHF-Tau-ir. Third, all plaques containing one of the two PHF-Tau isoforms also express the other isoform, that is, if a plaque contains PHFpS396, it also contains PHFAT8, and vice versa. Fourth, the coexpression study of both PHF-Tau isoforms in CA1 neurons revealed that most of the labeled neurons express only PHFpS396. Our findings further support the idea that AD is not a unique entity even within the same neuropathological stage, since the microanatomical/neurochemical changes that occur in the hippocampus greatly vary from one patient to another.

%B J Alzheimers Dis %V 64 %P 417-435 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914033?dopt=Abstract %R 10.3233/JAD-180173 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Subjective Cognitive Decline and APOE ɛ4: A Systematic Review. %A Ali, Jordan I %A Smart, Colette M %A Gawryluk, Jodie R %X

Individuals with subjective cognitive decline (SCD) report self-perceived declines in cognitive function but perform within normal limits on standardized tests. However, for some, these self-perceived changes may herald eventual decline to Alzheimer's disease (AD). In light of this, the relationship between SCD and APOE ɛ4, a known genetic risk factor for AD, has garnered interest; however, no systematic review of this literature exists. The current review (n = 36 articles) examined the prevalence of APOE ɛ4 in SCD samples relative to healthy and objectively impaired samples, and summarized APOE ɛ4-related risk of conversion from SCD to AD. Univariate ANOVA indicated that APOE ɛ4 frequency was comparable between healthy control and SCD samples, yet significantly higher in objectively impaired samples (i.e., MCI, AD) relative to either of these groups. Narrative review provided mixed evidence linking coincident APOE ɛ4-positive genotype and SCD to structural neuropathology. Though there was little evidence to suggest that APOE ɛ4 predisposes individuals to developing SCD, both APOE ɛ4 and SCD were found to confer individual and multiplicative risk of conversion to objective cognitive impairment. Combined, it is likely that a relationship between APOE ɛ4, SCD, and AD exists, though its exact nature remains undetermined. A clearer understanding of these relationships is hindered by a lack of standardization in SCD classification and a dearth of longitudinal outcome research. Wide-scale adoption of genetic screening for dementia risk in persons with SCD is considered premature at this time. Ethical considerations and clinical implications of genetic testing for dementia risk are discussed.

%B J Alzheimers Dis %V 65 %P 303-320 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040718?dopt=Abstract %R 10.3233/JAD-180248 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Subjective Cognitive Decline Is Associated with Greater White Matter Hyperintensity Volume. %A van Rooden, Sanneke %A van den Berg-Huysmans, Annette A %A Croll, Pauline H %A Labadie, Gerda %A Hayes, Jessica M %A Viviano, Raymond %A van der Grond, Jeroen %A Rombouts, Serge A R B %A Damoiseaux, Jessica S %X

BACKGROUND: Research in older adults with subjective cognitive decline (SCD) has mainly focused on Alzheimer's disease (AD)-related MRI markers, such as hippocampal volume. However, small vessel disease (SVD) is currently established as serious comorbidity in dementia and its preliminary stages. It is therefore important to examine SVD markers in addition to AD markers in older adults presenting with SCD.

OBJECTIVE: The aim of our study was to elucidate the role of SVD markers in late middle-aged to older adults with and without SCD in addition to the commonly found role of AD markers (hippocampal volume).

METHODS: 67 healthy late middle-aged to older adults participated in this study (mean age 68 years); 25 participants with SCD and 42 participants without SCD. We evaluated quantitative as well as qualitative AD markers (i.e., hippocampal volume and medial temporal lobe atrophy (MTA) scale) and SVD markers (i.e., white matter hyperintensities (WMH) volume, Fazekas scale, microbleeds, and lacunar infarcts), and neuropsychological function and amount of memory complaints.

RESULTS: We found a significant effect of SCD on hippocampal atrophy, as assessed using the MTA scale, but not on hippocampal volume. In addition, we found a significant effect of SCD, and amount of memory complaints, on WMH volume and Fazekas score, suggesting larger WMH volumes in participants with SCD.

CONCLUSION: SVD MRI markers are related to amount of memory complaints, in addition to the commonly observed AD MRI markers, as demonstrated by the greater WMHs in healthy late middle-aged to older adults with SCD.

%B J Alzheimers Dis %V 66 %P 1283-1294 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412485?dopt=Abstract %R 10.3233/JAD-180285 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Subjective Cognitive Decline, Objective Cognition, and Depression in Older Hispanics Screened for Memory Impairment. %A Zlatar, Zvinka Z %A Muniz, Martha C %A Espinoza, Sarah G %A Gratianne, Roberto %A Gollan, Tamar H %A Galasko, Douglas %A Salmon, David P %X

Subjective cognitive decline (SCD) is common in older adults and may be an early marker of future cognitive decline. Research suggest that SCD is more closely related to concurrent symptoms of depression than to objective cognitive performance in non-Hispanic Whites, but it is unknown whether the associations of SCD, cognition, and depression manifest differently in Hispanic older adults. We examined if SCD is associated with objective cognitive performance or with depression symptoms in 145 Hispanic individuals ages 60 or older referred by community health clinics for screening of cognitive complaints. All participants lived near the U.S.-Mexico border, spoke Spanish only, or were Spanish-English bilingual. Memory-only and global cognitive composites were created from scores on Spanish versions of several neuropsychological tests. The Geriatric Depression Scale (GDS) and a five-item SCD questionnaire developed by our group were also completed. Multiple regression analyses showed no significant associations between SCD and memory or global cognitive composite scores after adjusting for age, sex, education, and GDS score. In contrast, there was a significant association between GDS and SCD after adjusting for age, sex, education, global and memory composite scores. Findings suggest that SCD does not accurately reflect current cognitive status in older Hispanics who present to their primary care physician with cognitive complaints. Clinicians should interpret SCD in this population within the context of information about symptoms of depression. Longitudinal research is needed in older Hispanics to better characterize SCD in this population and to determine if it can predict future cognitive decline.

%B J Alzheimers Dis %V 63 %P 949-956 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689718?dopt=Abstract %R 10.3233/JAD-170865 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Subjective Cognitive Decline Prediction of Mortality: Results from the Einstein Aging Study. %A Katz, Mindy J %A Wang, Cuiling %A Derby, Carol A %A Lipton, Richard B %A Zimmerman, Molly E %A Sliwinski, Martin J %A Rabin, Laura A %X

BACKGROUND: The relation of pre-dementia stages to mortality has not been fully explored. Previous work examining subjective cognitive decline (SCD) and mortality is limited and mixed regarding methods used and consistency of findings.

OBJECTIVE: To examine SCD and mortality in a longitudinal, community-based cohort, using item response theory (IRT) methodology to form a composite SCD measure. Also, to assess whether this relationship was independent of clinical cognitive status.

METHODS: The Einstein Aging Study is a diverse longitudinal cohort of adults aged ≥70. SCD items were extracted from baseline CERAD questionnaires and a composite score was formed using IRT methodology. A total of 1,741 participants with complete data were clinically diagnosed as cognitively normal, or as having amnestic mild cognitive impairment (aMCI), nonamnestic mild cognitive impairment (naMCI), or dementia. 645 deaths occurred over a period of 8,912 person-years of follow-up. Cox proportional hazard models predicted time to death adjusting for covariates.

RESULTS: A one standard deviation unit increase in level of SCD was associated with >20% higher risk of mortality. However, when models were adjusted for clinical cognitive status, the association was no longer significant. Both dementia and aMCI predicted mortality. Furthermore, when analyses focused only on those without cognitive impairment, SCD level did not predict mortality.

CONCLUSIONS: The association of SCD with mortality may be due to the association of SCD with clinical cognitive status. Thus, SCD may be used as a community-based screen to initially identify those with cognitive impairment who may be at greatest risk for death.

%B J Alzheimers Dis %V 66 %P 239-248 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282356?dopt=Abstract %R 10.3233/JAD-180335 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Subjective Sleep Quality is not Associated with Incident Dementia: The Rotterdam Study. %A Lysen, Thom S %A Wolters, Frank J %A Luik, Annemarie I %A Ikram, M Kamran %A Tiemeier, Henning %A Ikram, M Arfan %X

BACKGROUND: Poor sleep is related to higher dementia risk, but this association is more equivocal for subjective sleep quality specifically. This study investigates the link between subjective sleep quality and dementia risk in the general population.

OBJECTIVE: To study the role of subjective sleep quality in the risk of dementia in the general population.

METHODS: In the prospective population-based Rotterdam Study, 4,835 persons (mean age 72 years, 58% women) underwent a home interview (2002- 2006) that included the validated Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality. Participants were followed until 2015 for incident dementia, through in-person screening and continuous monitoring of medical records. We used Cox regression models to associate sleep quality with dementia risk, adjusting for age, sex, education, smoking, employment, coffee consumption, alcohol consumption, activities of daily living, cardiovascular risk factors, anxiety, depressive symptoms, cognition, and snoring.

RESULTS: During 41,385 person-years (8.5 years mean), 420 participants developed dementia, of whom 320 Alzheimer's disease (AD). Poorer subjective sleep quality was not associated with the risk of all-cause dementia (hazard ratio [HR] per SD increase in PSQI score: 0.91, 95% CI 0.82- 1.02) or AD (HR 0.92, 95% CI 0.81- 1.05). Similarly, individual components of the PSQI were also not associated with dementia. Several sensitivity analyses, i.e., excluding last years of the follow-up time duration or restricting to those with best MMSE scores at baseline, did not reveal subgroups with increased risks.

CONCLUSION: In this study, we found no association of poor subjective sleep quality with higher risk of dementia.

%B J Alzheimers Dis %V 64 %P 239-247 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865066?dopt=Abstract %R 10.3233/JAD-180055 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Subtle Cognitive Impairment and Alzheimer's Disease-Type Pathological Changes in Cerebrospinal Fluid are Common Among Neurologically Healthy Subjects. %A Haapalinna, Fanni %A Kokki, Merja %A Jääskeläinen, Olli %A Hallikainen, Merja %A Helisalmi, Seppo %A Koivisto, Anne %A Kokki, Hannu %A Paajanen, Teemu %A Penttinen, Janne %A Pikkarainen, Maria %A Rautiainen, Minna %A Soininen, Hilkka %A Solje, Eino %A Remes, Anne M %A Herukka, Sanna-Kaisa %X

BACKGROUND: The neuropathology of Alzheimer's disease (AD) has previously been shown to be rather common among the elderly.

OBJECTIVE: The aim of this study was to inspect the associations between cerebrospinal fluid (CSF) AD biomarker concentrations, age, the APOEɛ4 allele, cardiovascular diseases, diabetes, and cognitive performance in a cohort of a neurologically healthy population.

METHODS: This study included 93 subjects (42 men, mean age 67 years) without previous neurological symptoms or subjective cognitive complaints. Their cognition was assessed, and CSF biomarkers and APOEɛ4 status were analyzed.

RESULTS: Of the studied subjects, 8.6% (n = 8) had a pathological CSF AD biomarker profile. An increase in age correlated positively with CSF tau pathology and negatively with global cognitive performance.

CONCLUSION: AD-type pathological changes in CSF and subtle cognitive impairment are common within a population with no previous memory complaints. Age was the main risk factor for the changes.

%B J Alzheimers Dis %V 62 %P 165-174 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439329?dopt=Abstract %R 10.3233/JAD-170534 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Subtypes Based on Neuropsychological Performance Predict Incident Dementia: Findings from the Rush Memory and Aging Project. %A Zammit, Andrea R %A Muniz-Terrera, Graciela %A Katz, Mindy J %A Hall, Charles B %A Ezzati, Ali %A Bennett, David A %A Lipton, Richard B %X

BACKGROUND: In a previous report, we used latent class analysis (LCA) to identify natural subgroups of older adults in the Einstein Aging Study (EAS) based on neuropsychological performance. These subgroups differed in demographics, genetic profile, and prognosis. Herein, we assess the generalizability of these findings to an independent sample, the Rush Memory and Aging Project (MAP), which used an overlapping, but distinct neuropsychological battery.

OBJECTIVE: Our aim was to identify the association of natural subgroups based on neuropsychological performance in the MAP cohort with incident dementia and compare them with the associations identified in the EAS.

METHODS: MAP is a community-dwelling cohort of older adults living in the northeastern Illinois, Chicago. Latent class models were applied to baseline scores of 10 neuropsychological measures across 1,662 dementia-free MAP participants. Results were compared to prior findings from the EAS.

RESULTS: LCA resulted in a 5-class model: Mixed-Domain Impairment (n = 71, 4.3%), Memory-specific-Impairment (n = 274, 16.5%), Average (n = 767, 46.1%), Frontal Impairment (n = 222, 13.4%), and a class of Superior Cognition (n = 328, 19.7%). Similar to the EAS, the Mixed-Domain Impairment, the Memory-Specific Impairment, and the Frontal Impairment classes had higher risk of incident Alzheimer's disease when compared to the Average class. By contrast, the Superior Cognition had a lower risk of Alzheimer's disease when compared to the Average class.

CONCLUSIONS: Natural cognitive subgroups in MAP are similar to those identified in EAS. These similarities, despite study differences in geography, sampling strategy, and cognitive tests, suggest that LCA is capable of identifying classes that are not limited to a single sample or a set of cognitive tests.

%B J Alzheimers Dis %8 2018 Nov 29 %G eng %R 10.3233/JAD-180737 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Sulforaphane Inhibits the Generation of Amyloid-β Oligomer and Promotes Spatial Learning and Memory in Alzheimer's Disease (PS1V97L) Transgenic Mice. %A Hou, Ting-Ting %A Yang, He-Yun %A Wang, Wei %A Wu, Qiao-Qi %A Tian, Yuan-Ruhua %A Jia, Jian-Ping %X

Abnormal amyloid-β (Aβ) aggregates are a striking feature of Alzheimer's disease (AD), and Aβ oligomers have been proven to be crucial in the pathology of AD. Any intervention targeting the generation or aggregation of Aβ can be expected to be useful in AD treatment. Oxidative stress and inflammation are common pathological changes in AD that are involved in the generation and aggregation of Aβ. In the present study, 6-month-old PS1V97L transgenic (Tg) mice were treated with sulforaphane, an antioxidant, for 4 months, and this treatment significantly inhibited the generation and aggregation of Aβ. Sulforaphane also alleviated several downstream pathological changes that including tau hyperphosphorylation, oxidative stress, and neuroinflammation. Most importantly, the cognition of the sulforaphane-treated PS1V97L Tg mice remained normal compared to that of wild-type mice at 10 months of age, when dementia typically emerges in PS1V97L Tg mice. Pretreating cultured cortical neurons with sulforaphane also protected against neuronal injury caused by Aβ oligomers in vitro. These findings suggest that sulforaphane may be a potential compound that can inhibit Aβ oligomer production in AD.

%B J Alzheimers Dis %V 62 %P 1803-1813 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614663?dopt=Abstract %R 10.3233/JAD-171110 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Supplemental Retinal Carotenoids Enhance Memory in Healthy Individuals with Low Levels of Macular Pigment in A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. %A Power, Rebecca %A Coen, Robert F %A Beatty, Stephen %A Mulcahy, Riona %A Moran, Rachel %A Stack, Jim %A Howard, Alan N %A Nolan, John M %K Adult %K Cognition %K Dietary Supplements %K Double-Blind Method %K Executive Function %K Female %K Healthy Volunteers %K Humans %K Lutein %K Macular Pigment %K Male %K Memory, Episodic %K Middle Aged %K Retina %K Vision Tests %K Zeaxanthins %X

BACKGROUND: There is a biologically plausible rationale whereby the dietary carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), which are collectively referred to as macular pigment (MP) in the central retina (macula), support the maintenance of cognition via their antioxidant and anti-inflammatory properties.

OBJECTIVE: To investigate the impact of supplemental L, Z, and MZ on memory, executive function, and verbal fluency among healthy individuals with low MP levels.

METHODS: In this double-blind, placebo-controlled, randomized clinical trial, subjects (n = 91; mean±SD age = 45.42±12.40; % male = 51.6) consumed a daily formulation of 10 mg L, 10 mg MZ, and 2 mg Z (n = 45) or placebo (n = 46) for 12 months. Cognitive domains assessed included verbal and visual learning, immediate and delayed memory, executive function, and verbal fluency. MP and serum carotenoid concentrations of L, Z, and MZ were also measured.

RESULTS: Following 12-month supplementation, individuals in the active group exhibited statistically significant improvements in memory when compared to the placebo group (paired associated learning [PAL] memory score [rANOVA, p = 0.009]; PAL errors [rANOVA, p = 0.017]). Furthermore, the observed reduction in the number of errors made in the PAL task among those in the intervention group was positively and significantly related to observed increases in MP volume (p = 0.005) and observed increases in serum concentrations of L (p = 0.009).

CONCLUSION: This randomized, double-blind, placebo-controlled clinical trial demonstrates a memory-enhancing effect of daily supplementation with L, Z, and MZ in healthy subjects with low MP at baseline. The implications of these findings for intellectual performance throughout life, and for risk of cognitive decline in later life, warrant further study.

%B J Alzheimers Dis %V 61 %P 947-961 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332050?dopt=Abstract %R 10.3233/JAD-170713 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Survey of Patient and Partner Outcome and Treatment Preferences in Mild Cognitive Impairment. %A Smith, Glenn E %A Chandler, Melanie %A Fields, Julie A %A Aakre, Jeremiah %A Locke, Dona E C %X

BACKGROUND: The patient-centered movement in health care is increasing efforts to design studies and interventions that address the outcomes that matter most to patients and their families. Research has not adequately addressed Alzheimer's disease patient and caregiver preferences.

OBJECTIVE: To survey the outcome and treatment preferences of patients and caregivers who had completed a multicomponent behavioral intervention for mild cognitive impairment (MCI).

METHODS: Extending prior work, we conducted an online survey regarding outcome and intervention preferences. Participants were patients with MCI and partners who completed the HABIT Healthy Action to Benefit Independence & Thinking ® program.

RESULTS: Both patient and partner respondents ranked patient quality of life as the highest priority, followed by patient self-efficacy, functional status, patient mood, and patient memory performance. Distressing behaviors and caregiver outcomes (burden, mood, and self-efficacy) had low rankings. Regarding the importance of HABIT ® program components, memory compensation training was ranked highest and wellness education lowest by all groups.

CONCLUSION: Additional research should compare patient preference for patient reported outcomes, traditional neuropsychological and clinician outcomes, and modern biomarker outcomes.

%B J Alzheimers Dis %V 63 %P 1459-1468 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843239?dopt=Abstract %R 10.3233/JAD-171161 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Sweet Mitochondria: A Shortcut to Alzheimer's Disease. %A Moreira, Paula I %X

A growing body of evidence supports a clear association between Alzheimer's disease and diabetes and several mechanistic links have been revealed. This paper is mainly devoted to the discussion of the role of diabetes-associated mitochondrial defects in the pathogenesis of Alzheimer's disease. The research experience and views of the author on this subject will be highlighted.

%B J Alzheimers Dis %V 62 %P 1391-1401 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562542?dopt=Abstract %R 10.3233/JAD-170931 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Synergistic Protective Effects of Mitochondrial Division Inhibitor 1 and Mitochondria-Targeted Small Peptide SS31 in Alzheimer's Disease. %A Reddy, P Hemachandra %A Manczak, Maria %A Yin, XiangLing %A Reddy, Arubala P %X

The purpose of our study was to determine the synergistic protective effects of mitochondria-targeted antioxidant SS31 and mitochondria division inhibitor 1 (Mdivi1) in Alzheimer's disease (AD). Using biochemical methods, we assessed mitochondrial function by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity, mitochondrial ATP, and GTPase Drp1 enzymatic activity in mutant AβPP cells. Using biochemical methods, we also measured cell survival and apoptotic cell death. Amyloid-β (Aβ) levels were measured using sandwich ELISA, and using real-time quantitative RT-PCR, we assessed mtDNA (mtDNA) copy number in relation to nuclear DNA (nDNA) in all groups of cells. We found significantly reduced levels of Aβ40 and Aβ42 in mutant AβPP cells treated with SS31, Mdivi1, and SS31+Mdivi1, and the reduction of Aβ42 levels were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. The levels of mtDNA copy number and cell survival were significantly increased in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AβPP cells; however, the increased levels of mtDNA copy number and cell survival were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. Mitochondrial dysfunction is significantly reduced in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AβPP cells; however, the reduction is much higher in cells treated with both SS31+Mdvi1. Similarly, GTPase Drp1 activity is reduced in all treatments, but reduced much higher in SS31+Mdivi1 treated cells. These observations strongly suggest that combined treatment of SS31+Mdivi1 is effective than individual treatments of SS31 and Mdivi1. Therefore, we propose that combined treatment of SS31+Mdivi1 is a better therapeutic strategy for AD. Ours is the first study to investigate combined treatment of mitochondria-targeted antioxidant SS31 and mitochondrial division inhibitor 1 in AD neurons.

%B J Alzheimers Dis %V 62 %P 1549-1565 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29400667?dopt=Abstract %R 10.3233/JAD-170988 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Synthetic Fragment of Receptor for Advanced Glycation End Products Prevents Memory Loss and Protects Brain Neurons in Olfactory Bulbectomized Mice. %A Volpina, Olga M %A Samokhin, Alexandr N %A Koroev, Dmitriy O %A Nesterova, Inna V %A Volkova, Tatyana D %A Medvinskaya, Natalia I %A Nekrasov, Pavel V %A Tatarnikova, Olga G %A Kamynina, Anna V %A Balasanyants, Samson M %A Voronina, Tamara A %A Kulikov, Alexey M %A Bobkova, Natalia V %K Administration, Intranasal %K Animals %K Behavior, Animal %K Brain %K Disease Models, Animal %K Male %K Maze Learning %K Memory Disorders %K Mice %K Mice, Transgenic %K Neurons %K Olfactory Bulb %K Peptide Fragments %K Receptor for Advanced Glycation End Products %X

Activation of receptor for advanced glycation end products (RAGE) plays an essential role in the development of Alzheimer's disease (AD). It is known that the soluble isoform of the receptor binds to ligands and prevents negative effects of the receptor activation. We proposed that peptide fragments from RAGE prevent negative effects of the receptor activation during AD neurodegeneration. We have synthesized peptide fragments from surface-exposed regions of RAGE. Peptides were intranasally administrated into olfactory bulbectomized (OBX) mice, which developed some characteristics similar to AD neurodegeneration. We have found that only insertion of fragment (60-76) prevents the memory of OBX mice. Immunization of OBX mice with peptides showed that again only (60-76) peptide protected the memory of animals. Both intranasal insertion and immunization decreased the amyloid-β (Aβ) level in the brain. Activity of shortened fragments of (60-76) peptide was tested and showed only the (60-70) peptide is responsible for manifestation of activity. Intranasal administration of (60-76) peptide shows most protective effect on morpho-functional characteristics of neurons in the cortex and hippocampal areas. Using Flu-(60-76) peptide, we revealed its penetration in the brain of OBX mice as well as colocalization of Flu-labeled peptide with Aβ in the brain regions in transgenic mice. Flu-(60-76) peptide complex with trimer of Aβ was detected by SDS-PAGE. These data indicate that Aβ can be one of the molecular target of (60-70) peptide. These findings provide a new peptide molecule for design of anti-AD drug and for investigation of RAGE activation ways in progression of AD neurodegeneration.

%B J Alzheimers Dis %V 61 %P 1061-1076 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332040?dopt=Abstract %R 10.3233/JAD-170483 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Systematic Review and Aggregated Analysis on the Impact of Amyloid PET Brain Imaging on the Diagnosis, Diagnostic Confidence, and Management of Patients being Evaluated for Alzheimer's Disease. %A Fantoni, Enrico R %A Chalkidou, Anastasia %A O' Brien, John T %A Farrar, Gill %A Hammers, Alexander %X

BACKGROUND: Amyloid PET (aPET) imaging could improve patient outcomes in clinical practice, but the extent of impact needs quantification.

OBJECTIVE: To provide an aggregated quantitative analysis of the value added by aPET in cognitively impaired subjects.

METHODS: Systematic literature searches were performed in Embase and Medline until January 2017. 1,531 cases over 12 studies were included (1,142 cases over seven studies in the primary analysis where aPET was the key biomarker; the remaining cases included as defined groups in the secondary analysis). Data was abstracted by consensus among two observers and assessed for bias. Clinical utility was measured by diagnostic change, diagnostic confidence, and patient management before and after aPET. Three groups were further analyzed: control patients for whom feedback of aPET scan results was delayed; aPET Appropriate Use Criteria (AUC+) cases; and patients undergoing additional FDG/CSF testing.

RESULTS: For 1,142 cases with only aPET, 31.3% of diagnoses were revised, whereas 3.2% of diagnoses changed in the delayed aPET control group (p < 0.0001). Increased diagnostic confidence following aPET was found for 62.1% of 870 patients. Management changes with aPET were found in 72.2% of 740 cases and in 55.5% of 299 cases in the control group (p < 0.0001). The diagnostic value of aPET in AUC+ patients or when FDG/CSF were additionally available did not substantially differ from the value of aPET alone in the wider population.

CONCLUSIONS: Amyloid PET contributed to diagnostic revision in almost a third of cases and demonstrated value in increasing diagnostic confidence and refining management plans.

%B J Alzheimers Dis %V 63 %P 783-796 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689725?dopt=Abstract %R 10.3233/JAD-171093 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Systematic Review and Meta-Analysis on the Prevalence of Dementia in Europe: Estimates from the Highest-Quality Studies Adopting the DSM IV Diagnostic Criteria. %A Bacigalupo, Ilaria %A Mayer, Flavia %A Lacorte, Eleonora %A Di Pucchio, Alessandra %A Marzolini, Fabrizio %A Canevelli, Marco %A Di Fiandra, Teresa %A Vanacore, Nicola %X

BACKGROUND: Dementia, including Alzheimer's disease (AD), is one of the most burdensome medical conditions. Usually, the reviews that aim at calculating the prevalence of dementia include estimates from studies without assessing their methodological quality. Alzheimer's Disease International (ADI) proposed a score to assess the methodological quality of population-based studies aimed at estimating the prevalence of dementia. During the last three years, the European Commission has funded three projects (Eurodem, EuroCoDe, and ALCOVE) in order to estimate the prevalence of dementia in Europe.

OBJECTIVE: The aim of this study was to perform a systematic review and meta-analysis of data on the prevalence of dementia in Europe derived from studies that included only subjects with a diagnosis of dementia according to the DSM IV criteria, and that had a high quality score according to ADI criteria.

METHODS: We considered the studies selected by the two projects EuroCoDe (1993-2007) and Alcove (2008-2011), and we performed a new bibliographic search. For the systematic review, we only selected the subset of articles that included subjects with a diagnosis of dementia according to the DSM IV criteria. The studies were qualitatively assessed using the ADI tool.

RESULTS: The meta-analysis considered 9 studies that were carried out in Europe between 1993 and 2018 including a total of 18,263 participants, of which 2,137 were diagnosed with dementia. The prevalence rate standardized for age and sex resulted 7.1%.

DISCUSSION: This is the first systematic review on the prevalence of dementia in Europe considering only high-quality studies adopting the same diagnostic criteria (i.e., DSM IV).

%B J Alzheimers Dis %V 66 %P 1471-1481 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412486?dopt=Abstract %R 10.3233/JAD-180416 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Targeted Assessment of Enlargement of the Perivascular Space in Alzheimer's Disease and Vascular Dementia Subtypes Implicates Astroglial Involvement Specific to Alzheimer's Disease. %A Boespflug, Erin L %A Simon, Matthew J %A Leonard, Emmalyn %A Grafe, Marjorie %A Woltjer, Randall %A Silbert, Lisa C %A Kaye, Jeffrey A %A Iliff, Jeffrey J %X

Waste clearance from the brain parenchyma occurs along perivascular pathways. Enlargement of the perivascular space (ePVS) is associated with pathologic features of Alzheimer's disease (AD), although the mechanisms and implications of this dilation are unclear. Fluid exchange along the cerebral vasculature is dependent on the perivascular astrocytic water channel aquaporin-4 (AQP4) and loss of perivascular AQP4 localization is found in AD. We directly measured ePVS in postmortem samples of pathologically characterized tissue from participants who were cognitively intact or had AD or mixed dementia (vascular lesions with AD). We found that both AD and mixed dementia groups had significantly increased ePVS compared to cognitively intact subjects. In addition, we found increased global AQP4 expression of the AD group over both control and mixed dementia groups and a qualitative reduction in perivascular localization of AQP4 in the AD group. Among these cases, increasing ePVS burden was associated with the presence of tau and amyloid-β pathology. These findings are consistent with the existing evidence of ePVS in AD and provide novel information regarding differences in AD and vascular dementia and the potential role of astroglial pathology in ePVS.

%B J Alzheimers Dis %V 66 %P 1587-1597 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30475760?dopt=Abstract %R 10.3233/JAD-180367 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Targeting Alzheimer's Disease at the Right Time and the Right Place: Validation of a Personalized Approach to Diagnosis and Treatment. %A Gauthier, Serge %A Ng, Kok Pin %A Pascoal, Tharick A %A Zhang, Hua %A Rosa-Neto, Pedro %X

Cautious optimism is appropriate for a near future (five years) time frame for a number of drugs acting on the different pathophysiological components of Alzheimer's disease (amyloid deposition, tau hyperphosphorylation, neuroinflammation, vascular changes, to name the most important known so far). Since the relative weight of these components will be different between individuals and will even change over time for each individual, a 'one drug fit for all' approach is no longer defensible. Precision medicine using biomarkers in the diagnosis and treatment of Alzheimer's disease is the new strategy.

%B J Alzheimers Dis %V 64 %P S23-S31 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504543?dopt=Abstract %R 10.3233/JAD-179924 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Targeting Insulin for Alzheimer's Disease: Mechanisms, Status and Potential Directions. %A Lee, Jung Hyun %A Jahrling, Jordan B %A Denner, Larry %A Dineley, Kelly T %X

Insulin resistance can occur when the body is unable to respond to insulin even in excess. In the brain, insulin manages glucose metabolism in regions such as the hippocampus and plays a key role in directly regulating ERK, a kinase required for the type of memory compromised in early Alzheimer's disease (AD). Human imaging studies show that brain glucose utilization declines with age and is notably impaired in subjects with early AD. Likewise, animal models of AD or insulin resistance, or both, demonstrate that dysfunctional insulin signaling and insulin resistance in the brain have reciprocity with neuroinflammation and aberrant accumulation of amyloid-β (Aβ), pathological hallmarks in AD. As such, the association between brain insulin activity and AD has led to clinical trials testing the efficacy of insulin and insulin-sensitizing drugs to intervene in AD. Based on recent inquiries to ClinicalTrials.gov, we evaluated thirty-three clinical studies related to AD and insulin. The search filtered for interventional clinical trials to test FDA-approved drugs or substances that impinge upon the insulin signaling pathway. Insulin, metformin, and thiazolidinediones were the three main interventions assessed. Overall, these strategies are expected to negate the effects of brain insulin resistance by targeting insulin signaling pathways involved in neuroinflammation, metabolic homeostasis, synaptic functional and structural integrity. The goal of this review is to provide an update on insulin and ERK signaling in relation to memory, its decline in early AD, and provide an overview of clinical trials related to insulin for early AD intervention.

%B J Alzheimers Dis %V 64 %P S427-S453 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710715?dopt=Abstract %R 10.3233/JAD-179923 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Tau and Amyloid Positron Emission Tomography Imaging Predict Driving Performance Among Older Adults with and without Preclinical Alzheimer's Disease. %A Roe, Catherine M %A Babulal, Ganesh M %A Mishra, Shruti %A Gordon, Brian A %A Stout, Sarah H %A Ott, Brian R %A Carr, David B %A Ances, Beau M %A Morris, John C %A Benzinger, Tammie L S %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Automobile Driving %K Biomarkers %K Carbolines %K Female %K Humans %K Logistic Models %K Male %K Neuroimaging %K Positron-Emission Tomography %K tau Proteins %X

Abnormal levels of Alzheimer's disease (AD) biomarkers, measured by positron emission tomography imaging using amyloid-based radiotracers and cerebrospinal fluid, are associated with impaired driving performance in older adults. We examined whether preclinical AD staging, defined using amyloid imaging and tau imaging using the radiotracer T807 (AKA flortaucipir or AV-1451), was associated with receiving a marginal/fail rating on a standardized road test (n = 42). Participants at Stage 2 (positive amyloid and tau scans) of preclinical AD were more likely to receive a marginal/fail rating compared to participants at Stage 0 or 1. Stage 2 preclinical AD may manifest in worse driving performance.

%B J Alzheimers Dis %V 61 %P 509-513 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171997?dopt=Abstract %R 10.3233/JAD-170521 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Tau Conformation as a Target for Disease-Modifying Therapy: The Role of Truncation. %A Novak, Petr %A Cehlar, Ondrej %A Skrabana, Rostislav %A Novak, Michal %X

Tau protein plays a major role in the pathogenesis of Alzheimer's disease. Despite many decades of intensive research, the cause of the conformational switch that leads to the remodeling of the highly flexible conformational ensemble of intrinsically disordered protein tau into insoluble filaments is still elusive. We show here that truncation of tau may play a causative role in this conformational change, as evidenced by results obtained from in vitro experiments and from transgenic animal models. This conformational change is a common denominator of pathological tau protein assemblies, and a salient drug target. The long-running research of truncated tau has led to the generation of the first active tau vaccine that has entered clinical trials.

%B J Alzheimers Dis %V 64 %P S535-S546 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865059?dopt=Abstract %R 10.3233/JAD-179942 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Tau Immunotherapies for Alzheimer's Disease and Related Tauopathies: Progress and Potential Pitfalls. %A Sigurdsson, Einar M %X

Tau immunotherapies have now advanced from proof-of-concept studies to Phase II clinical trials. This review briefly outlines developments in the field and discusses how these therapies may work, which involves multiple variables that are connected in complex ways. These various factors are likely to define therapeutic success in humans and have not been thoroughly investigated, at least based on published reports.

%B J Alzheimers Dis %V 64 %P S555-S565 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865056?dopt=Abstract %R 10.3233/JAD-179937 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Tau Protein Dysfunction after Brain Ischemia. %A Pluta, Ryszard %A Ułamek-Kozioł, Marzena %A Januszewski, Sławomir %A Czuczwar, Stanisław J %X

Brain ischemia comprises blood-brain barrier, glial, and neuronal cells. The blood-brain barrier controls permeability of different substances and the composition of the neuronal cells 'milieu', which is required for their physiological functioning. Recent evidence indicates that brain ischemia itself and ischemic blood-brain barrier dysfunction is associated with the accumulation of neurotoxic molecules within brain tissue, e.g., different parts of amyloid-β protein precursor and changed pathologically tau protein. All these changes due to ischemia can initiate and progress neurodegeneration of the Alzheimer's disease-type. This review presents brain ischemia and ischemic blood-brain barrier as a trigger for tau protein alterations. Thus, we hypothesize that the changes in pattern of phosphorylation of tau protein are critical to microtubule function especially in neurons, and contribute to the neurodegeneration following brain ischemia-reperfusion episodes with Alzheimer's disease phenotype.

%B J Alzheimers Dis %V 66 %P 429-437 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282370?dopt=Abstract %R 10.3233/JAD-180772 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Tau Proteolysis in the Pathogenesis of Tauopathies: Neurotoxic Fragments and Novel Biomarkers. %A Quinn, James P %A Corbett, Nicola J %A Kellett, Katherine A B %A Hooper, Nigel M %X

With predictions showing that 131.5 million people worldwide will be living with dementia by 2050, an understanding of the molecular mechanisms underpinning disease is crucial in the hunt for novel therapeutics and for biomarkers to detect disease early and/or monitor disease progression. The metabolism of the microtubule-associated protein tau is altered in different dementias, the so-called tauopathies. Tau detaches from microtubules, aggregates into oligomers and neurofibrillary tangles, which can be secreted from neurons, and spreads through the brain during disease progression. Post-translational modifications exacerbate the production of both oligomeric and soluble forms of tau, with proteolysis by a range of different proteases being a crucial driver. However, the impact of tau proteolysis on disease progression has been overlooked until recently. Studies have highlighted that proteolytic fragments of tau can drive neurodegeneration in a fragment-dependent manner as a result of aggregation and/or transcellular propagation. Proteolytic fragments of tau have been found in the cerebrospinal fluid and plasma of patients with different tauopathies, providing an opportunity to develop these fragments as novel disease progression biomarkers. A range of therapeutic strategies have been proposed to halt the toxicity associated with proteolysis, including reducing protease expression and/or activity, selectively inhibiting protease-substrate interactions, and blocking the action of the resulting fragments. This review highlights the importance of tau proteolysis in the pathogenesis of tauopathies, identifies putative sites during tau fragment-mediated neurodegeneration that could be targeted therapeutically, and discusses the potential use of proteolytic fragments of tau as biomarkers for different tauopathies.

%B J Alzheimers Dis %V 63 %P 13-33 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29630551?dopt=Abstract %R 10.3233/JAD-170959 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Tauopathies: Mechanisms and Therapeutic Strategies. %A Tan, Chen-Chen %A Zhang, Xiao-Yan %A Tan, Lan %A Yu, Jin-Tai %K Animals %K Biomarkers %K Brain %K Disease Models, Animal %K Humans %K Neuroimaging %K Phosphorylation %K Positron-Emission Tomography %K tau Proteins %K Tauopathies %X

Tauopathies are morphologically, biochemically, and clinically heterogeneous neurodegenerative diseases defined by the accumulation of abnormal tau proteins in the brain. There is no effective method to prevent and reverse the tauopathies, but this gloomy picture has been changed by recent research advances. Evidences from genetic studies, experimental animal models, and molecular and cell biology have shed light on the main mechanisms of the diseases. The development of radiology and biochemistry, especially the development of PET imaging, will provide important biomarkers for the clinical diagnosis and treatment. Given the central role of tau in tauopathies, many treatments have constantly emerged, including targeting phosphorylation, targeting aggregation, increasing microtubule stabilization, tau immunization, clearance of tau, anti-inflammatory treatment, and other therapeutics. There is still a long way to go before we obtain drug therapy targeted at multifactor mechanisms.

%B J Alzheimers Dis %V 61 %P 487-508 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29278892?dopt=Abstract %R 10.3233/JAD-170187 %0 Journal Article %J J Alzheimers Dis %D 2018 %T TDP-43 and Alzheimer's Disease Pathologic Subtype in Non-Amnestic Alzheimer's Disease Dementia. %A Sahoo, Aradhana %A Bejanin, Alexandre %A Murray, Melissa E %A Tosakulwong, Nirubol %A Weigand, Stephen D %A Serie, Amanda M %A Senjem, Matthew L %A Machulda, Mary M %A Parisi, Joseph E %A Boeve, Bradley F %A Knopman, David S %A Petersen, Ronald C %A Dickson, Dennis W %A Whitwell, Jennifer L %A Josephs, Keith A %X

BACKGROUND: TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer's disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with non-amnestic phenotype is unknown.

OBJECTIVE: To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD.

METHODS: All cases with pathologically confirmed intermediate-high probability AD from 1996-2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features.

RESULTS: Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset (p = 0.02) and age at death (p = 0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43.

CONCLUSION: In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43.

%B J Alzheimers Dis %V 64 %P 1227-1233 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010126?dopt=Abstract %R 10.3233/JAD-180169 %0 Journal Article %J J Alzheimers Dis %D 2018 %T TDP-43 Neuropathologic Associations in the Nun Study and the Honolulu-Asia Aging Study. %A Flanagan, Margaret E %A Cholerton, Brenna %A Latimer, Caitlin S %A Hemmy, Laura S %A Edland, Steven D %A Montine, Kathleen S %A White, Lon R %A Montine, Thomas J %X

Transactive response binding protein-43 (TDP-43) cytoplasmic neuronal and glial aggregates (pathologic TDP-43) have been described in multiple brain diseases. We describe the associations between neuropathologically confirmed TDP-43 and cognition in two population-based cohorts: the Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS). In the HAAS, there was a significant association between hippocampal sclerosis (HS) and TDP-43 (OR = 11.04, p < 0.0001, 95% CI 3.57-34.13). In the NS, there were significant associations between TDP-43 and HS (OR = 16.44, p > 0.001 95%, CI 7.10-38.00) and Alzheimer's disease (AD) severity (OR = 1.74, p = 0.009, 95% CI 1.15-2.64). When cognitive scores were added to the model, HS remained significant but the other variables were not. When HS was removed from the model, the overall model remained significant and the associations between cognitive performance and TDP-43 (OR = 2.11, p = 0.022, 95% CI 1.11-4.02) were significant. In the NS, there was a significant association between cognitive performance and TDP-43 (OR 1.94 p = 0.005, 95% CI 1.22-3.09) (HS remained significant, but AD did not). When HS was removed from the model, only CERAD was significant (OR = 2.43 p < 0.001, 95% CI 1.58-3.74). These results support a consistent association between pathologic TDP-43, HS, and the development of cognitive impairment in two large studies of brain aging, while the relationship between AD pathology and TDP-43 may vary according to cohort-specific features.

%B J Alzheimers Dis %V 66 %P 1549-1558 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30452409?dopt=Abstract %R 10.3233/JAD-180162 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Testamentary Capacity Assessment Tool (TCAT): A Brief Instrument for Patients with Dementia. %A Papageorgiou, Sokratis G %A Voskou, Panagiota %A Economou, Alexandra %A Beratis, Ion %A Douzenis, Athanasios %K Adult %K Aged %K Cognition Disorders %K Dementia %K Female %K Humans %K Male %K Memory %K Mental Competency %K Middle Aged %K Neuropsychological Tests %K Reproducibility of Results %K Sensitivity and Specificity %K Wills %X

BACKGROUND: In current practice, it is common for the medical practitioner to assess a person's testamentary capacity (TC) and give evidence to the Courts about a potential will contest. TC is an advanced cognitive activity that is both situation- and task-specific.

OBJECTIVE: The aim of the present study was the development of a brief, specialized instrument for TC assessment in patients with dementia.

METHOD: We developed a short tool consisting of four subtests, assessing the person's core functions which are required for TC: memory (orientation, autobiographical memory and realistic perception of beneficiaries), absence of serious psychopathology, knowledge of financial parameters (value of assets, everyday life products, bills), and intention (vignettes, theory of mind). For its validation, we examined 64 outpatients from the Cognitive Disorders/Dementia Unit, 2nd Department of Behavioral Neurology, University of Athens. The decision of the expert served as the gold standard for the evaluation of TC.

RESULTS: Of the 64 participants, 39 were judged by the expert as capable of TC and the remaining 25 as incapable. For the total scale (maximum score of 48), the best combination of sensitivity (82.6%) and specificity (100%) was obtained for a cut-off score of 32/33. Cronbach's alpha showed high levels of internal reliability for the scale (α= 0.86) and the point-biserial correlation coefficients showed high levels of criterion-related validity (rbp = 0.797, p < 0.001).

CONCLUSION: The new instrument appears to be a reliable screening tool for the evaluation of TC in dementia, which can be used by both the expert and the non-expert. Further research is needed to confirm these promising findings.

%B J Alzheimers Dis %V 61 %P 985-994 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254082?dopt=Abstract %R 10.3233/JAD-170297 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Testing Hippocampal Memory in Prodromal Dementia with Lewy Bodies. %A Bussè, Cinzia %A Caffarra, Paolo %A Rossi, Alice %A Zorzi, Giovanni %A Fragiacomo, Federica %A Camporese, Giulia %A Pompanin, Sara %A Di Bernardo, Gian Antonio %A Cagnin, Annachiara %X

The Free and Cued Selective Reminding test (FCSRT) was used to assess memory in 19 patients with prodromal dementia with Lewy bodies (DLB) and 25 Alzheimer's disease (AD) patients. DLB scored better than AD in selective measures of the FCSRT: immediate total recall (p = 0.01) and index of sensitivity of cueing (p = 0.001), while free delayed and total memory scores were similarly impaired. The index of sensitivity of cueing held a sensitivity of 76% and specificity of 79% in distinguishing DLB. FCSRT could help in disentangling hippocampal memory deficits from memory impairment due to ineffective recall strategies.

%B J Alzheimers Dis %V 64 %P 349-353 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914032?dopt=Abstract %R 10.3233/JAD-180166 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Is There a Characteristic Clinical Profile for Patients with Dementia and Sundown Syndrome? %A Angulo Sevilla, David %A Carreras Rodríguez, María Teresa %A Heredia Rodríguez, Patricia %A Fernández Sánchez, Marisa %A Vivancos Mora, José Aurelio %A Gago-Veiga, Ana Beatriz %X

BACKGROUND: Sundown syndrome (SS) is the onset or worsening of behavioral symptoms in the evening in patients with dementia.

OBJECTIVE: To identify the differential clinical profile of patients with dementia who present SS.

METHODS: A cross-sectional, case-control observational study was conducted by retrospectively reviewing the medical records of patients with dementia in a specialized Memory Unit. We compared the characteristics of patients with and without SS, including sociodemographic variables, etiology, and severity of the dementia, behavioral symptoms, sleep disorders (considering insomnia and hypersomnia), other diseases and treatments employed. We identified the factors related to SS and conducted a logistic regression analysis to establish a predictive nomogram.

RESULTS: Of the 216 study patients with dementia, 41 (19%) had SS. There was a predominance of women (2.4:1), advanced age (p = 0.0001), dependence (p < 0.0001), institutionalization (p < 0.0001), caregiver burden (p < 0.0001), anxiety (p < 0.0001), delirium (p < 0.0001), hallucinations (p < 0.0001), wandering (p < 0.0001), Lewy body dementia (p = 0.05), higher Global Deterioration Scale score (GDS; p < 0.0001), and sleep disorders (p < 0.0001). The multivariate analysis revealed that age (p = 0.048), GDS score (p = 0.01), and the presence of insomnia or hypersomnia (p < 0.0001) independently defined the presence of SS. We established a predictive nomogram for developing SS in patients with dementia, with a predictive capacity of 80.1%.

CONCLUSION: In our study, age, a higher score on the GDS, and the presence of insomnia or hypersomnia are differential clinical characteristics of patients with SS. We defined a nomogram that helps predicting the occurrence of SS in patients with dementia.

%B J Alzheimers Dis %V 62 %P 335-346 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439326?dopt=Abstract %R 10.3233/JAD-170488 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Three Decades of Dementia Research: Insights from One Small Community of Indomitable Rotterdammers. %A Wolters, Frank J %A Adams, Hieab H H %A Bos, Daniel %A Licher, Silvan %A Ikram, M Arfan %X

The most commonly encountered opening sentence in scientific publications about dementia undoubtedly relates to the overwhelming burden of disease. Finding an effective preventive or therapeutic intervention against dementia has been considered the most important unmet need in contemporary medicine. While efforts on tackling this devastating disease have increased exponentially, it is difficult to imagine that in the 1980s and early-1990s, the disease did not feature prominently on any public health report. Yet, it was already then that epidemiologists recognized the growing societal burden of dementia and rationalized that dementia is not necessarily part of aging. Indeed, the conviction that dementia is pathologically distinct from aging led to various efforts in search of unravelling its risk factors and understanding its pre-clinical phase. Among the early pioneers, the population-based Rotterdam Study was initiated in 1990 clearly aiming on chronic diseases including dementia, and among this Alzheimer's disease, as one of its focus points. Ever since, the Rotterdam Study has been an important cornerstone in increasing our knowledge about dementia from an epidemiological perspective. Here, we summarize the main findings originating from this study, and put these into perspective with previous and current work in the field. With an expanding scope of the Rotterdam Study over the years, we discuss findings on occurrence, modifiable risk factors, imaging, and its genetic underpinnings. Importantly, we conclude with recommendations- or, perhaps better stated, a wish list- for future research which may help us reach our finish line: finding an effective preventive or therapeutic intervention against dementia.

%B J Alzheimers Dis %V 64 %P S145-S159 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843240?dopt=Abstract %R 10.3233/JAD-179938 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Three VCP Mutations in Patients with Frontotemporal Dementia. %A Wong, Tsz Hang %A Pottier, Cyril %A Hondius, David C %A Meeter, Lieke H H %A van Rooij, Jeroen G J %A Melhem, Shami %A van Minkelen, Rick %A van Duijn, Cornelia M %A Rozemuller, Annemieke J M %A Seelaar, Harro %A Rademakers, Rosa %A van Swieten, John C %X

Valosin-containing protein (VCP) is involved in multiple cellular activities. Mutations in VCP lead to heterogeneous clinical presentations including inclusion body myopathy with Paget's disease of the bone, frontotemporal dementia and amyotrophic lateral sclerosis, even in patients carrying the same mutation. We screened a cohort of 48 patients with familial frontotemporal dementia (FTD) negative for MAPT, GRN, and C9orf72 mutations for other known FTD genes by using whole exome sequencing. In addition, we carried out targeted sequencing of a cohort of 37 patients with frontotemporal lobar degeneration with Transactive response DNA-binding protein 43 (TDP-43) subtype from the Netherlands Brain bank. Two novel (p.Thr262Ser and p.Arg159Ser) and one reported (p.Met158Val) VCP mutations in three patients with a clinical diagnosis of FTD were identified, and were absence in population-match controls. All three patients presented with behavioral changes, with additional semantic deficits in one. No signs of Paget or muscle disease were observed. Pathological examination of the patient with VCP p.Arg159Ser mutation showed numerous TDP-43 immunoreactive (IR) neuronal intranuclear inclusions (NII) and dystrophic neurites (DN), while a lower number of NII and DN were observed in the patient with the VCP p.Thr262Ser mutation. Pathological findings of both patients were consistent with FTLD-TDP subtype D. Furthermore, only rare VCP-IR NII was observed in both cases. Our study expands the clinical heterogeneity of VCP mutations carriers, and indicates that other additional factors, such as genetic modifiers, may determine the clinical phenotype.

%B J Alzheimers Dis %V 65 %P 1139-1146 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103325?dopt=Abstract %R 10.3233/JAD-180301 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Three-Factor Structure of Cognitive Functioning Among Unimpaired Carriers and Non-Carriers of Autosomal-Dominant Alzheimer's Disease. %A Guzmán-Vélez, Edmarie %A Jaimes, Sehily %A Aguirre-Acevedo, Daniel C %A Norton, Daniel J %A Papp, Kathryn V %A Amariglio, Rebecca %A Rentz, Dorene %A Baena, Ana %A Henao, Eliana %A Tirado, Victoria %A Munoz, Claudia %A Giraldo, Margarita %A Sperling, Reisa A %A Lopera, Francisco %A Quiroz, Yakeel T %X

BACKGROUND: There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline.

OBJECTIVE: We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members.

METHODS: 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol).

RESULTS: The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals' estimated age of clinical onset.

CONCLUSIONS: The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD.

%B J Alzheimers Dis %V 65 %P 107-115 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040714?dopt=Abstract %R 10.3233/JAD-180078 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Time Trends in the Prevalence of Neurocognitive Disorders and Cognitive Impairment in the United States: The Effects of Disease Severity and Improved Ascertainment. %A Akushevich, Igor %A Yashkin, Arseniy P %A Kravchenko, Julia %A Ukraintseva, Svetlana %A Stallard, Eric %A Yashin, Anatoliy I %X

BACKGROUND: Trends in the prevalence of cognitive impairment (CI) based on cognitive assessment instruments are often inconsistent with those of neurocognitive disorders (ND) based on Medicare claims records.

OBJECTIVE: We hypothesized that improved ascertainment and resulting decrease in disease severity at the time of diagnosis are responsible for this phenomenon.

METHODS: Using Medicare data linked to the Health and Retirement Study (1992-2012), we performed a joint analysis of trends in CI and ND to test our hypothesis.

RESULTS: We identified two major contributors to the divergent directions in CI and ND trends: reductions in disease severity explained more than 60% of the differences between CI and ND prevalence over the study period; the remaining 40% was explained by a decrease in the fraction of undiagnosed individuals.

DISCUSSION: Improvements in the diagnoses of ND diseases were a major contributor to reported trends in ND and CI. Recent forecasts of CI and ND trends in the U.S. may be overly pessimistic.

%B J Alzheimers Dis %V 64 %P 137-148 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865067?dopt=Abstract %R 10.3233/JAD-180060 %0 Journal Article %J J Alzheimers Dis %D 2018 %T TLR4 Gene Expression and Pro-Inflammatory Cytokines in Alzheimer's Disease and in Response to Hippocampal Deafferentation in Rodents. %A Miron, Justin %A Picard, Cynthia %A Frappier, Josée %A Dea, Doris %A Théroux, Louise %A Poirier, Judes %X

One important aspect in Alzheimer's disease pathology is the presence of chronic inflammation. Considering its role as a key receptor in the microglial innate immune system, TLR4 was shown to regulate the binding and phagocytosis of amyloid plaques by microglia in several mouse models of amyloidosis, as well as the production of pro-inflammatory cytokines. To our knowledge, TLR4 and its association with cytokines have not been thoroughly examined in the brains of subjects affected with Alzheimer's disease. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in postmortem human brains, we observed increased expression for the TLR4 and TNF genes (p = 0.001 and p = 0.025, respectively), as well as a trend for higher IL6 gene expression in the frontal cortex of AD subjects when compared to age-matched controls. Similarly, using a mouse model of hippocampal deafferentation without amyloidosis, (i.e., the entorhinal cortex lesioned mouse), we observed significant increases in the expression of both the Tlr4 (p = 0.0367 and p = 0.0193 compared to sham-lesioned mice or to the contralateral side, respectively) and Il1b (p = 0.0055 and p = 0.0066 compared to sham-lesioned mice or to the contralateral side, respectively) genes in the deafferentation phase, but not during the ensuing reinnervation process. In conclusion, we suggest that the modulation of cytokines by TLR4 is differentially regulated whether by the presence of amyloid plaques or by the ongoing deafferentation process.

%B J Alzheimers Dis %V 63 %P 1547-1556 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782315?dopt=Abstract %R 10.3233/JAD-171160 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Tocotrienol-Rich Fraction of Palm Oil Improves Behavioral Impairments and Regulates Metabolic Pathways in AβPP/PS1 Mice. %A Durani, Lina Wati %A Hamezah, Hamizah Shahirah %A Ibrahim, Nor Faeizah %A Yanagisawa, Daijiro %A Nasaruddin, Muhammad Luqman %A Mori, Masaki %A Azizan, Kamalrul Azlan %A Damanhuri, Hanafi Ahmad %A Makpol, Suzana %A Wan Ngah, Wan Zurinah %A Tooyama, Ikuo %X

We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo. However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AβPP/PS1 double transgenic (Tg) Alzheimer's disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aβ interaction or independent of Aβ interaction.

%B J Alzheimers Dis %V 64 %P 249-267 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889072?dopt=Abstract %R 10.3233/JAD-170880 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Total MRI Small Vessel Disease Burden Correlates with Cognitive Performance, Cortical Atrophy, and Network Measures in a Memory Clinic Population. %A Banerjee, Gargi %A Jang, Hyemin %A Kim, Hee Jin %A Kim, Sung Tae %A Kim, Jae Seung %A Lee, Jae Hong %A Im, Kiho %A Kwon, Hunki %A Lee, Jong Min %A Na, Duk L %A Seo, Sang Won %A Werring, David John %X

BACKGROUND: Recent evidence suggests that combining individual imaging markers of cerebral small vessel disease (SVD) may more accurately reflect its overall burden and better correlate with clinical measures.

OBJECTIVE: We wished to establish the clinical relevance of the total SVD score in a memory clinic population by investigating the association with SVD score and cognitive performance, cortical atrophy, and structural network measures, after adjusting for amyloid-β burden.

METHODS: We included 243 patients with amnestic mild cognitive impairment (MCI), Alzheimer's disease dementia, subcortical vascular MCI, or subcortical vascular dementia. All underwent MR and [11C] PiB-PET scanning and had standardized cognitive testing. Multiple linear regression was used to evaluate the relationships between SVD score and cognition, cortical thickness, and structural network measures. Path analyses were performed to evaluate whether network disruption mediates the effects of SVD score on cortical thickness and cognition.

RESULTS: Total SVD score was associated with the performance of frontal (β - 4.31, SE 2.09, p = 0.040) and visuospatial (β - 0.95, SE 0.44, p = 0.032) tasks, and with reduced cortical thickness in widespread brain regions. Total SVD score was negatively correlated with nodal efficiency, as well as changes in brain network organization, with evidence of reduced integration and increasing segregation. Path analyses showed that the associations between SVD score and frontal and visuospatial scores were partially mediated by decreases in their corresponding nodal efficiency and cortical thickness.

CONCLUSION: Total SVD burden has clinical relevance in a memory clinic population and correlates with cognition, and cortical atrophy, as well as structural network disruption.

%B J Alzheimers Dis %V 63 %P 1485-1497 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843234?dopt=Abstract %R 10.3233/JAD-170943 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Trajectories of Physiological Brain Aging and Related Factors in People Aged from 20 to over-80. %A Lee, Jin San %A Kim, Seonwoo %A Yoo, Heejin %A Park, Seongbeom %A Jang, Young Kyoung %A Kim, Hee Jin %A Kim, Ko Woon %A Kim, Yeshin %A Jang, Hyemin %A Park, Key-Chung %A Yaffe, Kristine %A Yang, Jin-Ju %A Lee, Jong-Min %A Na, Duk L %A Seo, Sang Won %X

BACKGROUND/OBJECTIVE: In this study, we investigated a long-term trajectory of brain aging (from the 20 s to over-80) in cognitively normal (CN) individuals. We further determined whether differences in sex, education years, and apolipoprotein E ε 4 status affect age-related cortical thinning.

METHODS: A total of 2,944 CN individuals who underwent high-resolution (3.0-Tesla) magnetic resonance imaging were included in this study. Cortical thickness was measured using a surface-based method. Multiple linear regression analyses were performed to evaluate age-related cortical thinning and related factors.

RESULTS: Compared to those in their 20 s/30 s, participants in their 40 s showed thinning primarily in the medial and lateral frontal and inferior parietal regions, and cortical thinning occurred across most of the cortices with increasing age. Notably, the precuneus, inferior temporal and lateral occipital regions were relatively spared until later in life. Male and lower education years were associated with greater cortical thinning with distinct regional specificity.

CONCLUSION: Our findings provide an important clue to understanding the mechanism of age-related cognitive decline and new strategies for preventing the acceleration of pathological brain aging.

%B J Alzheimers Dis %V 65 %P 1237-1246 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149442?dopt=Abstract %R 10.3233/JAD-170537 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Transcranial Sonography in Neurodegenerative Diseases with Cognitive Decline. %A Favaretto, Silvia %A Walter, Uwe %A Baracchini, Claudio %A Cagnin, Annachiara %K Cognition Disorders %K Humans %K Neurodegenerative Diseases %K Ultrasonography, Doppler, Transcranial %X

Transcranial sonography (TCS) of the brain parenchyma detects alterations in the substantia nigra (SN), raphe nuclei and basal ganglia; this technique has been established as a tool for the early diagnosis of Parkinson's disease and differential diagnosis from atypical parkinsonian syndromes. Here, we aimed to review the main applications of TCS in neurodegenerative diseases presenting with dementia syndrome, focusing on Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration, idiopathic normal pressure hydrocephalus, and atypical and secondary parkinsonisms. The finding of bilaterally marked hyperechogenicity of the SN appears as a characteristic feature of DLB, while it is found only in a minority of AD patients. SN hyperechogenicity is also detected in most patients with corticobasal degeneration and in about one third of patients with progressive supranuclear palsy, in which is constantly associated with hyperechogenic alterations of the basal ganglia. In conclusion, TCS is a valid supportive tool in the diagnostic workup of patients with dementia due to different neurodegenerative conditions. A promising new application is the differentiation of DLB from AD even at the early stages of these diseases.

%B J Alzheimers Dis %V 61 %P 29-40 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103031?dopt=Abstract %R 10.3233/JAD-170382 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Translational Research in Alzheimer's and Prion Diseases. %A Di Fede, Giuseppe %A Giaccone, Giorgio %A Salmona, Mario %A Tagliavini, Fabrizio %X

Translational neuroscience integrates the knowledge derived by basic neuroscience with the development of new diagnostic and therapeutic tools that may be applied to clinical practice in neurological diseases. This information can be used to improve clinical trial designs and outcomes that will accelerate drug development, and to discover novel biomarkers which can be efficiently employed to early recognize neurological disorders and provide information regarding the effects of drugs on the underlying disease biology. Alzheimer's disease (AD) and prion disease are two classes of neurodegenerative disorders characterized by incomplete knowledge of the molecular mechanisms underlying their occurrence and the lack of valid biomarkers and effective treatments. For these reasons, the design of therapies that prevent or delay the onset, slow the progression, or improve the symptoms associated to these disorders is urgently needed. During the last few decades, translational research provided a framework for advancing development of new diagnostic devices and promising disease-modifying therapies for patients with prion encephalopathies and AD. In this review, we provide present evidence of how supportive can be the translational approach to the study of dementias and show some results of our preclinical studies which have been translated to the clinical application following the 'bed-to-bench-and-back' research model.

%B J Alzheimers Dis %V 62 %P 1247-1259 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29172000?dopt=Abstract %R 10.3233/JAD-170770 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Traumatic Brain Injury and Age of Onset of Dementia with Lewy Bodies. %A Nguyen, Trung P %A Schaffert, Jeff %A LoBue, Christian %A Womack, Kyle B %A Hart, John %A Cullum, C Munro %X

BACKGROUND: Traumatic brain injury (TBI) with loss of consciousness (LOC) has been associated with earlier onset of mild cognitive impairment, frontotemporal dementia, Parkinson's disease, and Alzheimer's disease (AD), but has not been examined as a risk factor for earlier onset of dementia with Lewy bodies (DLB).

OBJECTIVE: The purpose of this study was to assess the association between a history of TBI and the age of onset of DLB.

METHOD: Data from 576 subjects with a clinical diagnosis of DLB were obtained from the National Alzheimer's Coordinating Center (NACC). Analyses of Covariance examined whether self-reported history of remote TBI with LOC (i.e., >1 year prior to the first Alzheimer's Disease Center visit) was associated with earlier DLB symptom onset.

RESULTS: Controlling for sex, those with a history of remote TBI had an approximately 1.5-year earlier clinician-estimated age of onset (F = 0.87, p = 0.35) and 0.75-years earlier age of diagnosis (F = 0.14, p = 0.71) of DLB compared to those without a history of TBI, though the differences did not reach statistical significance. Analysis of subjects with autopsy-confirmed diagnoses was underpowered due to the low number of TBI+ subjects.

CONCLUSIONS: Remote TBI with LOC was not significantly associated with DLB onset, despite being a significant risk factor for cognitive decline and earlier age of onset in other neurodegenerative conditions. Replication of these results using a larger cohort of DLB subjects with and without a TBI history who have undergone autopsy is indicated, as our TBI+ subjects did show a slightly earlier onset of about 1.5 years. Further investigations into other potential DLB risk factors are also warranted.

%B J Alzheimers Dis %V 66 %P 717-723 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320582?dopt=Abstract %R 10.3233/JAD-180586 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Treatment of Atrial Fibrillation in Patients with Dementia: A Cohort Study from the Swedish Dementia Registry. %A Subic, Ana %A Cermakova, Pavla %A Religa, Dorota %A Han, Shuang %A von Euler, Mia %A Kåreholt, Ingemar %A Johnell, Kristina %A Fastbom, Johan %A Bognandi, Liselia %A Winblad, Bengt %A Kramberger, Milica G %A Eriksdotter, Maria %A Garcia-Ptacek, Sara %K Aged %K Aged, 80 and over %K Anticoagulants %K Atrial Fibrillation %K Dementia %K Female %K Hemorrhage %K Humans %K Longitudinal Studies %K Male %K Registries %K Risk Factors %K Stroke %K Survival Analysis %K Sweden %K Warfarin %X

BACKGROUND: Patients with dementia might have higher risk for hemorrhagic complications with anticoagulant therapy prescribed for atrial fibrillation (AF).

OBJECTIVE: This study assesses the risks and benefits of warfarin, antiplatelets, and no treatment in patients with dementia and AF.

METHODS: Of 49,792 patients registered in the Swedish Dementia Registry 2007-2014, 8,096 (16%) had a previous diagnosis of AF. Cox proportional hazards models were used to calculate the risk for ischemic stroke (IS), nontraumatic intracranial hemorrhage, any-cause hemorrhage, and death.

RESULTS: Out of the 8,096 dementia patients with AF, 2,143 (26%) received warfarin treatment, 2,975 (37%) antiplatelet treatment, and 2,978 (37%) had no antithrombotic treatment at the time of dementia diagnosis. Patients on warfarin had fewer IS than those without treatment (5.2% versus 8.7%; p < 0.001) with no differences compared to antiplatelets. In adjusted analyses, warfarin was associated with a lower risk for IS (HR 0.76, CI 0.59-0.98), while antiplatelets were associated with increased risk (HR 1.25, CI 1.01-1.54) compared to no treatment. For any-cause hemorrhage, there was a higher risk with warfarin (HR 1.28, CI 1.03-1.59) compared to antiplatelets. Warfarin and antiplatelets were associated with a lower risk for death compared to no treatment.

CONCLUSIONS: Warfarin treatment in Swedish patients with dementia is associated with lower risk of IS and mortality, and a small increase in any-cause hemorrhage. This study supports the use of warfarin in appropriate cases in patients with dementia. The low percentage of patients on warfarin treatment indicates that further gains in stroke prevention are possible.

%B J Alzheimers Dis %V 61 %P 1119-1128 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29286925?dopt=Abstract %R 10.3233/JAD-170575 %0 Journal Article %J J Alzheimers Dis %D 2018 %T TREM1 mRNA Expression in Leukocytes and Cognitive Function in Japanese Patients with Alzheimer's Disease. %A Sao, Tomoko %A Yoshino, Yuta %A Yamazaki, Kiyohiro %A Ozaki, Yuki %A Mori, Yoko %A Ochi, Shinichiro %A Yoshida, Taku %A Mori, Takaaki %A Iga, Jun-Ichi %A Ueno, Shu-Ichi %X

BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) activates the innate immune system, promotes phagocytosis by microglia, and is associated with Alzheimer's disease (AD). The possible role of a related molecule, TREM1, in AD remains unknown.

OBJECTIVE: We investigated a possible role for TREM1 in AD by determining the gene expression and methylation levels of TREM1 in leukocytes from AD patients.

METHODS: Fifty patients with AD and 50 age-matched healthy controls were enrolled. AD patients underwent a battery of neuropsychiatric tests. Peripheral blood samples were obtained from each participant, RNA and DNA were extracted, and samples were assessed for TREM1 mRNA expression and methylation rates at three CpG sites in the TREM1 promoter.

RESULTS: TREM1 mRNA expression levels in AD patients were significantly higher than those in controls (p = 0.008). TREM1 mRNA expression levels were not correlated with sex, age, duration of illness, APOE genotype, donepezil treatment, or scores of most neuropsychiatric tests. TREM1 mRNA expression levels in AD patients were correlated with the total score of the Montgomery-Åsberg Depression Rating Scale (p = 0.047, r = - 0.344). Methylation rates at the three CpG sites were significantly lower in AD patients than in controls. We also found a significant correlation between TREM1 mRNA expression and TREM1 DNA methylation rates (p < 0.001).

CONCLUSION: TREM1 may be associated with the immune responses in AD, and along with hypomethylation at CpG sites in the TREM1 promoter, may become part of a biomarker panel for AD pathogenesis.

%B J Alzheimers Dis %V 64 %P 1275-1284 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010135?dopt=Abstract %R 10.3233/JAD-180418 %0 Journal Article %J J Alzheimers Dis %D 2018 %T TRPC1 Null Exacerbates Memory Deficit and Apoptosis Induced by Amyloid-β. %A Li, Mengzhu %A Liu, Enjie %A Zhou, Qiuzhi %A Li, Shihong %A Wang, Xin %A Liu, Yanchao %A Wang, Lin %A Sun, Dongsheng %A Ye, Jinwang %A Gao, Yuan %A Yang, Xifei %A Liu, Jianjun %A Yang, Ying %A Wang, Jian-Zhi %X

The transient receptor potential cation (TRPC) channels are widely expressed in nervous system but their functions remain largely unclear. Here, we found that TRPC1 deletion did not affect learning and memory in physiological conditions, while it aggravated learning and memory deficits induced by amyloid-β (Aβ), the major component of the senile plaques observed in the brains of Alzheimer's disease (AD). Further studies demonstrated that TRPC1 deletion did not affect cell apoptosis in physiological condition, but it exacerbated the Aβ-induced cell death in mouse hippocampus. Moreover, the level of TRPC1 was decreased in AD cell and mouse models, and upregulation of TRPC1 decreased Aβ levels with attenuation of apoptosis in the cells stably overexpressing amyloid-β protein precursor (AβPP). Finally, the transmembrane domain of TRPC1 could bind to AβPP and thus decreased Aβ production. These findings indicate that loss of TRPC1 exacerbates Aβ-induced memory deficit and cell apoptosis, though it does not impair cognitive function or induce cell death in physiological conditions.

%B J Alzheimers Dis %V 63 %P 761-772 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660945?dopt=Abstract %R 10.3233/JAD-180077 %0 Journal Article %J J Alzheimers Dis %D 2018 %T TTC7 and Hyccin Regulate Neuronal Aβ42 Accumulation and its Associated Neural Deficits in Aβ42-Expressing Drosophila. %A Sun, Minghao %A Zhao, Yinghui %A Han, Men %A Zhang, Baozhu %A Zhang, Xiao %A Zhang, Qichao %A Lim, Nastasia K-H %A Wang, Wen-An %A Huang, Fu-De %X

Neuronal amyloid-β (Aβ) accumulation plays an important role in the pathogenesis of Alzheimer's disease (AD). The conformation and toxicity of Aβ are regulated by lipids on the plasma membrane. Previously, we found downregulation of Rolling Blackout (RBO) or phosphatidylinositol-4-kinase type IIIα (PI4KIIIα) reduces neuronal Aβ accumulation and associated neural deficits in a Drosophila model expressing Aβ42. In mammals, the homologs of RBO and PI4KIIIα were reported to form a plasma membrane-localized complex with a scaffold protein TTC7 and cytosolic protein Hyccin/FAM126A to tightly control the plasmalemmal level of phosphatidylinositol-4-phosphate. Here, we show genetic downregulation of Drosophila TTC7 and Hyccin also reduces neuronal Aβ accumulation and associated synaptic and motor defects as well as premature death in Aβ42-expressing flies, while overexpression of TTC7 and Hyccin produced the opposite effect. These results, together with our previous study, demonstrate that RBO/TTC7/PI4KIIIα/Hyccin regulate neuronal Aβ accumulation and associated neural deficits in the Drosophila model, further supporting the RBO/Efr3-PI4KIIIα complex as a potential therapeutic target for AD.

%B J Alzheimers Dis %V 65 %P 1001-1010 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103315?dopt=Abstract %R 10.3233/JAD-170907 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Ubisol-Q10 (a Nanomicellar Water-Soluble Formulation of CoQ10) Treatment Inhibits Alzheimer-Type Behavioral and Pathological Symptoms in a Double Transgenic Mouse (TgAPEswe, PSEN1dE9) Model of Alzheimer's Disease. %A Muthukumaran, Krithika %A Kanwar, Annie %A Vegh, Caleb %A Marginean, Alexandra %A Elliott, Austin %A Guilbeault, Nicholas %A Badour, Alexander %A Sikorska, Marianna %A Cohen, Jerome %A Pandey, Siyaram %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Disease Models, Animal %K Male %K Maze Learning %K Memory %K Memory Disorders %K Mice %K Mice, Transgenic %K Microglia %K Mutation %K Nerve Tissue Proteins %K Peptide Fragments %K Presenilin-1 %K Ubiquinone %K Vitamins %X

 Alzheimer's disease (AD) is one of the most common neurodegenerative pathologies for which there are no effective therapies to halt disease progression. Given the increase in the incidence of this disorder, there is an urgent need for pharmacological intervention. Unfortunately, recent clinical trials produced disappointing results. Molecular mechanisms of AD are converging on the notion that mitochondrial dysfunction, oxidative stress, and accumulation of dysfunctional proteins are involved in AD pathology. Previously, we have shown that a water-soluble formulation of Coenzyme Q10 (Ubisol-Q10), an integral part of the electron transport chain, stabilizes mitochondria and prevents neuronal cell death caused by neurotoxins or oxidative stress both in vitro and in vivo. In this study, we evaluated the neuroprotective effects of Ubisol-Q10 treatment in double transgenic AD mice. In the present study, we report that providing Ubisol-Q10 in drinking water (at a dose of ∼6 mg/kg/day) reduced circulating amyloid-β (Aβ) peptide, improved long term memory, preserved working spatial memory, and drastically inhibited Aβ plaque formation in 18-month-old transgenic mice compared to an untreated transgenic group. Thus Ubisol-Q10 supplementation has the potential to inhibit the progression of neurodegeneration, leading to a better quality of life for humans suffering with AD.

%B J Alzheimers Dis %V 61 %P 221-236 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154270?dopt=Abstract %R 10.3233/JAD-170275 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Underlying Biological Processes in Mild Cognitive Impairment: Amyloidosis Versus Neurodegeneration. %A Santana, Isabel %A Baldeiras, Ines %A Santiago, Beatriz %A Duro, Diana %A Freitas, Sandra %A Pereira, Miguel Tábuas %A Almeida, Maria Rosário %A Oliveira, Catarina Resende %X

The amyloid cascade hypothesis proposes amyloid-β (Aβ) as the earliest and key pathological hallmark of Alzheimer's disease (AD), but this mandatory "amyloid-first pathway" has been contested. Longitudinal studies of mild cognitive impairment (MCI) patients represent an opportunity to investigate the intensity of underlying biological processes (amyloidosis versus neurodegeneration) and their relevance for progression to AD. We re-examined our cohort of amnestic MCI, grouped according to cerebrospinal fluid (CSF) biomarkers, aiming at establishing their prognostic value for Alzheimer-type dementia and testing the hypothetical model of biomarkers sequence, based on the amyloid cascade. Our baseline population consisted of 217 MCI patients, 63% with neurodegeneration markers and 47% with amyloidosis. Within the longitudinal study-group (n = 165), 85 progressed to AD and 80 remained cognitively stable. Age, CSF Aβ42, and t-Tau were identified as the best single predictors of conversion to AD. Regarding MCI classification according to the NIA-AA criteria, the high-AD-likelihood group (HL-both amyloid and neurodegeneration markers) was the most frequent (42%); followed by the Suspected Non-Alzheimer Pathophysiology group (SNAP-26%), the low-AD-likelihood group (LL-negative biomarkers-22%), and the Isolated Amyloid Pathology group (IAP-10%). Risk of progression to AD was higher in HL in relation to the LL group (HR = 6.1, 95% CI = 2.1-18.0, p = 0.001). SNAP and IAP groups were equivalent in terms of risk of progression to AD (IAP: HR = 2.6, 95% CI = 0.7-9.3, p = 0.141; SNAP: HR = 3.1, 95% CI = 1.1-9.6; p = 0.046), but only SNAP was significantly different from the LL group. These results support different neurobiological pathways to AD beyond the amyloid hypothesis, highlighting the alternative "neurodegeneration-first pathway" for further investigation.

%B J Alzheimers Dis %V 64 %P S647-S657 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562515?dopt=Abstract %R 10.3233/JAD-179908 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Understanding Epigenetics in the Neurodegeneration of Alzheimer's Disease: SAMP8 Mouse Model. %A Griñán-Ferré, Christian %A Corpas, Rubén %A Puigoriol-Illamola, Dolors %A Palomera-Ávalos, Verónica %A Sanfeliu, Coral %A Pallas, Merce %X

Epigenetics is emerging as the missing link among genetic inheritance, environmental influences, and body and brain health status. In the brain, specific changes in nucleic acids or their associated proteins in neurons and glial cells might imprint differential patterns of gene activation that will favor either cognitive enhancement or cognitive loss for more than one generation. Furthermore, derangement of age-related epigenetic signaling is appearing as a significant risk factor for illnesses of aging, including neurodegeneration and Alzheimer's disease (AD). In addition, better knowledge of epigenetic mechanisms might provide hints and clues in the triggering and progression of AD. Intense research in experimental models suggests that molecular interventions for modulating epigenetic mechanisms might have therapeutic applications to promote cognitive maintenance through an advanced age. The SAMP8 mouse is a senescence model with AD traits in which the study of epigenetic alterations may unveil epigenetic therapies against the AD.

%B J Alzheimers Dis %V 62 %P 943-963 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562529?dopt=Abstract %R 10.3233/JAD-170664 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Unexpected Role of Aβ1-42 Monomers in the Pathogenesis of Alzheimer's Disease. %A Tamagno, Elena %A Guglielmotto, Michela %A Monteleone, Debora %A Manassero, Giusi %A Vasciaveo, Valeria %A Tabaton, Massimo %X

Amyloid-β (Aβ) has been proposed as a biomarker and a drug target for the therapy of Alzheimer's disease (AD). The neurotoxic entity and relevance of each conformational form of Aβ to AD pathology is still under debate; Aβ oligomers are considered the major killer form of the peptide whereas monomers have been proposed to be involved in physiological process. Here we reviewed some different effects mediated by monomers and oligomers on mechanisms involved in AD pathogenesis such as autophagy and tau aggregation. Data reported in this review demonstrate that Aβ monomers could have a major role in sustaining the pathogenesis of AD and that AD therapy should be focused not only in the removal of oligomers but also of monomers.

%B J Alzheimers Dis %V 62 %P 1241-1245 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103036?dopt=Abstract %R 10.3233/JAD-170581 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Uniform Data Set, Czech Version: Normative Data in Older Adults from an International Perspective. %A Nikolai, Tomas %A Stepankova, Hana %A Kopecek, Miloslav %A Sulc, Zdenek %A Vyhnálek, Martin %A Bezdicek, Ondrej %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition %K Czech Republic %K Female %K Humans %K Internationality %K Male %K Middle Aged %K National Institute on Aging (U.S.) %K Neuropsychological Tests %K Psychometrics %K Reference Values %K Regression Analysis %K United States %X

BACKGROUND: Outside of the United States, international perspectives on normative data for neuropsychological test performance, within diverse populations, have been scarce. The neuropsychological test battery from the Uniform Data Set (UDS) of the Alzheimer's Disease Centers (ADC) program of the United States National Institute on Aging (NIA) is one of the most sensitive batteries for the evaluation of both normal cognitive aging and pathological cognitive decline.

OBJECTIVE: This study aimed to determine the feasibility of the Czech Neuropsychological Test Battery from the Uniform Data Set (UDS-Cz 2.0), while also evaluating the results obtained from an international perspective.

METHODS: This paper describes data from 520 cognitively normal participants. Regression analyses were used to describe the influence of demographic variables on UDS-Cz test performance.

RESULTS: Cognitive performance on all measures declined with age, with patient education level serving as a protective factor. Therefore, the present study provides normative data for the UDS-Cz, adjusted for the demographic variables of age and education.

CONCLUSION: The present study determines the psychometric properties of the UDS-Cz and establishes normative values in the aging Czech population, which can be used in clinical settings.

%B J Alzheimers Dis %V 61 %P 1233-1240 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332045?dopt=Abstract %R 10.3233/JAD-170595 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Untold New Beginnings: Adult Hippocampal Neurogenesis and Alzheimer's Disease. %A Teixeira, Catia M %A Pallas-Bazarra, Noemí %A Bolós, Marta %A Terreros-Roncal, Julia %A Avila, Jesús %A Llorens-Martín, María %X

Neurogenesis occurs in a limited number of brain regions during adulthood. Of these, the hippocampus has attracted great interest due to its involvement in memory processing. Moreover, both the hippocampus and the main area that innervates this structure, namely the entorhinal cortex, show remarkable atrophy in patients with Alzheimer's disease (AD). Adult hippocampal neurogenesis is a process that continuously gives rise to newborn granule neurons in the dentate gyrus. These cells coexist with developmentally generated granule neurons in this structure, and both cooperative and competition phenomena regulate the communication between these two types of cells. Importantly, it has been revealed that GSK-3β and tau proteins, which are two of the main players driving AD pathology, are cornerstones of adult hippocampal neurogenesis regulation. We have shown that alterations either promoting or impeding the actions of these two proteins have detrimental effects on the structural plasticity of granule neurons. Of note, these impairments occur both under basal conditions and in response to detrimental and neuroprotective stimuli. Thus, in order to achieve the full effectiveness of future therapies for AD, we propose that attention be turned toward identifying the pathological and physiological actions of the proteins involved in the pathogenesis of this condition.

%B J Alzheimers Dis %V 64 %P S497-S505 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562522?dopt=Abstract %R 10.3233/JAD-179918 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Unusual Clinical Presentations Challenging the Early Clinical Diagnosis of Creutzfeldt-Jakob Disease. %A Baiardi, Simone %A Capellari, Sabina %A Bartoletti Stella, Anna %A Parchi, Piero %X

The introduction of prion RT-QuIC, an ultrasensitive specific assay for the in vivo detection of the abnormal prion protein, has significantly increased the potential for an early and accurate clinical diagnosis of Creutzfeldt-Jakob disease (CJD). However, in the clinical setting, the early identification of patients with possible CJD is often challenging. Indeed, CJD patients may present with isolated symptoms that remain the only clinical manifestation for some time, or with neurological syndromes atypical for CJD. To enhance awareness of unusual disease presentations and promote earlier diagnosis, we reviewed the entire spectrum of atypical early manifestations of CJD, mainly reported to date as case descriptions or small case series. They included sensory either visual or auditory disturbances, seizures, isolated psychiatric manifestations, atypical parkinsonian syndromes (corticobasal syndrome, progressive supranuclear palsy-like), pseudobulbar syndrome, isolated involuntary movements (dystonia, myoclonus, chorea, blepharospasm), acute or subacute onsets mimicking a stroke, isolated aphasia, and neuropathy. Since CJD is a rare disease and its clinical course rapidly progressive, an in-depth understanding and awareness of early clinical features are mandatory to enhance the overall diagnostic accuracy in its very early stages and to recruit optimal candidates for future therapeutic trials.

%B J Alzheimers Dis %V 64 %P 1051-1065 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010123?dopt=Abstract %R 10.3233/JAD-180123 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Update on Vascular Cognitive Impairment Associated with Subcortical Small-Vessel Disease. %A Wallin, Anders %A Román, Gustavo C %A Esiri, Margaret %A Kettunen, Petronella %A Svensson, Johan %A Paraskevas, George P %A Kapaki, Elisabeth %K Animals %K Cerebrovascular Disorders %K Dementia %K Humans %X

Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer's disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42/Aβ40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder.

%B J Alzheimers Dis %V 62 %P 1417-1441 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170803?id=journal-of-alzheimers-disease%2Fjad170803 %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562536?dopt=Abstract %R 10.3233/JAD-170803 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Urine-Based Biomarkers for Alzheimer's Disease Identified Through Coupling Computational and Experimental Methods. %A Yao, Fang %A Hong, Xiaoyu %A Li, Shuiming %A Zhang, Yan %A Zhao, Qing %A Du, Wei %A Wang, Yong %A Ni, Jiazuan %X

Alzheimer's disease (AD) is a chronic neurodegenerative disorder contributing to nearly 70% of dementia cases. However, no diagnostic protein biomarkers are available in urine. In this study, we combined computational and experimental methods to identify urinary biomarkers for AD. First, by analyzing brain tissue-based gene expression data of AD, 2,754 differentially expressed genes were identified, 559 of which were predicted to encode urine-excretory proteins that might act as candidate protein biomarkers of AD. GO enrichment analyses implied that they were mainly involved in microtubule-based process, myelin sheath, and calcium ion binding, suggesting that they might be associated with AD pathogenesis. In order to verify these proteins in urine, an iTRAQ experiment was carried out to analyze urine samples from AD patients and healthy controls, and 15 proteins were detected. Based on the expression changes of these proteins, 4 proteins were chosen for further validation by ELISA experiment, and SPP1, GSN, and IGFBP7 were found to be differentially expressed in the urine of AD patients. After a literature survey, we found that they were involved in AD pathophysiology and might serve as new urine biomarkers for AD. To our knowledge, this is the first time that urine biomarkers for AD were identified by combining computational and experimental methods. Furthermore, this is the first time SPP1, GSN, and IGFBP7 have been reported as potential urine protein biomarkers for AD. Therefore, our findings might provide significant guidance for finding early biomarkers of AD in urine.

%B J Alzheimers Dis %V 65 %P 421-431 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040720?dopt=Abstract %R 10.3233/JAD-180261 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Use of Mobile Games to Assess Cognitive Function of Elderly with and without Cognitive Impairment. %A Bonnechère, Bruno %A Van Vooren, Mélissa %A Bier, Jean-Christophe %A De Breucker, Sandra %A Van Hove, Olivier %A Van Sint Jan, Serge %A Feipel, Véronique %A Jansen, Bart %X

BACKGROUND: In the past few years numerous mobile games have been developed to train the brain. There is a lack of information about the relation between the scores obtained in these games and the cognitive abilities of the patients.

OBJECTIVE: The aim of this study was to determine whether or not mobile games can be used to assess cognitive abilities of elderly.

METHODS: Twenty healthy young adults, 29 old patients with cognitive impairments (Mini-Mental State Exam (MMSE) [20- 24]) and 27-aged controls participated in this study. Scores obtained in 7 mobile games were correlated with MMSE and the Addenbrooke's Cognitive Evaluation revised (ACE-R).

RESULTS: Statistically significant differences were found for all games between patients with cognitive impairments and the aged controls. Correlations between the average scores of the games and the MMSE and ACE-R are significant (R = 0.72 [p < 0.001] and R = 0.81 [p < 0.001], respectively).

CONCLUSION: Scores of cognitive mobile games could be used as an alternative to MMSE and ACE-R to evaluate cognitive function of aged people with and without cognitive impairment at least when MMSE is higher than 20/30.

%B J Alzheimers Dis %V 64 %P 1285-1293 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29991133?dopt=Abstract %R 10.3233/JAD-180224 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Usefulness of Dual-Point Amyloid PET Scans in Appropriate Use Criteria: A Multicenter Study. %A Segovia, Fermín %A Gómez-Río, Manuel %A Sánchez-Vañó, Raquel %A Górriz, Juan Manuel %A Ramírez, Javier %A Triviño-Ibáñez, Eva %A Carnero-Pardo, Cristóbal %A Martínez-Lozano, María Dolores %A Sopena-Novales, Pablo %X

BACKGROUND: Biomarkers of neurodegeneration play a major role in the diagnosis of Alzheimer's disease (AD). Information on both amyloid-β accumulation, e.g., from amyloid positron emission tomography (PET), and downstream neuronal injury, e.g., from 18F-fluorodeoxyglucose (FDG) PET, would ideally be obtained in a single procedure.

OBJECTIVE: On the basis that the parallelism between brain perfusion and glucose metabolism is well documented, the objective of this work is to evaluate whether brain perfusion estimated in a dual-point protocol of 18F-florbetaben (FBB) PET can be a surrogate of FDG PET in appropriate use criteria (AUC) for amyloid PET.

METHODS: This study included 47 patients fulfilling international AUC for amyloid PET. FDG PET, early FBB (pFBB) PET (0-10 min post injection), and standard FBB (sFBB) PET (90-110 min post injection) scans were acquired. Results of clinical subjective reports and of quantitative region of interest (ROI)-based analyses were compared between procedures using statistical techniques such as Pearson's correlation coefficients and t-tests.

RESULTS: pFBB and FDG visual reports on the 47 patients showed good agreement (k  >  0.74); ROI quantitative analysis indicated that both data modalities are highly correlated; and the t-test analysis does not reject the null hypothesis that data from pFBB and FDG examinations comes from independent random samples from normal distributions with equal means and variances.

CONCLUSIONS: A good agreement was found between pFBB and FDG data as obtained by subjective visual and quantitative analyses. Dual-point FBB PET scans could offer complementary information (similar to that from FDG PET and FBB PET) in a single procedure, considering pFBB as a surrogate of FDG.

%B J Alzheimers Dis %V 65 %P 765-779 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103321?dopt=Abstract %R 10.3233/JAD-180232 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Using Neuropsychological Process Scores to Identify Subtle Cognitive Decline and Predict Progression to Mild Cognitive Impairment. %A Thomas, Kelsey R %A Edmonds, Emily C %A Eppig, Joel %A Salmon, David P %A Bondi, Mark W %X

BACKGROUND: We previously operationally-defined subtle cognitive decline (SCD) in preclinical Alzheimer's disease (AD) using total scores on neuropsychological (NP) tests. NP process scores (i.e., provide information about how a total NP score was achieved) may be a useful tool for identifying early cognitive inefficiencies prior to objective impairment seen in mild cognitive impairment (MCI) and dementia.

OBJECTIVE: We aimed to integrate process scores into the SCD definition to identify stages of SCD and improve early detection of those at risk for decline.

METHODS: Cognitively "normal" participants from the Alzheimer's Disease Neuroimaging Initiative were classified as "early" SCD (E-SCD; >1 SD below norm-adjusted mean on 2 process scores or on 1 process score plus 1 NP total score), "late" SCD (L-SCD; existing SCD criteria of >1 SD below norm-adjusted mean on 2 NP total scores in different domains), or "no SCD" (NC). Process scores considered in the SCD criteria were word-list intrusion errors, retroactive interference, and learning slope. Cerebrospinal fluid AD biomarkers were used to examine pathologic burden across groups.

RESULTS: E-SCD and L-SCD progressed to MCI 2.5-3.4 times faster than the NC group. Survival curves for E-SCD and L-SCD converged at 7-8 years after baseline. The combined (E-SCD+L-SCD) group had improved sensitivity to detect progression to MCI relative to L-SCD only. AD biomarker positivity increased across NC, SCD, and MCI groups.

CONCLUSIONS: Process scores can be integrated into the SCD criteria to allow for increased sensitivity and earlier identification of cognitively normal older adults at risk for decline prior to frank impairment on NP total scores.

%B J Alzheimers Dis %V 64 %P 195-204 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865077?dopt=Abstract %R 10.3233/JAD-180229 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Utility of Amyloid and FDG-PET in Clinical Practice: Differences Between Secondary and Tertiary Care Memory Units. %A Lage, Carmen %A Suarez, Andrea Gonzalez %A Pozueta, Ana %A Riancho, Javier %A Kazimierczak, Martha %A Bravo, María %A Jimenez Bonilla, Julio %A de Arcocha Torres, Marıa %A Quirce, Remedios %A Banzo, Ignacio %A Vázquez-Higuera, José Luis %A Rabinovici, Gil D %A Rodriguez-Rodriguez, Eloy %A Sánchez-Juan, Pascual %X

The clinical utility of amyloid positron emission tomography (PET) has not been fully established. Our aim was to evaluate the effect of amyloid imaging on clinical decision making in a secondary care unit and compare our results with a previous study in a tertiary center following the same methods. We reviewed retrospectively 151 cognitively impaired patients who underwent amyloid (Pittsburgh compound B [PiB]) PET and were evaluated clinically before and after the scan in a secondary care unit. One hundred and fifty concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed changes between the pre- and post-PET clinical diagnosis and Alzheimer's disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ2 and multivariate logistic regression. Concordance between classification based on scan readings and baseline diagnosis was 66% for PiB and 47% for FDG. The primary diagnosis changed after PET in 17.2% of cases. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (p = 0.0002). Changes in treatment were associated with concordant PiB (p = 0.009) while FDG had no effect on treatment decisions. Based on our regression model, patients with diagnostic dilemmas, a suspected non-amyloid syndrome, and Clinical Dementia Rating <1 were more likely to benefit from amyloid PET due to a higher likelihood of diagnostic change. We found that changes in diagnosis after PET in our secondary center almost doubled those of our previous analysis of a tertiary unit (9% versus 17.2%). Our results offer some clues about the rational use of amyloid PET in a secondary care memory unit stressing its utility in mild cognitive impairment patients.

%B J Alzheimers Dis %V 63 %P 1025-1033 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710706?dopt=Abstract %R 10.3233/JAD-170985 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Utility of Amyloid PET Scans in the Evaluation of Patients Presenting with Diverse Cognitive Complaints. %A Shea, Yat-Fung %A Barker, Warren %A Greig-Gusto, Maria T %A Loewenstein, David A %A DeKosky, Steven T %A Duara, Ranjan %X

BACKGROUND: The impact of amyloid positron emission tomography (Aβ-PET) in a "real-world" memory disorders clinic remains poorly studied.

OBJECTIVE: We studied the impact of Aβ-PET in diagnosis and management in the memory clinic and factors making the most impact in diagnosis and management.

METHODS: We studied 102 patients who had presented at a memory disorders clinic (the Wien Center for Alzheimer's Disease and Memory Disorders, Miami Beach, FL) and had a diagnostic work-up for cognitive complaints, including Aβ-PET scans.

RESULTS: Following Aβ-PET, changes were made in diagnosis (37.3%), in specific treatments for Alzheimer's disease (26.5%) and in psychiatric treatments (25.5%). The agreement between diagnosis pre-Aβ-PET versus post-Aβ-PET diagnosis was only fair, with a Cohen's kappa of 0.23 (95% CI 0-0.42). Patients with MRI findings suggestive of AD (medial temporal and/or parietal atrophy) were more frequently amyloid positive than amyloid negative (66.2% versus 33.8%, p = 0.04). Among patients with atypical clinical features for AD, but with MRI findings suggestive of AD, an amyloid negative PET scan had a greater impact than an amyloid positive PET scan on diagnosis (84.2% versus 17.1%, p < 0.001), management (84.2% versus 40%, p < 0.01) and discussion of results and advice on lifestyle (73.7% versus 22.9%, p < 0.001).

CONCLUSIONS: We conclude that MRI features suggestive of AD predict a positive amyloid PET scan. However, among those with MRI features suggestive of AD but with atypical clinical features of AD, the clinical impact on diagnosis and management is greater for an amyloid negative than an amyloid positive Aβ-PET scans.

%B J Alzheimers Dis %V 66 %P 1599-1608 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30475766?dopt=Abstract %R 10.3233/JAD-180683 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Utility of an Alzheimer's Disease Risk-Weighted Polygenic Risk Score for Predicting Rates of Cognitive Decline in Preclinical Alzheimer's Disease: A Prospective Longitudinal Study. %A Porter, Tenielle %A Burnham, Samantha C %A Milicic, Lidija %A Savage, Greg %A Maruff, Paul %A Lim, Yen Ying %A Li, Qiao-Xin %A Ames, David %A Masters, Colin L %A Rainey-Smith, Stephanie %A Rowe, Christopher C %A Salvado, Olivier %A Groth, David %A Verdile, Giuseppe %A Villemagne, Victor L %A Laws, Simon M %X

BACKGROUND: With the exception of APOE, genetic variants associated with increased Alzheimer's disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood.

OBJECTIVE: To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline.

METHODS: The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer's Cognitive Composite (PACC).

RESULTS: PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aβhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aβhigh CN older adults is due to a saturating effect of APOE genotype.

CONCLUSIONS: An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.

%B J Alzheimers Dis %V 66 %P 1193-1211 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412495?dopt=Abstract %R 10.3233/JAD-180713 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Utility of the LIBRA Index in Relation to Cognitive Functioning in a Clinical Health Seeking Sample. %A Pons, Anke %A LaMonica, Haley M %A Mowszowski, Loren %A Köhler, Sebastian %A Deckers, Kay %A Naismith, Sharon L %X

BACKGROUND: Dementia prevalence is expected to increase substantially over the next few decades. Since there is currently no cure for dementia available, there is an urgent need for the early identification of individuals at high risk for dementia, so that primary and secondary prevention strategies can be implemented. Recently, the LIfestyle for BRAin health (LIBRA) index was developed as a new dementia risk algorithm. It specifically focuses on modifiable risk and protective factors that can be targeted in midlife.

OBJECTIVE: The objective of this study was to evaluate the LIBRA index in relation to markers of cognitive functioning in a clinical, health-seeking sample of community-based older adults.

METHODS: 484 participants (mean age 62.7 years) were recruited from the Healthy Brain Ageing Clinic at the Brain and Mind Centre, Sydney. Participants underwent comprehensive clinical and neuropsychological assessment and completed a self-report survey pack. Participants were rated via consensus as having either subjective cognitive complaints (SCC) or meeting criteria for mild cognitive impairment (MCI). The LIBRA score was calculated based on 11 available risk and protective factors.

RESULTS: 65.4% of the sample met criteria for MCI. People with MCI showed a significantly higher LIBRA score compared to people with SCC. Furthermore, multiple cognitive domains, in particular executive functioning, were associated with a higher LIBRA score, with stronger correlations in people with MCI.

CONCLUSION: The LIBRA index might be a useful tool to determine lifestyle-attributable risk of cognitive decline in an older health-seeking population, including people with MCI.

%B J Alzheimers Dis %V 62 %P 373-384 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439337?dopt=Abstract %R 10.3233/JAD-170731 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Validation of the Delayed Matching-to-Sample Task 48 (DMS48) in Elderly Chinese. %A Feng, Xueyan %A Zhou, Aihong %A Liu, Zhixin %A Li, Fangyu %A Wei, Cuibai %A Zhang, Guili %A Jia, Jianping %K Aged %K Aged, 80 and over %K Alzheimer Disease %K China %K Cognitive Dysfunction %K Cross-Sectional Studies %K Female %K Humans %K Linear Models %K Male %K Memory Disorders %K Middle Aged %K Neuropsychological Tests %K ROC Curve %K Sensitivity and Specificity %K Severity of Illness Index %X

BACKGROUND: Delayed Matching-to-Sample Task 48 (DMS48), a brief tool measuring visual recognition memory, is valid to identify the early stage of Alzheimer's disease (AD) in Caucasians. However, little data is available in Chinese.

OBJECTIVE: To develop norms and optimal cutoff points for the DMS48 in Chinese elders.

METHODS: A cross-sectional study was conducted in seven memory clinics from five cities across China. DMS48 was applied to 369 Chinese aged 50 or older (138 cognitively normal [CN], 112 mild cognitive impairment due to AD (MCI-A), and 119 mild AD dementia). The demographic factors which influence DMS48 scores were investigated and the norms were established considering those factors. Receiver operating characteristic (ROC) analysis was used to determine the optimal cutoff points.

RESULTS: Age was shown to influence DMS48 scores (r = -0.36, p < 0.05), and we presented the age-stratified normative data for the DMS48. The optimal cutoff point is 42/43 for identifying cognitive impairment (MCI-A and AD dementia) against CN (sensitivity 97.80% and specificity 89.13%) and MCI-A against CN (sensitivity 86.60% and specificity 94.20%). A cutoff of 39/40 obtained good sensitivity (100.00%) and specificity (94.90%) in discriminating AD dementia from CN. The age-stratified optimal cutoff points for identifying MCI-A were 43/44 for individuals aged 50 to 59 years old, 42/43 for 60 to 69 years old, 41/42 for 70 to 79 years old, and 40/41 for 80 or older, respectively (sensitivity 84.80% and specificity 95.70%).

CONCLUSION: This study proved that DMS48 is of good validation in screening MCI-A in elderly Chinese.

%B J Alzheimers Dis %V 61 %P 1611-1618 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376851?dopt=Abstract %R 10.3233/JAD-170530 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Validation of the Spanish Version of the Dementia Knowledge Assessment Tool 2. %A Parra-Anguita, Laura %A Moreno-Cámara, Sara %A López-Franco, María Dolores %A Pancorbo-Hidalgo, Pedro L %X

BACKGROUND: There are currently no questionnaires to measure the knowledge of nurses about dementia or Alzheimer's disease care in the Spanish language.

OBJECTIVE: To validate the Spanish version of the Dementia Knowledge Assessment Tool 2 (DKAT2-Sp).

METHODS: The DKAT2 was translated into Spanish and then back-translated. The new Spanish version was validated in a sample of 361 members of the nursing staff from 24 nursing homes and a sample of 297 nursing students in Spain. Psychometric properties were assessed through an item analysis, a Rasch analysis, differential item functioning analysis, construct validity (known groups), and internal consistency (Cronbach's alpha).

RESULTS: The 21 items of the DKAT2-Sp fit the model well, showing a wide range of difficulty. Four items have differential items functioning between nursing professionals and students. The DKAT2-Sp shows acceptable internal consistency (Cronbach's alpha = 0.76 for nursing professionals and 0.83 for students). Scores obtained in the known groups test were as hypothesized (Nursing home staff mean = 15.57 versus Nursing student mean = 12.85; p < 0.0001 for mean difference), supporting construct validity.

CONCLUSION: The DKAT2-Sp is a reliable and valid questionnaire to measure knowledge about dementia in both nursing professionals and nursing students in Spanish-speaking contexts.

%B J Alzheimers Dis %V 65 %P 1175-1183 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30124445?dopt=Abstract %R 10.3233/JAD-180290 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Vascular Cognitive Impairment and the Gut Microbiota. %A Li, Sinian %A Shao, Yiming %A Li, Kanglan %A HuangFu, Changmei %A Wang, Wenjie %A Liu, Zhou %A Cai, Zhiyou %A Zhao, Bin %X

Vascular cognitive impairment (VCI), the second most common cause of dementia in elderly people, is a term that refers to all forms of cognitive disorders that can be attributed to cerebrovascular disease such as manifestations of discrete infarctions, brain hemorrhages, and white matter lesions. The gut microbiota (GM) has emerged recently as an essential player in the development of VCI. The GM may affect the brain's physiological, behavioral, and cognitive functions through the brain-gut axis via neural, immune, endocrine, and metabolic pathways. Therefore, microbiota dysbiosis may mediate or affect atherosclerosis, cerebrovascular disease, and endothelial dysfunction, which are the predominant risk factors for VCI. Moreover, the composition of the GM includes the bacterial component lipopolysaccharides and their metabolic products including trimethylamine-N-oxide and short-chain fatty acids. These products may increase the permeability of the intestinal epithelium, leading to systemic immune responses, low-grade inflammation, and altered signaling pathways that are associated with the pathogenesis of VCI. In this review, we discuss the proposed mechanisms of the GM in the maintenance of VCI and how it is implicated in acquired metabolic diseases, particularly in VCI regulation.

%B J Alzheimers Dis %V 63 %P 1209-1222 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689727?dopt=Abstract %R 10.3233/JAD-171103 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Vascular Effects on Depressive Symptoms in Cognitive Impairment. %A Kim, Yeshin %A Jang, Hyemin %A Kim, Seung Joo %A Cho, Soo Hyun %A Kim, Si Eun %A Kim, Sung Tae %A Kim, Hee Jin %A Moon, Seung Hwan %A Ewers, Michael %A Im, Kiho %A Kwon, Hunki %A Na, Duk L %A Seo, Sang Won %X

Late life depression is related to pathologic burdens, such as cerebral small vascular disease (CSVD) and amyloid, which are associated with brain network changes and cortical thinning. To examine the associations of various CSVD imaging markers, amyloid, and network changes with depression in cognitively impaired patients, we prospectively recruited 228 cognitively impaired patients having various degrees of amyloid and CSVD who underwent diffuse tensor image and PiB PET. Greater CSVD burden was associated with greater Geriatric Depression Scale (GDS) (white matter hyperintensities, WMH: p = 0.025, lacunes: p < 0.001) but not with amyloid (p = 0.095), and cortical thinning (p = 0.630) was not associated with greater GDS. The changes in white matter networks were related to GDS with decreasing integration (global efficiency: p < 0.001) and increasing segregation (clustering coefficient: p = 0.009). The network changes mediated the relationships of WMH and lacunes with GDS. Our findings provide insight to better understand how CSVD burdens contribute to depression in cognitively impaired patients having varying degrees of amyloid and vascular burdens.

%B J Alzheimers Dis %V 65 %P 597-605 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056427?dopt=Abstract %R 10.3233/JAD-180394 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Vascular Hypothesis of Alzheimer's Disease: A Key to Preclinical Prediction of Dementia Using Neuroimaging. %A de la Torre, Jack %X

The vascular hypothesis of Alzheimer's disease (VHAD) was proposed 24 years ago from observations made in our laboratory using aging rats subjected to chronic brain hypoperfusion. In recent years, VHAD has become a mother-lode to numerous neuroimaging studies targeting cerebral hemodynamic changes, particularly brain hypoperfusion in elderly patients at risk of developing Alzheimer's disease (AD). There is a growing consensus among neuroradiologists that brain hypoperfusion is likely involved in the pathogenesis of AD and that disturbed cerebral blood flow (CBF) can serve as a key biomarker for predicting conversion of mild cognitive impairment to AD. The use of cerebral hypoperfusion as a preclinical predictor of AD is becoming decisive in stratifying low and high risk patients that may develop cognitive decline and for assessing the effectiveness of therapeutic interventions. There is currently an international research drive from neuroimaging groups to seek new perspectives that can broaden our understanding of AD and improve lifestyle. Diverse neuroimaging methods are currently being used to monitor normal and dyscognitive brain activity. Some techniques are very powerful and can detect, diagnose, quantify, prognose, and predict cognitive decline before AD onset, even from a healthy cognitive state. Multimodal imaging offers new insights in the treatment and prevention of cognitive decline during advanced aging and better understanding of the functional and structural organization of the human brain. This review discusses the impact the VHAD and CBF are having on the neuroimaging technology that can usher practical strategies to help prevent AD.

%B J Alzheimers Dis %V 63 %P 35-52 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614675?dopt=Abstract %R 10.3233/JAD-180004 %0 Journal Article %J J Alzheimers Dis %D 2018 %T VEGFR1 and VEGFR2 in Alzheimer's Disease. %A Harris, Rachel %A Miners, James Scott %A Allen, Shelley %A Love, Seth %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Case-Control Studies %K Endothelial Cells %K Female %K Gene Expression Regulation %K Humans %K Male %K Middle Aged %K Neovascularization, Pathologic %K RNA, Messenger %K Signal Transduction %K Vascular Endothelial Growth Factor A %K Vascular Endothelial Growth Factor Receptor-1 %K Vascular Endothelial Growth Factor Receptor-2 %X

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer's disease (AD), probably in response to amyloid-β, vasoconstriction, and tissue hypoxia, there is no consequent increase in microvessel density. VEGF binds to and activates VEGF receptor 2 (VEGFR2), but also binds to VEGF receptor 1 (VEGFR1), which exists in less-active membrane-bound and inactive soluble (sVEGFR1) forms and inhibits pro-angiogenic signaling. We have investigated whether altered expression of VEGF receptors might account for the lack of angiogenic response to VEGF in AD. We assessed the cellular distribution and protein level of VEGFR1 and VEGFR2 in parietal cortex from 50 AD and 36 age-matched control brains, and related the findings to measurements of VEGF and von Willebrand factor level (a marker of microvessel density) in the same tissue samples. VEGFR2 was expressed by neurons, astrocytes and endothelial cells. VEGFR1 was expressed predominantly neuronally and was significantly reduced in AD (p = 0.02). Western blot analysis on a subset of brains showed reduction in VEGFR1:sVEGFR1 in AD (p = 0.046). The lack of angiogenesis despite cerebral hypoperfusion in AD is not explained by altered expression of VEGFR2 or total VEGFR1; indeed, the downregulation of VEGFR1 may represent a pro-angiogenic response to the hypoperfusion. However, the relative increase in sVEGFR1 would be expected to have an anti-angiogenic effect which may be a factor in AD.

%B J Alzheimers Dis %V 61 %P 741-752 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226875?dopt=Abstract %R 10.3233/JAD-170745 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Ventral Tegmental Area in Prodromal Alzheimer's Disease: Bridging the Gap between Mice and Humans. %A D'Amelio, Marcello %A Serra, Laura %A Bozzali, Marco %X

Alzheimer's disease (AD) is a progressive neurological disorder characterized by several cognitive and non-cognitive symptoms, with episodic memory being the earliest and most prominently impaired cognitive function. Dopaminergic signals are required for encoding hippocampal memory for new events and the ventral tegmental area (VTA), together with the locus coeruleus, are the primary sources of dopamine acting on dopaminergic receptors in the hippocampus. With this in mind, a recent study on a validated mouse model of AD highlighted on the hippocampal dysfunction and its correlation with an early degeneration of dopaminergic neurons in the VTA. In this issue, De Marco and Venneri test the hypothesis that the volume of the VTA nucleus in humans might be associated with cognitive features of AD.

%B J Alzheimers Dis %V 63 %P 181-183 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29630556?dopt=Abstract %R 10.3233/JAD-180094 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Vestibular Loss Predicts Poorer Spatial Cognition in Patients with Alzheimer's Disease. %A Wei, Eric X %A Oh, Esther S %A Harun, Aisha %A Ehrenburg, Matthew %A Agrawal, Yuri %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Bilateral Vestibulopathy %K Cognitive Dysfunction %K Cross-Sectional Studies %K Female %K Humans %K Linear Models %K Male %K Multivariate Analysis %K Neuropsychological Tests %K Prospective Studies %K Spatial Navigation %K Vestibular Function Tests %X

The vestibular system is an important contributor to balance control, spatial orientation, and falls risk. Recent evidence has shown that Alzheimer's disease (AD) patients have a higher prevalence of vestibular impairment relative to healthy controls. We sought to evaluate whether vestibular loss is specifically associated with poor spatial cognitive skills among patients with mild cognitive impairment (MCI) and AD. We enrolled 50 patients (22 MCI and 28 AD) from an interdisciplinary Memory Clinic and measured vestibular physiologic function in all patients. Spatial cognitive function was assessed using the Money Road Map Test (MRMT) and the Trail Making Test Part B (TMT-B). General cognitive function was assessed with the Mini-Mental Status Examination (MMSE). In multivariable linear regression analyses adjusted for age, gender, education level, and MMSE, MCI and AD patients with vestibular loss made significantly more errors on the MRMT relative to patients with normal vestibular function (β= 7.3, 95% CI 2.4, 12.1 for unilateral vestibular loss and β= 6.4, 95% CI 1.9, 10.9 for bilateral vestibular loss). We further stratified AD patients into "spatially normal" and "spatially impaired" groups based on MRMT performance, and found that the prevalence of vestibular loss was significantly higher in the spatially impaired AD group relative to the spatially normal AD group. These findings support the hypothesis that vestibular loss contributes specifically to a decline in spatial cognitive ability in MCI and AD patients, independently of general cognitive decline, and may predict a "spatially impaired" subtype of AD.

%B J Alzheimers Dis %V 61 %P 995-1003 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254098?dopt=Abstract %R 10.3233/JAD-170751 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Visit-To-Visit Blood Pressure Variability and the Risk of Dementia in Older People. %A van Middelaar, Tessa %A van Dalen, Jan W %A van Gool, Willem A %A van den Born, Bert-Jan H %A van Vught, Lonneke A %A Moll van Charante, Eric P %A Richard, Edo %K Aged %K Antihypertensive Agents %K Blood Pressure %K Cardiovascular Diseases %K Dementia %K Female %K Humans %K Hypertension %K Incidence %K Male %K Netherlands %K Proportional Hazards Models %K Risk Factors %X

BACKGROUND: High visit-to-visit variability (VVV) in blood pressure (BP) is associated with cerebrovascular lesions on neuroimaging.

OBJECTIVE: Our primary objective was to investigate whether VVV is associated with incident all-cause dementia. As a secondary objective, we studied the association of VVV with cognitive decline and cardiovascular disease (CVD).

METHODS: We included community-dwelling people (age 70-78 year) from the 'Prevention of Dementia by Intensive Vascular Care' (preDIVA) trial with three to five 2-yearly BP measurements during 6-8 years follow-up. VVV was defined using coefficient of variation (CV; SD/mean×100). Cognitive decline was assessed using the Mini-Mental State Examination (MMSE). Incident CVD was defined as myocardial infarction or stroke. We used a Cox proportional hazard regression and mixed-effects model adjusted for sociodemographic factors and cardiovascular risk factors.

RESULTS: In 2,305 participants (aged 74.2±2.5), mean systolic BP over all available visits was 150.1 mmHg (SD 13.6), yielding a CV of 9.0. After 6.4 years (SD 0.8) follow-up, 110 (4.8%) participants developed dementia and 140 (6.1%) CVD. Higher VVV was not associated with increased risk of dementia (hazard ratio [HR] 1.00 per point CV increase; 95% confidence interval [CI] 0.96-1.05), although the highest quartile of VVV was associated with stronger decline in MMSE (β -0.09, 95% CI -0.17 to -0.01). Higher VVV was associated with incident CVD (HR 1.07; 95% CI 1.04-1.11).

CONCLUSION: In our study among older people, high VVV is not associated with incident all-cause dementia. It is associated with decline in MMSE and incident CVD.

%B J Alzheimers Dis %V 62 %P 727-735 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480175?dopt=Abstract %R 10.3233/JAD-170757 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Visual Processing during Short-Term Memory Binding in Mild Alzheimer's Disease. %A Fernández, Gerardo %A Orozco, David %A Agamennoni, Osvaldo %A Schumacher, Marcela %A Sañudo, Silvana %A Biondi, Juan %A Parra, Mario A %X

Patients with Alzheimer's disease (AD) typically present with attentional and oculomotor abnormalities that can have an impact on visual processing and associated cognitive functions. Over the last few years, we have witnessed a shift toward the analyses of eye movement behaviors as a means to further our understanding of the pathophysiology of common disorders such as AD. However, little work has been done to unveil the link between eye moment abnormalities and poor performance on cognitive tasks known to be markers for AD patients, such as the short-term memory-binding task. We analyzed eye movement fixation behaviors of thirteen healthy older adults (Controls) and thirteen patients with probable mild AD while they performed the visual short-term memory binding task. The short-term memory binding task asks participants to detect changes across two consecutive arrays of two bicolored object whose features (i.e., colors) have to be remembered separately (i.e., Unbound Colors), or combined within integrated objects (i.e., Bound Colors). Patients with mild AD showed the well-known pattern of selective memory binding impairments. This was accompanied by significant impairments in their eye movements only when they processed Bound Colors. Patients with mild AD remarkably decreased their mean gaze duration during the encoding of color-color bindings. These findings open new windows of research into the pathophysiological mechanisms of memory deficits in AD patients and the link between its phenotypic expressions (i.e., oculomotor and cognitive disorders). We discuss these findings considering current trends regarding clinical assessment, neural correlates, and potential avenues for robust biomarkers.

%B J Alzheimers Dis %V 63 %P 185-194 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614644?dopt=Abstract %R 10.3233/JAD-170728 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Visual Processing of Emotional Faces is Preserved in Mild Cognitive Impairment. %A McCade, Donna L %A Guastella, Adam J %A Chen, Nigel T M %A Lewis, Simon J G %A Naismith, Sharon L %X

BACKGROUND: Research suggests that deficits in emotion recognition are evident in individuals with amnestic mild cognitive impairment (aMCI), a group 'at risk' of developing dementia. The mechanisms underlying this deficit, however, are unclear.

OBJECTIVE: In this study, we sought to determine whether there are alterations in the way in which individuals with MCI visually explore emotional facial stimuli.

METHODS: Eighteen healthy older controls (mean age = 64.6 years) and 32 individuals with MCI were recruited including 18 with the non-amnestic multiple domain (naMCI-md) subtype (mean age = 63.8 years) and 14 with the amnestic multiple domain (aMCI-md) subtype (mean age = 67.9 years). All participants were given a novel eye-tracking paradigm to investigate eye gaze while viewing images of emotional faces on a computer screen.

RESULTS: Analyses of eye gaze revealed no significant difference in the percentage of time that groups spent fixating on facial and peripheral facial regions when viewing emotional faces. All participants showed a relative preference for the eye region of faces relative to all other regions. Individuals with aMCI-md were found to be less accurate than controls and naMCI-md on emotion recognition measures. For naMCI-md individuals, significant relationships were found between efficiencies in visual scanning and increased fixation time on the eye region.

CONCLUSIONS: Visual processing strategies adopted by aMCI-md individuals when exploring emotional faces do not significantly differ from those of healthy controls or naMCI-md individuals. This suggests that impaired facial emotion recognition in aMCI-md is not likely accounted for by visual processing differences, but rather may reflect an eroded ability to extract meaningful cues from the eye region.

%B J Alzheimers Dis %V 66 %P 397-405 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282351?dopt=Abstract %R 10.3233/JAD-170175 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Visualization of Focal Thinning of the Ganglion Cell-Inner Plexiform Layer in Patients with Mild Cognitive Impairment and Alzheimer's Disease. %A Shao, Yi %A Jiang, Hong %A Wei, Yantao %A Shi, Yingying %A Shi, Ce %A Wright, Clinton B %A Sun, Xiaoyan %A Vanner, Elizabeth A %A Rodriguez, Anny D %A Lam, Byron L %A Rundek, Tatjana %A Baumel, Barry S %A Gameiro, Giovana Rosa %A Dong, Chuanhui %A Wang, Jianhua %X

BACKGROUND: A detailed analysis of the tomographic thickness of intraretinal layers may provide more information on neurodegeneration in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD).

OBJECTIVE: The goal was to analyze tomographic thickness patterns of intraretinal layers in patients with AD andMCI.

METHOD: Forty-nine patients (25 AD and 24 MCI) and 21 cognitively normal (CN) controls were imaged using ultra-high-resolution optical coherence tomography to obtain volumetric data centered on the fovea. The segmented intraretinal layers were retinal nerve fiber layer (RNFL), ganglion cell- inner plexiform layer (GCIPL), inner nuclear layer (INL), outer nuclear layer (ONL), outer plexiform layer (OPL), and retinal photoreceptor (PR), in addition to the total retinal thickness(TRT).

RESULTS: The thickness differences were negative (thinning) mainly in TRT, RNFL, and GCIPL in both AD and MCI groups in comparison to CN, while the thickness differences were positive (thickening) mainly in ONL and PR in AD. GCIPL of AD and MCI was thinner in superior, nasal superior, and temporal superior quadrants, compared to CN (p < 0.05). GCIPL of the inner superior, inner nasal superior, inner temporal superior, and outer nasal superior sectors was significantly thinner in AD than CN (p < 0.05). GCIPL of the outer superior, inner temporal superior, outer nasal, and temporal superior sectors was significantly thinner in MCI than CN (p < 0.05).

CONCLUSION: Focal thinning of the GCIPL was visualized and quantified by detailed partitions in AD and MCI, which provides specific information about neurodegeneration in MCI and AD.

%B J Alzheimers Dis %V 64 %P 1261-1273 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040712?dopt=Abstract %R 10.3233/JAD-180070 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Volume and Connectivity of the Ventral Tegmental Area are Linked to Neurocognitive Signatures of Alzheimer's Disease in Humans. %A De Marco, Matteo %A Venneri, Annalena %X

BACKGROUND: There is an urgent need to identify the earliest biological changes within the neuropathological cascade of Alzheimer's disease (AD) processes. Recent findings in a murine model of AD showed significant preclinical loss of dopaminergic neurons in the ventral tegmental area (VTA), accompanied by reduced hippocampal innervation and declining memory. It is unknown if these observations can be translated in humans.

OBJECTIVE: We tested the hypothesis that VTA volume is associated with the typical clinical markers of AD in a cohort of patients and healthy controls.

METHODS: Structural and resting state functional MRI scans, and neuropsychological scores were acquired for 51 healthy adults, 30 patients with a diagnosis of mild cognitive impairment, and 29 patients with a diagnosis of AD dementia. VTA volume was quantified together with other control nuclei. The association between nuclei volume, hippocampal size, memory performance, and linguistic-executive skills was tested. The effect of VTA functional connectivity was also tested.

RESULTS: VTA size, but not of control nuclei, yielded a strong association with both hippocampal size and memory competence (but not linguistic-executive performance), and this was particularly strong in healthy adults. In addition, functional connectivity between the VTA and hippocampus was significantly associated with both markers of AD.

CONCLUSION: Diminished dopaminergic VTA activity may be crucial for the earliest pathological features of AD and might suggest new strategies for early treatment. Memory encoding processes may represent cognitive operations susceptible to VTA neurodegeneration.

%B J Alzheimers Dis %V 63 %P 167-180 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578486?dopt=Abstract %R 10.3233/JAD-171018 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Voxel-Based Acetylcholinesterase PET Study in Early and Late Onset Alzheimer's Disease. %A Hirano, Shigeki %A Shinotoh, Hitoshi %A Shimada, Hitoshi %A Ota, Tsuneyoshi %A Sato, Koichi %A Tanaka, Noriko %A Zhang, Ming-Rong %A Higuchi, Makoto %A Fukushi, Kiyoshi %A Irie, Toshiaki %A Kuwabara, Satoshi %A Suhara, Tetsuya %X

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic progressive cognitive decline and displays underlying brain cholinergic dysfunction, providing a rationale for treatment with cholinomimetic medication. The clinical presentations and courses of AD patients may differ by age of onset.

OBJECTIVE: The objective of the present study was to illustrate the regional differences of brain acetylcholinesterase (AChE) activity as quantified by N-[11C]methylpiperidinyl-4-acetate ([11C]MP4A) and PET using parametric whole brain analysis and clarify those differences as a function of age.

METHODS: 22 early onset AD (EOAD) with age at onset under 65, the remaining 26 as late onset AD (LOAD), and 16 healthy controls (HC) were enrolled. Voxel-based AChE activity estimation of [11C]MP4A PET images was conducted by arterial input and unconstrained nonlinear least-squares method with subsequent parametrical analyses. Statistical threshold was set as Family Wise Error corrected, p-value <0.05 on cluster-level and cluster extent over 30 voxels.

RESULTS: Voxel-based group comparison showed that, compared to HC, both EOAD and LOAD showed cortical AChE decrement in parietal, temporal, and occipital cortices, with wider and stringent cortical involvement in the EOAD group, most prominently demonstrated in the temporal region. There was no significant correlation between age and regional cerebral AChE activity except for a small left superior temporal region in the AD group (Brodmann's area 22, Zmax = 5.13, 396 voxels), whereas no significant cluster was found in the HC counterpart.

CONCLUSION: Difference in cortical cholinergic dysfunction between EOAD and LOAD may shed some light on the cholinomimetic drug efficacy in AD.

%B J Alzheimers Dis %V 62 %P 1539-1548 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562505?dopt=Abstract %R 10.3233/JAD-170749 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Walnut Supplementation in the Diet Reduces Oxidative Damage and Improves Antioxidant Status in Transgenic Mouse Model of Alzheimer's Disease. %A Pandareesh, Mirazkar D %A Chauhan, Ved %A Chauhan, Abha %X

Our previous study has shown beneficial effects of walnuts on memory and learning skills in transgenic mouse model of Alzheimer's disease (AD-tg). To understand underlying mechanism, we studied here whether walnuts can reduce oxidative stress in AD. From 4 months of age, experimental AD-tg mice were fed diets containing 6% (T6) or 9% walnuts (T9) (equivalent to 1 or 1.5 oz, of walnuts per day in humans) for 5, 10, or 15 months. The control groups, i.e., AD-tg (T0) and wild-type (Wt) mice, were fed diets without walnuts. Free radicals, i.e., reactive oxygen species (ROS), lipid peroxidation, protein oxidation, and antioxidant enzymes were assessed in these mice at different ages. AD-tg mice on control diet (T0) showed significant age-dependent increase in ROS levels, lipid peroxidation, and protein oxidation coupled with impaired activities of antioxidant enzymes [superoxide dismutase, catalase, and glutathione peroxidase] compared to Wt mice. Oxidative stress was significantly reduced in AD-tg mice on diets with walnuts (T6, T9), as evidenced by decreased levels of ROS, lipid peroxidation, and protein oxidation, as well as by enhanced activities of antioxidant enzymes compared to T0 mice. Long-term supplementation with walnuts for 10 or 15 months was more effective in reducing oxidative stress in AD-tg mice. Our findings indicate that walnuts can reduce oxidative stress, not only by scavenging free radicals, but also by protecting antioxidant status, thus leading to reduced oxidative damage to lipids and proteins in AD. Therefore, by reducing oxidative stress, a walnut-enriched diet may help reduce the risk or delay the onset and progression of AD.

%B J Alzheimers Dis %V 64 %P 1295-1305 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040727?dopt=Abstract %R 10.3233/JAD-180361 %0 Journal Article %J J Alzheimers Dis %D 2018 %T What Do We Know About Behavioral Crises in Dementia? A Systematic Review. %A Backhouse, Tamara %A Camino, Julieta %A Mioshi, Eneida %X

BACKGROUND: Behavioral crises in dementia are represented by a wide variety of symptoms, regularly require external intervention from professionals, and are reported as a risk factor for hospital admission. Little is known about the factors that are associated with them.

OBJECTIVE: To determine the factors associated with dementia-related behavioral crises.

METHODS: We searched MEDLINE, CINAHL, PsycINFO, EMBASE, and AMED databases. An additional lateral search including reference lists was conducted. Two researchers screened all records for potential eligibility. Narrative synthesis was used to bring together the findings.

RESULTS: Out of the 5,544 records identified, 24 articles (18 distinct studies) met the eligibility criteria. Aggression and agitation were the most common behaviors present at crises. Delusions, wandering/absconding, and hallucinations were also key behaviors contributing to crises. Behavioral crises predominantly happened in the severe stages of dementia (according to MMSE scores), in people with dementia residing in their own homes and in long-term care, and were the catalyst for admissions to psychiatric inpatient settings, specialist-care units, long-term care settings, or for referrals to psychiatric community services. Lack of consistency in assessment of behavior, and management of agitation/aggression in dementia crises were evident.

CONCLUSION: Interventions to reduce the likelihood of people with dementia-related behaviors reaching crisis point need to focus on both family and care home settings and incorporate aggression and agitation management. Future research should focus on determining the factors that could be addressed to prevent behavioral crises and the interventions and models of care that may help to prevent crises.

%B J Alzheimers Dis %V 62 %P 99-113 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439334?dopt=Abstract %R 10.3233/JAD-170679 %0 Journal Article %J J Alzheimers Dis %D 2018 %T What Factors Predict Family Caregivers' Attendance at Dementia Cafés? %A Jones, Susan May %A Killett, Anne %A Mioshi, Eneida %X

BACKGROUND: Dementia Cafés are community support groups which provide post-diagnostic support for families affected by dementia. However, little is known about the characteristics of caregivers who attend Cafés.

OBJECTIVES: To describe the demographic and psychosocial characteristics of caregivers who attend Dementia Cafés, and to identify which of those factors may influence the likelihood of family caregivers attending Dementia Cafés.

METHODS: A cross-sectional study on caregivers (n = 80; July 2016- July 2017). Resilience (Brief Resilient Coping Scale), Subjective Wellbeing (Personal Wellbeing Index), and Social Support (MOS-Social Support Survey) were measured. Café attendees and non-attendees were compared in regards to demographic characteristics (Chi-Square tests), resilience, subjective wellbeing and social support (independent t-tests). Bivariate and multivariate regression analyses were run to detect associations between predictor variables and café attendance.

RESULTS: Caregivers who attended Cafés reported higher resilience (OR: 1.26; 95% CI 1.10-1.45; p = 0.001) and subjective wellbeing (OR: 1.63; 95% CI 1.24-2.142; p = 0.001); no significant difference in social support was detected. Female caregivers were more likely to attend a Café (OR: 3.23; 95% CI 1.14-9.10; p = 0.03). However, only higher subjective wellbeing (OR: 1.63; 95% CI 1.10-24.2; p = 0.02) and fewer years formal education (OR: 4.99; 95% CI 1.12-21.36; p = 0.03) predicted attendance at a café.

CONCLUSION: Dementia Cafés may bring about benefits in resilience and subjective wellbeing, or may be best suited to those with higher resilience and wellbeing. Cafes are not being accessed by all caregiver groups. Alternative models of post-diagnostic support should be considered to increase equity of care.

%B J Alzheimers Dis %V 64 %P 1337-1345 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29991136?dopt=Abstract %R 10.3233/JAD-180377 %0 Journal Article %J J Alzheimers Dis %D 2018 %T When Art Meets Gardens: Does It Enhance the Benefits? The Nancy Hypothesis of Care for Persons with Alzheimer's Disease. %A Jonveaux, Thérèse Rivasseau %A Fescharek, Reinhard %K Alzheimer Disease %K Art Therapy %K Cognition %K Cognitive Behavioral Therapy %K France %K Gardening %K Humans %X

The creation of healing gardens for persons with Alzheimer's disease and related diseases (ADRD) offers vast potential. They can play a role in the scaffolding of cognitive disorders, emotional stress, sensory processing, sense of harmony, and appeasement. These effects are achieved through a distributed interplay of psychological functions with the immediate environment and local culture on the one hand, and dialogue on the other. The garden, a natural canvas created by man, shares with art the ability to foster an esthetic sense for which the perception can be measured by functional neurological imaging exploration. Art represents a mediator for the collaborative realization of distributed psychological functions between different individuals. Based on the hypothesis of an optimization of the therapeutic potential of a garden by a design adapted to the neuro-psycho-social and cultural specificities of its users combined with the thoughtful introduction of an artistic dimension, the "art, memory and life" healing garden was created at the University Hospital of Nancy as a prototype for persons with ADRD. The design concept was based on two hypotheses that we formulate herein, discuss their theoretical foundation, and suggest enhanced design for therapeutic gardens based upon our experience.

%B J Alzheimers Dis %V 61 %P 885-898 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332052?dopt=Abstract %R 10.3233/JAD-170781 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Which Risk Factors Causally Influence Dementia? A Systematic Review of Mendelian Randomization Studies. %A Kuźma, Elżbieta %A Hannon, Eilis %A Zhou, Ang %A Lourida, Ilianna %A Bethel, Alison %A Levine, Deborah A %A Lunnon, Katie %A Thompson-Coon, Jo %A Hyppönen, Elina %A Llewellyn, David J %X

BACKGROUND: Numerous risk factors for dementia are well established, though the causal nature of these associations remains unclear.

OBJECTIVE: To systematically review Mendelian randomization (MR) studies investigating causal relationships between risk factors and global cognitive function or dementia.

METHODS: We searched five databases from inception to February 2017 and conducted citation searches including MR studies investigating the association between any risk factor and global cognitive function, all-cause dementia or dementia subtypes. Two reviewers independently assessed titles and abstracts, full-texts, and study quality.

RESULTS: We included 18 MR studies investigating education, lifestyle factors, cardiovascular factors and related biomarkers, diabetes related and other endocrine factors, and telomere length. Studies were of predominantly good quality, however eight received low ratings for sample size and statistical power. The most convincing causal evidence was found for an association of shorter telomeres with increased risk of Alzheimer's disease (AD). Causal evidence was weaker for smoking quantity, vitamin D, homocysteine, systolic blood pressure, fasting glucose, insulin sensitivity, and high-density lipoprotein cholesterol. Well-replicated associations were not present for most exposures and we cannot fully discount survival and diagnostic bias, or the potential for pleiotropic effects.

CONCLUSIONS: Genetic evidence supported a causal association between telomere length and AD, whereas limited evidence for other risk factors was largely inconclusive with tentative evidence for smoking quantity, vitamin D, homocysteine, and selected metabolic markers. The lack of stronger evidence for other risk factors may reflect insufficient statistical power. Larger well-designed MR studies would therefore help establish the causal status of these dementia risk factors.

%B J Alzheimers Dis %V 64 %P 181-193 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865062?dopt=Abstract %R 10.3233/JAD-180013 %0 Journal Article %J J Alzheimers Dis %D 2018 %T White Matter and Cognition in Traumatic Brain Injury. %A Filley, Christopher M %A Kelly, James P %X

Traumatic brain injury (TBI) is a leading cause of disability and produces a wide range of cognitive, emotional, and physical consequences. The impact of TBI on cognition is among the most important questions in this field but remains incompletely understood. The immediate cognitive effects of concussion, while usually short-lived, may be profound and lasting in some individuals, and long-term sequelae of TBI may include dementia of several varieties including post-traumatic leukoencephalopathy, chronic traumatic encephalopathy, and Alzheimer's disease. Whereas the etiopathogenesis of cognitive dysfunction after TBI remains uncertain, a reasonable point to begin is a focus on the white matter of the brain, where the neuropathological lesion known as diffuse axonal injury (DAI) is routinely identified. White matter is not typically accorded the significance granted to cortical gray matter in discussions of cognitive dysfunction and dementia, but increasing evidence is accumulating to suggest that cognitive decline after TBI is a direct result of white matter injury, and that lesions in this brain component are crucial in the sequence of events leading ultimately to dementia of several types. In this review, we consider the topic of white matter and cognition in TBI, beginning with DAI and proceeding to the role of inflammation in the pathogenesis of cognitive dysfunction and dementia that can follow. A brief review of possible therapeutic options will also be offered, including the use of anti-inflammatory agents and the exploitation of white matter plasticity, to treat acute and post-acute injuries, and lower the incidence of dementia resulting from TBI.

%B J Alzheimers Dis %V 65 %P 345-362 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040722?dopt=Abstract %R 10.3233/JAD-180287 %0 Journal Article %J J Alzheimers Dis %D 2018 %T White Matter Hyperintensities and Cognition in Mild Cognitive Impairment and Alzheimer's Disease: A Domain-Specific Meta-Analysis. %A van den Berg, Esther %A Geerlings, Mirjam I %A Biessels, Geert Jan %A Nederkoorn, Paul J %A Kloppenborg, Raoul P %X

BACKGROUND: White matter hyperintensities (WMHs) are related to cognitive dysfunction in the general population. The clinical relevance of WMHs in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) is, however, unclear.

OBJECTIVE: This meta-analysis aimed to quantify the association of WMHs and specific cognitive domains in patients with MCI or AD.

METHODS: PubMed (January 1990-January 2017) was searched for studies that used MRI to quantify WMHs, and measured cognitive functioning (≥1 predefined cognitive domain with ≥1 test) in a well-defined population of persons diagnosed with MCI or AD. Fischer's Z was used as the common metric for effect size. Modifying effects of demographics, MMSE, and WMH location were examined.

RESULTS: Twelve cross-sectional studies on AD (total n = 1,370, median age 75 years) and 10 studies on MCI (9 cross-sectional, 1 longitudinal; total n = 2,286, median age 73 years) were included. The association between WMHs and overall cognition was significantly stronger for MCI (-0.25, -0.36 to -0.14) than for AD (-0.11, -0.14 to -0.08; QM = 10.7, p < 0.05). For both groups, largest effect sizes were found in attention and executive functions (-0.26, -0.36 to -0.15) and processing speed (-0.21, -0.35 to -0.12). No significant modifying effects of age and gender were found.

CONCLUSION: WMHs have a medium-sized association with different cognitive functions in patients with MCI and a small, but statistically significant, association with cognition in AD. These result underscore the role of co-occurring vascular brain damage in MCI and AD.

%B J Alzheimers Dis %V 63 %P 515-527 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29630548?dopt=Abstract %R 10.3233/JAD-170573 %0 Journal Article %J J Alzheimers Dis %D 2018 %T White Matter Hyperintensity Predicts the Risk of Incident Cognitive Decline in Community Dwelling Elderly. %A Ding, Ding %A Xiong, Yunyun %A Zhao, Qianhua %A Guo, Qihao %A Chu, Shuguang %A Chu, Winnie W C %A Luo, Jianfeng %A Liang, Xiaoniu %A Zheng, Li %A Hong, Zhen %A Wong, Lawrence K S %A Mok, Vincent C T %K Aged %K China %K Cognitive Dysfunction %K Female %K Humans %K Independent Living %K Kaplan-Meier Estimate %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K White Matter %X

BACKGROUND: Unlike western countries, data on white matter hyperintensity (WMH) in community dwelling elderly in Asian population is very limited.

OBJECTIVE: To examine the relation between baseline WMH burden and the risk of incident cognitive decline in a community-based cohort with Chinese-dwelling elderly.

METHODS: We prospectively evaluated the incident cognitive decline for 226 participants in the Shanghai Aging Study. Baseline WMH severity was visually rated by the age-related white matter changes (ARWMC) scale based on MRI. Cox proportional hazards regression model was used to estimate the relative risk (RR) of total ARWMC scale, global ARWMC score, presence of lacune and microbleed, for incident cognitive decline by adjusting potential confounders.

RESULTS: Forty subjects were identified with incident cognitive decline (new onset 34 mild cognitive impairment and 6 dementia) during a median duration of 6 years follow-up. The incidence of cognitive decline was 3.0 (95% confidence interval [CI] 2.2-4.1) per 100 person-years. Increasing total ARWMC scale [RR1.21 (95% CI 1.06-1.39), p = 0.004)], confluent WMH [RR3.16 (95% CI 1.50-6.64), p = 0.002), and presence of lacunes [RR 2.73 (95% CI 1.21-6.15)] at baseline were independent predictors of incident cognitive decline.

CONCLUSION: Our study demonstrated that confluent WMH may increase the risk of incident cognitive decline by 3 folds in community dwelling subjects. Small vessel disease may cause heavy burden of cognitive impairment in the elderly in China.

%B J Alzheimers Dis %V 61 %P 1333-1341 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376875?dopt=Abstract %R 10.3233/JAD-170876 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Word and Picture Version of the Free and Cued Selective Reminding Test (FCSRT): Is There Any Difference? %A Arighi, Andrea %A Carandini, Tiziana %A Mercurio, Matteo %A Carpani, Giovanni %A Pietroboni, Anna Margherita %A Fumagalli, Giorgio %A Ghezzi, Laura %A Basilico, Paola %A Calvi, Alberto %A Scarioni, Marta %A De Riz, Milena %A Fenoglio, Chiara %A Scola, Elisa %A Triulzi, Fabio %A Galimberti, Daniela %A Scarpini, Elio %K Aged %K Aged, 80 and over %K Association Learning %K Cognitive Dysfunction %K Cues %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Recall %K Middle Aged %K Neuropsychological Tests %K Photic Stimulation %K Vocabulary %X

The Free and Cued Selective Reminding Test (FCSRT) is the most commonly used neuropsychological test to evaluate episodic memory. Two variants of FCSRT exist, using the recall of words (FCSRT-w) or pictures (FCSRT-p). Fourteen patients with mild cognitive impairment underwent neuropsychological evaluation and brain magnetic resonance. We found differences in FCSRT-w and FCSRT-p variants scores. FCSRT-p was correlated with atrophy in areas involved in visual stimuli processing while FCSRT-w was correlated to hippocampal atrophy. Our study suggests that FCSRT-w and FCSRT-p scores are not equivalent, but a larger cohort of patients is needed to validate these results.

%B J Alzheimers Dis %V 61 %P 47-52 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125489?dopt=Abstract %R 10.3233/JAD-170712 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Zinc Exacerbates Tau Pathology in a Tau Mouse Model. %A Craven, Kristen M %A Kochen, William R %A Hernandez, Carlos M %A Flinn, Jane M %X

Hyperphosphorylated tau protein is a key pathology in Alzheimer's disease (AD), frontotemporal dementia, chronic traumatic encephalopathy, and Parkinson's disease. The essential trace element zinc exacerbates tauopathy in vitro as well as in a Drosophila model of AD. However, the interaction has never been assessed behaviorally or biochemically in mammals. Zinc supplementation is prevalent in society, finding use as a treatment for macular degeneration and cataracts, and is also taken as an immune system booster with high levels appearing in multivitamins marketed toward the elderly. Using a transgenic mouse model that contains the human gene for tau protein (P301L), we assessed the effects of excess chronic zinc supplementation on tau pathology. Behavioral tests included nest building, circadian rhythm, Morris Water Maze, fear conditioning, and open field. Biochemically, total tau and Ser396 phosphorylation were assessed using western blot. Number of tangles were assessed by Thioflavin-S and free zinc levels were assessed by Zinpyr-1. Tau mice demonstrated behavioral deficits compared to control mice. Zinc supplementation exacerbated tauopathic deficits in circadian rhythm, nesting behavior, and Morris Water Maze. Biochemically, zinc-supplemented tau mice showed increased phosphorylation at pSer396. Zinc supplementation in tau mice also increased tangle numbers in the hippocampus while decreasing free-zinc levels, demonstrating that tangles were sequestering zinc. These results show that zinc intensified the deficits in behavior and biochemistry caused by tau.

%B J Alzheimers Dis %V 64 %P 617-630 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914030?dopt=Abstract %R 10.3233/JAD-180151 %0 Journal Article %J J Alzheimers Dis %D 2017 %T 18F-AV-1451 PET Imaging in Three Patients with Probable Cerebral Amyloid Angiopathy. %A Kim, Hee Jin %A Cho, Hanna %A Werring, David J %A Jang, Young Kyoung %A Kim, Yeo Jin %A Lee, Jin San %A Lee, Juyoun %A Jun, Soomin %A Park, Seongbeom %A Ryu, Young Hoon %A Choi, Jae Yong %A Cho, Young Seok %A Moon, Seung Hwan %A Na, Duk L %A Lyoo, Chul Hyoung %A Seo, Sang Won %K Aged %K Aged, 80 and over %K Aniline Compounds %K Brain %K Carbolines %K Cerebral Amyloid Angiopathy %K Female %K Humans %K Image Processing, Computer-Assisted %K Male %K Positron-Emission Tomography %K Thiazoles %X

Cerebrovascular deposition of amyloid-β, known as cerebral amyloid angiopathy (CAA), is associated with MRI findings of lobar hemorrhage, cerebral microbleeds, and cortical superficial siderosis. Although pathological studies suggest that tau may co-localize with vascular amyloid, this has not yet been investigated in CAA in vivo. Three patients with probable CAA underwent 11C-Pittsburgh Compound B (PiB) PET or 18F-florbetaben PET to evaluate amyloid burden, and 18F-AV-1451 PET to evaluate paired helical filament tau burden. Regions that had cerebral microbleeds or cortical superficial siderosis largely overlapped with those showing increased 18F-AV-1451. Our preliminary study raised the possibility that lobar cerebral microbleeds, and cortical superficial siderosis, which are characteristic markers of vascular amyloid, may be associated with local production of paired helical filament tau.

%B J Alzheimers Dis %V 57 %P 711-716 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28282808?dopt=Abstract %R 10.3233/JAD-161139 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The 2002 NIMH Provisional Diagnostic Criteria for Depression of Alzheimer's Disease (PDC-dAD): Gauging their Validity over a Decade Later. %A Sepehry, Amir A %A Lee, Philip E %A Hsiung, Ging-Yuek R %A Beattie, B Lynn %A Feldman, Howard H %A Jacova, Claudia %X

Presented herein is evidence for criterion, content, and convergent/discriminant validity of the NIMH-Provisional Diagnostic Criteria for depression of Alzheimer's Disease (PDC-dAD) that were formulated to address depression in Alzheimer's disease (AD). Using meta-analytic and systematic review methods, we examined criterion validity evidence in epidemiological and clinical studies comparing the PDC-dAD to Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV), and International Classification of Disease (ICD 9) depression diagnostic criteria. We estimated prevalence of depression by PDC, DSM, and ICD with an omnibus event rate effect-size. We also examined diagnostic agreement between PDC and DSM. To gauge content validity, we reviewed rates of symptom endorsement for each diagnostic approach. Finally, we examined the PDC's relationship with assessment scales (global cognition, neuropsychiatric, and depression definition) for convergent validity evidence. The aggregate evidence supports the validity of the PDC-dAD. Our findings suggest that depression in AD differs from other depressive disorders including Major Depressive Disorder (MDD) in that dAD is more prevalent, with generally a milder presentation and with unique features not captured by the DSM. Although the PDC are the current standard for diagnosis of depression in AD, we identified the need for their further optimization based on predictive validity evidence.

%B J Alzheimers Dis %V 58 %P 449-462 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453472?dopt=Abstract %R 10.3233/JAD-161061 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A 24-Week Multi-Modality Exercise Program Improves Executive Control in Older Adults with a Self-Reported Cognitive Complaint: Evidence from the Antisaccade Task. %A Heath, Matthew %A Shellington, Erin %A Titheridge, Sam %A Gill, Dawn P %A Petrella, Robert J %X

Exercise programs involving aerobic and resistance training (i.e., multiple-modality) have shown promise in improving cognition and executive control in older adults at risk, or experiencing, cognitive decline. It is, however, unclear whether cognitive training within a multiple-modality program elicits an additive benefit to executive/cognitive processes. This is an important question to resolve in order to identify optimal training programs that delay, or ameliorate, executive deficits in persons at risk for further cognitive decline. In the present study, individuals with a self-reported cognitive complaint (SCC) participated in a 24-week multiple-modality (i.e., the M2 group) exercise intervention program. In addition, a separate group of individuals with a SCC completed the same aerobic and resistance training as the M2 group but also completed a cognitive-based stepping task (i.e., multiple-modality, mind-motor intervention: M4 group). Notably, pre- and post-intervention executive control was examined via the antisaccade task (i.e., eye movement mirror-symmetrical to a target). Antisaccades are an ideal tool for the study of individuals with subtle executive deficits because of its hands- and language-free nature and because the task's neural mechanisms are linked to neuropathology in cognitive decline (i.e., prefrontal cortex). Results showed that M2 and M4 group antisaccade reaction times reliably decreased from pre- to post-intervention and the magnitude of the decrease was consistent across groups. Thus, multi-modality exercise training improved executive performance in persons with a SCC independent of mind-motor training. Accordingly, we propose that multiple-modality training provides a sufficient intervention to improve executive control in persons with a SCC.

%B J Alzheimers Dis %V 56 %P 167-183 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911298?dopt=Abstract %R 10.3233/JAD-160627 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A 3-Month Aerobic Training Program Improves Brain Energy Metabolism in Mild Alzheimer's Disease: Preliminary Results from a Neuroimaging Study. %A Castellano, Christian-Alexandre %A Paquet, Nancy %A Dionne, Isabelle J %A Imbeault, Hélène %A Langlois, Francis %A Croteau, Etienne %A Tremblay, Sébastien %A Fortier, Mélanie %A Matte, J Jacques %A Lacombe, Guy %A Fülöp, Tamás %A Bocti, Christian %A Cunnane, Stephen C %X

BACKGROUND: Aerobic training has some benefits for delaying the onset or progression of Alzheimer's disease (AD). Little is known about the implication of the brain's two main fuels, glucose and ketones (acetoacetate), associated with thesebenefits.

OBJECTIVE: To determine whether aerobic exercise training modifies brain energy metabolism in mild AD.

METHODS: In this uncontrolled study, ten patients with mild AD participated in a 3-month, individualized, moderate-intensity aerobic training on a treadmill (Walking). Quantitative measurement of brain uptake of glucose (CMRglu) and acetoacetate (CMRacac) using neuroimaging and cognitive testing were done before and after the Walking program.

RESULTS: Four men and six women with an average global cognitive score (MMSE) of 26/30 and an average age of 73 y completed the Walking program. Average total distance and treadmill speed were 8 km/week and 4 km/h, respectively. Compared to the Baseline, after Walking, CMRacac was three-fold higher (0.6±0.4 versus 0.2±0.1 μmol/100 g/min; p = 0.01). Plasma acetoacetate concentration and the blood-to-brain acetoacetate influx rate constant were also increased by 2-3-fold (all p≤0.03). CMRglu was unchanged after Walking (28.0±0.1 μmol/100 g/min; p = 0.96). There was a tendency toward improvement in the Stroop-color naming test (-10% completion time, p = 0.06). Performance on the Trail Making A&B tests was also directly related to plasma acetoacetate and CMRacac (all p≤0.01).

CONCLUSION: In mild AD, aerobic training improved brain energy metabolism by increasing ketone uptake and utilization while maintaining brain glucose uptake, and could potentially be associated with some cognitive improvement.

%B J Alzheimers Dis %V 56 %P 1459-1468 %G eng %N 4 %R 10.3233/JAD-161163 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A 9-microRNA Signature in Serum Serves as a Noninvasive Biomarker in Early Diagnosis of Alzheimer's Disease. %A Guo, Rui %A Fan, Gang %A Zhang, Jian %A Wu, Chunxiao %A Du, Yifeng %A Ye, Hui %A Li, Zhang %A Wang, Lili %A Zhang, Zhihui %A Zhang, Lu %A Zhao, Yueran %A Lu, Zhiming %X

Alzheimer's disease (AD) is the most common type of age-related neurodegenerative disorder; nevertheless, nowadays there are no reliable biomarkers or non-invasive techniques available for its early detection. Recent studies have indicated that the circulating level profiles of microRNAs (miRNAs) have the potential to be used as valuable biomarkers for diagnosis, staging, and progress monitoring of various diseases. Here we report a novel 9-miRNA signature (hsa-miR-26a-5p, hsa-miR-181c-3p, hsa-miR-126-5p, hsa-miR-22-3p, hsa-miR-148b-5p, hsa-miR-106b-3p, hsa-miR-6119-5p, hsa-miR-1246, and hsa-miR-660-5p) that can be utilized as biomarker for detecting AD. We respectively profiled the serum miRNAs from 19 AD patients and 9 healthy control (HC) participants using the Next-Generation Sequencing (NGS). The NGS results were validated by quantitative real-time polymerase chain reaction (qRT-PCR) on a larger cohort of 121 AD and 86 HC cases. All the patients were divided into three groups (mild, moderate, and severe AD) based on the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Our research indicates that abnormal expression of distinct serum miRNAs occurs at different stages of AD. The difference of the area under the receiver operator characteristics curve (AUC) between the AD and the HC is between 70% and 85%. Among the 9 miRNAs, hsa-miR-22-3p has the best sensitivity (81.8%) and specificity (70.9%). The miRNA-panel is more valuable for AD diagnosis. The data suggest that the differentially expressed serum miRNAs could be used as biomarkers to improve the diagnosis of AD, particularly at the early stage, and to classify its clinical stages.

%B J Alzheimers Dis %V 60 %P 1365-1377 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036818?dopt=Abstract %R 10.3233/JAD-170343 %0 Journal Article %J J Alzheimers Dis %D 2017 %T ABCA1 Deficiency Affects Basal Cognitive Deficits and Dendritic Density in Mice. %A Fitz, Nicholas F %A Carter, Alexis Y %A Tapias, Victor %A Castranio, Emilie L %A Kodali, Ravindra %A Lefterov, Iliya %A Koldamova, Radosveta %X

ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoproteins and regulates the generation of high density lipoproteins. Previously, we have shown that lack of Abca1 significantly increases amyloid deposition and cognitive deficits in Alzheimer's disease model mice expressing human amyloid-β protein precursor (APP). The goal of this study was to determine if ABCA1 plays a role in memory deficits caused by amyloid-β (Aβ) oligomers and examine neurite architecture of pyramidal hippocampal neurons. Our results confirm previous findings that Abca1 deficiency significantly impairs spatial memory acquisition and retention in the Morris water maze and long-term memory in novel object recognition of APP transgenic mice at a stage of early amyloid pathology. Neither test demonstrated a significant difference between Abca1ko and wild-type (WT) mice. We also examined the effect of intra-hippocampal infused Aβ oligomers on cognitive performance of Abca1ko mice, compared to control infusion of scrambled Aβ peptide. Age-matched WT mice undergoing the same infusions were also used as controls. In this model system, we found a statistically significant difference between WT and Abca1ko mice infused with scrambled Aβ, suggesting that Abca1ko mice are vulnerable to the effect of mild stresses. Moreover, examination of neurite architecture in the hippocampi revealed a significant decrease in neurite length, number of neurite segments, and branches in Abca1ko mice when compared to WT mice. We conclude that mice lacking ABCA1 have basal cognitive deficits that prevent them from coping with additional stressors, which is in part due to impairment of neurite morphology in the hippocampus.

%B J Alzheimers Dis %V 56 %P 1075-1085 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106559?dopt=Abstract %R 10.3233/JAD-161056 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Aberrant Co-localization of Synaptic Proteins Promoted by Alzheimer's Disease Amyloid-β Peptides: Protective Effect of Human Serum Albumin. %A Domínguez-Prieto, Marta %A Velasco, Ana %A Vega, Lourdes %A Tabernero, Arantxa %A Medina, José M %X

Amyloid-β (Aβ), Aβ40, Aβ42, and, recently, Aβ25-35 have been directly implicated in the pathogenesis of Alzheimer's disease. We have studied the effects of Aβ on neuronal death, reactive oxygen species (ROS) production, and synaptic assembling in neurons in primary culture. Aβ25-35, Aβ40, and Aβ42 significantly decreased neuronal viability, although Aβ25-35 showed a higher effect. Aβ25-35 showed a more penetrating ability to reach mitochondria while Aβ40 did not enter the neuronal cytosol and Aβ42 was scarcely internalized. We did not observe a direct correlation between ROS production and cell death because both Aβ40 and Aβ42 decreased neuronal viability but Aβ40 did not change ROS production. Rather, ROS production seems to correlate with the penetrating ability of each Aβ. No significant differences were found between Aβ40 and Aβ42 regarding the extent of the deleterious effects of both peptides on neuronal viability or synaptophysin expression. However, Aβ40 elicited a clear delocalization of PSD-95 and synaptotagmin from prospective synapsis to the neuronal soma, suggesting the occurrence of a crucial effect of Aβ40 on synaptic disassembling. The formation of Aβ40- or Aβ42-serum albumin complexes avoided the effects of these peptides on neuronal viability, synaptophysin expression, and PSD-95/synaptotagmin disarrangement suggesting that sequestration of Aβ by albumin prevents deleterious effects of these peptides. We can conclude that Aβ borne by albumin can be safely transported through body fluids, a fact that may be compulsory for Aβ disposal by peripheral tissues.

%B J Alzheimers Dis %V 55 %P 171-182 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662292?dopt=Abstract %R 10.3233/JAD-160346 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Abnormalities of Cerebral Deep Medullary Veins on 7 Tesla MRI in Amnestic Mild Cognitive Impairment and Early Alzheimer's Disease: A Pilot Study. %A Bouvy, Willem H %A Kuijf, Hugo J %A Zwanenburg, Jaco J M %A Koek, Huiberdina L %A Kappelle, L Jaap %A Luijten, Peter R %A Ikram, M Kamran %A Biessels, Geert Jan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Brain %K Cerebral Small Vessel Diseases %K Cognitive Dysfunction %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %X

Cerebral small vessel disease (SVD) contributes to cognitive impairment and dementia. SVD may affect veins, but veins are difficult to detect with 1.5 and 3T MRI. We compared deep medullary veins (DMVs) visualized on 7T-MRI between patients with early Alzheimer's disease (eAD; n = 17) or amnestic MCI (aMCI; n = 12) and controls (n = 40). The number and density of DMVs was similar in patients and controls, but tortuosity was higher in eAD (Cohen's d = 0.7, 95% CI: 0.1-1.2, p = 0.02) and aMCI (Cohen's d = 0.8, 95% CI: 0.2-1.5, p = 0.01), independent of brain atrophy. Venous changes provide a new perspective on vascular involvement in dementia.

%B J Alzheimers Dis %V 57 %P 705-710 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28282806?dopt=Abstract %R 10.3233/JAD-160952 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Abnormalities of Cortical Neural Synchronization Mechanisms in Subjects with Mild Cognitive Impairment due to Alzheimer's and Parkinson's Diseases: An EEG Study. %A Babiloni, Claudio %A Del Percio, Claudio %A Lizio, Roberta %A Noce, Giuseppe %A Cordone, Susanna %A Lopez, Susanna %A Soricelli, Andrea %A Ferri, Raffaele %A Pascarelli, Maria Teresa %A Nobili, Flavio %A Arnaldi, Dario %A Famá, Francesco %A Aarsland, Dag %A Orzi, Francesco %A Buttinelli, Carla %A Giubilei, Franco %A Onofrj, Marco %A Stocchi, Fabrizio %A Stirpe, Paola %A Fuhr, Peter %A Gschwandtner, Ute %A Ransmayr, Gerhard %A Caravias, Georg %A Garn, Heinrich %A Sorpresi, Fabiola %A Pievani, Michela %A D'Antonio, Fabrizia %A de Lena, Carlo %A Güntekin, Bahar %A Hanoğlu, Lutfu %A Başar, Erol %A Yener, Görsev %A Emek-Savaş, Derya Durusu %A Triggiani, Antonio Ivano %A Franciotti, Raffaella %A Frisoni, Giovanni B %A Bonanni, Laura %A De Pandis, Maria Francesca %X

The aim of this retrospective and exploratory study was that the cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms might reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and Parkinson's disease (PDMCI) as compared to healthy subjects. Clinical and rsEEG data of 75 ADMCI, 75 PDMCI, and 75 cognitively normal elderly (Nold) subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) was matched between the ADMCI and PDMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROC) classified these sources across individuals. Results showed that compared to the Nold group, the posterior alpha2 and alpha3 source activities were more abnormal in the ADMCI than the PDMCI group, while the parietal delta source activities were more abnormal in the PDMCI than the ADMCI group. The parietal delta and alpha sources correlated with MMSE score and correctly classified the Nold and diseased individuals (area under the ROC = 0.77-0.79). In conclusion, the PDMCI and ADMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test these rsEEG markers for clinical applications and drug discovery.

%B J Alzheimers Dis %V 59 %P 339-358 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28621693?dopt=Abstract %R 10.3233/JAD-160883 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Acceleration of Amyloidosis by Inflammation in the Amyloid-Beta Marmoset Monkey Model of Alzheimer's Disease. %A Philippens, Ingrid H %A Ormel, Paul R %A Baarends, Guus %A Johansson, Maja %A Remarque, Ed J %A Doverskog, Magnus %X

BACKGROUND: The immune system is increasingly mentioned as a potential target for Alzheimer's disease (AD) treatment.

OBJECTIVE: In the present pilot study, the effect of (neuro)inflammation on amyloidopathy was investigated in the marmoset monkey, which has potential as an AD animal model due to its natural cerebral amyloidosis similar to humans.

METHODS: Six adult/aged marmosets (Callithrix jacchus) were intracranial injected with amyloid-beta (Aβ) fibrils at three cortical locations in the right hemisphere. Additionally, in half of the monkeys, lipopolysaccharide (LPS) was co-injected with the Aβ fibrils and injected in the other hemisphere without Aβ fibrils. The other three monkeys received phosphate buffered saline instead of LPS, as a control for the inflammatory state. The effect of inflammation on amyloidopathy was also investigated in an additional monkey that suffered from chronic inflammatory wasting syndrome. Mirror histology sections were analyzed to assess amyloidopathy and immune reaction, and peripheral blood for AD biomarker expression.

RESULTS: All LPS-injected monkeys showed an early AD immune blood cell expression profile on CD95 and CD45RA. Two out of three monkeys injected with Aβ and LPS and the additional monkey, suffering from chronic inflammation, developed plaques. None of the controls, injected with Aβ only, developed any plaques.

CONCLUSION: This study shows the importance of immune modulation on the susceptibility for amyloidosis, a hallmark of AD, which offers new perspectives for disease modifying approaches in AD.

%B J Alzheimers Dis %V 55 %P 101-113 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662314?dopt=Abstract %R 10.3233/JAD-160673 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Accuracy of Clinical Diagnosis of Dementia with Lewy Bodies versus Neuropathology. %A Skogseth, Ragnhild %A Hortobágyi, Tibor %A Soennesyn, Hogne %A Chwiszczuk, Luiza %A Ffytche, Dominic %A Rongve, Arvid %A Ballard, Clive %A Aarsland, Dag %X

BACKGROUND: The first consensus criteria for dementia with Lewy bodies (DLB) published in 1996 were revised in 2005, partly because the original clinical criteria had suboptimal sensitivity. Few studies have assessed the accuracy of the 2005 criteria applied prospectively in newly diagnosed patients who have been followed longitudinally.

OBJECTIVE: To explore the correlation between clinical and pathological diagnoses in patients with DLB and Parkinson's disease with dementia (PDD).

METHODS: From a prospective referral cohort study with enriched recruitment of patients with DLB and PDD, we included the first 56 patients coming to autopsy. Patients had mild dementia at inclusion and were followed annually until death with standardized clinical assessments. Pathological assessment was performed blind to clinical information according to standardized protocols and consensus criteria for DLB.

RESULTS: 20 patients received a pathological diagnosis of Lewy body disease; the corresponding clinical diagnoses were probable DLB (n = 11), PDD (n = 5), probable (n = 2) or possible (n = 2) Alzheimer's disease (AD). Of 14 patients with a clinical diagnosis of probable DLB, 11 had DLB/PDD and 3 had AD at pathology. One patient with clinically possible DLB fulfilled criteria for pathological AD. Sensitivity, specificity, positive predictive value, and negative predictive values for probable DLB were 73%, 93%, 79%, and 90%.

CONCLUSION: Our findings suggest that the international clinical consensus criteria for DLB perform reasonably well. However, false positive and false negative diagnoses still occur, indicating that the criteria need to be improved, that biomarkers may be needed, and that neuropathological feedback is vital to improve accuracy.

%B J Alzheimers Dis %V 59 %P 1139-1152 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731443?dopt=Abstract %R 10.3233/JAD-170274 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Acidity and Acid-Sensing Ion Channels in the Normal and Alzheimer's Disease Brain. %A Gonzales, Eric B %A Sumien, Nathalie %X

Alzheimer's disease prevalence has reached epidemic proportion with very few treatment options, which are associated with a multitude of side effects. A potential avenue of research for new therapies are protons, and their associated receptor: acid-sensing ion channels (ASIC). Protons are often overlooked neurotransmitters, and proton-gated currents have been identified in the brain. Furthermore, ASICs have been determined to be crucial for proper brain function. While there is more work to be done, this review is intended to highlight protons as neurotransmitters and their role along with the role of ASICs within physiological functioning of the brain. We will also cover the pathophysiological associations between ASICs and modulators of ASICs. Finally, this review will sum up how the studies of protons, ASICs and their modulators may generate new therapeutic molecules for Alzheimer's disease and other neurodegenerative diseases.

%B J Alzheimers Dis %V 57 %P 1137-1144 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28211811?dopt=Abstract %R 10.3233/JAD-161131 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Activation of Macrophages and Microglia by Interferon-γ and Lipopolysaccharide Increases Methylglyoxal Production: A New Mechanism in the Development of Vascular Complications and Cognitive Decline in Type 2 Diabetes Mellitus? %A Dhananjayan, Karthik %A Gunawardena, Dhanushka %A Hearn, Nerissa %A Sonntag, Tanja %A Moran, Chris %A Gyengesi, Erika %A Srikanth, Velandai %A Münch, Gerald %X

Methylglyoxal (MGO), a dicarbonyl compound derived from glucose, is elevated in diabetes mellitus and contributes to vascular complications by crosslinking collagen and increasing arterial stiffness. It is known that MGO contributes to inflammation as it forms advanced glycation end products (AGEs), which activate macrophages via the receptor RAGE. The aim of study was to investigate whether inflammatory activation can increase MGO levels, thereby completing a vicious cycle. In order to validate this, macrophage (RAW264.7, J774A.1) and microglial (N11) cells were stimulated with IFN-γ and LPS (5 + 5 and 10 + 10 IFN-γ U/ml or μg/ml LPS), and extracellular MGO concentration was determined after derivatization with 5,6-Diamino-2,4-dihydroxypyrimidine sulfate by HPLC. MGO levels in activated macrophage cells (RAW264.7) peaked at 48 h, increasing 2.86-fold (3.14±0.4 μM) at 5 U/ml IFN-γ+5 μg/ml LPS, and 4.74-fold (5.46±0.30 μM) at 10 U/ml IFN-γ+10 μg/ml LPS compared to the non-activated controls (1.15±0.02 μM). The other two cell lines, J774A.1 macrophages and N11 microglia, showed a similar response. We suggest that inflammation increases MGO production, possibly exacerbating arterial stiffness, cardiovascular complications, and diabetes-related cognitive decline.

%B J Alzheimers Dis %V 59 %P 467-479 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582854?dopt=Abstract %R 10.3233/JAD-161152 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Adherence to Clinical Practice Guidelines during Dementia Work-Up in a Real-World Setting: A Study from the Registry of Dementias of Girona. %A Turró-Garriga, Oriol %A Calvó-Perxas, Laia %A Vilalta-Franch, Joan %A Hernández-Ferrándiz, Marta %A Flaqué, Margarita %A Linares, Marta %A Cullell, Marta %A Gich, Jordi %A Casas, Isabel %A Perkal, Héctor %A Garre-Olmo, Josep %X

BACKGROUND: There are several position statements and clinical practice guidelines (CPG) for diagnosing dementia.

OBJECTIVE: Our aims were to evaluate the adherence to CPG among specialists in the 7 memory clinics included in the Registry of Dementias of Girona (ReDeGi), and to compare the results between 2007-2011 and 2012-2015. We also determined the time and number of visits required to achieve a diagnosis, the supplementary tests ordered, and the drugs prescribed according to dementia subtypes.

METHODS: Medical charts of a stratified random sample of 475 ReDeGi cases were reviewed. Basic dementia work-up was evaluated using as a reference evidence-based CPG. An Index of Adherence (AI) was calculated using the following items in the medical chart: cognitive symptomatology; functional disability evaluation; physical examination; neurological examination; psychiatric examination; brief cognitive examination; activities of daily living performance examination; blood test; structural neuroimaging (CT-scan or MRI).

RESULTS: The mean AI to CPG among specialists was of 8.2 points, and it improved from 7.9 points in 2007-2011 to 8.5 points in 2012-2015 (Cohen's d = 0.46). A lower adherence was detected in the most severe cases. A dementia diagnosis required 3.5 visits, regardless of the subtype of dementia, although milder cases required more time, more visits, and more supplementary tests than severe cases.

CONCLUSION: The adherence to CPG in the catchment area of the ReDeGi is high, and an epidemiological surveillance system such as the ReDeGi may help in improving it. Dementia guidelines should establish procedures adapted to clinical practice, with simplified recommendations for most severe cases.

%B J Alzheimers Dis %V 59 %P 997-1007 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697570?dopt=Abstract %R 10.3233/JAD-170284 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Adult-Onset Epilepsy in Presymptomatic Alzheimer's Disease: A Retrospective Study. %A DiFrancesco, Jacopo C %A Tremolizzo, Lucio %A Polonia, Valeria %A Giussani, Giorgia %A Bianchi, Elisa %A Franchi, Carlotta %A Nobili, Alessandro %A Appollonio, Ildebrando %A Beghi, Ettore %A Ferrarese, Carlo %X

BACKGROUND: The prevalence of epilepsy with onset in adulthood increases with age, mainly due to the accumulation of brain damage. However, a significant proportion of patients experience seizures of unknown cause. Alzheimer's disease (AD) is associated with an increased risk of seizures. Seizure activity is interpreted as a secondary event related to hyperexcitability caused by amyloid-β aggregation.

OBJECTIVE: Since neurodegenerative processes begin several years before clinical symptoms, epilepsy could be more frequent in the presymptomatic stages of dementia.

METHODS: We retrospectively reviewed the prevalence of epilepsy of unknown origin with adult onset before cognitive decline in a large cohort of AD patients (EPS-AD) recruited based on clinical and neuropsychological data. Data of patients with epilepsy followed by AD were compared with two control groups: patients with AD without seizures (no EPS-AD) and a large reference population (RP).

RESULTS: In AD patients, the prevalence of epilepsy of unknown origin, with onset in the adulthood before cognitive decline is 17.1 times higher compared with the RP (95% CI: 10.3-28.3). In EPS-AD, seizures begin on average 4.6 years (median 2.0) before the onset of cognitive symptoms and cognitive decline starts 3.6 years earlier compared with noEPS-AD.

CONCLUSIONS: Neurodegenerative processes of dementia could play a key role in the pathogenesis of epilepsy in a subgroup of individuals intended to develop cognitive decline. Adult-onset epilepsy of undefined cause could thus represent a risk factor for the ongoing neurodegenerative damage, even preceding by years the onset of clinical symptoms of dementia.

%B J Alzheimers Dis %V 60 %P 1267-1274 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28968234?dopt=Abstract %R 10.3233/JAD-170392 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Aerosol Delivery of Curcumin Reduced Amyloid-β Deposition and Improved Cognitive Performance in a Transgenic Model of Alzheimer's Disease. %A McClure, Richard %A Ong, Henry %A Janve, Vaibhab %A Barton, Shawn %A Zhu, Meiying %A Li, Bo %A Dawes, Mary %A Jerome, W Gray %A Anderson, Adam %A Massion, Pierre %A Gore, John C %A Pham, Wellington %X

We report a novel approach for the delivery of curcumin to the brain via inhalation of the aerosol for the potential treatment of Alzheimer's disease. The percentage of plaque fraction in the subiculum and hippocampus reduced significantly when young 5XFAD mice were treated with inhalable curcumin over an extended period of time compared to age-matched nontreated counterparts. Further, treated animals demonstrated remarkably improved overall cognitive function, no registered systemic or pulmonary toxicity associated with inhalable curcumin observed during the course of this work.

%B J Alzheimers Dis %V 55 %P 797-811 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802223?dopt=Abstract %R 10.3233/JAD-160289 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Age and Graphomotor Decision Making Assessed with the Digital Clock Drawing Test: The Framingham Heart Study. %A Piers, Ryan J %A Devlin, Kathryn N %A Ning, Boting %A Liu, Yulin %A Wasserman, Ben %A Massaro, Joseph M %A Lamar, Melissa %A Price, Catherine C %A Swenson, Rod %A Davis, Randall %A Penney, Dana L %A Au, Rhoda %A Libon, David J %X

BACKGROUND: Digital Clock Drawing Test (dCDT) technology enables the examination of detailed neurocognitive behavior as behavior unfolds in real time; a capability that cannot be obtained using a traditional pen and paper testing format.

OBJECTIVE: Parameters obtained from the dCDT were used to investigate neurocognitive constructs related to higher-order neurocognitive decision making and information processing speed. The current research sought to determine the effect of age as related to combined motor and non-motor components of drawing, and higher-order decision making latencies.

METHODS: A large group of stroke- and dementia- free Framingham Heart Study participants were administered the dCDT to command and copy with hands set for "10 after 11". Six age groups (age range 28-98) were constructed.

RESULTS: Differences between age groups were found for total time to completion, total pen stroke count, and higher-order decision making latencies in both command and copy test conditions.

CONCLUSION: Longer age-related decision making latencies may reflect a greater need for working memory and increased self-monitoring in older subjects. These latency measures have potential to serve as neurocognitive biomarkers of Alzheimer's disease and other insidious neurodegenerative disorders.

%B J Alzheimers Dis %V 60 %P 1611-1620 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036819?dopt=Abstract %R 10.3233/JAD-170444 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alcohol Intake and Cognitively Healthy Longevity in Community-Dwelling Adults: The Rancho Bernardo Study. %A Richard, Erin L %A Kritz-Silverstein, Donna %A Laughlin, Gail A %A Fung, Teresa T %A Barrett-Connor, Elizabeth %A McEvoy, Linda K %X

To better understand the association of alcohol intake with cognitively healthy longevity (CHL), we explored the association between amount and frequency of alcohol intake and CHL among 1,344 older community-dwelling adults. Alcohol intake was assessed by questionnaire in 1984-1987. Cognitive function was assessed in approximate four-year intervals between 1988 and 2009. Multinomial logistic regression, adjusting for multiple lifestyle and health factors, was used to examine the association between alcohol consumption and CHL (living to age 85 without cognitive impairment), survival to age 85 with cognitive impairment (MMSE score >1.5 standard deviations below expectation for age, sex, and education), or death before age 85. Most participants (88%) reported some current alcohol intake; 49% reported a moderate amount of alcohol intake, and 48% reported drinking near-daily. Relative to nondrinkers, moderate and heavy drinkers (up to 3 drinks/day for women and for men 65 years and older, up to 4 drinks/day for men under 65 years) had significantly higher adjusted odds of survival to age 85 without cognitive impairment (p's < 0.05). Near-daily drinkers had 2-3 fold higher adjusted odds of CHL versus living to at least age 85 with cognitive impairment (odds ratio (OR) = 2.06; 95% confidence interval (CI): 1.21, 3.49) or death before 85 (OR = 3.24; 95% CI: 1.92, 5.46). Although excessive drinking has negative health consequences, these results suggest that regular, moderate drinking may play a role in cognitively healthy longevity.

%B J Alzheimers Dis %V 59 %P 803-814 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671111?dopt=Abstract %R 10.3233/JAD-161153 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Algoplus® Scale in Older Patients with Dementia: A Reliable Real-World Pain Assessment Tool. %A Monacelli, Fiammetta %A Signori, Alessio %A Roffredo, Laura %A Pace, Katiuscia %A Nencioni, Alessio %A Pickering, Gisele %A Nicolas, Macian %A Odetti, Patrizio %X

Pain is still a neglected clinical issue in elderly people with dementia and/or communicative disorders, with an unacceptable higher rate of under diagnosis and under treatment. Cognitive deficit and emotional and psychological disturbances entangle pain symptoms, affecting patient self-report. So far, observational pain tools do not have fully adequate clinimetric properties and quality requirements for easy-to-use daily rating. Older patients with dementia represent a clinical challenge. The assessment of pain is important for improving clinical outcomes, such as functional status, frailty trajectories, comorbidity, and quality of life. The PAINAID scale appears to be the most accurate pain tool in people with dementia along with the Algoplus® scale, a recently developed tool to rapidly assess acute pain in hospitals settings. The present study aimed to assess the clinimetric properties of the Algoplus®, as compared to PAINAID, for detecting acute pain in a real-world cohort of hospitalized older patients with dementia.

%B J Alzheimers Dis %V 56 %P 519-527 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27935555?dopt=Abstract %R 10.3233/JAD-160790 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Alteration of ZiBuPiYin Recipe on Proteomic Profiling of Forebrain Postsynaptic Density of db/db Mice with Diabetes-Associated Cognitive Decline. %A Chen, Jing %A Zhan, Libin %A Lu, Xiaoguang %A Xiao, Chi %A Sun, Nijing %X

Diabetes-associated cognitive decline (DACD) is a brain injury induced by diabetes mellitus, with cognitive impairment as the major symptom. Growing evidence has revealed that DACD is correlated with disruptions in synapses involved in cognition. Within synapses, more specifically in areas of postsynaptic density (PSD), there is a high concentration of proteins that receive and transduce synaptic information. In the present study, to identify the differentially expressed PSD proteins among DACD mice, ZiBuPiYin recipe (ZBPYR)-treated DACD mice and control mice, we applied isobaric tags for relative and absolute quantitation (iTRAQ) with LC-MS/MS technology, by which three biological replicates and three technical replicates were examined. A total of 24 and 23 differentially expressed proteins were observed in control versus DACD mice and in DACD versus ZBPYR-treated DACD mice, respectively. Notably, we found 'Protein processing in endoplasmic reticulum' and 'PI3K-Akt signaling pathway' might be impaired in DACD pathogenesis, while Growth factor receptor-bound protein 2 might be a crucial protein as a molecular target of the neuroprotective effects of ZBPYR. To our knowledge, this is the first study to provide a reference proteome map for DACD and ZBPYR-treated DACD mouse forebrain PSD to aid understanding the underlying mechanisms of DACD and ZBPYR.

%B J Alzheimers Dis %V 56 %P 471-489 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27886008?dopt=Abstract %R 10.3233/JAD-160691 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alterations in the Balance of Amyloid-β Protein Precursor Species in the Cerebrospinal Fluid of Alzheimer's Disease Patients. %A Lopez-Font, Inmaculada %A Boix, Claudia P %A Zetterberg, Henrik %A Blennow, Kaj %A Sáez-Valero, Javier %X

We recently demonstrated that soluble forms of the amyloid-β protein precursor (sAβPP) assemble into multimeric complexes in cerebrospinal fluid (CSF), which contributes to the underestimation of specific sAβPP species when assessed by ELISA. To circumvent this issue, we analyzed by SDS-PAGE large fragments of sAβPP and their variants in the CSF from Alzheimer's disease (AD; n = 20) and control (n = 20) subjects, probing with specific antibodies against particular domains. Similar levels of sAβPPα and sAβPPβ protein were found in CSF samples from AD and controls, yet there appeared to be a shift in the balance of the soluble full-length AβPP (sAβPPf) species in AD samples, with a decrease in the proportion of the lower (∼100 kDa) band relative to the upper (∼120 kDa) band. Similar differences were observed in the contribution of the major KPI-immunoreactive AβPP species. CSF samples also displayed differences in the correlations of AβPP species with classical AD biomarkers, particularly with respect to the Aβ42 peptide. The differences reveal alterations that probably reflect pathophysiological changes in the brain.

%B J Alzheimers Dis %V 57 %P 1281-1291 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372336?dopt=Abstract %R 10.3233/JAD-161275 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alterations in the Peripheral Immune System in Dementia. %A Busse, Mandy %A Michler, Enrico %A von Hoff, Franz %A Dobrowolny, Henrik %A Hartig, Roland %A Frodl, Thomas %A Busse, Stefan %X

Alterations in the immune response that result in inflammation might play a role in the pathology of dementias. In order to analyze changes of the peripheral immune system associated with different types of dementias, we determined several innate and adaptive cell populations in whole blood using flow cytometry. We included patients with Alzheimer's disease (AD; n = 60), vascular dementia (VaD; n = 20), and frontotemporal dementia (FTD; n = 12) at the time point of diagnosis and 24 age-matched neuropsychiatric healthy persons. Monocytes and NK cells were diminished in VaD, but not in AD and FTD. B cell and T cell numbers were decreased in all investigated forms of dementia. Changes in the contribution of naïve/memory T cells were only present in AD. Correlation and regression analyses revealed associations between altered immune cell populations and Q Albumin as marker for the integrity of the blood-cerebrospinal fluid-barrier, Mini-Mental State Examination values, and age. The peripheral immune system is altered in AD, VaD, and FTD. However, each disorder presents unique changes in the investigated cell types indicating different mechanisms underlying the pathology.

%B J Alzheimers Dis %V 58 %P 1303-1313 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582858?dopt=Abstract %R 10.3233/JAD-161304 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alterations of Clock Gene RNA Expression in Brain Regions of a Triple Transgenic Model of Alzheimer's Disease. %A Bellanti, Francesco %A Iannelli, Giuseppina %A Blonda, Maria %A Tamborra, Rosanna %A Villani, Rosanna %A Romano, Adele %A Calcagnini, Silvio %A Mazzoccoli, Gianluigi %A Vinciguerra, Manlio %A Gaetani, Silvana %A Giudetti, Anna Maria %A Vendemiale, Gianluigi %A Cassano, Tommaso %A Serviddio, Gaetano %X

A disruption to circadian rhythmicity and the sleep/wake cycle constitutes a major feature of Alzheimer's disease (AD). The maintenance of circadian rhythmicity is regulated by endogenous clock genes and a number of external Zeitgebers, including light. This study investigated the light induced changes in the expression of clock genes in a triple transgenic model of AD (3×Tg-AD) and their wild type littermates (Non-Tg). Changes in gene expression were evaluated in four brain areas¾suprachiasmatic nucleus (SCN), hippocampus, frontal cortex and brainstem¾of 6- and 18-month-old Non-Tg and 3×Tg-AD mice after 12 h exposure to light or darkness. Light exposure exerted significant effects on clock gene expression in the SCN, the site of the major circadian pacemaker. These patterns of expression were disrupted in 3×Tg-AD and in 18-month-old compared with 6-month-old Non-Tg mice. In other brain areas, age rather than genotype affected gene expression; the effect of genotype was observed on hippocampal Sirt1 expression, while it modified the expression of genes regulating the negative feedback loop as well as Rorα, Csnk1ɛ and Sirt1 in the brainstem. In conclusion, during the early development of AD, there is a disruption to the normal expression of genes regulating circadian function after exposure to light, particularly in the SCN but also in extra-hypothalamic brain areas supporting circadian regulation, suggesting a severe impairment of functioning of the clock gene pathway. Even though this study did not demonstrate a direct association between these alterations in clock gene expression among brain areas with the cognitive impairments and chrono-disruption that characterize the early onset of AD, our novel results encourage further investigation aimed at testing this hypothesis.

%B J Alzheimers Dis %V 59 %P 615-631 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671110?dopt=Abstract %R 10.3233/JAD-160942 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Altered Gut Microbiome Composition and Tryptic Activity of the 5xFAD Alzheimer's Mouse Model. %A Brandscheid, Carolin %A Schuck, Florian %A Reinhardt, Sven %A Schäfer, Karl-Herbert %A Pietrzik, Claus U %A Grimm, Marcus %A Hartmann, Tobias %A Schwiertz, Andreas %A Endres, Kristina %X

The regulation of physiological gut functions such as peristalsis or secretion of digestive enzymes by the central nervous system via the Nervus vagus is well known. Recent investigations highlight that pathological conditions of neurological or psychiatric disorders might directly interfere with the autonomous neuronal network of the gut - the enteric nervous system, or even derive from there. By using a murine Alzheimer's disease model, we investigated a potential influence of disease-associated changes on gastrointestinal properties. 5xFAD mice at three different ages were compared to wild type littermates in regard to metabolic parameters and enzymes of the gut by fluorimetric enzyme assay and western blotting. Overexpression of human amyloid-β protein precursor (AβPP) within the gut was assessed by qPCR and IHC; fecal microbiome analysis was conducted by 16SrRNA quantitation of selected phyla and species. While general composition of fecal samples, locomotion, and food consumption of male 5xFAD animals were not changed, we observed a reduced body weight occurring at early pathological stages. Human AβPP was not only expressed within the brain of these mice but also in gut tissue. Analysis of fecal proteins revealed a reduced trypsin amount in the 5xFAD model mice as compared to the wild type. In addition, we observed changes in fecal microbiota composition along with age. We therefore suggest that the presence of the mutated transgenes (AβPP and PS1), which are per se the basis for the genetic form of Alzheimer's disease in humans, directly interferes with gut function as shown here for the disease model mice.

%B J Alzheimers Dis %V 56 %P 775-788 %G eng %N 2 %R 10.3233/JAD-160926 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Altered Gut Microbiota in a Mouse Model of Alzheimer's Disease. %A Zhang, Ling %A Wang, Ying %A Xiayu, Xia %A Shi, Changhua %A Chen, Wei %A Song, Nan %A Fu, Xinjing %A Zhou, Rui %A Xu, Yan-Feng %A Huang, Lan %A Zhu, Hua %A Han, Yunlin %A Qin, Chuan %X

The topic of gut microbiota is currently attracting considerable interest as a potential factor in Alzheimer's disease (AD). However, the extent and time course of alterations in the gut microbiota, and their effects on AD pathology remain uncertain. Herein, we compared the fecal microbiomes and fecal short chain fatty acid composition (SCFAs) between wild-type and AD model mice at different ages under strictly controlled specific pathogen free conditions, and also conducted microscopic investigations of intestinal structures. Our results showed that the microbiota composition and diversity were perturbed and the level of SCFAs was reduced in AD mice, predicting alterations in more than 30 metabolic pathways, which may be associated with amyloid deposition and ultrastructural abnormalities in AD mouse intestine. These findings indicate that AD pathology might not only affect brain function directly, but also exacerbate cognitive deficits through reducing the level of SCFAs via alterations of gut microbiota induced by intestinal amyloid deposition. Our data may support a role of gut microbiota, and suggest a novel route for therapeutic intervention in AD.

%B J Alzheimers Dis %V 60 %P 1241-1257 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036812?dopt=Abstract %R 10.3233/JAD-170020 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Altered Sphingolipid Balance in Capillary Cerebral Amyloid Angiopathy. %A de Wit, Nienke M %A Snkhchyan, Hripsime %A den Hoedt, Sandra %A Wattimena, Darcos %A de Vos, Rob %A Mulder, Monique T %A Walter, Jochen %A Martinez-Martinez, Pilar %A Hoozemans, Jeroen J %A Rozemuller, Annemieke J %A De Vries, Helga E %X

BACKGROUND: The majority of patients with Alzheimer's disease (AD) exhibit amyloid-β (Aβ) deposits at the brain vasculature, a process referred to as cerebral amyloid angiopathy (CAA). In over 51% of AD cases, Aβ also accumulates in cortical capillaries, which is termed capillary CAA (capCAA). It has been postulated that the presence of capCAA in AD is a specific subtype of AD, although underlying mechanisms are not yet fully understood. Sphingolipids (SLs) are implicated in neurodegenerative disorders, including AD. However, to date it remains unknown whether alterations in the SL pathway are involved in capCAA pathogenesis and if these differ from AD.

OBJECTIVE: To determine whether AD cases with capCAA have an altered SL profile compared to AD cases without capCAA.

METHODS: Immunohistochemistry was performed to assess the expression and localization of ceramide, acid sphingomyelinase (ASM), and sphingosine-1-phosphate receptors (S1P1, S1P3). In addition, we determined the concentrations of S1P as well as different chain-lengths of ceramides using HPLC-MS/MS.

RESULTS: Immunohistochemical analysis revealed an altered expression of ceramide, ASM, and S1P receptors by reactive astrocytes and microglial cells specifically associated with capCAA. Moreover, a shift in the balance of ceramides with different chain-lengths and S1P content is observed in capCAA.

CONCLUSION: Here we provide evidence of a deregulated SL balance in capCAA. The increased levels of ASM and ceramide in activated glia cells suggest that the SL pathway is involved in the neuroinflammatory response in capCAA pathogenesis. Future research is needed to elucidate the role of S1P in capCAA.

%B J Alzheimers Dis %V 60 %P 795-807 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662305?dopt=Abstract %R 10.3233/JAD-160551 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease as the Product of a Progressive Energy Deficiency Syndrome in the Central Nervous System: The Neuroenergetic Hypothesis. %A Blonz, Edward R %X

The decreased availability of metabolizable energy resources in the central nervous system is hypothesized to be a key factor in the pathogenesis of Alzheimer's disease. More specifically, the age-related decline in the ability of glucose to cross the blood-brain barrier creates a metabolic stress that shifts the normal, benign processing of amyloid-β protein precursor toward pathways associated with the production of amyloid-β plaques and tau-containing neurofibrillary tangles that are characteristic of the disease. The neuroenergetic hypothesis provides insight into the etiology of Alzheimer's disease and illuminates new approaches for diagnosis, monitoring, and treatment.

%B J Alzheimers Dis %V 60 %P 1223-1229 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28946565?dopt=Abstract %R 10.3233/JAD-170549 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease Biomarkers and Future Decline in Cognitive Normal Older Adults. %A Dumurgier, Julien %A Hanseeuw, Bernard J %A Hatling, Frances B %A Judge, Kelly A %A Schultz, Aaron P %A Chhatwal, Jasmeer P %A Blacker, Deborah %A Sperling, Reisa A %A Johnson, Keith A %A Hyman, Bradley T %A Gómez-Isla, Teresa %X

BACKGROUND: Identifying older adults at risk of cognitive decline represents a challenge as Alzheimer's disease (AD) modifying therapies move toward preclinical stages.

OBJECTIVE: To investigate the relationship between AD biomarkers and subsequent change in cognition in a cohort of cognitively intact older adults.

METHODS: 84 cognitively normal subjects (mean age 72.0 years, 59% women) were recruited through the Massachusetts Alzheimer's Disease Research Center and the Harvard Aging Brain Study and followed over 3 years. Measurements of amyloid-β 1-42 (Aβ42), total Tau (t-Tau), and Tau phosphorylated at threonine 181 (p-Tau181) in the cerebrospinal fluid (CSF) at study entry were available in all cases. Baseline brain MRI, FDG-PET, and PiB-PET data were available in the majority of participants. Relationship between baseline AD biomarkers and longitudinal change in cognition was assessed using Cox proportional hazard regression and linear mixed models.

RESULTS: 14% participants increased their global Clinical Dementia Rating (CDR) score from 0 to 0.5 during follow-up. A CDR score increase was associated with higher baseline CSF t-Tau and p-Tau181, higher global cortical PiB retention, and lower hippocampal volume. The combination of high CSF t-Tau and low Aβ42 or low hippocampal volume was more strongly related to cognitive outcome than each single biomarker. Higher CSF t-Tau was the only biomarker associated with subsequent decline in MMSE score.

CONCLUSIONS: Baseline CSF t-Tau and p-Tau181, in vivo amyloid load, and hippocampal volume were all independently associated with future decline in cognition. The discriminatory ability of these biomarkers to predict risk of cognitive decline, however, was only modest.

%B J Alzheimers Dis %V 60 %P 1451-1459 %G eng %N 4 %R 10.3233/JAD-170511 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease Biomarkers Interactively Influence Physical Activity, Mobility, and Cognition Associations in a Non-Demented Aging Population. %A Thibeau, Sherilyn %A McFall, G Peggy %A Camicioli, Richard %A Dixon, Roger A %X

BACKGROUND: Alzheimer's disease (AD) risk-reduction strategies (e.g., increasing physical activity, improving mobility) have garnered increasing attention in the literature. However, the effect of such modifiable factors on the preclinical trajectories of brain and cognitive health may be moderated by non-modifiable biomarkers associated with AD.

OBJECTIVE: In a longitudinal sample of non-demented older adults, we examine the independent predictors everyday physical activity (EPA) and mobility on executive function (EF) performance and change. Next, we test whether these predictions are modified by interactions between age and AD genetic risk.

METHODS: This accelerated longitudinal design included adults (n = 532, M age = 70.4, age range 53-95) from the Victoria Longitudinal Study. We tested the independent effects of EPA and Mobility (i.e., gait, balance), moderation by Apolipoprotein E (i.e., APOEɛ4+, ɛ4-) and age (young-old, middle-old, old-old), and interactions between APOE and age on performance and 9-year change in an EF latent variable.

RESULTS: First, higher levels of both EPA and Mobility were associated with better EF performance and less decline. Second, the interaction between age and APOE showed that low EPA and older age was associated with poorer EF performance and steeper EF decline for APOEɛ4 + carriers, and low mobility was associated with poorer EF performance and steeper EF decline for APOEɛ4 + carriers than the non-risk carriers.

CONCLUSION: In non-demented older adults, age moderated the effects of both EPA and Mobility on EF performance and change. However, this moderation occurs differentially across APOE4 status.

%B J Alzheimers Dis %V 60 %P 69-86 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28800331?dopt=Abstract %R 10.3233/JAD-170130 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease: Characterization of the Brain Sites of the Initial Tau Cytoskeletal Pathology Will Improve the Success of Novel Immunological Anti-Tau Treatment Approaches. %A Rüb, Udo %A Stratmann, Katharina %A Heinsen, Helmut %A Seidel, Kay %A Bouzrou, Mohamed %A Korf, Horst-Werner %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Humans %K Immunotherapy %K tau Proteins %X

Alzheimer's disease (AD) represents the most frequent neurodegenerative disease of the human brain worldwide. Currently practiced treatment strategies for AD only include some less effective symptomatic therapeutic interventions, which unable to counteract the disease course of AD. New therapeutic attempts aimed to prevent, reduce, or remove the extracellular depositions of the amyloid-β protein did not elicit beneficial effects on cognitive deficits or functional decline of AD. In view of the failure of these amyloid-β-based therapeutic trials and the close correlation between the brain pathology of the cytoskeletal tau protein and clinical AD symptoms, therapeutic attention has since shifted to the tau cytoskeletal protein as a novel drug target. The abnormal hyperphosphorylation and intraneuronal aggregation of this protein are early events in the evolution of the AD-related neurofibrillary pathology, and the brain spread of the AD-related tau aggregation pathology may possibly follow a corruptive protein templating and seeding-like mechanism according to the prion hypothesis. Accordingly, immunotherapeutic targeting of the tau aggregation pathology during the very early pre-tangle phase is currently considered to represent an effective and promising therapeutic approach for AD. Recent studies have shown that the initial immunoreactive tau aggregation pathology already prevails in several subcortical regions in the absence of any cytoskeletal changes in the cerebral cortex. Thus, it may be hypothesized that the subcortical brain regions represent the "port of entry" for the pathogenetic agent from which the disease ascends anterogradely as an "interconnectivity pathology".

%B J Alzheimers Dis %V 57 %P 683-696 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269779?dopt=Abstract %R 10.3233/JAD-161102 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease Diagnosis Relies on a Twofold Clinical-Biological Algorithm: Three Memory Clinic Case Reports. %A Levy Nogueira, Marcel %A Samri, Dalila %A Epelbaum, Stéphane %A Lista, Simone %A Suppa, Per %A Spies, Lothar %A Hampel, Harald %A Dubois, Bruno %A Teichmann, Marc %X

The International Working Group recently provided revised criteria of Alzheimer's disease (AD) proposing that the diagnosis of typical amnesic AD should be established by a clinical-biological signature, defined by the phenotype of an "amnesic syndrome of the hippocampal type" (ASHT) combined with positive in vivo evidence of AD pathophysiology in the cerebrospinal fluid (CSF) or on amyloid PET imaging. The application and clinical value of this refined diagnostic algorithm, initially intended for research purposes, is explored in three memory clinic cases presenting with different cognitive profiles including an ASHT, hippocampal atrophy, and CSF AD-biomarker data. The case reports highlight that the isolated occurrence of one of the two proposed AD criteria, ASHT or positive pathophysiological markers, does not provide a reliable diagnosis of typical AD. It is proposed that the twofold diagnostic IWG algorithm can be applied and operationalized in memory clinic settings to improve the diagnostic accuracy of typical amnesic AD in clinical practice.

%B J Alzheimers Dis %V 60 %P 577-583 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869481?dopt=Abstract %R 10.3233/JAD-170574 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease Genetics and ABCA7 Splicing. %A Vasquez, Jared B %A Simpson, James F %A Harpole, Ryan %A Estus, Steven %X

Both common and rare polymorphisms within ABCA7 have been associated with Alzheimer's disease (AD). In particular, the rare AD associated polymorphism rs200538373 was associated with altered ABCA7 exon 41 splicing and an AD risk odds ratio of ∼1.9. To probe the role of this polymorphism in ABCA7 splicing, we used minigene studies and qPCR of human brain RNA. We report aberrant ABCA7 exon 41 splicing in the brain of a carrier of the rs200538373 minor C allele. Moreover, minigene studies show that rs200538373 acts as a robust functional variant in vitro. Lastly, although the ABCA7 isoform with an extended exon 41 is predicted to undergo nonsense mediated RNA decay, this was not supported by qPCR analyses, which showed relatively normal ABCA7 mRNA levels in the carrier of the rs200538373 minor C allele. In summary, rs200538373 is a functional polymorphism that alters ABCA7 exon 41 splicing without grossly altering the level of ABCA7 mRNA.

%B J Alzheimers Dis %V 59 %P 633-641 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28655137?dopt=Abstract %R 10.3233/JAD-170872 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease Histological and Behavioral Manifestations in Transgenic Mice Correlate with Specific Gut Microbiome State. %A Shen, Liang %A Liu, Lu %A Ji, Hong-Fang %X

Alzheimer's disease (AD) is a neurodegenerative brain disease and is the most common form of dementia. In recent years, many studies indicated the association of gut microbiota changes with metabolic diseases. However, the gut microbiota of AD has not been investigated. The present study aims to compare the gut microbiota in APP/PS1 transgenic mice of AD and C57/Bl6 wild-type (WT) mice by pyrosequencing the V3 and V4 regions of the bacterial 16S ribosomal RNA genes. The 3-, 6-, and 8-month-old APP/PS1 and WT mice were used to explore the effects of age on the gut microbiota. First, the results indicated that impaired spatial learning and memory appeared in 6-month-old APP/PS1 mice and was further aggravated in the 8-month-old group, which was consistent with immunohistochemical studies of amyloid plaque. Second, AD histological and behavioral manifestations in the APP/PS1 mice were found to be correlated with a specific gut microbiome state. Third, the microbiota diversity of APP/PS1 mice decreased with increased age. Fourth, further inspection showed that the abundance of Helicobacteraceae and Desulfovibrionaceae at the family level and Odoribacter and Helicobacter at the genus level increased significantly in APP/PS1 mice than in WT mice, while Prevotella abundance in WT mice was significantly higher than in APP/PS1 mice. More human studies are warranted to explore the potential of gut microbiota as diagnostic biomarkers or therapeutic target for AD.

%B J Alzheimers Dis %V 56 %P 385-390 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911317?dopt=Abstract %R 10.3233/JAD-160884 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease in the Latino Community: Intersection of Genetics and Social Determinants of Health. %A Vega, Irving E %A Cabrera, Laura Y %A Wygant, Cassandra M %A Velez-Ortiz, Daniel %A Counts, Scott E %X

Alzheimer's disease (AD) is the most common type of dementia among individuals 65 or older. There are more than 5 million diagnosed cases in the US alone and this number is expected to triple by 2050. Therefore, AD has reached epidemic proportions with significant socioeconomic implications. While aging in general is the greatest risk factor for AD, several additional demographic factors that have contributed to the rise in AD in the US are under study. One such factor is associated with the relatively fast growth of the Latino population. Several reports indicate that AD is more prevalent among blacks and Latinos. However, the reason for AD disparity among different ethnic groups is still poorly understood and highly controversial. The Latino population is composed of different groups based on nationality, namely South and Central America, Mexico, and Caribbean Hispanics. This diversity among the Latino population represents an additional challenge since there are distinct characteristics associated with AD and comorbidities. In this review, we aim to bring attention to the intersection between social determinants of health and genetic factors associated with AD within the Latino community. We argue that understanding the interplay between identified social determinants of health, co-morbidities, and genetic factors could lead to community empowerment and inclusiveness in research and healthcare services, contributing to improved diagnosis and treatment of AD patients. Lastly, we propose that inserting a neuroethics perspective could help understand key challenges that influence healthcare disparities and contribute to increased risk of AD among Latinos.

%B J Alzheimers Dis %V 58 %P 979-992 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527211?dopt=Abstract %R 10.3233/JAD-161261 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease Severity is Not Significantly Associated with Short Sleep: Survey by Actigraphy on 208 Mild and Moderate Alzheimer's Disease Patients. %A Leger, Damien %A Elbaz, Maxime %A Dubois, Alexandre %A Rio, Stéphane %A Mezghiche, Hocine %A Carita, Paulo %A Stemmelin, Jeanne %A Strauss, Melanie %X

BACKGROUND: In epidemiological surveys, cognitive decline has been found to be associated with both short and long sleep duration.

OBJECTIVE: Our goal was to objectively determine how total sleep time (TST) at night was associated or not with apathy or severity scores in patients with Alzheimer 's disease (AD).

METHODS: During an observational first step of a clinical trial, sleep was assessed in institutionalized patients with mild or moderate AD using actigraphy (MW8, Camtech, Cambridge, UK) for 14 consecutive 24-hour periods. Sleep parameters analyzed were: TST, time in bed (TIB), wake after sleep onset (WASO), sleep efficiency (SE) defined by the ratio TST/TIB, in percentage), the number and length of awakenings, the night fragmentation index, the interdaily stability, and intradaily variability indexes. Statistical association analyses were tested between these values and AD apathy and severity scores.

RESULTS: 208 individuals coming from 82 centers worldwide (France, Germany, Spain, Italy, Portugal, Poland, United States, Canada, and Australia) and≥50 years old participated. Their average TST was 7 hours and 35 minutes and the average WASO 58 minutes. TST and SE were significantly higher in patients with apathy and the number of awakenings was significantly lower. TST was also positively associated with functional disability (ADCS-ADL scores), but it was not found significantly greater in patients with a moderate AD severity compared to the mild.

CONCLUSION: Despite several and long awakenings, TST was not shorter in patients with AD. TST was even significantly increased with disability and apathy.

%B J Alzheimers Dis %V 55 %P 321-331 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662321?dopt=Abstract %R 10.3233/JAD-160754 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease: The Alternative Serotonergic Hypothesis of Cognitive Decline. %A Vakalopoulos, Costa %X

The pathognomonic feature of Alzheimer's disease is a loss of declarative memory. This has generally been attributed to early involvement of medial temporal lobe structures with neurofibrillary tangles and loss of neurons in the entorhinal cortex. However, there has been a re-emerging emphasis on the causal role of brainstem monoaminergic nuclei as involvement of the cholinergic basal forebrain loses prominence. The rejection of this latter theory of cognitive decline is related to inconsistencies in time course and modest effects of treatment using cholinergic agents. The amyloid hypothesis of cortical dysfunction is also losing favor as current trials of plaque dissolution are proving again disappointing. Recent pre-clinical studies on APP/PS1 (familial Alzheimer's disease) transgenic mouse models using serotonergic receptor modulating agents, demonstrate clear neuroprotective effects. The involvement of midbrain raphe in the earliest stages of dementia requires a reassessment of relevant pathophysiology beyond behavioral and affective dimensions. Indeed, a theory of serotonergic modulation of explicit memory formation by direct enhancement of synaptic strength could change the view of the role of these nuclei in AD and lead to more effective treatments.

%B J Alzheimers Dis %V 60 %P 859-866 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984594?dopt=Abstract %R 10.3233/JAD-170364 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease-Associated Cerebrospinal Fluid (CSF) Biomarkers do not Correlate with CSF Volumes or CSF Production Rate. %A Edsbagge, Mikael %A Andreasson, Ulf %A Ambarki, Khalid %A Wikkelsø, Carsten %A Eklund, Anders %A Blennow, Kaj %A Zetterberg, Henrik %A Tullberg, Mats %X

BACKGROUND: Neuropathologically, Alzheimer's disease (AD) is characterized by accumulation of a 42 amino acid peptide called amyloid-β (Aβ42) in extracellular senile plaques together with intraneuronal inclusions of hyperphosphorylated tau protein in neurofibrillary tangles and neuronal degeneration. These changes are reflected in the cerebrospinal fluid (CSF), the volumes and production rates of which vary considerably between individuals, by reduced concentration of Aβ42, increased concentration of phosphorylated tau (P-tau) protein, and increased concentration of total tau (T-tau) protein, respectively.

OBJECTIVE: To examine the outstanding question if CSF concentrations of AD associated biomarkers are influenced by variations in CSF volumes, CSF production rate, and intracranial pressure in healthy individuals.

METHODS: CSF concentrations of Aβ42, P-tau, and T-tau, as well as a number of other AD-related CSF biomarkers were analyzed together with intracranial subarachnoid, ventricular, and spinal CSF volumes, as assessed by magnetic resonance imaging volumetric measurements, and CSF production rate in 19 cognitively normal healthy subjects (mean age 70.6, SD 3.6 years).

RESULTS: Negative correlations were seen between the concentrations of three CSF biomarkers (albumin ratio, Aβ38, and Aβ40), and ventricular CSF volume, but apart from this finding, no significant correlations were observed.

CONCLUSION: These results speak against inter-individual variations in CSF volume and production rate as important confounds in the AD biomarker research field.

%B J Alzheimers Dis %V 58 %P 821-828 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505972?dopt=Abstract %R 10.3233/JAD-161257 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease-Related Polymorphisms in Shunt-Responsive Idiopathic Normal Pressure Hydrocephalus. %A Huovinen, Joel %A Helisalmi, Seppo %A Paananen, Jussi %A Laiterä, Tiina %A Kojoukhova, Maria %A Sutela, Anna %A Vanninen, Ritva %A Laitinen, Marjo %A Rauramaa, Tuomas %A Koivisto, Anne M %A Remes, Anne M %A Soininen, Hilkka %A Kurki, Mitja %A Haapasalo, Annakaisa %A Jääskeläinen, Juha E %A Hiltunen, Mikko %A Leinonen, Ville %X

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a late onset, surgically treated progressive brain disease caused by impaired cerebrospinal fluid dynamics and subsequent ventriculomegaly. Comorbid Alzheimer's disease (AD) seems to be frequent in iNPH.

OBJECTIVE: We aim to evaluate the role of AD-related polymorphisms in iNPH.

METHODS: Overall 188 shunt-operated iNPH patients and 688 controls without diagnosed neurodegenerative disease were included into analysis. Twenty-three single-nucleotide polymorphisms (SNPs FRMD4A [rs7081208_A, rs2446581_A, rs17314229_T], CR1, BIN, CD2AP, CLU, MS4A6A, MS4A4E, PICALM, ABCA7, CD33, INPP5D, HLA_DRB5, EPHA1, PTK2B, CELF1, SORL1, FERMT2, SLC24A, DSG2, CASS4, and NME8) adjusted to APOE were analyzed between groups by using binary logistic regression analysis. Neuroradiological characteristics and AD-related changes in the right frontal cortical brain biopsies were available for further analysis.

RESULTS: Logistic regression analysis adjusted to age, gender, and other SNPs indicated allelic variation of NME8 between iNPH patients and non-demented controls (p = 0.014). The allelic variation of NME8 was not related to the neuropathological changes in the brain biopsies of iNPH patients. However, periventricular white matter changes (p = 0.017) were more frequent in the iNPH patients with the AA-genotype, an identified risk factor of AD.

CONCLUSIONS: Our findings increase the evidence that iNPH is characterized by genetic and pathophysiological mechanisms independent from AD. Considering that NME8 plays a role in the ciliary function and displays SNP-related diversity in white matter changes, the mechanisms of NME8 in iNPH and other neurodegenerative processes are worth further study.

%B J Alzheimers Dis %V 60 %P 1077-1085 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984604?dopt=Abstract %R 10.3233/JAD-170583 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Amygdala α-Synuclein Pathology in the Population-Based Vantaa 85+ Study. %A Raunio, Anna %A Myllykangas, Liisa %A Kero, Mia %A Polvikoski, Tuomo %A Paetau, Anders %A Oinas, Minna %X

We investigated the frequency of Lewy-related pathology (LRP) in the amygdala among the population-based Vantaa 85+ study. Data of amygdala samples (N = 304) immunostained with two α-synuclein antibodies (clone 42 and clone 5G4) was compared with the previously analyzed LRP and AD pathologies from other brain regions. The amygdala LRP was present in one third (33%) of subjects. Only 5% of pure AD subjects, but 85% of pure DLB subjects had LRP in the amygdala. The amygdala LRP was associated with dementia; however, the association was dependent on LRP on other brain regions, and thus was not an independent risk factor. The amygdala-predominant category was a rare (4%) and heterogeneous group.

%B J Alzheimers Dis %V 58 %P 669-674 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28482633?dopt=Abstract %R 10.3233/JAD-170104 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Amylin Enhances Amyloid-β Peptide Brain to Blood Efflux Across the Blood-Brain Barrier. %A Mohamed, Loqman A %A Zhu, Haihao %A Mousa, Youssef M %A Wang, Erming %A Qiu, Wei Qiao %A Kaddoumi, Amal %X

Findings from Alzheimer's disease (AD) mouse models showed that amylin treatment improved AD pathology and enhanced amyloid-β (Aβ) brain to blood clearance; however, the mechanism was not investigated. Using the Tg2576 AD mouse model, a single intraperitoneal injection of amylin significantly increased Aβ serum levels, and the effect was abolished by AC253, an amylin receptor antagonist, suggesting that amylin effect could be mediated by its receptor. Subsequent mechanistic studies showed amylin enhanced Aβ transport across a cell-based model of the blood-brain barrier (BBB), an effect that was abolished when the amylin receptor was inhibited by two amylin antagonists and by siRNA knockdown of amylin receptor Ramp3. To explain this finding, amylin effect on Aβ transport proteins expressed at the BBB was evaluated. Findings indicated that cells treated with amylin induced LRP1 expression, a major receptor involved in brain Aβ efflux, in plasma membrane fraction, suggesting intracellular translocation of LRP1 from the cytoplasmic pool. Increased LRP1 in membrane fraction could explain, at least in part, the enhanced uptake and transport of Aβ across the BBB. Collectively, our findings indicated that amylin induced Aβ brain to blood clearance through amylin receptor by inducing LRP1 subcellular translocation to the plasma membrane of the BBB endothelium.

%B J Alzheimers Dis %V 56 %P 1087-1099 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059785?dopt=Abstract %R 10.3233/JAD-160800 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Amylin Treatment Reduces Neuroinflammation and Ameliorates Abnormal Patterns of Gene Expression in the Cerebral Cortex of an Alzheimer's Disease Mouse Model. %A Wang, Erming %A Zhu, Haihao %A Wang, Xiaofan %A Gower, Adam %A Wallack, Max %A Blusztajn, Jan Krzysztof %A Kowall, Neil %A Qiu, Wei Qiao %X

Our recent study has demonstrated that peripheral amylin treatment reduces the amyloid pathology in the brain of Alzheimer's disease (AD) mouse models, and improves their learning and memory. We hypothesized that the beneficial effects of amylin for AD was beyond reducing the amyloids in the brain, and have now directly tested the actions of amylin on other aspects of AD pathogenesis, especially neuroinflammation. A 10-week course of peripheral amylin treatment significantly reduced levels of cerebral inflammation markers, Cd68 and Iba1, in amyloid precursor protein (APP) transgenic mice. Mechanistic studies indicated the protective effect of amylin required interaction with its cognate receptor because silencing the amylin receptor expression blocked the amylin effect on Cd68 in microglia. Using weighted gene co-expression network analysis, we discovered that amylin treatment influenced two gene modules linked with amyloid pathology: 1) a module related to proinflammation and transport/vesicle process that included a hub gene of Cd68, and 2) a module related to mitochondria function that included a hub gene of Atp5b. Amylin treatment restored the expression of most genes in the APP cortex toward levels observed in the wild-type (WT) cortex in these two modules including Cd68 and Atp5b. Using a human dataset, we found that the expression levels of Cd68 and Atp5b were significantly correlated with the neurofibrillary tangle burden in the AD brain and with their cognition. These data suggest that amylin acts on the pathological cascade in animal models of AD, and further supports the therapeutic potential of amylin-type peptides for AD.

%B J Alzheimers Dis %V 56 %P 47-61 %G eng %N 1 %R 10.3233/JAD-160677 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Amyloid Burden in Obstructive Sleep Apnea. %A Yun, Chang-Ho %A Lee, Ho-Young %A Lee, Seung Ku %A Kim, Hyun %A Seo, Hyung Suk %A Bang, Seong Ae %A Kim, Sang Eun %A Greve, Douglas N %A Au, Rhoda %A Shin, Chol %A Thomas, Robert J %X

To test the hypothesis that excessive amyloid deposition is a biological link between obstructive sleep apnea (OSA) and Alzheimer's disease, we determined whether OSA increases cerebral amyloid burden, relative to controls, using Pittsburgh Compound B (PiB) PET imaging. The subjects were adult participants (age 50-65 years) from the Korean Genome and Epidemiology Study. Polysomnography, brain MRI including 3D images, and a detailed neuro-cognitive function test battery were done in 2011-2012. Nineteen OSA subjects (Apnea-Hypopnea Index [AHI] ≥15/h, 21.2±5.1/h; age 58.5±4.1 years; 9 male) and 19 controls (AHI 1.8±1.3/h; age 58.5±4.2 years; 9 male) underwent 60-min dynamic 11C-PiB PET. All subjects were right-handed with normal cognitive function and brain MRI. Controls were matched by age, gender, education, and APOE genotype. A voxel-wise comparison of PiB-PET images between the two groups was performed after spatial and count normalization with cerebellar gray matter as a reference. Covariates included the status of sleep duration, hypertension, diabetes, body mass index, exercise, depressive mood, smoking, and alcohol drinking. Cortical thickness on 3D MRI was also measured and compared between the two groups. The OSA group showed a higher PiB deposition in the right posterior cingulate gyrus and right temporal cortex (corrected p < 0.05). There was no area of higher uptake in the control compared with OSA. Regional differences in cortical thickness were not significant. The study suggests that OSA accelerates amyloid deposition and may contribute to the development or progression of Alzheimer's disease.

%B J Alzheimers Dis %V 59 %P 21-29 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550245?dopt=Abstract %R 10.3233/JAD-161047 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Amyloid Plaques Show Binding Capacity of Exogenous Injected Amyloid-β. %A Gureviciene, Irina %A Gurevicius, Kestutis %A Mugantseva, Ekaterina %A Kislin, Mikhail %A Khiroug, Leonard %A Tanila, Heikki %X

Amyloid plaques, although inducing damage to the immediately surrounding neuropil, have been proposed to provide a relatively innocuous way to deposit toxic soluble amyloid-β (Aβ) species. Here we address this hypothesis by exploring spread and absorption of fluorescent Aβ to pre-existing amyloid plaques after local application in wild-type mice versus APP/PS1 transgenic mice with amyloid plaques. Local intracortical or intracerebroventricular injection of fluorescently-labeled Aβ in APP/PS1 mice with a high plaque density resulted in preferential accumulation of the peptide in amyloid plaques in both conventional postmortem histology and in live imaging using two-photon microscopy. These findings support the contention that amyloid plaques may act as buffers to protect neurons from the toxic effects of momentary high concentrations of soluble Aβ oligomers.

%B J Alzheimers Dis %V 55 %P 147-157 %8 2016 Sep 13 %G eng %N 1 %R 10.3233/JAD-160453 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Amyloid-Beta and Phosphorylated Tau Accumulations Cause Abnormalities at Synapses of Alzheimer's disease Neurons. %A Rajmohan, Ravi %A Reddy, P Hemachandra %X

Amyloid-beta (Aβ) and hyperphosphorylated tau are hallmark lesions of Alzheimer's disease (AD). However, the loss of synapses and dysfunctions of neurotransmission are more directly tied to disease severity. The role of these lesions in the pathoetiological progression of the disease remains contested. Biochemical, cellular, molecular, and pathological studies provided several lines of evidence and improved our understanding of how Aβ and hyperphosphorylated tau accumulation may directly harm synapses and alter neurotransmission. In vitro evidence suggests that Aβ and hyperphosphorylated tau have both direct and indirect cytotoxic effects that affect neurotransmission, axonal transport, signaling cascades, organelle function, and immune response in ways that lead to synaptic loss and dysfunctions in neurotransmitter release. Observations in preclinical models and autopsy studies support these findings, suggesting that while the pathoetiology of positive lesions remains elusive, their removal may reduce disease severity and progression. The purpose of this article is to highlight the need for further investigation of the role of tau in disease progression and its interactions with Aβ and neurotransmitters alike.

%B J Alzheimers Dis %V 57 %P 975-999 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567878?dopt=Abstract %R 10.3233/JAD-160612 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Amyloid-Related Imaging Abnormalities in an Aged Squirrel Monkey with Cerebral Amyloid Angiopathy. %A Heuer, Eric %A Jacobs, Jessica %A Du, Rebecca %A Wang, Silun %A Keifer, Orion P %A Cintron, Amarallys F %A Dooyema, Jeromy %A Meng, Yuguang %A Zhang, Xiaodong %A Walker, Lary C %X

Amyloid-related imaging abnormalities (ARIA) in magnetic resonance imaging scans have emerged as indicators of potentially serious side effects in clinical trials of therapeutics for Alzheimer's disease. These anomalies include an edematous type (ARIA-E) that appears as hyperintense (bright) regions by T2-weighted MRI, and a type characterized by the deposition of hemosiderin (ARIA-H) that elicits a hypointense signal, especially in T2* susceptibility weighted images. ARIA in general has been linked to the presence of amyloid-β (Aβ)-type cerebral amyloid angiopathy, an accumulation of misfolded Aβ protein in the vascular wall that impairs the integrity of brain blood vessels. However, the pathobiology of ARIA remains poorly understood, in part due to the absence of an animal model of the disorder that would enable a contemporaneous analysis of tissue integrity in the affected region. Here we describe both ARIA-E and ARIA-H in an aged squirrel monkey (Saimiri sciureus), a nonhuman primate model of naturally occurring cerebral amyloid angiopathy. Histopathologic examination of the anomalous region revealed reactive astrocytosis and microgliosis, infiltration of systemic inflammatory/immune cells, damage to axons and myelin, and hemosiderin deposition. The disruption of axons in particular suggests that ARIA-E could have functional consequences for affected regions. The squirrel monkey model can be useful for studying the pathogenesis and long-term effects of ARIA, and for testing the safety and efficacy of emerging therapies for Alzheimer's disease.

%B J Alzheimers Dis %V 57 %P 519-530 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269776?dopt=Abstract %R 10.3233/JAD-160981 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Amyloid-β Deposition and Long-Term Progression in Mild Cognitive Impairment due to Alzheimer's Disease Defined with Amyloid PET Imaging. %A Hatashita, Shizuo %A Wakebe, Daichi %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Aniline Compounds %K Cognitive Dysfunction %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Positron-Emission Tomography %K Thiazoles %X

The aim was to evaluate brain amyloid-β (Aβ) deposition in patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) using amyloid PET imaging and clarify the relationship between the annual change in Aβ deposition and disease progression. Forty-eight MCI patients underwent neuropsychological assessment and amyloid PET imaging using [11C]-PIB over a follow-up of 5.7±1.5 years. Thirty-nine MCI patients who had an amyloid-positive scan were defined as MCI due to AD, and 9 MCI patients who had an amyloid-negative scan were included. Regions of interest were defined on co-registered MRI, and the PIB standardized uptake value ratio (SUVR) on the same regions was used over follow-up. Annual change in PIB SUVR was calculated. Patients with MCI due to AD had higher baseline PIB SUVR (1.81±0.32, n = 39, p < 0.01) and a greater annual rate of change in PIB SUVR (0.044±0.027, n = 39, p < 0.01) compared to amyloid-negative MCI patients. Twenty-eight (71.8%) progressed to AD. In patients who progressed during a short duration of 1.7±0.8 years, the annual rate of increase in PIB SUVR was 0.101±0.094 (n = 16, p < 0.05), which was greater compared to patients with long conversion or stable patients. There was a negative correlation between the annual rate of increase in PIB SUVR and duration of progression to AD among individual MCI converters (r = -0.47, n = 28, p < 0.05). The patients defined as MCI due to AD could progress to AD with a shorter period if they have a greater increased annual rate in brain Aβ deposition.

%B J Alzheimers Dis %V 57 %P 765-773 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304292?dopt=Abstract %R 10.3233/JAD-161074 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Analytical Strategy to Prioritize Alzheimer's Disease Candidate Genes in Gene Regulatory Networks Using Public Expression Data. %A Kawalia, Shweta Bagewadi %A Raschka, Tamara %A Naz, Mufassra %A de Matos Simoes, Ricardo %A Senger, Philipp %A Hofmann-Apitius, Martin %X

Alzheimer's disease (AD) progressively destroys cognitive abilities in the aging population with tremendous effects on memory. Despite recent progress in understanding the underlying mechanisms, high drug attrition rates have put a question mark behind our knowledge about its etiology. Re-evaluation of past studies could help us to elucidate molecular-level details of this disease. Several methods to infer such networks exist, but most of them do not elaborate on context specificity and completeness of the generated networks, missing out on lesser-known candidates. In this study, we present a novel strategy that corroborates common mechanistic patterns across large scale AD gene expression studies and further prioritizes potential biomarker candidates. To infer gene regulatory networks (GRNs), we applied an optimized version of the BC3Net algorithm, named BC3Net10, capable of deriving robust and coherent patterns. In principle, this approach initially leverages the power of literature knowledge to extract AD specific genes for generating viable networks. Our findings suggest that AD GRNs show significant enrichment for key signaling mechanisms involved in neurotransmission. Among the prioritized genes, well-known AD genes were prominent in synaptic transmission, implicated in cognitive deficits. Moreover, less intensive studied AD candidates (STX2, HLA-F, HLA-C, RAB11FIP4, ARAP3, AP2A2, ATP2B4, ITPR2, and ATP2A3) are also involved in neurotransmission, providing new insights into the underlying mechanism. To our knowledge, this is the first study to generate knowledge-instructed GRNs that demonstrates an effective way of combining literature-based knowledge and data-driven analysis to identify lesser known candidates embedded in stable and robust functional patterns across disparate datasets.

%B J Alzheimers Dis %V 59 %P 1237-1254 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28800327?dopt=Abstract %R 10.3233/JAD-170011 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Anesthesia/Surgery Induces Cognitive Impairment in Female Alzheimer's Disease Transgenic Mice. %A Zhang, Ce %A Zhang, Yiying %A Shen, Yuan %A Zhao, Guoqing %A Xie, Zhongcong %A Dong, Yuanlin %X

Anesthesia and/or surgery may promote Alzheimer's disease (AD) by accelerating its neuropathogenesis. Other studies showed different findings. However, the potential sex difference among these studies has not been well considered, and it is unknown whether male or female AD patients are more vulnerable to develop postoperative cognitive dysfunction. We therefore set out to perform a proof of concept study to determine whether anesthesia and surgery can have different effects in male and female AD transgenic (Tg) mice, and in female AD Tg plus Cyclophilin D knockout (CypD KO) mice. The mice received an abdominal surgery under sevoflurane anesthesia (anesthesia/surgery). Fear Conditioning System (FCS) was used to assess the cognitive function. Hippocampal levels of synaptic marker postsynaptic density 95 (PSD-95) and synaptophysin (SVP) were measured using western blot analysis. Here we showed that the anesthesia/surgery decreased the freezing time in context test of FCS at 7 days after the anesthesia/surgery in female, but not male, mice. The anesthesia/surgery reduced hippocampus levels of synaptic marker PSD-95 and SVP in female, but not male, mice. The anesthesia/surgery induced neither reduction in freezing time in FCS nor decreased hippocampus levels of PSD-95 and SVP in the AD Tg plus CypD KO mice. These data suggest that the anesthesia/surgery induced a sex-dependent cognitive impairment and reduction in hippocampus levels of synaptic markers in AD Tg mice, potentially via a mitochondria-associated mechanism. These findings could promote clinical investigations to determine whether female AD patients are more vulnerable to the development of postoperative cognitive dysfunction.

%B J Alzheimers Dis %V 57 %P 505-518 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269788?dopt=Abstract %R 10.3233/JAD-161268 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Angiotensin-III is Increased in Alzheimer's Disease in Association with Amyloid-β and Tau Pathology. %A Kehoe, Patrick Gavin %A Hibbs, Elliott %A Palmer, Laura E %A Miners, J Scott %X

Hyperactivity of the renin-angiotensin system (RAS) is associated with the pathogenesis of Alzheimer's disease (AD) believed to be mediated by angiotensin-II (Ang-II) activation of the angiotensin type 1 receptor (AT1R). We previously showed that angiotensin-converting enzyme-1 (ACE-1) activity, the rate-limiting enzyme in the production of Ang-II, is increased in human postmortem brain tissue in AD. Angiotensin-III (Ang-III) activates the AT1R and angiotensin type-2 receptor (AT2R), but its potential role in the pathophysiology of AD remains unexplored. We measured Ang-II and Ang-III levels by ELISA, and the levels and activities of aminopeptidase-A (AP-A) and aminopeptidase-N (AP-N) (responsible for the production and metabolism of Ang-III, respectively) in human postmortem brain tissue in the mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59), for which we had previous measurements of ACE-1 activity, Aβ level, and tau pathology (also in the mid-frontal cortex). We found that both Ang-II and Ang-III levels were significantly higher in AD compared to age-matched controls and that Ang-III, rather than Ang-II, was strongly associated with Aβ load and tau load. Levels of AP-A were significantly reduced in AD but AP-A enzyme activity was unchanged whereas AP-N activity was reduced in AD but AP-N protein level was unchanged. Together, these data indicate that the APA/Ang-III/APN/Ang-IV/AT4R pathway is dysregulated and that elevated Ang-III could contribute to the pathogenesis of AD.

%B J Alzheimers Dis %V 58 %P 203-214 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387670?dopt=Abstract %R 10.3233/JAD-161265 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Anomalous White Matter Structure and the Effect of Age in Down Syndrome Patients. %A Fenoll, Raquel %A Pujol, Jesus %A Esteba-Castillo, Susanna %A de Sola, Susana %A Ribas-Vidal, Núria %A García-Alba, Javier %A Sánchez-Benavides, Gonzalo %A Martínez-Vilavella, Gerard %A Deus, Joan %A Dierssen, Mara %A Novell-Alsina, Ramón %A de la Torre, Rafael %X

BACKGROUND: Neural tissue alterations in Down syndrome are fully expressed at relatively late developmental stages. In addition, there is an early presence of neurodegenerative changes in the late life stages.

OBJECTIVE: The aims of this study were both to characterize white matter abnormalities in the brain of adult Down syndrome patients using diffusion tensor imaging (DTI) and to investigate whether degenerative alterations in white matter structure are detectable before dementia is clinically evident.

METHODS: Forty-five adult non-demented Down syndrome patients showing a wide age range (18-52 years) and a matched 45-subject control group were assessed. DTI fractional anisotropy (FA) brain maps were generated and selected cognitive tests were administered.

RESULTS: Compared with healthy controls, non-demented Down syndrome patients showed lower DTI FA in white matter involving the major pathways, but with more severe alterations in the frontal-subcortical circuits. White matter FA decreased with age at a similar rate in both DS and control groups.

CONCLUSIONS: Our results contribute to characterizing the expression of white matter structural alterations in adult Down syndrome. However, an accelerated aging effect was not demonstrated, which may suggest that the FA measurements used are not sufficiently sensitive or, alternatively, age-related white matter neurodegeneration is not obvious prior to overt clinical dementia.

%B J Alzheimers Dis %V 57 %P 61-70 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222523?dopt=Abstract %R 10.3233/JAD-161112 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Anti-Amyloid-β and Neuroprotective Properties of a Novel Tricyclic Pyrone Molecule. %A Maezawa, Izumi %A Zou, Bende %A Di Lucente, Jacopo %A Cao, William S %A Pascual, Conrado %A Weerasekara, Sahani %A Zhang, Man %A Xie, Xinmin Simon %A Hua, Duy H %A Jin, Lee-Way %X

There is an urgent unmet need for new therapeutics for Alzheimer's disease (AD), the most common cause of dementia in the elderly. Therapeutic approaches targeting amyloid-β (Aβ) and its downstream toxicities have become major strategies in AD drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone (TP) compounds that show anti-Aβ and other neuroprotective actions. The in vivo efficacy of a lead TP named CP2 to ameliorate AD-like pathologies has been shown in mouse models. Here we report the selection and initial characterization of a new lead TP70, which exhibited an anti-Aβ therapeutic index even higher than CP2. Moreover, TP70 was able to reduce oxidative stress, inhibit acyl-coenzyme A:cholesterol acyltransferase (ACAT), and upregulate the expression of ATP-binding cassette subfamily A, member 1 (ABCA1), actions considered neuroprotective in AD. TP70 further showed excellent pharmacokinetic properties, including brain penetration and oral availability. When administered to 5xFAD mice via intraperitoneal or oral route, TP70 enhanced the overall solubility and decreased the level of cerebral Aβ, including both fibrillary and soluble Aβ species. Interestingly, TP70 enhanced N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potential (EPSP) in the hippocampal CA1 area, increased the magnitude of NMDA-dependent hippocampal long-term potentiation (LTP), a cellular model of learning and memory, and prevented the Aβ oligomer-impaired LTP. Significantly, a single dose of TP70 administered to aged 5xFAD mice was effective in mitigating the impaired LTP induction, recorded at 24 h after administration. Our results support a potential of TP70 in clinical development for AD in view of its synergistic neuroprotective actions, ability to positively modulate NMDA receptor-mediated hippocampal plasticity, and favorable pharmacokinetic properties in rodents.

%B J Alzheimers Dis %V 58 %P 559-574 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28482635?dopt=Abstract %R 10.3233/JAD-161175 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Antibodies to Signaling Molecules and Receptors in Alzheimer's Disease are Associated with Psychomotor Slowing, Depression, and Poor Visuospatial Function. %A Giil, Lasse M %A Vedeler, Christian A %A Kristoffersen, Einar K %A Nordrehaug, Jan Erik %A Heidecke, Harald %A Dechend, Ralf %A Schulze-Forster, Kai %A Muller, Dominik N %A von Goetze, Victoria S %A Cabral-Marques, Otavio %A Riemekasten, Gabriela %A Vogelsang, Petra %A Nygaard, Staale %A Lund, Anders %A Aarsland, Dag %X

BACKGROUND: Alzheimer's disease (AD) is associated with several antibodies as well as signaling molecules and receptors. These may be detrimental in the presence of a disrupted blood-brain barrier (BBB).

OBJECTIVE: To investigate whether the levels of antibodies toward 33 signaling molecules involved in neurotransmitter, vascular, and immune functions were associated with AD and, within the AD group; cognitive function and mood.

METHODS: Antibodies in sera from patients with mild AD [(n = 91) defined as a Mini-Mental State Examination ≥ 20 or a Clinical Dementia Rating Scale≤1] and healthy controls (n = 102) were measured with enzyme-linked immunosorbent assays. Levels in AD and controls were compared by Mann-Whitney test. In the AD group, associations between antibodies and psychometric test scores were analyzed by robust regression. The false discovery threshold was set to 0.05.

RESULTS: Antibodies to serotonin receptors [5-HT2AR (effect size (r) = 0.21, p = 0.004), 5-HT2CR (r = 0.25, p = 0.0005) and 5-HT7R (r = 0.21, p = 0.003)], vascular endothelial growth factor receptor 1 [VEGFR1 (r = 0.29, p < 0.001)] and immune-receptors (Stabilin-1 (r = 0.23, p = 0.001) and C5aR1 (r = 0.21, p = 0.004) were higher in AD. Psychomotor speed was associated with D1R-abs (β 0.49, p < 0.001), depression with ETAR-abs (β 0.31, p < 0.001), and visuospatial function with 5-HT1AR-abs (β 0.27, p = 0.004) despite similar antibody levels compared to controls.

CONCLUSIONS: Antibody levels to VEGFR1, serotonergic receptors, and receptors in the immune system were increased in AD. Antibodies at similar levels as in controls were associated cognitive dysfunction and depression in AD.

%B J Alzheimers Dis %V 59 %P 929-939 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697567?dopt=Abstract %R 10.3233/JAD-170245 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Anticholinergic Exposure and Risk of Pneumonia in Persons with Alzheimer's Disease: A Nested Case-Control Study. %A Lampela, Pasi %A Tolppanen, Anna-Maija %A Tanskanen, Antti %A Tiihonen, Jari %A Hartikainen, Sirpa %A Taipale, Heidi %X

BACKGROUND: Risk of pneumonia is increased in persons with Alzheimer's disease (AD). In some studies, anticholinergic drugs (AC) have been associated with an increased pneumonia risk.

OBJECTIVE: We analyzed the risk of pneumonia associated with ACs in persons with AD.

METHODS: We performed a nested case-control study using register-based data from a Finnish nationwide MEDALZ cohort including all community-dwelling persons diagnosed with AD during 2005-2011. Cases were identified based on pneumonia diagnoses (n = 12,442) from hospital discharge and causes of death registers. Up to two controls without pneumonia were matched based on time since AD diagnoses, age, and gender for each case; AC use was measured using Anticholinergic Drug Scale.

RESULTS: Use of AC was associated with an increased risk of pneumonia (adjusted odds ratio (OR) 1.36, 95% confidence interval (CI) 1.29-1.43). However, there was no increased pneumonia risk in persons using level 3 ACs. Incident use was associated with higher risk of pneumonia (OR 2.68, 95% CI 2.15-3.34) than prevalent use (OR 1.48, 95% CI 1.40-1.57). Among persons using cholinesterase inhibitors (AChEIs), risk of pneumonia was increased in persons using also ACs (OR 1.53, 95% CI 1.41-1.66).

CONCLUSION: ACs were associated with an increased risk of pneumonia in persons with AD, especially at the time of initiation of these drugs. AC use was associated with increased pneumonia risk also in persons using AChEIs. This risk should be carefully considered when treating AD patients.

%B J Alzheimers Dis %V 56 %P 119-128 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911327?dopt=Abstract %R 10.3233/JAD-160956 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Antihypertensive Treatment is associated with MRI-Derived Markers of Neurodegeneration and Impaired Cognition: A Propensity-Weighted Cohort Study. %A Edwards, Jodi D %A Ramirez, Joel %A Callahan, Brandy L %A Tobe, Sheldon W %A Oh, Paul %A Berezuk, Courtney %A Lanctôt, Krista %A Swardfager, Walter %A Nestor, Sean %A Kiss, Alexander %A Strother, Stephen %A Black, Sandra E %X

BACKGROUND: Hypertension is an important risk factor for Alzheimer's disease (AD) and cerebral small vessel disease. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are common anti-hypertensive treatments, but have differential effects on cortical amyloid.

OBJECTIVE: The objective of this study was to evaluate associations between anti-hypertensive treatment, brain volume, and cognition, using a propensity-weighted analysis to account for confounding by indication.

METHODS: We identified a cohort of normal elderly adults and individuals with mild cognitive impairment (MCI) or AD (N = 886; mean age = 75.0) from the Alzheimer's Disease Neuroimaging Initiative. Primary outcomes were brain parenchymal fraction, total hippocampal volume, and white matter hyperintensity (WMH) volume. Secondary outcomes were standardized scores on neuropsychological tests. Propensity-weighted adjusted multivariate linear regression was used to estimate associations between anti-hypertensive treatment class and MRI volumes and cognition.

RESULTS: Individuals treated with ARBs showed larger hippocampal volumes (R2 = 0.83, p = 0.05) and brain parenchymal fraction (R2 = 0.83, p = 0.01) than those treated with ACEIs. When stratified by diagnosis, this effect remained only in normal elderly adults and MCI patients, and a significant association between ARBs and lower WMH volume (R2 = 0.83, p = 0.03) emerged for AD patients only. ARBs were also associated with significantly better performance on tests of episodic and verbal memory, language, and executive function (all p < 0.05).

CONCLUSIONS: Findings are consistent with evidence for a neuroprotective effect of treatment with ARBs for brain structure and cognition. This study has potential implications for the treatment of hypertension, particularly in elderly adults at risk of cognitive decline and AD.

%B J Alzheimers Dis %V 59 %P 1113-1122 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731439?dopt=Abstract %R 10.3233/JAD-170238 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Aortic Valve Calcification and the Risk of dementia: A Population-Based Study. %A Wolters, Frank J %A Bos, Daniel %A Vernooij, Meike W %A Franco, Oscar H %A Hofman, Albert %A Koudstaal, Peter J %A van der Lugt, Aad %A Ikram, M Arfan %X

The association of aortic valve calcification (AVC) with dementia remains unknown. In 2,428 non-demented participants from the population-based Rotterdam Study, we investigated the association of CT-assessed AVC with risk of dementia and cognitive decline. AVC was present in 33.1% of the population. During a median follow-up of 9.3 years, 160 participants developed dementia. We found no association between presence of AVC and risk of all-cause dementia [hazard ratio (HR): 0.89 (95% confidence interval (CI):0.63;1.26)]. Presence of AVC was not associated with cognitive decline on any of the cognitive tests, nor with a measure of global cognition.

%B J Alzheimers Dis %V 55 %P 893-897 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767996?dopt=Abstract %R 10.3233/JAD-160871 %0 Journal Article %J J Alzheimers Dis %D 2017 %T APOE ε4 Modulation of Training Outcomes in Several Cognitive Domains in a Sample of Cognitively Intact Older Adults. %A López-Higes, Ramón %A Rodríguez-Rojo, Inmaculada C %A Prados, José M %A Montejo, Pedro %A Del-Río, David %A Delgado-Losada, María Luisa %A Montenegro, Mercedes %A López-Sanz, David %A Barabash, Ana %X

BACKGROUND: Most research points to the ɛ4 allele of the apolipoprotein E (APOE) gene as the most recognizable genetic risk factor associated with Alzheimer's disease pathogenesis. It has been also suggested that the APOEɛ4 allele has a negative influence on cognitive functioning, which begins long before cognitive impairment becomes manifest. However, still, little is known about the APOEɛ4 interaction with cognitive intervention programs.

OBJECTIVE: The main goal of this study was to explore whether there was a differential APOE genotype modulation effect after cognitive training in different domains, such as language comprehension, executive functions, and memory. Contrary to other studies, hippocampal volume was controlled for.

METHODS: Fifty older adults (65+ years; 30 women and 20 men) participated in a multi-domain cognitive training that involved 30 sessions taking place over 12 weeks. Half of the participants were APOEɛ4 carriers. The control group was matched in age, gender, normalized hippocampal volume, cognitive reserve, Mini-Mental State Examination score, and Geriatric Depression Scale-Short Version.

RESULTS: The study revealed that there were consistent treatment benefits in complex sentence comprehension (noncanonical sentences and sentences with two propositions), a domain that was not directly trained, but only in the A POEɛ4 noncarrier group.

CONCLUSION: Genetic profile modulates training outcomes in sentence comprehension.

%B J Alzheimers Dis %V 58 %P 1201-1215 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550244?dopt=Abstract %R 10.3233/JAD-161014 %0 Journal Article %J J Alzheimers Dis %D 2017 %T APOEɛ4 Genotype, Amyloid, and Clinical Disease Progression in Cognitively Normal Older Adults. %A Hollands, Simone %A Lim, Yen Ying %A Laws, Simon M %A Villemagne, Victor L %A Pietrzak, Robert H %A Harrington, Karra %A Porter, Tenielle %A Snyder, Peter %A Ames, David %A Fowler, Christopher %A Rainey-Smith, Stephanie R %A Martins, Ralph N %A Salvado, Olivier %A Robertson, Joanne %A Rowe, Christopher C %A Masters, Colin L %A Maruff, Paul %X

BACKGROUND: In cognitively normal (CN) older adults, carriage of the apolipoprotein E (APOE) ɛ4 allele is associated with increased risk for dementia of the Alzheimer type (AD-dementia). It is unclear whether this occurs solely through APOEɛ4 increasing amyloid-β (Aβ) accumulation or through processes independent of Aβ.

OBJECTIVE: To determine the extent and nature to which APOEɛ4 increases risk for clinical disease progression in CN older adults.

METHODS: Data from the total (n = 765) and Aβ-imaged (n = 423) CN cohort in the Australian Imaging, Biomarker and Lifestyle (AIBL) Study of Ageing was analyzed using Cox proportional hazard models to estimate ɛ4 risk for clinical disease progression over a 72-month follow-up.

RESULTS: With Aβ status unknown and risk from demographic characteristics controlled, ɛ4 carriage increased risk for clinical disease progression over 72 months by 2.66 times compared to risk of non-ɛ4 carriage. Re-analysis with Aβ status included showed that abnormally high Aβ increased risk for clinical disease progression over 72 months by 2.11 times compared to risk of low Aβ. However, with Aβ level known, ɛ4 carriage was no longer predictive of clinical disease progression.

CONCLUSION: In CN older adults, the risk of ɛ4 for clinical disease progression occurs through the effect of ɛ4 increasing Aβ levels.

%B J Alzheimers Dis %V 57 %G eng %N 2 %& 411-422 %R 10.3233/JAD-161019 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Apolipoprotein A1 in Cerebrospinal Fluid and Plasma and Progression to Alzheimer's Disease in Non-Demented Elderly. %A Slot, Rosalinde E R %A Van Harten, Argonde C %A Kester, Maartje I %A Jongbloed, Wesley %A Bouwman, Femke H %A Teunissen, Charlotte E %A Scheltens, Philip %A Veerhuis, Robert %A van der Flier, Wiesje M %X

BACKGROUND: HDL-cholesterol transporter Apolipoprotein A1 (ApoA1) holds neuroprotective properties, such as inhibition of amyloid-β aggregation. Low plasma ApoA1 concentrations are associated with Alzheimer's disease (AD). Little is known about ApoA1 levels in the pre-dementia stages of AD.

OBJECTIVE: To investigate associations between cerebrospinal fluid (CSF) and plasma ApoA1 levels and clinical progression toward AD in non-demented elderly.

METHODS: From the Amsterdam Dementia Cohort, we included 429 non-demented elderly with subjective cognitive decline (SCD; n = 206, 61±9 years, Mini-Mental State Exam (MMSE) 28±2) and mild cognitive impairment (MCI; n = 223, 67±8 years, MMSE 27±2), with a mean follow-up of 2.5±1.6 years. We used Cox proportional hazard models to investigate relations between CSF and plasma ApoA1 concentrations and clinical progression, defined as progression to MCI or AD for SCD, and progression to AD for MCI. Analyses were adjusted for age, gender, MMSE, and plasma cholesterol levels. Analyses were stratified for diagnosis and APOEɛ4 carriership.

RESULTS: 117 patients (27%) showed clinical progression. One standard deviation increase of CSF ApoA1 was associated with a 30% increased risk of clinical progression (hazard ratio (HR) (95% CI)  = 1.3(1.0-1.6)). The effect appeared to be attributable to the APOEɛ4 carriers with SCD (HR 3.3(1.0-10.9)). Lower plasma ApoA1 levels were associated with an increased risk of clinical progression in APOEɛ4 carriers with SCD (HR 5.0(1.3-18.9)).

CONCLUSION: Higher CSF and lower plasma ApoA1 levels were associated with an increased risk of clinical progression in APOEɛ4 carriers with SCD; suggesting that ApoA1 may be involved in the earliest stages of AD.

%B J Alzheimers Dis %V 56 %P 687-697 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035918?dopt=Abstract %R 10.3233/JAD-151068 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Apolipoprotein E Isoforms Differentially Regulate Alzheimer's Disease and Amyloid-β-Induced Inflammatory Response in vivo and in vitro. %A Dorey, Evan %A Bamji-Mirza, Michelle %A Najem, Dema %A Li, Yan %A Liu, Hong %A Callaghan, Debbie %A Walker, Douglas %A Lue, Lih-Fen %A Stanimirovic, Danica %A Zhang, Wandong %X

Neuroinflammation plays a critical role in neuronal dysfunction and death of Alzheimer's disease (AD). ApoE4 is a major risk factor of AD, while ApoE2 is neuroprotective. Little is known about the roles of ApoE isoforms in the neuroinflammation seen in AD. Their roles and mechanisms in Aβ-induced/neuroinflammation were investigated in this study using in vivo and in vitro models. Rat astrocytes were treated with lipid-poor recombinant hApoE and/or Aβ42. Mouse astrocyte lines-expressing lipidated hApoE were treated with Aβ42 and/or vitamin D receptor (VDR) agonist, 1α,25-dihydroxyvitamin D3. Cells and media were harvested for cytokine ELISA, RNA isolated for qRT-PCR, and nuclear protein for transcription factor (TF) arrays and EMSA. hApoE-transgenic and AD mice were mated to generate hApoE2/AD and hApoE4/AD mice. Mice were euthanized at 6 months of age. Brain tissues were collected for cytokine ELISA array, Aβ ELISA, immunoblotting, and immunohistochemistry. hApoE4/AD mice had significantly higher levels of inflammatory cytokines than hApoE2/AD mice. Lipidated hApoE4 significantly promoted inflammatory gene expression induced by Aβ42 but not recombinant hApoE4 in astrocytes as compared to controls. Lipidated hApoE3 provided a certain degree of protection against Aβ42-induced inflammatory response but not recombinant hApoE3 as compared to controls. Both lipidated and recombinant hApoE2 provided protection against Aβ42-induced inflammatory response compared to controls. TF array revealed that ApoE2 strongly activated VDR in Aβ42-treated astrocytes. Application of 1α,25-dihydroxyvitamin D3 completely inhibited Aβ-induced inflammatory gene expression in hApoE4-expressing astrocytes. The results suggest that ApoE4 promotes, but ApoE2 inhibits, AD/Aβ-induced neuroinflammation via VDR signaling. Targeting VDR signaling or active form of VD3 may relieve AD neuroinflammation or/and neurodegeneration.

%B J Alzheimers Dis %V 57 %P 1265-1279 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372324?dopt=Abstract %R 10.3233/JAD-160133 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Apolipoprotein E4 Elicits Lysosomal Cathepsin D Release, Decreased Thioredoxin-1 Levels, and Apoptosis. %A Persson, Torbjörn %A Lattanzio, Francesca %A Calvo-Garrido, Javier %A Rimondini, Roberto %A Rubio-Rodrigo, Marta %A Sundström, Erik %A Maioli, Silvia %A Sandebring-Matton, Anna %A Cedazo-Minguez, Angel %X

The major genetic risk factor for Alzheimer's disease (AD), apolipoprotein E4 (ApoE4), has been suggested to have detrimental effects on neurons, including direct toxicity via apoptosis. Thioredoxin-1 (Trx1) is an endogenous antioxidant protein important for redox regulation and participates in the regulation of apoptosis through the inhibition of apoptosis signal-regulating kinase-1 (Ask-1). In this study, we have investigated the effects of ApoE on Trx1 in the brain. Our results showed that the protein levels of Trx1 were reduced in the hippocampus of ApoE4 targeted replacement (TR) mice compared to ApoE3 TR mice. The reduction was also seen in vitro after treatment of both human primary cortical neurons and neuroblastoma cells with human recombinant ApoE4 (rApoE4). Furthermore, ApoE4 caused a disruption of lysosomal integrity and a shift in the localization of Cathepsin D, an enzyme known to degrade Trx1. ApoE4 treatment induced in addition apoptosis through translocation of Death-domain associated protein-6 (Daxx) from the nucleus to the cytosol, suggesting an activation of the Ask-1 pathway. This toxicity was prevented by overexpression of Trx1 and other endogenous Ask-1 inhibitors. Our data suggests that down-regulation of Trx1 is involved in the toxicity caused by ApoE4. An activated ASK-1 pathway might indeed make cells more vulnerable to other insults such as amyloid-β, which could partially explain the mechanism behind the strongest genetic risk factor for AD.

%B J Alzheimers Dis %V 56 %P 601-617 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035917?dopt=Abstract %R 10.3233/JAD-150738 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Apolipoprotein E4, Gender, Body Mass Index, Inflammation, Insulin Resistance, and Air Pollution Interactions: Recipe for Alzheimer's Disease Development in Mexico City Young Females. %A Calderón-Garcidueñas, Lilian %A de la Monte, Suzanne M %X

Given the epidemiological trends of increasing Alzheimer's disease (AD) and growing evidence that exposure and lifestyle factors contribute to AD risk and pathogenesis, attention should be paid to variables such as air pollution, in order to reduce rates of cognitive decline and dementia. Exposure to fine particulate matter (PM2.5) and ozone (O3) above the US EPA standards is associated with AD risk. Mexico City children experienced pre- and postnatal high exposures to PM2.5, O3, combustion-derived iron-rich nanoparticles, metals, polycyclic aromatic hydrocarbons, and endotoxins. Exposures are associated with early brain gene imbalance in oxidative stress, inflammation, innate and adaptive immune responses, along with epigenetic changes, accumulation of misfolded proteins, cognitive deficits, and brain structural and metabolic changes. The Apolipoprotein E (APOE) 4 allele, the most prevalent genetic risk for AD, plays a key role in the response to air pollution in young girls. APOE 4 heterozygous females with >75% to <94% BMI percentiles are at the highest risk of severe cognitive deficits (1.5-2 SD from average IQ). This review focused on the relationships between gender, BMI, systemic and neural inflammation, insulin resistance, hyperleptinemia, dyslipidemia, vascular risk factors, and central nervous system involvement in APOE4 urbanites exposed to PM2.5 and magnetite combustion-derived iron-rich nanoparticles that can reach the brain. APOE4 young female heterozygous carriers constitute a high-risk group for a fatal disease: AD. Multidisciplinary intervention strategies could be critical for prevention or amelioration of cognitive deficits and long-term AD progression in young individuals at high risk.

%B J Alzheimers Dis %V 58 %P 613-630 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527212?dopt=Abstract %R 10.3233/JAD-161299 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Apomorphine Therapy for Neuronal Insulin Resistance in a Mouse Model of Alzheimer's Disease. %A Nakamura, Norimichi %A Ohyagi, Yasumasa %A Imamura, Tomohiro %A Yanagihara, Yuki T %A Iinuma, Kyoko M %A Soejima, Naoko %A Murai, Hiroyuki %A Yamasaki, Ryo %A Kira, Jun-Ichi %X

Apomorphine (APO) promotes intraneuronal amyloid-β (Aβ) degradation and improves memory function in an Alzheimer's disease (AD) model, 3xTg-AD mice. Since insulin resistance is increased in AD neurons, we investigated the effects of APO on brain insulin resistance in 3xTg-AD mice at early and late stages. After 1-month subcutaneous injection of Apokyn® to 3xTg-AD mice at 6 or 12 months of age, memory function was significantly improved in both age groups. Protein levels of insulin-degrading enzyme (IDE), which is linked to insulin signaling and degrades Aβ, significantly increased in the 3xTg-AD mice brain compared with non-transgenic mice, and were further increased by APO. Protein levels of two types of serine-phosphorylated insulin receptor substrate-1 (IRS-1), pS616 and pS636/639, significantly decreased following APO treatment in the 13-month-old 3xTg-AD mice brain, suggesting improved brain insulin resistance. Immunostaining of the IDE, pS616 and pS636/639 IRS-1 demonstrated similar changes due to APO treatment. Thus, brain insulin resistance is considered an important therapeutic target in AD, and APO may provide improved neuronal insulin resistance.

%B J Alzheimers Dis %V 58 %P 1151-1161 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550243?dopt=Abstract %R 10.3233/JAD-160344 %0 Journal Article %J J Alzheimers Dis %D 2017 %T APP Mutations in Cerebral Amyloid Angiopathy with or without Cortical Calcifications: Report of Three Families and a Literature Review. %A Sellal, François %A Wallon, David %A Martinez-Almoyna, Laurent %A Marelli, Cecilia %A Dhar, Abhinav %A Oesterlé, Héléne %A Rovelet-Lecrux, Anne %A Rousseau, Stéphane %A Kourkoulis, Christina E %A Rosand, Jon %A DiPucchio, Zora Y %A Frosch, Matthew %A Gombert, Claudine %A Audoin, Bertrand %A Miné, Manuèle %A Riant, Florence %A Frebourg, Thierry %A Hannequin, Didier %A Campion, Dominique %A Greenberg, Steven M %A Tournier-Lasserve, Elisabeth %A Nicolas, Gaël %X

BACKGROUND: Specific APP mutations cause cerebral amyloid angiopathy (CAA) with or without Alzheimer's disease (AD).

OBJECTIVE: We aimed at reporting APP mutations associated with CAA, describe the clinical, cerebrospinal fluid AD biomarkers, and neuroimaging features, and compare them with the data from the literature.

METHODS: We performed a retrospective study in two French genetics laboratories by gathering all clinical and neuroimaging data from patients referred for a genetic diagnosis of CAA with an age of onset before 66 years and fulfilling the other Boston revised criteria. We studied the segregation of mutations in families and performed a comprehensive literature review of all cases reported with the same APP mutation.

RESULTS: We screened APP in 61 unrelated French patients. Three mutations, located in the Aβ coding region, were detected in five patients from three families: p.Ala692Gly (Flemish), p.Glu693Lys (Italian), and p.Asp694Asn (Iowa). Patients exhibited CAA and progressive cognitive impairment associated with cortical calcifications in the Iowa and Italian mutation carriers, but not the patient carrying the Flemish mutation.

CONCLUSIONS: This is the first evidence of cortical calcification in patients with an APP mutation other than the Iowa mutation. We discuss the radiological, cerebrospinal fluid, and clinical phenotype of patients carrying these mutations in the literature.

%B J Alzheimers Dis %V 56 %P 37-46 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858710?dopt=Abstract %R 10.3233/JAD-160709 %0 Journal Article %J J Alzheimers Dis %D 2017 %T AQP4 Association with Amyloid Deposition and Astrocyte Pathology in the Tg-ArcSwe Mouse Model of Alzheimer's Disease. %A Yang, Jing %A Zhang, Rui %A Shi, Changhe %A Mao, Chengyuan %A Yang, Zhihua %A Suo, Zhenhe %A Torp, Reidun %A Xu, Yuming %X

Amyloid-β deposition in senile plaques is one of the main pathological changes in Alzheimer's disease (AD). We previously reported that aquaporin-4 (AQP4) is redistributed within the astrocytes in cerebral amyloid angiopathy in the tg-ArcSwe mouse model of AD, suggesting that AQP4 may participate in amyloid-β deposition. However, the role of AQP4 in plaque formation is not currently clear. The objective of the current study was to explore the AQP4 distribution within plaques in the tg-ArcSwe mice in more depth by the combined application of immunofluorescence cytochemistry and immunogold electron microscopy. In addition, the astrocyte marker, glial fibrillary acidic protein (GFAP), was studied in association with AQP4. We demonstrated a robust upregulation of AQP4 expression in areas of plaques. Compared to GFAP, AQP4 appeared predominantly at later stages of plaque formation, in older mice, and within the processes of astrocytes. In combination with GFAP, AQP4 differentiated plaques into three progression stages under light microscopy. This suggests that AQP4 expression was associated with amyloid deposition and astrocyte pathology in the Tg-ArcSwe mouse model of AD. This provides novel proof for the involvement of AQP4 in the process of amyloid deposition in AD.

%B J Alzheimers Dis %V 57 %P 157-169 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222512?dopt=Abstract %R 10.3233/JAD-160957 %0 Journal Article %J J Alzheimers Dis %D 2017 %T An Arabic Version of the Cognitive Subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog): Reliability, Validity, and Normative Data. %A Ben Jemaa, Sonia %A Attia Romdhane, Neila %A Bahri-Mrabet, Amel %A Jendli, Adel %A Le Gall, Didier %A Bellaj, Tarek %X

The Alzheimer's Disease Assessment Scale's cognitive subscale (ADAS-Cog) is the most widely used instrument for screening cognitive dysfunction in Alzheimer's disease. The aim of the present study was to develop an Arabic version of this scale (A-ADAS-Cog), examine its psychometric properties (reliability and validity), and provide normative data. The A-ADAS-Cog), an Arabic version of the Mini-Mental State Examination (A-MMSE), and a Standardized Clinical Dementia Rating Scale (CDR) were administered to three Tunisian groups: 124 normal controls (NC), 33 patients with non-Alzheimer dementia (N-AD), and 25 patients with Alzheimer's disease (AD). The A-ADAS-Cog scores were significantly affected by age and education. A correction table was constructed to control these effects. The results showed that the A-ADAS-Cog has good internal consistency and reliability (α= 0.82 for AD). The test-retest reliability of the A-ADAS-Cog was stable over time (r = 0.97). An evaluation of the construct validity of the A-ADAS-Cog using principal component analysis led to a solution with three factors (memory, language and praxis), which explained 72% of the variance. The concurrent validity of the A-ADAS-Cog was established using the A-MMSE score (r = -0.86), CDR Sum of Boxes score (CDR-SB; r = 0.87), and global CDR score (CDR-Global; r = 0.74). Finally, the A-ADAS-Cog has an excellent discriminating power in the diagnosis of AD (ROC area = 0.92). A cut-off score of 10 (sensitivity = 84% and specificity = 91%) is indicated for the screening of the AD. Overall, the results indicated that the A-ADAS-Cog is psychometrically reliable and valid and provides promising results for screening of dementia in Arabic speaking patients.

%B J Alzheimers Dis %V 60 %P 11-21 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505978?dopt=Abstract %R 10.3233/JAD-170222 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Are Major Dementias Triggered by Poor Blood Flow to the Brain? Theoretical Considerations. %A de la Torre, Jack C %X

There is growing evidence that chronic brain hypoperfusion plays a central role in the development of Alzheimer's disease (AD) long before dyscognitive symptoms or amyloid-β accumulation in the brain appear. This commentary proposes that dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD) may also develop from chronic brain hypoperfusion following a similar but not identical neurometabolic breakdown as AD. The argument to support this conclusion is that chronic brain hypoperfusion, which is found at the early stages of the three dementias reviewed here, will reduce oxygen delivery and lower oxidative phosphorylation promoting a steady decline in the synthesis of the cell energy fuel adenosine triphosphate (ATP). This process is known to lead to oxidative stress. Virtually all neurodegenerative diseases, including FTD, DLB, and CJD, are characterized by oxidative stress that promotes inclusion bodies which differ in structure, location, and origin, as well as which neurological disorder they typify. Inclusion bodies have one thing in common; they are known to diminish autophagic activity, the protective intracellular degradative process that removes malformed proteins, protein aggregates, and damaged subcellular organelles that can disrupt neuronal homeostasis. Neurons are dependent on autophagy for their normal function and survival. When autophagic activity is diminished or impaired in neurons, high levels of unfolded or misfolded proteins overwhelm and downregulate the neuroprotective activity of unfolded protein response which is unable to get rid of dysfunctional organelles such as damaged mitochondria and malformed proteins at the synapse. The endpoint of this neuropathologic process results in damaged synapses, impaired neurotransmission, cognitive decline, and dementia.

%B J Alzheimers Dis %V 57 %P 353-371 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28211814?dopt=Abstract %R 10.3233/JAD-161266 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Assessment of Driving Safety in Older Adults with Mild Cognitive Impairment. %A Anstey, Kaarin J %A Eramudugolla, Ranmalee %A Chopra, Sidhant %A Price, Jasmine %A Wood, Joanne M %X

BACKGROUND: With population aging, drivers with mild cognitive impairment (MCI) are increasing; however, there is little evidence available regarding their safety.

OBJECTIVE: We aimed to evaluate risk of unsafe on-road driving performance among older adults with MCI.

METHOD: The study was a cross-sectional observational study, set in Canberra, Australia. Participants were non-demented, current drivers (n = 302) aged 65 to 96 years (M = 75.7, SD = 6.18, 40% female) recruited through the community and primary and tertiary care clinics. Measures included a standardized on-road driving test (ORT), a battery of screening measures designed to evaluate older driver safety (UFOV®, DriveSafe, Multi-D), a neurocognitive test battery, and questionnaires on driving history and behavior.

RESULTS: Using Winblad criteria, 57 participants were classified as having MCI and 245 as cognitively normal (CN). While the MCI group had a significantly lower overall safety rating on the ORT (5.61 versus 6.05, p = 0.03), there was a wide range of driving safety scores in the CN and MCI groups. The MCI group performed worse than the CN group on the off-road screening tests. The best fitting model of predictors of ORT performance across the combined sample included age, the Multi-D, and DriveSafe, classifying 90.4% of the sample correctly.

CONCLUSION: Adults with MCI exhibit a similar range of driving ability to CN adults, although on average they scored lower on off-road and on-road assessments. Driving specific tests were more strongly associated with safety ratings than traditional neuropsychological tests.

%B J Alzheimers Dis %V 57 %P 1197-1205 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372333?dopt=Abstract %R 10.3233/JAD-161209 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association between Anti-Dementia Treatment Persistence and Daily Dosage of the First Prescription: A Retrospective Analysis in Neuropsychiatric Practices in Germany. %A Bohlken, Jens %A Jacob, Louis %A Kostev, Karel %X

BACKGROUND: High adherence and persistence are important for the efficacy of anti-dementia treatments.

OBJECTIVE: The goal of this study was to analyze the association between anti-dementia treatment persistence and daily dosage of the first prescription in patients treated in neuropsychiatric practices in Germany.

METHODS: This study included patients aged 60 years or over who were diagnosed with Alzheimer's disease and received anti-dementia prescriptions (galantamine, donepezil, memantine, and rivastigmine) for the first time between 2005 and 2014. The main outcome measure was the treatment persistence rate within 12 months after the index date as a function of the first dose. Cox proportional hazards regression models were used to estimate the relation between persistence and daily dosages after adjusting for age, gender, and residence in nursing homes.

RESULTS: In this study, 2,442, 5,669, 4,416, 642, and 2,334 patients received galantamine, donepezil, memantine, oral rivastigmine, and patch rivastigmine, respectively. After 12 months of follow-up, continuation rates were similar for individuals using different doses of galantamine, donepezil, oral rivastigmine, and patch rivastigmine, but were significantly different for those taking memantine. Patients using 20 mg of memantine were less likely to discontinue their treatment than patients using 10 mg (HR = 0.88, 95% CI: 0.80-0.96). There was no significant association between daily dosages and persistence for the other drugs (HRs ranging from 0.86 to 1.15).

CONCLUSIONS: There was no significant association between treatment persistence and daily dosages in patients with Alzheimer's disease in Germany who were treated with galantamine, donepezil, or rivastigmine.

%B J Alzheimers Dis %V 58 %P 37-44 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372337?dopt=Abstract %R 10.3233/JAD-170091 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association between Cholesterol Exposure and Neuropathological Findings: The ACT Study. %A Bettcher, Brianne M %A Ard, M Colin %A Reed, Bruce R %A Benitez, Andreana %A Simmons, Amanda %A Larson, Eric B %A Sonnen, Josh A %A Montine, Thomas J %A Li, Ge %A Keene, C Dirk %A Crane, Paul K %A Mungas, Dan %X

We characterized the relationship between late life cholesterol exposure and neuropathological outcomes in a community-based, older adult cohort. Adult Changes in Thought (ACT) is a cohort study that enrolls consenting, randomly selected, non-demented people aged ≥65 from a healthcare delivery system. We used late life HDL and total cholesterol lab values from Group Health computerized records, and calculated HDL and non-HDL levels. We evaluated neuropathological outcomes of Alzheimer's disease, cerebral amyloid angiopathy, vascular brain injury, and Lewy body disease. Using linear mixed models with age and antilipemic medication as predictors, we obtained predicted cholesterol values at age 70 and 10 years prior to death for individuals with available cholesterol data in 10-year exposure windows. We used logistic regression to determine whether predicted late life cholesterol levels were associated with neuropathological outcomes controlling for age at death, APOE genotype, sex, and their interactions with cholesterol levels. 525 decedents came to autopsy by 08/2014. Of these, plasma cholesterol concentration was available for 318 (age 70, model 1) and 396 (10 years prior to death, model 2) participants. We did not find associations between late life cholesterol and Alzheimer's disease neuropathological changes, and there were no associations between cholesterol levels and amyloid angiopathy or vascular brain injury. We observed an association between predicted non-HDL cholesterol at age 70 and Lewy body disease. Our study suggests an association between late life non-HDL cholesterol exposure and Lewy body disease. We did not observe associations between late life cholesterol levels and Braak stage or CERAD score.

%B J Alzheimers Dis %V 59 %P 1307-1315 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731431?dopt=Abstract %R 10.3233/JAD-161224 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association between Cognitive Status before Surgery and Outcomes in Elderly Patients with Hip Fracture in a Dedicated Orthogeriatric Care Pathway. %A Zerah, Lorene %A Cohen-Bittan, Judith %A Raux, Mathieu %A Meziere, Anthony %A Tourette, Cendrine %A Neri, Christian %A Verny, Marc %A Riou, Bruno %A Khiami, Frederic %A Boddaert, Jacques %X

BACKGROUND: Dementia is associated with a worse prognosis of hip fracture, but the impact of a dedicated geriatric care pathway on the prognosis of these patients has not been evaluated.

OBJECTIVE: According to the cognitive status before surgery, our main objective was to compare mortality rate at 6 months; secondary outcomes were to compare in-hospital complications, the risk of new institutionalization, and the ability to walk at 6 months.

METHODS: Between 2009 and 2015, all patients (>70 years) admitted after hip fracture surgery into a dedicated unit of peri-operative geriatric care were included: patients with dementia (DP), without dementia (NDP), and with cognitive status not determined (CSND). Data are expressed as hazard ratio (HR) for multivariate cox analysis or odds ratio (OR) for multivariate logistic regression analysis and their 95% confidence interval (CI).

RESULTS: We included 650 patients (86±6 years): 168 DP, 400 NDP, and 82 CSND. After adjustment for age, sex, comorbidities, polypharmacy, pre-fracture autonomy, time-to-surgery, and delirium, there were no significant differences for 6-month mortality (DP versus NDP: HR = 0.7[0.4-1.2], DP versus CSND: HR = 0.6[0.3-1.4], CSND versus NDP: HR = 0.8[0.4-1.7]); but DP and CSND were more likely to be newly institutionalized after 6 months compared to NDP (OR DP = 2.6[1.4-4.9], p = 0.003, OR CSND = 2.9[1.4-6.1], p = 0.004). 92% of population was walking after 6 months (63% with assistance): no difference was found between the three groups.

CONCLUSION: In a dedicated geriatric care pathway, DP and CSND undergoing hip surgery have the same 6-month mortality and walking ability as NDP.

%B J Alzheimers Dis %V 56 %P 145-156 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911302?dopt=Abstract %R 10.3233/JAD-160655 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association Between Later Life Lifestyle Factors and Alzheimer's Disease Biomarkers in Non-Demented Individuals: A Longitudinal Descriptive Cohort Study. %A Reijs, Babette L R %A Vos, Stephanie J B %A Soininen, Hilkka %A Lötjönen, Jyrki %A Koikkalainen, Juha %A Pikkarainen, Maria %A Hall, Anette %A Vanninen, Ritva %A Liu, Yawu %A Herukka, Sanna-Kaisa %A Freund-Levi, Yvonne %A Frisoni, Giovanni B %A Frölich, Lutz %A Nobili, Flavio %A Rikkert, Marcel Olde %A Spiru, Luiza %A Tsolaki, Magda %A Wallin, Asa K %A Scheltens, Philip %A Verhey, Frans %A Visser, Pieter Jelle %X

BACKGROUND: Lifestyle factors have been associated with the risk of dementia, but the association with Alzheimer's disease (AD) remains unclear.

OBJECTIVE: To examine the association between later life lifestyle factors and AD biomarkers (i.e., amyloid-β 1-42 (Aβ42) and tau in cerebrospinal fluid (CSF), and hippocampal volume) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). In addition, to examine the effect of later life lifestyle factors on developing AD-type dementia in individuals with MCI.

METHODS: We selected individuals with SCD (n = 111) and MCI (n = 353) from the DESCRIPA and Kuopio Longitudinal MCI studies. CSF Aβ42 and tau concentrations were assessed with ELISA assay and hippocampal volume with multi-atlas segmentation. Lifestyle was assessed by clinical interview at baseline for: social activity, physical activity, cognitive activity, smoking, alcohol consumption, and sleep. We performed logistic and Cox regression analyses adjusted for study site, age, gender, education, and diagnosis. Prediction for AD-type dementia was performed in individuals with MCI only.

RESULTS: Later life lifestyle factors were not associated with AD biomarkers or with conversion to AD-type dementia. AD biomarkers were strongly associated with conversion to AD-type dementia, but these relations were not modulated by lifestyle factors. Apolipoprotein E (APOE) genotype did not influence the results.

CONCLUSIONS: Later life lifestyle factors had no impact on key AD biomarkers in individuals with SCD and MCI or on conversion to AD-type dementia in MCI.

%B J Alzheimers Dis %V 60 %P 1387-1395 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036813?dopt=Abstract %R 10.3233/JAD-170039 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association between Mid-Regional Proadrenomedullin Levels and Progression of Deep White Matter Lesions in the Brain Accompanying Cognitive Decline. %A Kuriyama, Nagato %A Ihara, Masafumi %A Mizuno, Toshiki %A Ozaki, Etsuko %A Matsui, Daisuke %A Watanabe, Isao %A Koyama, Teruhide %A Kondo, Masaki %A Tokuda, Takahiko %A Tamura, Aiko %A Yamada, Kei %A Akazawa, Kentaro %A Takeda, Kazuo %A Takada, Akihiro %A Mizuno, Shigeto %A Nakagawa, Masanori %A Watanabe, Yoshiyuki %X

BACKGROUND: Adrenomedullin (ADM) is a vasoreactive physiological peptide with anti-inflammatory effects and vasodilative and immunomodulatory actions that is widely distributed throughout the vascular system of the brain.

OBJECTIVE: To investigate mid-regional proADM (MR-proADM), a stable fragment of the ADM precursor, and cerebral deep white matter lesions (DWMLs) in association with cognitive decline.

METHODS: The study participants were 288 patients (194 men, 94 women) who gave consent to participate in a 5-year longitudinal survey on arteriosclerosis from 2008 to 2013. The Fazekas classification system (Grade [G] 0 [normal] to G3 [severe]) was used for the evaluation of DWMLs on brain magnetic resonance imaging (MRI). In addition, all participants were asked to undergo cognitive function tests regarding word/letter fluency, the results of which were assessed for correlations with MR-proADM levels.

RESULTS: MR-proADM levels significantly increased with DWML grade progression. The odds ratio for high MR-proADM levels was 3.08 (95% confidence interval: 1.49-5.17) in the groups graded G3 on brain MRI, suggesting that a high level of MR-proADM is an independent risk factor for DWMLs. A significant inverse correlation was observed between MR-proADM levels and cognitive test scores. MR-proADM levels were significantly increased in the G3 group in 2013 compared with 2008.

CONCLUSION: MR-proADM levels were significantly different between the DWML groups and inversely correlated with cognitive function test scores, suggesting that high MR-proADM levels and DWMLs are associated with cognitive decline. Therefore, the MR-proADM level may be an effective candidate as a potential diagnostic surrogate marker of cognitive decline.

%B J Alzheimers Dis %V 56 %P 1253-1262 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28234256?dopt=Abstract %R 10.3233/JAD-160901 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Association between Montreal Cognitive Assessment Memory Scores and Hippocampal Volume in a Neurodegenerative Disease Sample. %A Ritter, Aaron %A Hawley, Nanako %A Banks, Sarah J %A Miller, Justin B %X

Despite widespread use, there have been few investigations into the neuroanatomical correlates of the Montreal Cognitive Assessment (MoCA). In a sample of 138 consecutive patients presenting with cognitive complaints, we report significant correlations between lower MoCA memory scores and smaller hippocampal volumes (r = 0.36-0.41, p < 0.001). We also report that the newly devised memory index score, designed to better capture encoding deficits than the standard delayed recall score, was not significantly better for predicting hippocampal volume. These initial results suggest that poor performance on the MoCA's memory section should prompt further evaluation for hippocampal atrophy.

%B J Alzheimers Dis %V 58 %P 695-699 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453481?dopt=Abstract %R 10.3233/JAD-161241 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association between Plasma Ceramides and Phosphatidylcholines and Hippocampal Brain Volume in Late Onset Alzheimer's Disease. %A Kim, Min %A Nevado-Holgado, Alejo %A Whiley, Luke %A Snowden, Stuart G %A Soininen, Hilkka %A Kloszewska, Iwona %A Mecocci, Patrizia %A Tsolaki, Magda %A Vellas, Bruno %A Thambisetty, Madhav %A Dobson, Richard J B %A Powell, John F %A Lupton, Michelle K %A Simmons, Andy %A Velayudhan, Latha %A Lovestone, Simon %A Proitsi, Petroula %A Legido-Quigley, Cristina %X

Lipids such as ceramides and phosphatidylcholines (PC) have been found altered in the plasma of Alzheimer's disease (AD) patients in a number of discovery studies. For this reason, the levels of 6 ceramides and 3 PCs, with different fatty acid length and saturation levels, were measured in the plasma from 412 participants (AD n = 205, Control n = 207) using mass spectrometry coupled with ultra-performance liquid chromatography. After this, associations with AD status, brain atrophy, and age-related effects were studied. In the plasma of AD participants, cross-sectional analysis revealed elevated levels of three ceramides (Cer16:0 p < 0.01, Cer18:0 p < 0.01, Cer24:1 p < 0.05). In addition, two PCs in AD plasma (PC36:5 p < 0.05, PC38:6 p < 0.05) were found to be depleted compared to the control group, with PC36:5 also associating with hippocampal atrophy (p < 0.01). Age-specific analysis further revealed that levels of Cer16:0, Cer18:0, and Cer20:0 were associated with hippocampal atrophy only in younger participants (age < 75, p < 0.05), while all 3 PCs did so in the older participants (age > 75, p < 0.05). PC36:5 was associated with AD status in the younger group (p < 0.01), while PC38:6 and 40:6 did so in the older group (p < 0.05). In this study, elevated ceramides and depleted PCs were found in the plasma from 205 AD volunteers. Our findings also suggest that dysregulation in PC and ceramide metabolism could be occurring in different stages of AD progression.

%B J Alzheimers Dis %V 60 %P 809-817 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911300?dopt=Abstract %R 10.3233/JAD-160645 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association of Cancer History with Alzheimer's Disease Dementia and Neuropathology. %A Yarchoan, Mark %A James, Bryan D %A Shah, Raj C %A Arvanitakis, Zoe %A Wilson, Robert S %A Schneider, Julie %A Bennett, David A %A Arnold, Steven E %X

BACKGROUND: Cancer and Alzheimer's disease (AD) are common diseases of aging and share many risk factors. Surprisingly, however, epidemiologic data from several recent independent cohort studies suggest that there may be an inverse association between these diseases.

OBJECTIVE: To determine the relationship between history of cancer and odds of dementia proximate to death and neuropathological indices of AD.

METHODS: Using data from two separate clinical-pathologic cohort studies of aging and AD, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP), we compared odds of AD dementia proximate to death among participants with and without a history of cancer. We then examined the relation of history of cancer with measures of AD pathology at autopsy, i.e., paired helical filament tau (PHFtau) neurofibrillary tangles and amyloid-β load.

RESULTS: Participants reporting a history of cancer had significantly lower odds of AD (OR 0.70 [0.55-0.89], p = 0.0040) proximate to death as compared to participants reporting no prior history of cancer. The results remained significant after adjusting for multiple risk factors including age, sex, race, education, and presence of an APOEɛ4 allele. At autopsy, participants with a history of cancer had significantly fewer PHFtau tangles (p < 0.001) than participants without a history of cancer, but similar levels of amyloid-β.

CONCLUSIONS: Cancer survivors have reduced odds of developing AD and a lower burden of neurofibrillary tangle deposition.

%B J Alzheimers Dis %V 56 %P 699-706 %G eng %N 2 %R 10.3233/JAD-160977 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association of Central Arterial Stiffness and Pressure Pulsatility with Mild Cognitive Impairment and Dementia: The Atherosclerosis Risk in Communities Study-Neurocognitive Study (ARIC-NCS). %A Meyer, Michelle L %A Palta, Priya %A Tanaka, Hirofumi %A Deal, Jennifer A %A Wright, Jacqueline %A Knopman, David S %A Griswold, Michael E %A Mosley, Thomas H %A Heiss, Gerardo %X

BACKGROUND: The association of central arterial stiffness and pressure pulsatility with mild cognitive impairment (MCI) and dementia is not well characterized in the population-based setting.

OBJECTIVE: The aim of this study was to quantify the cross-sectional association of arterial stiffness and pressure pulsatility with MCI and dementia among 4,461 older white and black adults from the population-based Atherosclerosis Risk in Communities Study-Neurocognitive Study.

METHODS: We used race-stratified multinomial logistic regression to evaluate associations of percentile cut points of carotid-femoral pulse wave velocity, central systolic blood pressure, central pulse pressure, and pulse pressure amplification with MCI and dementia versus no cognitive impairment.

RESULTS: Among whites, those with carotid-femoral pulse wave velocity or central systolic blood pressure ≥75th percentile had a higher prevalence of MCI compared to participants <75th percentile (conditional odds ratio (OR); 95% confidence interval (CI): 1.27 (1.02, 1.56) and 1.28 (1.04, 1.57), respectively) and those with central pulse pressure ≥75th percentile had a higher prevalence of MCI (OR 1.27 (95% CI: 1.03, 1.58)) and dementia (OR 1.76 (95% CI: 1.06, 2.92) compared to participants <75th percentile. Also among whites, those with pulse pressure amplification ≤25th percentile had a higher prevalence of dementia compared to participants >25th percentile (OR 1.65; (95% CI: 1.01, 2.70). Weaker associations were seen among black participants.

CONCLUSION: Higher arterial stiffness and pulsatility were associated with MCI and dementia in white participants. Longitudinal characterization of the observed associations is warranted to assess whether arterial stiffness and pressure pulsatility predict MCI and dementia among older adults.

%B J Alzheimers Dis %V 57 %P 195-204 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222517?dopt=Abstract %R 10.3233/JAD-161041 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association of Gait Speed, Psychomotor Speed, and Dementia. %A Kuate-Tegueu, Callixte %A Avila-Funes, José-Alberto %A Simo, Nadine %A Le Goff, Mélanie %A Amiéva, Hélène %A Dartigues, Jean-François %A Tabue-Teguo, Maturin %X

BACKGROUND: Gait speed (GS) and psychomotor speed (PS) could be considered as two different dimensions of age-related slowness and both measures are associated with higher risk of adverse health-related outcomes among elderly people.

OBJECTIVE: To determine the association between GS, PS, and incident dementia among community-dwelling older adults.

METHODS: Twelve-year longitudinal study of 1,265 participants in the Bordeaux Three-City Study, a French prospective cohort designed to determine the risk of dementia and cognitive impairment attributable to cardiovascular risk factors. Participants completed a battery of cognitive tests, including time to complete the Trail Making Test A, and a walking speed test. The incidence of dementia was determined over the 12-year follow-up period. Cox proportional hazards models with delayed entry were used to estimate the cumulative risk of dementia and were adjusted for sex, education, and ApoE4 genotype.

RESULTS: Mean age of participants was 74.0 years (SD 4.8). Over the 12-year follow-up, 203 participants developed dementia. GS and PS were both independent predictors of incident all-cause dementia after 12 years of follow-up. For a one SD increase of either GS or PS, the hazard ratio (HR) for Alzheimer's disease was 1.2 (95% CI = 1.02-1.32) and 1.4 (95% CI = 1.2-1.61), respectively; whereas for incident vascular dementia, the HR was 1.3 (95% CI = 1.05-1.71) and 1.5 (95% CI = 1.16-2.08), respectively. No significant interaction between GS and PS was observed.

CONCLUSIONS: In older French people aged 65+, our findings showed that both low GS and PS were independently associated with risk of incident Alzheimer's disease and vascular dementia.

%B J Alzheimers Dis %V 60 %P 585-592 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869468?dopt=Abstract %R 10.3233/JAD-170267 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association of Kidney Function Biomarkers with Brain MRI Findings: The BRINK Study. %A Vemuri, Prashanthi %A Knopman, David S %A Jack, Clifford R %A Lundt, Emily S %A Weigand, Stephen D %A Zuk, Samantha M %A Thostenson, Kaely B %A Reid, Robert I %A Kantarci, Kejal %A Slinin, Yelena %A Lakshminarayan, Kamakshi %A Davey, Cynthia S %A Murray, Anne %X

BACKGROUND: Chronic kidney disease (CKD) studies have reported variable prevalence of brain pathologies, in part due to low inclusion of participants with moderate to severe CKD.

OBJECTIVE: To measure the association between kidney function biomarkers and brain MRI findings in CKD.

METHODS: In the BRINK (BRain IN Kidney Disease) study, MRI was used to measure gray matter volumes, cerebrovascular pathologies (white matter hyperintensity (WMH), infarctions, microhemorrhages), and microstructural changes using diffusion tensor imaging (DTI). We performed regression analyses with estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR) as primary predictors, and joint models that included both predictors, adjusted for vascular risk factors.

RESULTS: We obtained 240 baseline MRI scans (150 CKD with eGFR <45 in ml/min/1.73 m2; 16 mild CKD: eGFR 45-59; 74 controls: eGFR≥60). Lower eGFR was associated with greater WMH burden, increased odds of cortical infarctions, and worsening diffusion changes throughout the brain. In eGFR models adjusted for UACR, only cortical infarction associations persisted. However, after adjusting for eGFR, higher UACR provided additional information related to temporal lobe atrophy, increased WMH, and whole brain microstructural changes as measured by increased DTI mean diffusivity.

CONCLUSIONS: Biomarkers of kidney disease (eGFR and UACR) were associated with MRI brain changes, even after accounting for vascular risk factors. UACR adds unique additional information to eGFR regarding brain structural and diffusion biomarkers. There was a greater impact of kidney function biomarkers on cerebrovascular pathologies and microstructural brain changes, suggesting that cerebrovascular etiology may be the primary driver of cognitive impairment in CKD.

%B J Alzheimers Dis %V 55 %P 1069-1082 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767995?dopt=Abstract %R 10.3233/JAD-160834 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association of Radon Background and Total Background Ionizing Radiation with Alzheimer's Disease Deaths in U.S. States. %A Lehrer, Steven %A Rheinstein, Peter H %A Rosenzweig, Kenneth E %X

BACKGROUND: Exposure of the brain to ionizing radiation might promote the development of Alzheimer's disease (AD).

OBJECTIVE: Analysis of AD death rates versus radon background radiation and total background radiation in U.S. states.

METHODS: Total background, radon background, cosmic and terrestrial background radiation measurements are from Assessment of Variations in Radiation Exposure in the United States and Report No. 160 - Ionizing Radiation Exposure of the Population of the United States. 2013 AD death rates by U.S. state are from the Alzheimer's Association.

RESULTS: Radon background ionizing radiation was significantly correlated with AD death rate in 50 states and the District of Columbia (r = 0.467, p = 0.001). Total background ionizing radiation was also significantly correlated with AD death rate in 50 states and the District of Columbia (r = 0.452, p = 0.001). Multivariate linear regression weighted by state population demonstrated that AD death rate was significantly correlated with radon background (β= 0.169, p < 0.001), age (β= 0.231, p < 0.001), hypertension (β= 0.155, p < 0.001), and diabetes (β= 0.353, p < 0.001).

CONCLUSION: Our findings, like other studies, suggest that ionizing radiation is a risk factor for AD. Intranasal inhalation of radon gas could subject the rhinencephalon and hippocampus to damaging radiation that initiates AD. The damage would accumulate over time, causing age to be a powerful risk factor.

%B J Alzheimers Dis %V 59 %P 737-741 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671130?dopt=Abstract %R 10.3233/JAD-170308 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Associations of CAIDE Dementia Risk Score with MRI, PIB-PET measures, and cognition. %A Stephen, Ruth %A Liu, Yawu %A Ngandu, Tiia %A Rinne, Juha O %A Kemppainen, Nina %A Parkkola, Riitta %A Laatikainen, Tiina %A Paajanen, Teemu %A Hänninen, Tuomo %A Strandberg, Timo %A Antikainen, Riitta %A Tuomilehto, Jaakko %A Keinänen Kiukaanniemi, Sirkka %A Vanninen, Ritva %A Helisalmi, Seppo %A Levälahti, Esko %A Kivipelto, Miia %A Soininen, Hilkka %A Solomon, Alina %X

BACKGROUND: CAIDE Dementia Risk Score is the first validated tool for estimating dementia risk based on a midlife risk profile.

OBJECTIVES: This observational study investigated longitudinal associations of CAIDE Dementia Risk Score with brain MRI, amyloid burden evaluated with PIB-PET, and detailed cognition measures.

METHODS: FINGER participants were at-risk elderly without dementia. CAIDE Risk Score was calculated using data from previous national surveys (mean age 52.4 years). In connection to baseline FINGER visit (on average 17.6 years later, mean age 70.1 years), 132 participants underwent MRI scans, and 48 underwent PIB-PET scans. All 1,260 participants were cognitively assessed (Neuropsychological Test Battery, NTB). Neuroimaging assessments included brain cortical thickness and volumes (Freesurfer 5.0.3), visually rated medial temporal atrophy (MTA), white matter lesions (WML), and amyloid accumulation.

RESULTS: Higher CAIDE Dementia Risk Score was related to more pronounced deep WML (OR 1.22, 95% CI 1.05-1.43), lower total gray matter (β-coefficient -0.29, p = 0.001) and hippocampal volume (β-coefficient -0.28, p = 0.003), lower cortical thickness (β-coefficient -0.19, p = 0.042), and poorer cognition (β-coefficients -0.31 for total NTB score, -0.25 for executive functioning, -0.33 for processing speed, and -0.20 for memory, all p < 0.001). Higher CAIDE Dementia Risk Score including APOE genotype was additionally related to more pronounced MTA (OR 1.15, 95% CI 1.00-1.30). No associations were found with periventricular WML or amyloid accumulation.

CONCLUSIONS: The CAIDE Dementia Risk Score was related to indicators of cerebrovascular changes and neurodegeneration on MRI, and cognition. The lack of association with brain amyloid accumulation needs to be verified in studies with larger sample sizes.

%B J Alzheimers Dis %V 59 %P 695-705 %G eng %N 2 %R 10.3233/JAD-170092 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Associations of Spatial Disparities of Alzheimer's Disease Mortality Rates with Soil Selenium and Sulfur Concentrations and Four Common Risk Factors in the United States. %A Sun, Hongbing %X

BACKGROUND: Associations between environmental factors and spatial disparity of mortality rates of Alzheimer's disease (AD) in the US are not well understood.

OBJECTIVE: To find associations between 41 trace elements, four common risk factors, and AD mortality rates in the48 contiguous states.

METHODS: Isopleth maps of AD mortality rates of the 48 states and associated factors were examined. Correlations between state average AD mortality rates and concentrations of 41 soil elements, wine consumption, percentage of current smokers, obesity, and diagnosed diabetes of the 48 states between 1999 and 2014 were analyzed.

RESULTS: Among 41 elements, soil selenium concentrations have the most significant inverse correlations with AD mortality rates. Rate ratio (RR) of the 6 states with the lowest product of soil selenium and sulfur concentrations is 53% higher than the 6 states with the highest soil selenium sulfur product in the 48 states (RR = 1.53, CI95% 1.51-1.54). Soil tin concentrations have the most significant inverse correlation with AD mortality growth rates between 1999 and 2014, followed by soil sulfur concentrations. Percentages of obesity, diagnosed diabetes, smoking, and wine consumption per capita also correlate significantly with AD mortality growth rates.

CONCLUSIONS: High soil selenium and sulfur concentrations and wine consumption are associated with low AD mortality rates. Given that average soil selenium and sulfur concentrations are indicators of their intakes from food, water, and air by people in a region, long-term exposure to high soil selenium and sulfur concentrations might be beneficial to AD mortality rate reduction in a region.

%B J Alzheimers Dis %V 58 %P 897-907 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527214?dopt=Abstract %R 10.3233/JAD-170059 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Atrial Fibrillation is Independently Associated with Cognitive Impairment after Ischemic Stroke. %A Chander, Russell Jude %A Lim, Levinia %A Handa, Sagarika %A Hiu, Shaun %A Choong, Angeline %A Lin, Xuling %A Singh, Rajinder %A Oh, Daniel %A Kandiah, Nagaendran %X

BACKGROUND: While atrial fibrillation (AF) is an important risk factor for ischemic strokes and mild cognitive impairment (MCI) in Alzheimer's disease, the association between AF and post-stroke cognitive impairment (PSCI), and the factors mediating this association, is unclear.

OBJECTIVE: To investigate the role of AF in PSCI, especially in relation to other markers of cerebrovascular disease.

METHODS: 445 subjects with mild ischemic stroke without pre-stroke cognitive decline were assessed 3-6 months post-stroke for cognitive deficits. MRIs were reviewed by trained raters for acute infarct characteristics, global cortical atrophy, white matter hyperintensities, cerebral microbleeds, and intracranial stenosis. Logistic regression analysis was used to identify factors independently associated with PSCI. Subjects were also categorized according to paroxysmal (pAF) or persistent/chronic AF (p/cAF), and presence or absence of AF or large cortical infarcts (LCI) to study cognitive trends.

RESULTS: 80 (18.0%) subjects had AF. 76.3% of AF subjects and 42.7% of subjects without AF had PSCI. The odds ratio (OR) of AF in developing PSCI was 2.31 (95% CI: 1.12-4.75; p = 0.035), after correcting for other risk factors. pAF subjects and AF subjects with LCIs had higher ORs for PSCI. AF subjects performed worse in neuropsychological tasks associated with global cognition, episodic memory, and executive function.

CONCLUSION: AF is a significant risk factor for PSCI, even after correcting for AF-related infarcts. Other mechanisms, such as hypoperfusion, microhemorrhages, and neuroinflammation, may be at play. All stroke patients with AF, regardless of the type of infarction, should be closely monitored for PSCI.

%B J Alzheimers Dis %V 60 %P 867-875 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922154?dopt=Abstract %R 10.3233/JAD-170313 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Attitudes toward Potential Participant Registries. %A Grill, Joshua D %A Holbrook, Andrew %A Pierce, Aimee %A Hoang, Dan %A Gillen, Daniel L %X

Difficult participant recruitment is a consistent barrier to successful medical research. Potential participant registries represent an increasingly common intervention to overcome this barrier. A variety of models for registries exist, but few data are available to instruct their design and implementation. To provide such data, we surveyed 110 cognitively normal research participants enrolled in a longitudinal study of aging and dementia. Seventy-four (67%) individuals participated in the study. Most (78%, CI: 0.67, 0.87) participants were likely to enroll in a registry. Willingness to participate was reduced for registries that required enrollment through the Internet using a password (26%, CI: 0.16, 0.36) or through email (38%, CI: 0.27, 0.49). Respondents acknowledged their expectations that researchers share information about their health and risk for disease and their concerns that their data could be shared with for-profit companies. We found no difference in respondent preferences for registries that shared contact information with researchers, compared to honest broker models that take extra precautions to protect registrant confidentiality (28% versus 30%; p = 0.46). Compared to those preferring a shared information model, respondents who preferred the honest broker model or who lacked model preference voiced increased concerns about sharing registrant data, especially with for-profit organizations. These results suggest that the design of potential participant registries may impact the population enrolled, and hence the population that will eventually be enrolled in clinical studies. Investigators operating registries may need to offer particular assurances about data security to maximize registry enrollment but also must carefully manage participant expectations.

%B J Alzheimers Dis %V 56 %P 939-946 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106553?dopt=Abstract %R 10.3233/JAD-160873 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Autonomic Cardiac Function in Preclinical Alzheimer's Disease. %A Santos, Cláudia Y %A Machan, Jason T %A Wu, Wen-Chih %A Snyder, Peter J %X

To explore early autonomic cardiac changes in pre-clinical Alzheimer's disease (AD), we have evaluated electrocardiologic measures of vagal tone for 63 adults (ages 55-75) at rest, during cognitive testing, and then again at rest. All subjects had multiple risk factors for AD, and all completed amyloid PET scans (18F-Florbetapir) to determine amyloid positivity (Aβ+). No change in electrocardiographic measures were observed for Aβ+ participants under each testing condition, whereas Aβ-subjects showed an expected increase in vagal tone during the cognitive stress condition. These findings suggest an early relationship between cortical Aβ accumulation, a precursor to AD development, and autonomic cardiac function.

%B J Alzheimers Dis %V 59 %P 1057-1065 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697563?dopt=Abstract %R 10.3233/JAD-170217 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Autonomic Nervous System Dysfunctions as a Basis for a Predictive Model of Risk of Neurological Disorders in Subjects with Prior History of Traumatic Brain Injury: Implications in Alzheimer's Disease. %A Ho, Lap %A Legere, Marc %A Li, Tongbin %A Levine, Samara %A Hao, Ke %A Valcarcel, Breanna %A Pasinetti, Giulio M %X

Autonomic dysfunction is very common in patients with dementia, and its presence might also help in differential diagnosis among dementia subtypes. Various central nervous system structures affected in Alzheimer's disease (AD) are also implicated in the central autonomic nervous system (ANS) regulation. For example, deficits in central cholinergic function in AD could likely lead to autonomic dysfunction. We recently developed a simple, readily applicable evaluation for monitoring ANS disturbances in response to traumatic brain injury (TBI). This ability to monitor TBI allows for the possible detection and targeted prevention of long-term, detrimental brain responses caused by TBI that lead to neurodegenerative diseases such as AD. We randomly selected and extracted de-identified medical record information from subjects who have been assessed using the ANS evaluation protocol. Using machine learning strategies in the analysis of information from individual as well as a combination of ANS evaluation protocol components, we identified a novel prediction model that is effective in correctly segregating between cases with or without a documented history of TBI exposure. Results from our study support the hypothesis that trauma-induced ANS dysfunctions may contribute to clinical TBI features. Because autonomic dysfunction is very common in AD patients it is possible that TBI may also contribute to AD and/or other forms of dementia through these novel mechanisms. This study provides a novel prediction model to physiologically assess the likelihood of subjects with prior history of TBI to develop clinical TBI complications, such as AD.

%B J Alzheimers Dis %V 56 %P 305-315 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911325?dopt=Abstract %R 10.3233/JAD-160948 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Autophagy-ERK1/2-Involved Disinhibition of Hippocampal Neurons Contributes to the Pre-Synaptic Toxicity Induced by Aβ42 Exposure. %A Yin, Yanling %A Zhao, Yuanyuan %A Han, Song %A Zhang, Nan %A Chen, Hanyu %A Wang, Xiaomin %X

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most frequent cause of progressive cognitive decline in the elderly population. To date, there is still no effective treatment for AD, requiring more underlying mechanisms. In the present study, we investigated the effects of Aβ42 on the inhibitory synaptic transmission in the cultured hippocampal neurons, and explored the possible mechanism. The frequency, but not amplitude, of miniature inhibitory post-synaptic currents was significantly suppressed by Aβ42, indicating that Aβ42 played its role in inhibitory transmitter release at the pre-synaptic sites. Aβ42 had no effect on miniature excitatory post-synaptic currents, suggesting GABAergic synapses are more susceptible to Aβ42 exposure. However, the number of GABAergic neurons or synapses was not influenced, suggesting the corresponding stage may be a preclinical one. The effect of Aβ42 can be mimicked by PD98059 (an inhibitor of ERK1/2) and blocked by curcumin (an activator of MEK), which reveals Aβ-involved influence is via the decreased phosphorylation of MAPK-ERK1/2. In addition, synaptophysin is confirmed to be a downstream protein of MAPK-ERK1/2 at the pre-synaptic site. At the same time, suppressed autophagy was observed after Aβ42 exposure, and the activation of autophagy increased pERK1/2 level and salvaged the disinhibition of hippocampal neurons. These data suggest that diminished GABAergic tone likely starts from the preclinical stage of AD, so some GABAergic stress test may be effective for identifying cognitively normal elder adults. Strategies against the dysfunction of autophagy should be adopted in the early stage of AD because of its initial effects.

%B J Alzheimers Dis %V 59 %P 851-869 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697568?dopt=Abstract %R 10.3233/JAD-170246 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Autotaxin is Related to Metabolic Dysfunction and Predicts Alzheimer's Disease Outcomes. %A McLimans, Kelsey E %A Willette, Auriel A %X

BACKGROUND: Obesity and insulin resistance are associated with neuropathology and cognitive decline in Alzheimer's disease (AD).

OBJECTIVE: Ecto-nucleotide pyrophosphatase/phosphodiesterase 2, also called autotaxin, is produced by beige adipose tissue, regulates metabolism, and is higher in AD prefrontal cortex (PFC). Autotaxin may be a novel biomarker of dysmetabolism and AD.

METHODS: We studied Alzheimer's Disease Neuroimaging Initiative participants who were cognitively normal (CN; n = 86) or had mild cognitive impairment (MCI; n = 135) or AD (n = 66). Statistical analyses were conducted using SPSS software. Multinomial regression analyses tested if higher autotaxin was associated with higher relative risk for MCI or AD diagnosis, compared to the CN group. Linear mixed model analyses were used to regress autotaxin against MRI, FDG-PET, and cognitive outcomes. Spearman correlations were used to associate autotaxin and CSF biomarkers due to non-normality. FreeSurfer 4.3 derived mean cortical thickness in medial temporal lobe and prefrontal regions of interest.

RESULTS: Autotaxin levels were significantly higher in MCI and AD. Each point increase in log-based autotaxin corresponded to a 3.5 to 5 times higher likelihood of having MCI and AD, respectively. Higher autotaxin in AD predicted hypometabolism in the medial temporal lobe [R2 = 0.343, p < 0.001] and PFC [R2 = 0.294, p < 0.001], and worse performance on executive function and memory factors. Autotaxin was associated with less cortical thickness in PFC areas like orbitofrontal cortex [R2 = 0.272, p < 0.001], as well as levels of total tau, p-tau181, and total tau/Aβ1-42.

CONCLUSIONS: These results are comparable to previous reports using insulin resistance. CSF autotaxin may be a useful dysmetabolism biomarker for examining AD outcomes and risk.

%B J Alzheimers Dis %V 56 %P 403-413 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911319?dopt=Abstract %R 10.3233/JAD-160891 %0 Journal Article %J J Alzheimers Dis %D 2017 %T AVN-492, A Novel Highly Selective 5-HT6R Antagonist: Preclinical Evaluation. %A Ivachtchenko, Alexandre V %A Okun, Ilya %A Aladinskiy, Vladimir %A Ivanenkov, Yan %A Koryakova, Angela %A Karapetyan, Ruben %A Mitkin, Oleg %A Salimov, Ramiz %A Ivashchenko, Andrey %X

Discovery of 5-HT6 receptor subtype and its exclusive localization within the central nervous system led to extensive investigations of its role in Alzheimer's disease, schizophrenia, and obesity. In the present study, we present preclinical evaluation of a novel highly-potent and highly-selective 5-HT6R antagonist, AVN-492. The affinity of AVN-492 to bind to 5-HT6R (Ki = 91 pM) was more than three orders of magnitude higher than that to bind to the only other target, 5-HT2BR, (Ki = 170 nM). Thus, the compound displayed great 5-HT6R selectivity against all other serotonin receptor subtypes, and is extremely specific against any other receptors such as adrenergic, GABAergic, dopaminergic, histaminergic, etc. AVN-492 demonstrates good in vitro and in vivo ADME profile with high oral bioavailability and good brain permeability in rodents. In behavioral tests, AVN-492 shows anxiolytic effect in elevated plus-maze model, prevents an apomorphine-induced disruption of startle pre-pulse inhibition (the PPI model) and reverses a scopolamine- and MK-801-induced memory deficit in passive avoidance model. No anti-obesity effect of AVN-492 was found in a murine model. The data presented here strongly indicate that due to its high oral bioavailability, extremely high selectivity, and potency to block the 5-HT6 receptor, AVN-492 is a very promising tool for evaluating the role the 5-HT6 receptor might play in cognitive and neurodegenerative impairments. AVN-492 is an excellent drug candidate to be tested for treatment of such diseases, and is currently being tested in Phase I trials.

%B J Alzheimers Dis %V 58 %P 1043-1063 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550249?dopt=Abstract %R 10.3233/JAD-161262 %0 Journal Article %J J Alzheimers Dis %D 2017 %T AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease. %A Cebers, Gvido %A Alexander, Robert C %A Haeberlein, Samantha Budd %A Han, David %A Goldwater, Ronald %A Ereshefsky, Larry %A Olsson, Tina %A Ye, Naidong %A Rosen, Laura %A Russell, Muir %A Maltby, Justine %A Eketjäll, Susanna %A Kugler, Alan R %X

AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of ≥5 mg, a ≥70% reduction was observed in mean plasma Aβ40 and Aβ42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (≥64% at 15 mg and ≥78% at ≥50 mg) and cerebrospinal fluid (≥51% at 15 mg and ≥76% at ≥50 mg) Aβ peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing.

%B J Alzheimers Dis %V 55 %P 1039-1053 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767991?dopt=Abstract %R 10.3233/JAD-160701 %0 Journal Article %J J Alzheimers Dis %D 2017 %T BACE1 Dynamics Upon Inhibition with a BACE Inhibitor and Correlation to Downstream Alzheimer's Disease Markers in Elderly Healthy Participants. %A Timmers, Maarten %A Barão, Soraia %A Van Broeck, Bianca %A Tesseur, Ina %A Slemmon, John %A de Waepenaert, Katja %A Bogert, Jennifer %A Shaw, Leslie M %A Engelborghs, Sebastiaan %A Moechars, Dieder %A Mercken, Marc %A Van Nueten, Luc %A Tritsmans, Luc %A De Strooper, Bart %A Streffer, Johannes Rolf %X

The β-site amyloid-β protein precursor (AβPP) cleaving enzyme-1 (BACE1) is the rate limiting enzyme in the generation of amyloid-β peptide (Aβ) from AβPP, one of the major pathways in Alzheimer's disease (AD) pathology. Increased BACE1 levels and activity have been reported in the brain of patients with sporadic AD. Therefore, changes of BACE1 levels in the cerebrospinal fluid (CSF) have also been investigated as a possible biomarker of the disease. We analyzed BACE1 levels in CSF of elderly healthy participants before and after chronic treatment with a BACE inhibitor (BACEi) and evaluated the correlation between BACE1 levels and downstream AD markers. Overall, BACE1 CSF levels showed strong correlations to all downstream AD markers investigated. This is the first reported finding that shows BACE1 levels in CSF were well correlated to its end product Aβ1 - 42. As previously described, BACE1 levels were strongly correlated to total-tau and phosphorylated tau levels in CSF. Generally, chronic BACE inhibition did not influence BACE1 CSF protein levels. Follow-up studies including early-stage AD pathophysiology and prodromal AD patients will help to understand the importance of measuring BACE1 routinely in daily clinical practice and AD clinical trials.

%B J Alzheimers Dis %V 56 %P 1437-1449 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157093?dopt=Abstract %R 10.3233/JAD-160829 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Baseline Predictors of Antipsychotic Treatment Continuation and Response at Week 8 in Patients with Alzheimer's Disease with Psychosis or Aggressive Symptoms: An Analysis of the CATIE-AD Study. %A Nagata, Tomoyuki %A Nakajima, Shinichiro %A Shinagawa, Shunichiro %A Plitman, Eric %A Nakayama, Kazuhiko %A Graff-Guerrero, Ariel %A Mimura, Masaru %X

BACKGROUND/OBJECTIVE: The aim of the present study was to investigate predictors of atypical antipsychotic (AAP) treatment continuation and response by week 8 in patients with Alzheimer's disease (AD) who have psychotic/aggressive symptoms using the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) dataset.

METHODS: Clinical data was utilized from 421 AD outpatients with psychotic/aggressive symptoms who needed interventional treatment. Logistic regression analyses were performed to examine which baseline sociodemographic and clinical characteristics contributed to treatment 'continuation' and 'response', the latter of which was evaluated by the Clinical Global Impression of Change (CGI-C), Neuropsychiatric Inventory (NPI), and Brief Psychiatric Scale (BPRS).

RESULTS: The treatment continuation rate was 48.7%, and CGI-C, NPI, and BPRS response rate by the last observation carried forward method were 42.7%, 48.6%, and 37.5%, respectively. No significant predictor was identified for treatment continuation in the Caucasian patients (n = 331), while better treatment response was predicted by a lower Mini-Mental State Examination score, treatment with risperidone (versus olanzapine and quetiapine), history of diabetes mellitus, healthier physical status, and more severe initial psychotic symptoms.

CONCLUSIONS: Comparatively high intolerability from AAPs in the short term was confirmed. We found that baseline clinical predictors to treatment response in Caucasian AD patients with psychotic/aggressive symptoms include treatment with risperidone (versus quetiapine and olanzapine), diabetes mellitus, global physical status, cognitive impairment, and psychotic symptoms. Going forward, these findings may help to determine treatment strategies or care plans.

%B J Alzheimers Dis %V 60 %P 263-272 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28800334?dopt=Abstract %R 10.3233/JAD-170412 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Baseline Telomere Length and Effects of a Multidomain Lifestyle Intervention on Cognition: The FINGER Randomized Controlled Trial. %A Sindi, Shireen %A Ngandu, Tiia %A Hovatta, Iiris %A Kåreholt, Ingemar %A Antikainen, Riitta %A Hänninen, Tuomo %A Levälahti, Esko %A Laatikainen, Tiina %A Lindström, Jaana %A Paajanen, Teemu %A Peltonen, Markku %A Khalsa, Dharma Singh %A Wolozin, Benjamin %A Strandberg, Timo %A Tuomilehto, Jaakko %A Soininen, Hilkka %A Kivipelto, Miia %A Solomon, Alina %X

Leukocyte telomere length (LTL) is a biomarker of aging, and it is associated with lifestyle. It is currently unknown whether LTL is associated with the response to lifestyle interventions. The goal is to assess whether baseline LTL modified the cognitive benefits of a 2-year multidomain lifestyle intervention (exploratory analyses). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a 2-year randomized controlled trial including 1,260 people at risk of cognitive decline, aged 60-77 years identified from the general population. Participants were randomly assigned to the lifestyle intervention (diet, exercise, cognitive training, and vascular risk management) and control (general health advice) groups. Primary outcome was change in cognition (comprehensive neuropsychological test battery). Secondary outcomes were changes in cognitive domains: memory, executive functioning, and processing speed. 775 participants (392 control, 383 intervention) had baseline LTL (peripheral blood DNA). Mixed effects regression models with maximum likelihood estimation were used to analyze change in cognition as a function of randomization group, time, baseline LTL, and their interaction. Intervention and control groups did not significantly differ at baseline. Shorter LTL was related to less healthy baseline lifestyle. Intervention benefits on executive functioning were more pronounced among those with shorter baseline LTL (p-value for interaction was 0.010 adjusted for age and sex, and 0.007 additionally adjusted for baseline lifestyle factors). The FINGER intervention cognitive benefits were more pronounced with shorter baseline LTL, particularly for executive functioning, indicating that the multidomain lifestyle intervention was especially beneficial among higher-risk individuals.

%B J Alzheimers Dis %V 59 %P 1459-1470 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28777749?dopt=Abstract %R 10.3233/JAD-170123 %0 Journal Article %J J Alzheimers Dis %D 2017 %T BDNF Responses in Healthy Older Persons to 35 Minutes of Physical Exercise, Cognitive Training, and Mindfulness: Associations with Working Memory Function. %A Håkansson, Krister %A Ledreux, Aurélie %A Daffner, Kirk %A Terjestam, Yvonne %A Bergman, Patrick %A Carlsson, Roger %A Kivipelto, Miia %A Winblad, Bengt %A Granholm, Ann-Charlotte %A Mohammed, Abdul Kadir H %X

Brain-derived neurotrophic factor (BDNF) has a central role in brain plasticity by mediating changes in cortical thickness and synaptic density in response to physical activity and environmental enrichment. Previous studies suggest that physical exercise can augment BDNF levels, both in serum and the brain, but no other study has examined how different types of activities compare with physical exercise in their ability to affect BDNF levels. By using a balanced cross over experimental design, we exposed nineteen healthy older adults to 35-minute sessions of physical exercise, cognitive training, and mindfulness practice, and compared the resulting changes in mature BDNF levels between the three activities. We show that a single bout of physical exercise has significantly larger impact on serum BDNF levels than either cognitive training or mindfulness practice in the same persons. This is the first study on immediate BDNF effects of physical activity in older healthy humans and also the first study to demonstrate an association between serum BDNF responsivity to acute physical exercise and working memory function. We conclude that the BDNF increase we found after physical exercise more probably has a peripheral than a central origin, but that the association between post-intervention BDNF levels and cognitive function could have implications for BDNF responsivity in serum as a potential marker of cognitive health.

%B J Alzheimers Dis %V 55 %P 645-657 %G ENG %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716670?dopt=Abstract %R 10.3233/JAD-160593 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Benefits of Occupational Therapy in Dementia Patients: Findings from a Real-World Observational Study. %A Pimouguet, Clément %A Le Goff, Mélanie %A Wittwer, Jérôme %A Dartigues, Jean-François %A Helmer, Catherine %X

BACKGROUND: There is a growing interest in developing non-pharmacological approaches in dementia. Clinical efficacy of occupational therapy (OT) under routine care conditions has not been investigated yet.

OBJECTIVE: To analyze the short-term effects of OT in patients with dementia; and to identify factors related to greater benefit.

METHODS: Patients referred to OT were evaluated before starting a 3-month intervention and at 3 and 6 months later. Measures included: Mini-Mental State Examination (MMSE), Disability Assessment in Dementia (DAD), Neuropsychiatric Inventory (NPI) Questionnaire, patients' quality of life (EQ 5D-VAS), caregivers' burden (Zarit scale), and amount of informal care. Linear mixed models were used to analyze trajectories of outcomes. Logistic regressions with stepwise descending selection were used to study factors associated with benefits.

RESULTS: 421 dementia patients benefited from OT (mean MMSE = 17.3). Patients remained cognitively stable over time. Functional performances also remained stable at 3 months and significantly decreased at 6 months (crude reduction of 2.8 points, p < 0.01). Behavioral troubles were significantly reduced over the intervention period and remained stable after (p < 0.01). Patients' quality of life increased over the 3-month intervention (p = 0.16) and significantly decreased thereafter. Caregivers' burden and informal care significantly decreased over the 3-month intervention and remained stable thereafter. Patients who benefited from OT with regard to function were less educated and had higher cognitive level.

CONCLUSION: OT may be an effective intervention to maintain cognition and functionality and to reduce psychiatric symptoms in dementia patients. Mild stages of dementia could gain more benefits from OT with regard to functional decline.

%B J Alzheimers Dis %V 56 %P 509-517 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983551?dopt=Abstract %R 10.3233/JAD-160820 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Beyond a Differential Diagnosis: Cognitive and Morphometric Decoding of Information Processing Speed in Senior Adults with DSM-5 Mild Neurocognitive Disorders. %A Lu, Hanna %A Chan, Sandra S M %A Fung, Ada W T %A Lam, Linda C W %X

BACKGROUND: Processing speed has been highlighted as a diagnostic item for neurocognitive disorders (NCD) in DSM-5. The utility of information processing speed (IPS) enclosed with multiscale constructs in the diagnosis of NCD warrants exploration.

OBJECTIVE: We aimed to investigate the IPS with two types of measurements in the patients with NCD due to vascular disease (NCD-vascular) and NCD due to Alzheimer's disease (NCD-AD), and examine the associations between IPS measures and morphometric features.

METHODS: The IPS was evaluated using trail making test (TMT) and flanker test (n = 204). Direct scores, derived scores, and reaction time (RT) were used as IPS measures. Further, surface-based morphometry cortical volume was calculated in a subsample (n = 44) with structural MRI data.

RESULTS: All IPS measures showed a significant value to differentiate NCD patients from healthy subjects. Only mean RT could distinguish NCD-AD from NCD-vascular groups. TMT-B score and difference score were correlated with gray matter volume (GMV) of inferior frontal gyrus, precuneus and superior temporal cortex. Mean RT was associated with the GMV of post-central gyrus (r = -0.327, p = 0.035), and executive speed was associated with inferior frontal cortex (r = -0.475, p = 0.001), cingulate gyrus (r = -0.497, p = 0.001), and superior temporal gyrus (r = -0.36, p = 0.019).

CONCLUSION: The cognitive and morphometric correlates of IPS measures indicate that complex IPS might be decomposed into the domain-specific components with corresponding neural underpinnings. Our findings may also provide essential insights into the diagnostic item of NCD.

%B J Alzheimers Dis %V 58 %P 927-937 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527207?dopt=Abstract %R 10.3233/JAD-161122 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Bilingualism and Cognitive Decline: A Story of Pride and Prejudice. %A Woumans, Evy %A Versijpt, Jan %A Sieben, Anne %A Santens, Patrick %A Duyck, Wouter %X

In a recent review, Mukadam, Sommerlad, and Livingston (2017) argue that bilingualism offers no protection against cognitive decline. The authors examined the results of 13 studies (five prospective, eight retrospective) in which monolinguals and bilinguals were compared for cognitive decline and onset of dementia symptoms. Analysis of four of the five prospective studies resulted in the conclusion that there was no difference between monolinguals and bilinguals, whereas seven of the eight retrospective studies actually showed bilingualism to result in a four-to-five year delay of symptom onset. The authors decided to ignore the results from the retrospective studies in favor of those from the prospective studies, reasoning that the former may be confounded by participants' cultural background and education levels. In this commentary, we argue that most of these studies actually controlled for these two variables and still found a positive effect of bilingualism. Furthermore, we argue that the meta-analysis of the prospective studies is not complete, lacking the results of two crucial reports. We conclude that the literature offers substantial evidence for a bilingual effect on the development of cognitive decline and dementia.

%B J Alzheimers Dis %V 60 %P 1237-1239 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922163?dopt=Abstract %R 10.3233/JAD-170759 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Bimanual Gesture Imitation in Alzheimer's Disease. %A Sanin, G Nter %A Benke, Thomas %X

BACKGROUND/OBJECTIVE: Unimanual gesture production or imitation has often been studied in Alzheimer's disease (AD) during apraxia testing. In the present study, it was hypothesized that bimanual motor tasks may be a sensitive method to detect impairments of motor cognition in AD due to increased demands on the cognitive system.

METHODS: We investigated bimanual, meaningless gesture imitation in 45 AD outpatients, 38 subjects with mild cognitive impairment (MCI), and 50 normal controls (NC) attending a memory clinic. Participants performed neuropsychological background testing and three tasks: the Interlocking Finger Test (ILF), Imitation of Alternating Hand Movements (AHM), and Bimanual Rhythm Tapping (BRT).

RESULTS: The tasks were short and easy to administer. Inter-rater reliability was high across all three tests. AD patients performed significantly poorer than NC and MCI participants; a deficit to imitate bimanual gestures was rarely found in MCI and NC participants. Sensitivity to detect AD ranged from 0.5 and 0.7, specificity beyond 0.9. ROC analyses revealed good diagnostic accuracy (0.77 to 0.92). Impairment to imitate bimanual gestures was mainly predicted by diagnosis and disease severity.

CONCLUSION: Our findings suggest that an impairment to imitate bimanual, meaningless gestures is a valid disease marker of mild to moderate AD and can easily be assessed in memory clinic settings. Based on our preliminary findings, it appears to be a separate impairment which can be distinguished from other cognitive deficits.

%B J Alzheimers Dis %V 57 %P 53-59 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222504?dopt=Abstract %R 10.3233/JAD-160680 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Biomarkers and Functional Decline in Prodromal Alzheimer's Disease. %A Robb, Catherine %A Udeh-Momoh, Chinedu %A Wagenpfeil, Stefan %A Schöpe, Jakob %A Alexopoulos, Panagiotis %A Perneczky, Robert %X

BACKGROUND: Little is known of possible associations between Alzheimer's disease (AD) biomarkers and instrumental activities of daily living (IADL) change over time.

OBJECTIVE: The present study seeks to identify relationships between baseline imaging and fluid biomarker profiles, and decline in IADL utilizing data collated from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.

METHODS: Generalized estimating equations analysis, adjusted for cognitive deterioration, was applied to a cohort of 509 individuals from all stages of ADNI, including 156 healthy controls, 189 early mild cognitive impairment (MCI) patients and 164 MCI patients.

RESULTS: A significant correlation was found between baseline biomarkers, specifically CSF Aβ and FDG PET, and IADL change over a 3-year period in individuals with MCI. Importantly, comparable correlations between presence of pathological biomarker levels and temporal decline in both functional and cognitive performance were also noted.

DISCUSSION: We show that distinct baseline biomarkers may predict latent changes in IADL. Our results necessitate a revision of the commonly held view upholding cognitive changes as the predominant endpoint measure associated with presence of abnormal baseline biomarkers.

%B J Alzheimers Dis %V 58 %P 69-78 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372331?dopt=Abstract %R 10.3233/JAD-161162 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Biomarkers for Early Diagnosis of Alzheimer's Disease in the Oldest Old: Yes or No? %A Paolacci, Lucia %A Giannandrea, David %A Mecocci, Patrizia %A Parnetti, Lucilla %X

In recent years, many efforts have been spent to identify sensitive biomarkers able to improve the accuracy of Alzheimer's disease (AD) diagnosis. Two different workgroups (NIA-AA and IWG) included cerebrospinal fluid (CSF) and neuroimaging findings in their sets of criteria in order to improve diagnostic accuracy as well as early diagnosis. The number of subjects with cognitive impairment increases with aging but the oldest old (≥85 years of age), the fastest growing age group, is still the most unknown from a biological point of view. For this reason, the aim of our narrative mini-review is to evaluate the pertinence of the new criteria for AD diagnosis in the oldest old. Moreover, since different subgroups of oldest old have been described in scientific literature (escapers, delayers, survivors), we want to outline the clinical profile of the oldest old who could really benefit from the use of biomarkers for early diagnosis. Reviewing the literature on biomarkers included in the diagnostic criteria, we did not find a high degree of evidence for their use in the oldest old, although CSF biomarkers seem to be still the most useful for excluding AD diagnosis in the "fit" subgroup of oldest old subjects, due to the high negative predictive value maintained in this age group.

%B J Alzheimers Dis %V 58 %P 323-335 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28436390?dopt=Abstract %R 10.3233/JAD-161127 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Bipolar Disorder and Frontotemporal Dementia: An Intriguing Association. %A Papazacharias, Apostolos %A Lozupone, Madia %A Barulli, Maria Rosaria %A Capozzo, Rosa %A Imbimbo, Bruno P %A Veneziani, Federica %A De Blasi, Roberto %A Nardini, Marcello %A Seripa, Davide %A Panza, Francesco %A Logroscino, Giancarlo %X

Bipolar disorder (BD) could represent a prodromal state of frontotemporal dementia (FTD). Two patients affected by lifelong BD with a progressive decline of cognitive functions, behavioral, and neurological signs, reached the early diagnosis of FTD before the age of 60. They were diagnosed as affected by primary progressive aphasia and FTD with parkinsonism, respectively. A diagnosis of FTD should therefore be taken into account, in case of unexpected cognitive and behavioral decline in patients with a long history of BD. Follow-up studies with genetic, neuropsychological, and neuroimaging markers of these BD/FTD patients could further explore some of the underlying association, opening new viable therapeutic options.

%B J Alzheimers Dis %V 55 %P 973-979 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802240?dopt=Abstract %R 10.3233/JAD-160860 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Blood Pressure and Hispanic/Latino Cognitive Function: Hispanic Community Health Study/Study of Latinos Results. %A Tarraf, Wassim %A Rodríguez, Carlos J %A Daviglus, Martha L %A Lamar, Melissa %A Schneiderman, Neil %A Gallo, Linda %A Talavera, Gregory A %A Kaplan, Robert C %A Fornage, Myriam %A Conceicao, Alan %A González, Hector M %X

BACKGROUND: Hispanics/Latinos are at increased risk for cardiovascular disease and cognitive decline and dementias. High blood pressure (BP) has been implicated in both stroke and dementias. Associations between BP and cognition among diverse Latinos are still unpublished.

OBJECTIVE: We examined associations between cognition and four BP based measures among diverse Hispanics/Latinos. We hypothesized that higher BP, particularly systolic pressure, and increased arterial stiffness (i.e., pulse pressure), would be associated with lower cognitive function.

METHODS: We used baseline (2008-2011) Hispanic Community Health Study/Study of Latinos (HCHS/SOL; n = 9,019; ages 45-74 years) data to examine cognition in relation to BP measures.

RESULTS: In age, sex, and education adjusted models, systolic, pulse, and mean arterial pressure were consistently negatively associated with executive function, psychomotor speed and sustained attention, verbal episodic learning and memory, speech fluency, and mental status measures. These associations were attenuated but remained statistically significant in fully adjusted models.

CONCLUSION: Among middle-aged and older diverse Hispanics/Latinos, we found modest but consistent associations between indicators of arterial stiffness, and compromised blood flow and lower cognitive function. Clinical management and public health interventions to raise awareness and enhance BP management beginning in midlife could reduce disparities and improve population health by reducing cognitive decline burdens.

%B J Alzheimers Dis %V 59 %P 31-42 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582859?dopt=Abstract %R 10.3233/JAD-170017 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Blood-Based Oligomeric and Other Protein Variant Biomarkers to Facilitate Pre-Symptomatic Diagnosis and Staging of Alzheimer's Disease. %A Williams, Stephanie M %A Schulz, Philip %A Rosenberry, Terrone L %A Caselli, Richard J %A Sierks, Michael R %X

Oligomeric forms of amyloid-β (Aβ), tau, and TDP-43 play important roles in Alzheimer's disease (AD), and therefore are promising biomarkers. We previously generated single chain antibody fragments (scFvs) that selectively bind disease-related variants of these proteins including A4, C6T, and E1, which bind different oligomeric Aβ variants; D11C, which binds oligomeric tau; and AD-TDP1 and AD-TDP2, which bind disease related TDP-43 variants. To determine the utility of these disease-related variants as early biomarkers, we first analyzed 11 human sera samples obtained ∼2 years prior to an initial mild cognitive impairment (MCI) diagnosis. While the subsequent diagnoses for the cases covered several different conditions, all samples had elevated protein variant levels relative to the plasma controls although with different individual biomarker profiles. We then analyzed a set of longitudinal human plasma samples from four AD (encompassing time points prior to MCI diagnosis and continuing until after conversion to AD) and two control cases. Pre-MCI samples were characterized by high TDP-43 variant levels, MCI samples by high Aβ variant levels, and AD samples by high Aβ and tau variant levels. Sample time points ranged from ∼7 years pre-MCI to ∼9 years after AD conversion. Bivariate correlations showed a negative correlation with TDP-43 levels and positive correlations with cumulative Aβ and oligomeric tau levels indicating an increase in neurodegenerative processes with time in AD. Detection of disease related protein variants not only readily selects AD cases from controls, but also stages progression of AD and holds promise for a pre-symptomatic blood-based biomarker profile for AD.

%B J Alzheimers Dis %V 58 %P 23-35 %G eng %N 1 %R 10.3233/JAD-161116 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Blunted Respiratory Responses in the Streptozotocin-Induced Alzheimer's Disease Rat Model. %A Ebel, Dalton L %A Torkilsen, Christopher G %A Ostrowski, Tim D %X

Alzheimer's disease (AD) is known for the progressive decline of cognition and memory. In addition to these disease-defining symptoms, impairment of respiratory function is frequently observed and often expressed by sleep-disordered breathing or reduced ability to adjust respiration when oxygen demand is elevated. The mechanisms for this are widely unknown. Postmortem analysis from the brainstem of AD patients reveals pathological alterations, including in nuclei responsible for respiratory control. In this study, we analyzed respiratory responses and morphological changes in brainstem nuclei following intracerebroventricular (ICV) injections of streptozotocin (STZ), a rat model commonly used to mimic sporadic AD. ICV-STZ induced significant astrogliosis in the commissural part of the nucleus tractus solitarii, an area highly involved in respiration control. The astrogliosis was identified by a significant increase in S100B-immunofluorescence that is similar to the astrogliosis found in the CA1 region of the hippocampus. Using plethysmography, the control group displayed a typical age-dependent decrease of ventilation that was absent in the STZ rat group. This is indicative of elevated minute ventilation at rest after STZ treatment. Peripheral chemoreflex responses were significantly blunted in STZ rats as seen by a reduced respiratory rate and minute ventilation to hypoxia. Central chemoreflex responses to hypercapnia, on the other hand, only decreased in respiratory rate following STZ treatment. Overall, our results show that ICV-STZ induces respiratory dysfunction at rest and in response to hypoxia. This provides a new tool to study the underlying mechanisms of breathing disorders in clinical AD.

%B J Alzheimers Dis %V 56 %P 1197-1211 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106557?dopt=Abstract %R 10.3233/JAD-160974 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Body Mass Index, Height, and Socioeconomic Position in Adolescence, Their Trajectories into Adulthood, and Cognitive Function in Midlife. %A Cohen-Manheim, Irit %A Doniger, Glen M %A Sinnreich, Ronit %A Simon, Ely S %A Murad, Havi %A Pinchas-Mizrachi, Ronit %A Kark, Jeremy D %X

BACKGROUND: Whether life course anthropometric indices relate to cognitive function in midlife remains insufficiently explored. Rarely was socioeconomic position (SEP) adequately accounted for.

OBJECTIVE: To examine the association of the cumulative life course burden of high-ranked body mass index (BMI), its trajectory, and stature with cognitive function in midlife.

METHODS: Weight and height were measured from age 17 across a 33-year follow-up. 507 individuals completed a NeuroTrax computerized cognitive assessment at ages 48-52. Life course SEP was assessed by multiple methods. Using mixed models we calculated the area under the curve (AUC), representing both the life-course burden of BMI (total AUC) and trends in BMI (incremental AUC) from age 17 to midlife. The associations of BMI and height with global cognition and its five component domains were assessed by multiple regression.

RESULTS: Higher BMI in late adolescence and total AUC over the life course were associated with poorer global cognition (Standardized beta (Beta) = -0.111, p = 0.005 and Beta = -0.105, p = 0.018, respectively), adjusted for childhood and adulthood SEP, and demographic characteristics. The associations with higher adolescent and midlife BMI were both restricted to those with low childhood SEP (p < 0.05 for interaction). Short adolescent stature was related to poorer cognition (Beta = 0.084, p = 0.044), whereas late final growth in women was associated with better cognition (Beta = 0.213, p = 0.007).

CONCLUSION: An adverse association of higher BMI with cognitive function began in adolescence and was restricted to low childhood SEP. Taller stature in both sexes and late growth in women were associated with better midlife cognitive performance.

%B J Alzheimers Dis %V 55 %P 1207-1221 %G eng %N 3 %R 10.3233/JAD-160843 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Brain Biomarkers in Familial Alzheimer's Disease Mouse Models. %A Kuttner-Hirshler, Yafit %A Venkatasubramanian, Palamadai N %A Apolinario, Joan %A Bonds, Jacqueline %A Wyrwicz, Alice M %A Lazarov, Orly %X

Alzheimer's disease (AD) is characterized by progressive loss of memory and cognitive deterioration. It is thought that the onset of the disease takes place several decades before memory deficits are apparent. Reliable biomarkers for the diagnosis or prognostication of the disease are highly desirable. Neural stem cells (NSC) exist in the adult brain throughout life and give rise to neural progenitor cells (NPC), which differentiate into neurons or glia. The level of NPC proliferation and new neuron formation is significantly compromised in mouse models of familial Alzheimer's disease (FAD). These deficits are readily detected in young adults, at 2-3 months of age, preceding amyloid deposition and cognitive impairments, which may indicate that impaired neurogenesis can be an early biomarker for cognitive deficits in AD. Recent studies suggest that NSC can be detected in live rodents, noninvasively, using proton magnetic resonance spectroscopy (1H-MRS) signal at 1.28 ppm. Here we examined the use of 1H-MRS for determining the extent of neurogenesis in the brains of FAD mice. We observed that the reduction in neurogenesis in the FAD mice as observed by immunohistochemistry, was not manifested by a reduction in the 1.28 ppm signal, suggesting that this marker is either not specific for neurogenesis or not sensitive enough for the detection of alterations in hippocampal neurogenesis in the brains of FAD mice.

%B J Alzheimers Dis %V 60 %P 949-958 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922152?dopt=Abstract %R 10.3233/JAD-170269 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Brain Regions Involved in Arousal and Reward Processing are Associated with Apathy in Alzheimer's Disease and Frontotemporal Dementia. %A Huey, Edward D %A Lee, Seonjoo %A Cheran, Gayathri %A Grafman, Jordan %A Devanand, Davangere P %X

BACKGROUND: Apathy is a common and problematic symptom of several neurodegenerative illnesses, but its neuroanatomical bases are not understood.

OBJECTIVE: To determine the regions associated with apathy in subjects with mild Alzheimer's disease (AD) using a method that accounts for the significant co-linearity of regional atrophy and neuropsychiatric symptoms.

METHODS: We identified 57 subjects with mild AD (CDR = 1) and neuropsychiatric symptoms in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We performed a multivariate multiple regression with LASSO regularization on all symptom subscales of the Neuropsychiatric Inventory and the whole-brain ROI volumes calculated from their baseline MRIs with FreeSurfer. We compared our results to those from a previous study using the same method in patients with frontotemporal dementia (FTD) and corticobasal syndrome (CBS).

RESULTS: Of neuropsychiatric symptoms, apathy showed the most robust neuroanatomical associations in the AD subjects. Atrophy of the following regions were independently associated with apathy: the ventromedial prefrontal cortex; ventrolateral prefrontal cortex; posterior cingulate cortex and adjacent lateral cortex; and the bank of the superior temporal sulcus. These results replicate previous studies using FTD and CBS patients, mostly agree with the previous literature on apathy in AD, and correspond to the Medial and Orbital Prefrontal Cortex networks identified in non-human primates.

CONCLUSION: The current study, previous studies from our laboratory, and the previous literature suggest that impairment of the same brain networks involved in arousal, threat response, and reward processing are associated with apathy in AD and FTD.

%B J Alzheimers Dis %V 55 %P 551-558 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802220?dopt=Abstract %R 10.3233/JAD-160107 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Brain's Structural Connectome Mediates the Relationship between Regional Neuroimaging Biomarkers in Alzheimer's Disease. %A Pandya, Sneha %A Kuceyeski, Amy %A Raj, Ashish %X

Alzheimer's disease (AD), one of the most common causes of dementia in adults, is a progressive neurodegenerative disorder exhibiting well-defined neuropathological hallmarks. It is known that disease pathology involves misfolded amyloid-β (Aβ) and tau proteins, and exhibits a relatively stereotyped progression over decades. The relationship between AD neuropathological hallmarks (Aβ, hypometabolism, and tau proteins) and imaging biomarkers (MRI, AV-45/FDG-PET) is not fully understood. In addition, biomarker pathologies are oftentimes discordant, wherein it may show varying levels of abnormality across brain regions. Evidence based on recent elucidation of trans-neuronal "prion-like" transmission and other available data already suggests that disease spread follows the brain's fiber connectivity network. Thereby, the brain's connectome information can be used to predict the process of disease spread in AD. A recently established mathematical model of AD pathology spread using a connectome-based network diffusion model was successful in encapsulating neurodegenerative progression. Motivated by these network-based findings, the current study explores whether and how network connectivity mediates the interactions between various AD biomarkers. We hypothesized that the structural connectivity matrix will mediate the cross-sectional association between regional AD-associated hypometabolism and Aβ deposition. Given recent reports of inherent or lifetime activity of brain regions as strong predictors of Aβ deposition in patients, we also tested whether healthy metabolism exerts a network-mediated effect on Aβ deposition and hypometabolism in AD patients. We found that regional Aβ deposition is best predicted by a linear combination of both regional healthy local metabolism and connectome-mediated regional healthy metabolism.

%B J Alzheimers Dis %V 55 %P 1639-1657 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911289?dopt=Abstract %R 10.3233/JAD-160090 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Bryostatin Effects on Cognitive Function and PKCɛ in Alzheimer's Disease Phase IIa and Expanded Access Trials. %A Nelson, Thomas J %A Sun, Miao-Kun %A Lim, Chol %A Sen, Abhik %A Khan, Tapan %A Chirila, Florin V %A Alkon, Daniel L %X

Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer's disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion. Of 9 patients with a clinical diagnosis of AD, of which 6 received drug and 3 received vehicle within a double-blind protocol, bryostatin increased the Mini-Mental State Examination (MMSE) score by +1.83±0.70 unit at 3 h versus -1.00±1.53 unit for placebo. Bryostatin was well tolerated in these AD patients and no drug-related adverse events were reported. The 25 μg/m2 administered dose was based on prior clinical experience with three Expanded Access advanced AD patients treated with bryostatin, in which return of major functions such as swallowing, vocalization, and word recognition were noted. In one Expanded Access patient trial, elevated PKCɛ levels closely tracked cognitive benefits in the first 24 weeks as measured by MMSE and ADCS-ADL psychometrics. Pre-clinical mouse studies showed effective activation of PKCɛ and increased levels of BDNF and PSD-95. Together, these Phase IIa, Expanded Access, and pre-clinical results provide initial encouragement for bryostatin 1 as a potential treatment for AD.

%B J Alzheimers Dis %V 58 %P 521-535 %8 2017 %G eng %N 2 %R 10.3233/JAD-170161 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Can Better Management of Periodontal Disease Delay the Onset and Progression of Alzheimer's Disease? %A Harding, Alice %A Robinson, Sarita %A Crean, StJohn %A Singhrao, Sim K %X

A risk factor relationship exists between periodontal disease and Alzheimer's disease (AD) via tooth loss, and improved memory following dental intervention. This links the microbial contribution from indigenous oral periodontal pathogens to the manifestation of chronic conditions, such as AD. Here, we use Porphyromonas gingivalis infection to illustrate its effect on mental health. P. gingivalis infection, in its primary sub-gingival niche, can cause polymicrobial synergy and dysbiosis. Dysbiosis describes the residency of select commensals from the oral cavity following co-aggregation around the dominant keystone pathogen, such as P. gingivalis, to gain greater virulence. The initial process involves P. gingivalis disturbing neutrophil mediated innate immune responses in the healthy gingivae and then downregulating adaptive immune cell differentiation and development to invade, and subsequently, establish new dysbiotic bacterial communities. Immune responses affect the host in general and functionally via dietary adjustments caused by tooth loss. Studies from animals orally infected with P. gingivalis confirm this bacterium can transmigrate to distant organ sites (the brain) and contribute toward peripheral and intracerebral inflammation, and compromise vascular and microvascular integrity. In another study, P. gingivalis infection caused sleep pattern disturbances by altering glial cell light/dark molecular clock activity, and this, in turn, can affect the clearance of danger associated molecular patterns, such as amyloid-β, via the glymphatic system. Since P. gingivalis can transmigrate to the brain and modulate organ-specific inflammatory innate and adaptive immune responses, this paper explores whether better management of indigenous periodontal bacteria could delay/prevent the onset and/or progression of dementia.

%B J Alzheimers Dis %V 58 %P 337-348 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453484?dopt=Abstract %R 10.3233/JAD-170046 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Can Musical or Painting Interventions Improve Chronic Pain, Mood, Quality of Life, and Cognition in Patients with Mild Alzheimer's Disease? Evidence from a Randomized Controlled Trial. %A Pongan, Elodie %A Tillmann, Barbara %A Leveque, Yohana %A Trombert, Béatrice %A Getenet, Jean Claude %A Auguste, Nicolas %A Dauphinot, Virginie %A El Haouari, Hanane %A Navez, Malou %A Dorey, Jean-Michel %A Krolak-Salmon, Pierre %A Laurent, Bernard %A Rouch, Isabelle %X

BACKGROUND: Among non-pharmacological therapies, musical intervention is often used for patients with Alzheimer's disease (AD) and patients presenting chronic pain. However, their efficacy is still under debate.

OBJECTIVE: Our aim was to determine the efficacy of choral singing versus painting sessions on chronic pain, mood, quality of life, and cognition in AD patients.

METHODS: In this multicenter randomized controlled trial, 59 mild AD patients were randomized to a 12-week singing (SG; n = 31) or painting group (PG; n = 28). Chronic pain, anxiety, depression, and quality of life were assessed before, after, and 1 month after the sessions. Cognitive abilities were assessed before and after interventions. The evolution of these different measures was assessed with mixed linear models. The primary data analysis was by intention-to-treat, and completed by a 'per protocol' approach.

RESULTS: Both singing and painting interventions led to significant pain reduction (Time effect: F = 4.71; p = 0.01), reduced anxiety (Time effect: F = 10.74; p < 0.0001), improved Quality of Life (Time effect: F = 6.79; p = 0.002), improved digit span (F = 12.93; p = 0.001), and inhibitory processes (Time effect: F = 4.93; p = 0.03). Depression was reduced over time in PG only (Time x Group effect: F = 4.53; p = 0.01). Verbal Memory performance remained stable over time in SG, but decreased in PG (Time x group effect: F = 9.29; p = 0.004).

CONCLUSION: Findings suggest that singing and painting interventions may reduce pain and improve mood, quality of life, and cognition in patients with mild AD, with differential effects of painting for depression and singing for memory performance.

%B J Alzheimers Dis %V 60 %P 663-677 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922159?dopt=Abstract %R 10.3233/JAD-170410 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Capsaicin Attenuates Amyloid-β-Induced Synapse Loss and Cognitive Impairments in Mice. %A Chen, Long %A Huang, Zhilin %A Du, Yehong %A Fu, Min %A Han, Huili %A Wang, Yutian %A Dong, Zhifang %X

Alzheimer's disease (AD) is the most common cause of progressive cognitive impairment in the aged. The aggregation of the amyloid β-protein (Aβ) is a hallmark of AD and is linked to synapse loss and cognitive impairment. Capsaicin, a specific agonist of the transient receptor potential vanilloid 1 (TRPV1), has been proven to ameliorate stress-induced AD-like pathological and cognitive impairments, but it is unclear whether TRPV1 activation can affect cognitive and synaptic functions in Aβ-induced mouse model of AD. In this study, we investigated the effects of TRPV1 activation on spatial memory and synaptic plasticity in mice treated with Aβ. To induce AD-like pathological and cognitive impairments, adult C57Bl/6 mice were microinjected with Aβ42 (100 μM, 2.5 μl/mouse, i.c.v.). Two weeks after Aβ42 microinjection, spatial learning and memory as well as hippocampal long-term potentiation (LTP) were examined. The results showed that Aβ42 microinjection significantly impaired spatial learning and memory in the Morris water maze and novel object recognition tests compared with controls. These behavioral changes were accompanied by synapse loss and impaired LTP in the CA1 area of hippocampus. More importantly, daily capsaicin (1 mg/kg, i.p.) treatment throughout the experiment dramatically improved spatial learning and memory and synaptic function, as reflected by enhanced hippocampal LTP and reduced synapse loss, whereas the TRPV1 antagonist capsazepine (1 mg/kg, i.p.) treatment had no effects on cognitive and synaptic function in Aβ42-treated mice. These results indicate that TRPV1 activation by capsaicin rescues cognitive deficit in the Aβ42-induced mouse model of AD both structurely and functionally.

%B J Alzheimers Dis %V 59 %P 683-694 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671132?dopt=Abstract %R 10.3233/JAD-170337 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Care Plan Improvement in Nursing Homes: An Integrative Review. %A Mariani, Elena %A Chattat, Rabih %A Vernooij-Dassen, Myrra %A Koopmans, Raymond %A Engels, Yvonne %X

BACKGROUND: Care planning nowadays is a key activity in the provision of services to nursing home residents. A care plan describes the residents' needs and the actions to address them, providing both individualized and standardized interventions and should be updated as changes in the residents' conditions occur.

OBJECTIVE: The aim of this review was to identify the core elements of the implementation of changes in nursing homes' care plans, by providing an overview of the type of stakeholders involved, describing the implementation strategies used, and exploring how care plans changed.

METHODS: An integrative literature review was used to evaluate intervention studies taking place in nursing homes. Data were collected from PubMed, CINHAL-EBSCO, and PsycINFO. English language articles published between 1995 and April 2015 were included. Data analysis followed the strategy of Knafl and Whittemore.

RESULTS: Twenty-six articles were included. The stakeholders involved were professionals, family caregivers, and patients. Only a few studies directly involved residents and family caregivers in the quality improvement process. The implementation strategies used were technology implementation, audit, training, feedback, and supervision. The majority of interventions changed the residents' care plans in terms of developing a more standardized care documentation that primarily focuses on its quality. Only some interventions developed more tailored care plans that focus on individualized needs.

CONCLUSION: Care plans generally failed in providing both standardized and personalized interventions. Efforts should be made to directly involve residents in care planning and provide professionals with efficient tools to report care goals and actions in care plans.

%B J Alzheimers Dis %V 55 %P 1621-1638 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911293?dopt=Abstract %R 10.3233/JAD-160559 %0 Journal Article %J J Alzheimers Dis %D 2017 %T CD44 Splice Variants as Potential Players in Alzheimer's Disease Pathology. %A Pinner, Elhanan %A Gruper, Yaron %A Ben Zimra, Micha %A Kristt, Don %A Laudon, Moshe %A Naor, David %A Zisapel, Nava %X

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, deposition of amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles, and neuronal cell death. Neuroinflammation is commonly believed to participate in AD pathogenesis. CD44 is an inflammation-related gene encoding a widely-distributed family of alternatively spliced cell surface glycoproteins that have been implicated in inflammation, metastases, and inflammation-linked neuronal injuries. Here we investigated the expression patterns of CD44S (which does not contain any alternative exon) and CD44 splice variants in postmortem hippocampal samples from AD patients and matched non-AD controls. The expression of CD44S and CD44 splice variants CD44V3, CD44V6, and CD44V10 was significantly higher in AD patients compared to non-AD controls. Immunohistochemistry of human hippocampal sections revealed that CD44S differentially localized to neuritic plaques and astrocytes, whereas CD44V3, CD44V6, and CD44V10 expression was mostly neuronal. Consistent with these findings, we found that the expression of CD44V6 and CD44V10 was induced by Aβ peptide in neuroblastoma cells and primary neurons. Furthermore, in loss of function studies we found that both CD44V10-specific siRNA and CD44V10 antibody protected neuronal cells from Aβ-induced toxicity, suggesting a causal relationship between CD44V10 and neuronal cell death. These data indicate that certain CD44 splice variants contribute to AD pathology and that CD44V10 inhibition may serve as a new neuroprotective treatment strategy for this disease.

%B J Alzheimers Dis %V 58 %P 1137-1149 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550248?dopt=Abstract %R 10.3233/JAD-161245 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Central Olfactory Dysfunction in Alzheimer's Disease and Mild Cognitive Impairment: A Functional MRI Study. %A Vasavada, Megha M %A Martinez, Brittany %A Wang, Jianli %A Eslinger, Paul J %A Gill, David J %A Sun, Xiaoyu %A Karunanayaka, Prasanna %A Yang, Qing X %X

BACKGROUND: Olfactory deficits are present in early Alzheimer's disease (AD) and mild cognitively impaired (MCI) patients. However, whether these deficits are due to dysfunction of the central or peripheral olfactory nervous system remains uncertain. This question is fundamentally important for developing imaging biomarkers for AD using olfactory testing.

OBJECTIVE: This study sought to use olfactory functional magnetic resonance imaging (fMRI) to further demonstrate the involvement of the central olfactory system in olfactory deficits in MCI and AD.

METHODS: We investigated the central olfactory system in 27 cognitively normal controls (CN), 21 MCI, and 15 AD subjects using olfactory fMRI with an odor-visual association paradigm during which a visual cue was paired with lavender odorant (odor condition) or odorless air (no-odor condition).

RESULTS: The CN subjects had significantly greater activated volume in the primary olfactory cortex during both the odor and no-odor conditions compared to either the MCI or AD groups (p < 0.05). No significant differences were observed between the odor and no-odor conditions within each group. No-odor condition activation in AD and MCI correlated with the cognitive and olfactory assessments.

CONCLUSION: The no-odor condition, allowing investigation of activation patterns when the peripheral olfactory system was not directly involved, elicited the same functional response as the odor condition for each of the three groups. Thus, the olfactory activation deficits present in AD and MCI patients are most likely caused by degeneration of the central olfactory nervous system.

%B J Alzheimers Dis %V 59 %P 359-368 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671131?dopt=Abstract %R 10.3233/JAD-170310 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Central Review of Amyloid-Related Imaging Abnormalities in Two Phase III Clinical Trials of Bapineuzumab in Mild-To-Moderate Alzheimer's Disease Patients. %A Ketter, Nzeera %A Brashear, H Robert %A Bogert, Jennifer %A Di, Jianing %A Miaux, Yves %A Gass, Achim %A Purcell, Derk D %A Barkhof, Frederik %A Arrighi, H Michael %X

BACKGROUND: Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]).

OBJECTIVES: To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer's disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ4 allele carriers or noncarriers).

METHODS: Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described.

RESULTS: In the Final Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs <10 mm (cerebral microhemorrhages) was higher in active groups versus placebo.

CONCLUSION: ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study.

%B J Alzheimers Dis %V 57 %P 557-573 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269765?dopt=Abstract %R 10.3233/JAD-160216 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebral Amyloid Angiopathy-Related Microbleeds and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease. %A Noguchi-Shinohara, Moeko %A Komatsu, Junji %A Samuraki, Miharu %A Matsunari, Ichiro %A Ikeda, Tokuhei %A Sakai, Kenji %A Hamaguchi, Tsuyoshi %A Ono, Kenjiro %A Nakamura, Hiroyuki %A Yamada, Masahito %X

BACKGROUND: Alzheimer's disease (AD) commonly accompanies cerebral amyloid angiopathy (CAA).

OBJECTIVE: We aimed to reveal associations between CAA-related brain microbleeds and cerebrospinal fluid (CSF) markers in AD patients.

METHODS: Patients with probable AD (n = 88) from consecutive patients in our memory clinic were evaluated for patient demographics, vascular risk factors, neuropsychological tests, apolipoprotein E phenotype, MRI including T2*-weighted image and fluid attenuated inversion recovery sequence, and CSF amyloid and tau markers.

RESULTS: The 88 patients with AD included 15 with microbleeds only in cortical/subcortical regions (cortical microbleeds) that could be CAA-related, 16 with microbleeds only in deep locations (deep microbleeds), 3 with microbleeds in both cortical and deep locations (mixed microbleeds), and 54 without microbleeds. The CSF levels of amyloid β-protein 1-40 (Aβ40) and amyloid β-protein 1-42 (Aβ42) were significantly lower in patients with cortical microbleeds than in those without microbleeds (p = 0.001 and p = 0.027, respectively). The result remained unchanged after adjustment for age, sex, apolipoprotein E E4 presence, and leukoaraiosis.

CONCLUSIONS: CAA-related cortical microbleeds would be associated with lower CSF levels of Aβ40 and Aβ42 in AD, reflecting the deposition of both Aβ40 and Aβ42 in the cerebrovasculature.

%B J Alzheimers Dis %V 55 %P 905-913 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802236?dopt=Abstract %R 10.3233/JAD-160651 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebral Artery Pulsatility is Associated with Cognitive Impairment and Predicts Dementia in Individuals with Subjective Memory Decline or Mild Cognitive Impairment. %A Chung, Chih-Ping %A Lee, Hsiang-Ying %A Lin, Po-Chen %A Wang, Pei-Ning %X

The concept that excess pulsation in cerebral arteries might be involved at the early stage of dementia is based on the results of studies on aorta stiffness. In these studies, aorta stiffness is cross-sectionally associated with cognitive impairment and longitudinally related to cognitive decline in non-demented subjects. However, a direct measure of cerebral artery pulsatility is absent in the literature. We aimed to investigate the associations between cerebral artery pulsatility and (1) different cognitive-domains and (2) conversion to dementia in non-demented individuals at the prodromal-stage of Alzheimer's disease (AD). Non-demented individuals with subjective memory decline or mild cognitive impairment were included. Neuropsychological tests at baseline and cognitive status at 6 years were evaluated. Cerebral pulsatility was assessed in the middle cerebral artery (MCA) and posterior cerebral artery by transcranial color-coded sonography. Multivariate-analyses of 79 subjects with robust acoustic windows showed that increased pulsatility in cerebral arteries was significantly associated with impairment in corresponding cognitive domains. Analyses in 54 subjects who completed 6-year follow up revealed that high left MCA pulsation (pulsatility index≥1.1) independently predicted conversion to AD with an odds-ratio of 11.2. Our results demonstrate the spatio-temporal relationship between increased cerebral artery pulsation and cognitive impairment and suggest that increased cerebrovascular pulsation might be involved in the early pathogenesis of AD. Cerebrovascular pulsation may be a therapeutic target to prevent/delay AD onset. Future studies with other AD biomarkers and animal/cell models of increased vascular-pulsation are needed to elucidate the mechanisms by which cerebrovascular pulsatile injury initiates or precipitates neurodegeneration in AD.

%B J Alzheimers Dis %V 60 %P 625-632 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826186?dopt=Abstract %R 10.3233/JAD-170349 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebral Hemodynamics in Mild Cognitive Impairment: A Systematic Review. %A Beishon, Lucy %A Haunton, Victoria J %A Panerai, Ronney B %A Robinson, Thompson G %X

BACKGROUND: The incidence of dementia is projected to rise over the coming decades, but with no sensitive diagnostic tests available. Vascular pathology precedes the deposition of amyloid and is an attractive early target.

OBJECTIVE: The aim of this review was to investigate the use of cerebral hemodynamics and oxygenation as a novel biomarker for mild cognitive impairment (MCI), focusing on transcranial Doppler ultrasonography (TCD) and near-infrared spectroscopy (NIRS).

METHODS: 2,698 articles were identified from Medline, Embase, PsychINFO, and Web of Science databases. 306 articles were screened and quality assessed independently by two reviewers; 26 met the inclusion criteria. Meta-analyses were performed for each marker with two or more studies and limited heterogeneity.

RESULTS: Eleven studies were TCD, 8 NIRS, 5 magnetic resonance imaging, and 2 positron/single photon emission tomography. Meta-analyses showed reduced tissue oxygenation index, cerebral blood flow and velocity, with higher pulsatility index, phase and cerebrovascular resistance in MCI compared to controls. The majority of studies found reduced CO2 reactivity in MCI, with mixed findings in neuroactivation studies.

CONCLUSION: Despite small sample sizes and heterogeneity, meta-analyses demonstrate clear abnormalities in cerebral hemodynamic and oxygenation parameters, even at an early stage of cognitive decline. Further work is required to investigate the use of cerebral hemodynamic and oxygenation parameters as a sensitive biomarker for dementia.

%B J Alzheimers Dis %V 59 %P 369-385 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671118?dopt=Abstract %R 10.3233/JAD-170181 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebral Oxidative Stress and Microvasculature Defects in TNF-α Expressing Transgenic and Porphyromonas gingivalis-Infected ApoE-/- Mice. %A Rokad, Farheen %A Moseley, Ryan %A Hardy, Rowan S %A Chukkapalli, Sasanka %A Crean, StJohn %A Kesavalu, Lakshmyya %A Singhrao, Sim K %X

The polymicrobial dysbiotic subgingival biofilm microbes associated with periodontal disease appear to contribute to developing pathologies in distal body sites, including the brain. This study examined oxidative stress, in the form of increased protein carbonylation and oxidative protein damage, in the tumor necrosis factor-α (TNF-α) transgenic mouse that models inflammatory TNF-α excess during bacterial infection; and in the apolipoprotein knockout (ApoE-/-) mouse brains, following Porphyromonas gingivalis gingival monoinfection. Following 2,4-dinitrophenylhydrazine derivatization, carbonyl groups were detected in frontal lobe brain tissue lysates by immunoblotting and immunohistochemical analysis of fixed tissue sections from the frontotemporal lobe and the hippocampus. Immunoblot analysis confirmed the presence of variable carbonyl content and oxidative protein damage in all lysates, with TNF-α transgenic blots exhibiting increased protein carbonyl content, with consistently prominent bands at 25 kDa (p = 0.0001), 43 kDa, and 68 kDa, over wild-type mice. Compared to sham-infected ApoE-/- mouse blots, P. gingivalis-infected brain tissue blots demonstrated the greatest detectable protein carbonyl content overall, with numerous prominent bands at 25 kDa (p = 0.001) and 43 kDa (p = 0.0001) and an exclusive band to this group between 30-43 kDa* (p = 0.0001). In addition, marked immunostaining was detected exclusively in the microvasculature in P. gingivalis-infected hippocampal tissue sections, compared to sham-infected, wild-type, and TNF-α transgenic mice. This study revealed that the hippocampal microvascular structure of P. gingivalis-infected ApoE-/- mice possesses elevated oxidative stress levels, resulting in the associated tight junction proteins being susceptible to increased oxidative/proteolytic degradation, leading to a loss of functional integrity.

%B J Alzheimers Dis %V 60 %P 359-369 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28800332?dopt=Abstract %R 10.3233/JAD-170304 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Amyloid-β 42, Total Tau and Phosphorylated Tau are Low in Patients with Normal Pressure Hydrocephalus: Analogies and Differences with Alzheimer's Disease. %A Santangelo, Roberto %A Cecchetti, Giordano %A Bernasconi, Maria Paola %A Cardamone, Rosalinda %A Barbieri, Alessandra %A Pinto, Patrizia %A Passerini, Gabriella %A Scomazzoni, Francesco %A Comi, Giancarlo %A Magnani, Giuseppe %X

Co-existence of Alzheimer's disease (AD) in normal pressure hydrocephalus (NPH) is a frequent finding, thus a common pathophysiological basis between AD and NPH has been postulated. We measured CSF amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) concentrations in a sample of 294 patients with different types of dementia and 32 subjects without dementia. We then compared scores on neuropsychological tests of NPH patients with pathological and normal CSF Aβ42 values. Aβ42 levels were significantly lower in NPH than in control patients, with no significant differences between AD and NPH. On the contrary, t-tau and p-tau levels were significantly lower in NPH than in AD, with no differences between NPH and controls. NPH patients with pathological Aβ42 levels did not perform worse than NPH patients with normal Aβ42 levels in any cognitive domains. Our data seem to support the hypothesis of amyloid accumulation in brains of NPH patients. Nevertheless, amyloid does not seem to play a pathogenetic role in the development of cognitive deficits in NPH.

%B J Alzheimers Dis %V 60 %P 183-200 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826180?dopt=Abstract %R 10.3233/JAD-170186 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Cerebrospinal Fluid Aβ1-42/Aβ1-40 Ratio Improves Concordance with Amyloid-PET for Diagnosing Alzheimer's Disease in a Clinical Setting. %A Niemantsverdriet, Ellis %A Ottoy, Julie %A Somers, Charisse %A De Roeck, Ellen %A Struyfs, Hanne %A Soetewey, Femke %A Verhaeghe, Jeroen %A Van den Bossche, Tobi %A Van Mossevelde, Sara %A Goeman, Johan %A De Deyn, Peter Paul %A Mariën, Peter %A Versijpt, Jan %A Sleegers, Kristel %A Van Broeckhoven, Christine %A Wyffels, Leonie %A Albert, Adrien %A Ceyssens, Sarah %A Stroobants, Sigrid %A Staelens, Steven %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

BACKGROUND: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-β (Aβ) increases when the CSF Aβ1-42/Aβ1-40 ratio is used as compared to CSF Aβ1-42 levels alone.

OBJECTIVE: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting.

METHODS: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [18F]Florbetapir ([18F]AV45) PET scan, [18F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (Aβ1-42, Aβ1-40, T-tau, P-tau181).

RESULTS: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Aβ1-42/Aβ1-40 was applied compared to Aβ1-42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matterConclusions:The concordance between CSF Aβ and [18F]AV45 PET increases when the CSF Aβ1-42/Aβ1-40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

%B J Alzheimers Dis %V 60 %P 561-576 %8 2017 %G eng %N 2 %R 10.3233/JAD-170327 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Aβ42/40 Corresponds Better than Aβ42 to Amyloid PET in Alzheimer's Disease. %A Lewczuk, Piotr %A Matzen, Anja %A Blennow, Kaj %A Parnetti, Lucilla %A Molinuevo, José Luis %A Eusebi, Paolo %A Kornhuber, Johannes %A Morris, John C %A Fagan, Anne M %X

BACKGROUND: Decreased concentrations of amyloid-β 1-42 (Aβ42) in cerebrospinal fluid (CSF) and increased retention of Aβ tracers in the brain on positron emission tomography (PET) are considered the earliest biomarkers of Alzheimer's disease (AD). However, a proportion of cases show discrepancies between the results of the two biomarker modalities which may reflect inter-individual differences in Aβ metabolism. The CSF Aβ42/40 ratio seems to be a more accurate biomarker of clinical AD than CSF Aβ42 alone.

OBJECTIVE: We tested whether CSF Aβ42 alone or the Aβ42/40 ratio corresponds better with amyloid PET status and analyzed the distribution of cases with discordant CSF-PET results.

METHODS: CSF obtained from a mixed cohort (n = 200) of cognitively normal and abnormal research participants who had undergone amyloid PET within 12 months (n = 150 PET-negative, n = 50 PET-positive according to a previously published cut-off) was assayed for Aβ42 and Aβ40 using two recently developed immunoassays. Optimal CSF cut-offs for amyloid positivity were calculated, and concordance was tested by comparison of the areas under receiver operating characteristic (ROC) curves (AUC) and McNemar's test for paired proportions.

RESULTS: CSF Aβ42/40 corresponded better than Aβ42 with PET results, with a larger proportion of concordant cases (89.4% versus 74.9%, respectively, p < 0.0001) and a larger AUC (0.936 versus 0.814, respectively, p < 0.0001) associated with the ratio. For both CSF biomarkers, the percentage of CSF-abnormal/PET-normal cases was larger than that of CSF-normal/PET-abnormal cases.

CONCLUSION: The CSF Aβ42/40 ratio is superior to Aβ42 alone as a marker of amyloid-positivity by PET. We hypothesize that this increase in performance reflects the ratio compensating for general between-individual variations in CSF total Aβ.

%B J Alzheimers Dis %V 55 %P 813-822 %G ENG %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27792012?dopt=Abstract %R 10.3233/JAD-160722 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Aβ42/Aβ40 as a Means to Limiting Tube- and Storage-Dependent Pre-Analytical Variability in Clinical Setting. %A Gervaise-Henry, Christelle %A Watfa, Gasshan %A Albuisson, Eliane %A Kolodziej, Allan %A Dousset, Brigitte %A Olivier, Jean-Luc %A Jonveaux, Thérèse Rivasseau %A Malaplate-Armand, Catherine %X

BACKGROUND: Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers have recently been included in the criteria for AD diagnosis. Unfortunately, their wider use in routine and interpretation require more standardization, particularly for the pre-analytical steps. In particular, amyloid-β (Aβ)42 peptide measurement is strongly influenced by the type of collection tube and by repeated freeze/thaw cycles.

OBJECTIVE: The objectives of this study were to compare, in clinical setting, the impact of collection tubes and the repetition of freeze/thaw cycles on Aβ42 and Aβ40 concentrations and consequently determine if the Aβ42/Aβ40 ratio could resolve the diagnosis difficulties related to these pre-analytical parameters.

METHODS: CSF from 35 patients was collected in different polypropylene (PP) and stored at - 80°C after sampling. For CSF collected in the reference tube, three successive freeze-thaw cycles were done. Aβ42 and Aβ40 concentrations were determined in each condition in order to calculate the Aβ42/Aβ40 ratio.

RESULTS: Our results showed that CSF Aβ42 and Aβ40 values were significantly different according to the type of collection tube and the number of freeze/thaw cycles. Although the calculation of the Aβ42/Aβ40 ratio eliminated the effect of PP tube-dependent variation, this was not the case for freeze-thaw cycle-associated variation.

CONCLUSION: The use of Aβ42/Aβ40 ratio rather than Aβ42 alone could contribute toward pre-analytical standardization, thus allowing the general use of CSF AD biomarkers in routine practice.

%B J Alzheimers Dis %V 57 %P 437-445 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269771?dopt=Abstract %R 10.3233/JAD-160865 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Biomarkers and Clinical Progression in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment. %A Wolfsgruber, Steffen %A Polcher, Alexandra %A Koppara, Alexander %A Kleineidam, Luca %A Frölich, Lutz %A Peters, Oliver %A Hüll, Michael %A Rüther, Eckart %A Wiltfang, Jens %A Maier, Wolfgang %A Kornhuber, Johannes %A Lewczuk, Piotr %A Jessen, Frank %A Wagner, Michael %X

BACKGROUND: There is very limited data on the prevalence of abnormal cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and their predictive value for clinical progression in memory clinic patients with subjective cognitive decline (SCD).

OBJECTIVE: To assess the frequency of abnormal CSF biomarkers of AD and their predictive value for clinical progression in memory clinic patients with SCD in comparison to patients with mild cognitive impairment (MCI) from the same cohort.

METHODS: We analyzed prospective data from memory clinic patients of the German Competence Network Dementia cohort with a baseline diagnosis of SCD (n = 82) or MCI (n = 134), distinguished by actuarial neuropsychological MCI criteria ("Jak-Bondi criteria"). Risk of clinical progression during 3-year follow-up was evaluated with Cox-Proportional-Hazard models.

RESULTS: Prevalence of abnormal values in CSF markers of tau-mediated neurodegeneration (67.8% versus 46.3%) but not of amyloid deposition (40.3% versus 35.4%) was significantly higher in MCI compared to SCD. The rate of incident AD dementia (26.1% versus 12.2%) was also significantly higher in MCI. In SCD, additional 22% progressed to MCI during follow-up. Combined amyloid/tau abnormality was the strongest predictor of clinical progression in both groups.

CONCLUSION: High prevalence of biomarker abnormality and clinical progression, together with the predictive value of CSF biomarkers, in memory clinic patients with SCD support the validity and usefulness of this condition as a "pre-MCI" at risk stage of AD.

%B J Alzheimers Dis %V 58 %P 939-950 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527210?dopt=Abstract %R 10.3233/JAD-161252 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Biomarkers as a Diagnostic Tool of the Underlying Pathology of Primary Progressive Aphasia. %A Paraskevas, George P %A Kasselimis, Dimitrios %A Kourtidou, Evie %A Constantinides, Vasilios %A Bougea, Anastasia %A Potagas, Costas %A Evdokimidis, Ioannis %A Kapaki, Elisabeth %X

BACKGROUND: Primary progressive aphasia (PPA) may present with three main clinical variants, namely nonfluent agrammatic (nfaPPA), semantic (sPPA), and logopenic (lPPA) subtypes. Frontotemporal lobar degenerations (FTLD) or Alzheimer's disease (AD) are the most common etiologies.

OBJECTIVE: To study the potential of cerebrospinal fluid (CSF) biomarkers for identifying the underlying pathology in patients with PPA.

METHODS: CSF levels of total tau protein (τT), amyloid-β peptide (Aβ42), and tau phosphorylated at threonine-181 (τP - 181) were measured by double sandwich, enzyme-linked immunosorbent assay (ELISA) in 43 patients with PPA, 26 patients with AD, and 17 healthy controls.

RESULTS: All patients could be classified as compatible with the AD or non-AD biomarker profile, either with the three biomarkers (90.7%) or their ratios, especially the τP - 181/Aβ42 ratio (9.3%). An AD-compatible biomarker profile was present in 39.5% of all PPA patients, specifically 22.2%, 35.7%, and 75% of nfaPPA, sPPA, and lPPA, respectively. In PPA patients with a non-AD profile (presumably FTLD), two different clusters could be identified according to the τP - 181/τT ratio, possibly corresponding to the two major FTLD pathologies (tau and TDP-43).

CONCLUSION: CSF biomarkers may be a valuable tool for the discrimination between PPA patients with AD and non-AD pathophysiology and possibly between FTLD patients with tau and TDP-43 pathology.

%B J Alzheimers Dis %V 55 %P 1453-1461 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858708?dopt=Abstract %R 10.3233/JAD-160494 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Biomarkers for Alzheimer's Disease: A View of the Regulatory Science Qualification Landscape from the Coalition Against Major Diseases CSF Biomarker Team. %A Arnerić, Stephen P %A Batrla-Utermann, Richard %A Beckett, Laurel %A Bittner, Tobias %A Blennow, Kaj %A Carter, Leslie %A Dean, Robert %A Engelborghs, Sebastiaan %A Genius, Just %A Gordon, Mark Forrest %A Hitchcock, Janice %A Kaplow, June %A Luthman, Johan %A Meibach, Richard %A Raunig, David %A Romero, Klaus %A Samtani, Mahesh N %A Savage, Mary %A Shaw, Leslie %A Stephenson, Diane %A Umek, Robert M %A Vanderstichele, Hugo %A Willis, Brian %A Yule, Susan %X

Alzheimer's disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development.

%B J Alzheimers Dis %V 55 %P 19-35 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662307?dopt=Abstract %R 10.3233/JAD-160573 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Biomarkers for the Differential Diagnosis between Alzheimer's Disease and Frontotemporal Lobar Degeneration: Systematic Review, HSROC Analysis, and Confounding Factors. %A Rivero-Santana, Amado %A Ferreira, Daniel %A Perestelo-Pérez, Lilisbeth %A Westman, Eric %A Wahlund, Lars-Olof %A Sarría, Antonio %A Serrano-Aguilar, Pedro %X

BACKGROUND: Differential diagnosis in dementia is at present one of the main challenges both in clinical practice and research. Cerebrospinal fluid (CSF) biomarkers are included in the current diagnostic criteria of Alzheimer's disease (AD) but their clinical utility is still unclear.

OBJECTIVE: We performed a systematic review of studies analyzing the diagnostic performance of CSF Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in the discrimination between AD and frontotemporal lobar degeneration (FTLD) dementias.

METHODS: The following electronic databases were consulted until May 2016: Medline and PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane Library, and CRD. For the first-time in the field, a Hierarchical Summary Receiver Operating Characteristic (HRSOC) model was applied, which avoids methodological problems of meta-analyses based on summary points of sensitivity and specificity values. We also investigated relevant confounders of CSF biomarkers' diagnostic performance such as age, disease duration, and global cognitive impairment.

RESULTS: The p-tau/Aβ42 ratio showed the best diagnostic performance. No statistically significant effects of the confounders were observed. Nonetheless, the p-tau/Aβ42 ratio may be especially indicated for younger patients. P-tau may be preferable for less cognitively impaired patients (high MMSE scores) and the t-tau/Aβ42 ratio for more cognitively impaired patients (low MMSE scores).

CONCLUSION: The p-tau/Aβ42 ratio has potential for being implemented in the clinical routine for the differential diagnosis between AD and FTLD. It is of utmost importance that future studies report information on confounders such as age, disease duration, and cognitive impairment, which should also stimulate understanding of the role of these factors in disease mechanisms and pathophysiology.

%B J Alzheimers Dis %V 55 %P 625-644 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716663?dopt=Abstract %R 10.3233/JAD-160366 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Neurogranin as a Biomarker of Neurodegenerative Diseases: A Cross-Sectional Study. %A Lista, Simone %A Toschi, Nicola %A Baldacci, Filippo %A Zetterberg, Henrik %A Blennow, Kaj %A Kilimann, Ingo %A Teipel, Stefan J %A Cavedo, Enrica %A Dos Santos, Antonio Melo %A Epelbaum, Stéphane %A Lamari, Foudil %A Dubois, Bruno %A Nisticò, Robert %A Floris, Roberto %A Garaci, Francesco %A Hampel, Harald %X

We investigated cerebrospinal fluid (CSF) concentrations of the postsynaptic biomarker neurogranin at baseline in cognitively healthy controls (HC) compared to individuals with mild cognitive impairment (MCI), patients with Alzheimer's disease (AD) dementia, and patients with frontotemporal dementia (FTD). CSF neurogranin was quantified using an in-house immunoassay in a cross-sectional multicenter study of 108 participants [AD dementia (n = 35), FTD (n = 9), MCI (n = 41), cognitively HC (n = 23)]. CSF neurogranin concentrations were significantly higher in AD patients compared with both HC subjects and FTD patients, suggesting that increased CSF neurogranin concentrations may indicate AD-related pathophysiology. CSF neurogranin was independently associated with both total tau and hyperphosphorylated tau proteins, whereas a non-significant correlation with the 42-amino acid-long amyloid-β peptide was evident. CSF neurogranin, however, was not superior to core AD biomarkers in differentiating HC from the three diagnostic groups, and it did not improve their diagnostic accuracy. We conclude that further classification and longitudinal studies are required to shed more light into the potential role of neurogranin as a pathophysiological biomarker of neurodegenerative diseases.

%B J Alzheimers Dis %V 59 %P 1327-1334 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731449?dopt=Abstract %R 10.3233/JAD-170368 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Challenges and Considerations Related to Studying Dementia in Blacks/African Americans. %A Ighodaro, Eseosa T %A Nelson, Peter T %A Kukull, Walter A %A Schmitt, Frederick A %A Abner, Erin L %A Caban-Holt, Allison %A Bardach, Shoshana H %A Hord, Derrick C %A Glover, Crystal M %A Jicha, Gregory A %A Van Eldik, Linda J %A Byrd, Alexander X %A Fernander, Anita %X

Blacks/African Americans have been reported to be ∼2-4 times more likely to develop clinical Alzheimer's disease (AD) compared to Whites. Unfortunately, study design challenges (e.g., recruitment bias), racism, mistrust of healthcare providers and biomedical researchers, confounders related to socioeconomic status, and other sources of bias are often ignored when interpreting differences in human subjects categorized by race. Failure to account for these factors can lead to misinterpretation of results, reification of race as biology, discrimination, and missed or delayed diagnoses. Here we provide a selected historical background, discuss challenges, present opportunities, and suggest considerations for studying health outcomes among racial/ethnic groups. We encourage neuroscientists to consider shifting away from using biologic determination to interpret data, and work instead toward a paradigm of incorporating both biological and socio-environmental factors known to affect health outcomes with the goal of understanding and improving dementia treatments for Blacks/African Americans and other underserved populations.

%B J Alzheimers Dis %V 60 %P 1-10 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731440?dopt=Abstract %R 10.3233/JAD-170242 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Challenges in Screening and Recruitment for a Neuroimaging Study in Cognitively Impaired Geriatric Inpatients. %A Apostolova, Ivayla %A Lange, Catharina %A Roberts, Anna %A Igel, Hans Joachim %A Mäurer, Anja %A Liese, Stephanie %A Estrella, Melanie %A Prasad, Vikas %A Stechl, Elisabeth %A Lämmler, Gernot %A Steinhagen-Thiessen, Elisabeth %A Buchert, Ralph %X

BACKGROUND: Neuroimaging-based biomarkers have the potential to improve etiological diagnosis of cognitive impairment in elderly inpatients. However, there is a relative lack of studies on neuroimaging-based biomarkers in hospitalized geriatric patients, as the vast majority of neuroimaging studies in dementia have focused on memory clinic outpatients. An important aspect of study planning is a priori estimation of the rate of screen failures.

OBJECTIVE: To report on the rate and causes of screen failures in a prospective study on the utility of neuroimaging (PET, MRI) for the etiological diagnosis of newly manifested cognitive impairment in acutely hospitalized geriatric patients.

METHODS: Ten acute care geriatrics clinics with 802 beds participated in the study. The potential recruitment rate had been estimated to 5 patients/100 beds/week.

RESULTS: Seventeen months of pre-screening resulted in 322 potential participants. 109 of these patients were enrolled, i.e., the screen failure rate was 66%. 58% of the screen failures were due to refusal of participation by the patient, most often due to lack of interest in clarifying the cause of the cognitive impairment or due to reluctance to engage in additional diagnostic procedures associated with physical stress. 42% of pre-screened patients were excluded because of violation of the eligibility criteria.

CONCLUSION: Enrollment for neuroimaging studies presents considerable additional challenges in acutely hospitalized geriatric patients compared to outpatient settings. Low rate of approaching potential candidates by attending geriatricians and a high rate of screen failures have to be anticipated in the study design.

%B J Alzheimers Dis %V 56 %P 197-204 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911313?dopt=Abstract %R 10.3233/JAD-160797 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Change in Odor Identification Impairment is Associated with Improvement with Cholinesterase Inhibitor Treatment in Mild Cognitive Impairment. %A Devanand, D P %A Lentz, Cody %A Chunga, Richard E %A Ciarleglio, Adam %A Scodes, Jennifer M %A Andrews, Howard %A Schofield, Peter W %A Stern, Yaakov %A Huey, Edward D %A Bell, Karen %A Pelton, Gregory H %X

BACKGROUND: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease pathology.

OBJECTIVE: To determine if decline in odor identification ability with anticholinergic challenge can predict improvement with donepezil, a cholinesterase inhibitor (ChEI), in patients with mild cognitive impairment (MCI).

METHODS: At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and then the dose was kept constant for 52 weeks. Main outcomes were change in Selective Reminding Test (SRT) total immediate recall and ADAS-Cog total score from baseline to 26 and 52 weeks.

RESULTS: In 37 participants, mean age 70.4 (SD 9.8) y, greater atropine-induced decrease in UPSIT score at baseline was associated with greater improvement in SRT total recall score from baseline to 26 and 52 weeks (p < 0.03). This effect remained after adjusting for time, age, education, gender, APOE ɛ4 status, and baseline cognitive score (p < 0.05). Decrease in UPSIT score was associated with global improvement (CIBIC-plus) over 52 weeks (p < 0.02). After excluding patients with congential anosmia, increase in UPSIT score from 0 to 8 weeks showed a trend-level association with improvement on the ADAS-Cog (p = 0.07).

CONCLUSIONS: Anticholinergic challenge-induced odor identification decline was associated with cognitive improvement, and short-term improvement in odor identification tended to predict longer term cognitive improvement. These simple inexpensive strategies have the potential to improve selection of patients with MCI for ChEI treatment.

%B J Alzheimers Dis %V 60 %P 1525-1531 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29081417?dopt=Abstract %R 10.3233/JAD-170497 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Changes in Plasma β-NGF and Its Receptors Expression on Peripheral Blood Monocytes During Alzheimer's Disease Progression. %A Crispoltoni, Lucia %A Stabile, Anna Maria %A Pistilli, Alessandra %A Venturelli, Massimo %A Cerulli, Giuliano %A Fonte, Cristina %A Smania, Nicola %A Schena, Federico %A Rende, Mario %X

Alzheimer's disease (AD), the most common cause of dementia, is characterized by the deposition of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles, and by neuroinflammation. During the pathogenesis of AD, monocyte-macrophage lineage cells become increasingly ineffective in clearing Aβ deposits, less able to differentiate, and shift toward pro-inflammatory processes. Beta-nerve growth factor (β-NGF) and its receptors, TrKA and p75NTR, produce several biological responses, including cell apoptosis and survival, and inflammation. In the central nervous system, the involvement of these receptors in several critical hallmarks of AD is well known, but their role in circulating monocytes during the progression of dementia is unclear. We investigated the relationship between plasma β-NGF concentration and TrkA/p75NTR receptor expression in monocytes of patients with mild cognitive impairment (MCI), mild AD, and severe AD. We observed that plasma β-NGF concentration was increased with a higher expression of TrKA, but not of p75NTR, in monocytes from patients with MCI and mild AD, whereas β-NGF concentration and TrKA expression were decreased and p75NTR expression was increased, associated with caspase 3-mediated apoptosis, in patients with severe AD. In our study, we show evidence of variation in plasmatic β-NGF and monocytic TrkA/p75NTR receptor expression during the progression of dementia. These novel findings add evidence to support the hypothesis for the involvement of β-NGF and its receptors on monocytes during AD progression.

%B J Alzheimers Dis %V 55 %P 1005-1017 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802234?dopt=Abstract %R 10.3233/JAD-160625 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Changes in Synaptic Plasticity and Glutamate Receptors in Type 2 Diabetic KK-Ay Mice. %A Yin, Huajing %A Wang, Weiping %A Yu, Wenwen %A Li, Jiang %A Feng, Nan %A Wang, Ling %A Wang, Xiaoliang %X

In the present study, the progressive alteration of cognition and the mechanisms of reduction in long-term potentiation (LTP) in spontaneous obese KK-Ay type 2 diabetic mice were investigated. In the study, 3-, 5-, and 7-month-old KK-Ay mice were used. The results indicated that KK-Ay mice showed cognitive deficits in the Morris water maze test beginning at the age of 3 months. LTP was significantly impaired in KK-Ay mice during whole study period (3 to 7 months). The above deficits were reversible at an early stage (3 to 5 months old) by diet intervention. Moreover, we found the underlying mechanisms of LTP impairment in KK-Ay mice might be attributed to abnormal phosphorylation or expression of postsynaptic glutamate receptor subunits instead of alteration of basal synaptic transmission. The expression levels of NR1, NR2A, and NR2B subunits of N-methyl-d-aspartate receptors (NMDARs) were unchanged while the Tyr-dependent phosphorylation of both NR2A and NR2B subunits were significantly reduced in KK-Ay mice. The level of p-Src expression mediating this process was decreased, and the level of αCaMKII autophosphorylation was also reduced. Meanwhile, the GluR1 of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) was decreased, and GluR2 was significantly increased. These data suggest that deficits in synaptic plasticity in KK-Ay mice may arise from the abnormal phosphorylation of the NR2 subunits and the alteration of subunit composition of AMPARs. Diet intervention at an early stage of diabetes might alleviate the cognitive deficits and LTP reduction in KK-Ay mice.

%B J Alzheimers Dis %V 57 %P 1207-1220 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304288?dopt=Abstract %R 10.3233/JAD-160858 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Changes of Cerebrospinal Fluid Peptides due to Tauopathy. %A Majerova, Petra %A Barath, Peter %A Michalicova, Alena %A Katina, Stanislav %A Novak, Michal %A Kovac, Andrej %X

Alzheimer's disease (AD) and progressive supranuclear palsy are two common neurodegenerative tauopathies, and the most common cause of progressive brain dementia in elderly affecting more than 35 million people. The tauopathies are characterized by abnormal deposition of microtubule associated protein tau into intracellular neurofibrillary tangles composed mainly of the hyperphosphorylated form of the protein. The diagnosis of tauopathies is based on the presence of clinical features and pathological changes. Over the last decade, there has been an intensive search for novel biochemical markers for clinical diagnosis of AD and other tauopathies. In the present study, we used transgenic rat model for tauopathy expressing human truncated tau protein (aa 151-391/4R) to analyze the cerebrospinal fluid (CSF) peptidome using liquid chromatography - matrix assisted laser desorption/ionization mass spectrometry (LC-MALDI TOF/TOF). From 345 peptides, we identified a total of 175 proteins. Among them, 17 proteins were significantly altered in the CSF of transgenic rats. The following proteins were elevated in the CSF of transgenic rats when compared to the control animals: neurofilament light and medium chain, apolipoprotein E, gamma-synuclein, chromogranin A, reticulon-4, secretogranin-2, calsyntein-1 and -3, endothelin-3, neuroendocrine protein B72A, alpha-1-macroglobulin, and augurin. Interestingly most of the identified proteins were previously linked to AD and other tauopathies, indicating the significance of transgenic animals in biomarker validation.

%B J Alzheimers Dis %V 58 %P 507-520 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453489?dopt=Abstract %R 10.3233/JAD-170110 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Chinese Calligraphy Writing for Augmenting Attentional Control and Working Memory of Older Adults at Risk of Mild Cognitive Impairment: A Randomized Controlled Trial. %A Chan, Sam C C %A Chan, Chetwyn C H %A Derbie, Abiot Y %A Hui, Irene %A Tan, Davynn G H %A Pang, Marco Y C %A Lau, Stephen C L %A Fong, Kenneth N K %X

BACKGROUND: Nonpharmacological intervention for individuals with mild cognitive impairment (MCI) needs further investigation.

OBJECTIVE: Test efficacy of an eight-week Chinese calligraphy writing training course in improving attentional control and working memory.

METHODS: Ninety-nine participants with MCI were randomized into the eight-week calligraphy writing (n = 48) or control (tablet computer) training (n = 51). Outcomes of the interventions were attentional control, working memory, visual scan and processing speed. They were measured at baseline, post-training, and six-month follow-up.

RESULTS: Calligraphy writing, when compared with control, significantly improved working memory as reflected from DST-Backward sequence (p = 0.009) and span scores (p = 0.002), and divided attention as reflected from CTT2 (p < 0.001), and at the post-training. The unique improvement in working memory (span: p < 0.001; sequence: p = 0.008) of the intervention group was also found at follow-up when comparing with those at baseline. Changes in the other outcome measures were not statistically significant.

CONCLUSION: The findings provide support that Chinese calligraphy writing training for eight weeks using a cognitive approach would improve working memory and to a lesser extent attentional control functions of patients with early MCI. They also demonstrate the usefulness of using mind-and-body practice for improving specific cognitive functions.

%B J Alzheimers Dis %V 58 %P 735-746 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28482639?dopt=Abstract %R 10.3233/JAD-170024 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cholinergic Basal Forebrain Lesion Decreases Neurotrophin Signaling without Affecting Tau Hyperphosphorylation in Genetically Susceptible Mice. %A Turnbull, Marion T %A Coulson, Elizabeth J %X

Alzheimer's disease (AD) is a progressive, irreversible neurodegenerative disease that destroys memory and cognitive function. Aggregates of hyperphosphorylated tau protein are a prominent feature in the brain of patients with AD, and are a major contributor to neuronal toxicity and disease progression. However, the factors that initiate the toxic cascade that results in tau hyperphosphorylation in sporadic AD are unknown. Here we investigated whether degeneration of basal forebrain cholinergic neurons (BFCNs) and/or a resultant decrease in neurotrophin signaling cause aberrant tau hyperphosphorylation. Our results reveal that the loss of BFCNs in pre-symptomatic pR5 (P301L) tau transgenic mice results in a decrease in hippocampal brain-derived neurotrophic factor levels and reduced TrkB receptor activation. However, there was no exacerbation of the levels of phosphorylated tau or its aggregation in the hippocampus of susceptible mice. Furthermore the animals' performance in a hippocampal-dependent learning and memory task was unaltered, and no changes in hippocampal synaptic markers were observed. This suggests that tau pathology is likely to be regulated independently of BFCN degeneration and the corresponding decrease in hippocampal neurotrophin levels, although these features may still contribute to disease etiology.

%B J Alzheimers Dis %V 55 %P 1141-1154 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767994?dopt=Abstract %R 10.3233/JAD-160805 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cholinergic Modification of Neurogenesis and Gliosis Improves the Memory of AβPPswe/PSEN1dE9 Alzheimer's Disease Model Mice Fed a High-Fat Diet. %A Matsuda, Takeshi %A Hisatsune, Tatsuhiro %X

We previously reported that neuroinflammation contributes to the amnesia of AβPPswe/PSEN1dE9 Alzheimer's disease model mice fed a high-fat diet to induce type-2 diabetes (T2DM-AD mice), but the underlying mechanism for the memory decline remained unclear. Recent studies have suggested that cholinergic modulation is involved in neuroinflammatory cellular reactions including neurogenesis and gliosis, and in memory improvement. In this study, we administered a broad-spectrum cholinesterase inhibitor, rivastigmine (2 mg/kg/day, s.c.), into T2DM-AD mice for 6 weeks, and evaluated their memory performance, neurogenesis, and neuroinflammatory reactions. By two hippocampal-dependent memory tests, the Morris water maze and contextual fear conditioning, rivastigmine improved the memory deterioration of the T2DM-AD mice (n = 8, p < 0.01). The number of newborn neurons in the hippocampal dentate gyrus was 1138±324 (Ave±SEM) in wild-type littermates, 2573±442 in T2DM-AD-Vehicle, and 2165±300 in T2DM-AD-Rivastigmine mice, indicating that neurogenesis was accelerated in the two T2DM-AD groups (n = 5, p < 0.05). The dendritic maturation of new neurons in T2DM-AD-Vehicle mice was severely abrogated, and rivastigmine treatment reversed this retarded maturation. In addition, the hippocampus of T2DM-AD-Vehicle mice showed increased proinflammatory cytokines IL-1β and TNF-α and gliosis, and rivastigmine treatment blocked these inflammatory reactions. Rivastigmine did not change the insulin abnormality or amyloid pathology in these mice. Thus, cholinergic modulation by rivastigmine treatment led to enhanced neurogenesis and the suppression of gliosis, which together ameliorated the memory decline in T2DM-AD model mice.

%B J Alzheimers Dis %V 56 %P 1-23 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911310?dopt=Abstract %R 10.3233/JAD-160761 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cholinesterase Inhibitor Therapy in Alzheimer's Disease: The Limits and Tolerability of Irreversible CNS-Selective Acetylcholinesterase Inhibition in Primates. %A Moss, Donald E %A Perez, Ruth G %A Kobayashi, Haruo %K Acetylcholinesterase %K Alzheimer Disease %K Animals %K Brain %K Cholinesterase Inhibitors %K Dose-Response Relationship, Drug %K Drug Evaluation, Preclinical %K Erythrocytes %K Injections, Intramuscular %K Macaca fascicularis %K Male %K Nootropic Agents %K Time Factors %X

Irreversible acetylcholinesterase (AChE) inhibition accumulates to high levels in the central nervous system (CNS) because AChE turnover in the brain is much slower than in peripheral tissues. As expected from this CNS selectivity, the irreversible AChE inhibitor methanesulfonyl fluoride (MSF) produces significant cognitive improvement in Alzheimer's disease patients without the gastrointestinal toxicity that plagues other AChE inhibitors. However, without dose-limiting gastrointestinal toxicity, one shortcoming of the prior human studies of MSF is that the upper limits of CNS AChE inhibition that might be tolerated could not be tested. Therefore, in this study, monkeys were treated with escalating intramuscular (IM) doses of MSF that culminated with several weeks of 1.5 mg/kg dosing, more than eight times the prior human clinical dose, still without signs of toxicity. Brain biopsies showed that ∼80% AChE inhibition had been produced and that the new synthesis of cortical AChE had a half-time (t1/2) of ∼12 days. A single IM dose of 1.5 mg/kg MSF produced ∼59% inhibition in cerebrospinal fluid (CSF) AChE as measured one day later. This corresponds to a peak of ∼80% inhibition in CSF AChE at the time of the injection, recovering with a t1/2 of 2.4 days. Computational analyses suggest that MSF at clinically relevant doses could theoretically produce a steady-state AChE inhibition between 65% and 85% in the CNS. These data suggest that the full therapeutic advantage of AChE inhibition therapy can be realized without interference from dose-limiting gastrointestinal toxicity if an irreversible inhibitor is employed.

%B J Alzheimers Dis %V 55 %P 1285-1294 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858711?dopt=Abstract %R 10.3233/JAD-160733 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson's Disease. %A Vasquez, Velmarini %A Mitra, Joy %A Hegde, Pavana M %A Pandey, Arvind %A Sengupta, Shiladitya %A Mitra, Sankar %A Rao, K S %A Hegde, Muralidhar L %X

Alpha-synuclein (α-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson's disease (PD). The neurotoxicity of α-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although α-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear α-Syn is unclear. Following up on our earlier report that α-Syn directly binds DNA in vitro, here we confirm the nuclear localization and chromatin association of α-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis. Moderate (∼2-fold) increase in α-Syn expression in neural lineage progenitor cells (NPC) derived from induced pluripotent human stem cells (iPSCs) or differentiated SHSY-5Y cells caused DNA strand breaks in the nuclear genome, which was further enhanced synergistically by Fe salts. Furthermore, α-Syn required nuclear localization for inducing genome damage as revealed by the effect of nucleus versus cytosol-specific mutants. Enhanced DNA damage by oxidized and misfolded/oligomeric α-Syn suggests that DNA nicking activity is mediated by the chemical nuclease activity of an oxidized peptide segment in the misfolded α-Syn. Consistent with this finding, a marked increase in Fe-dependent DNA breaks was observed in NPCs from a PD patient-derived iPSC line harboring triplication of the SNCA gene. Finally, α-Syn combined with Fe significantly promoted neuronal cell death. Together, these findings provide a novel molecular insight into the direct role of α-Syn in inducing neuronal genome damage, which could possibly contribute to neurodegeneration in PD.

%B J Alzheimers Dis %8 2017 Jul 17 %G eng %R 10.3233/JAD-170342 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Chronic Lithium Treatment in a Rat Model of Basal Forebrain Cholinergic Depletion: Effects on Memory Impairment and Neurodegeneration. %A Gelfo, Francesca %A Cutuli, Debora %A Nobili, Annalisa %A De Bartolo, Paola %A D'Amelio, Marcello %A Petrosini, Laura %A Caltagirone, Carlo %X

Alzheimer's disease (AD) is an age-related neurodegenerative disorder with multifactorial etiopathogenesis, characterized by progressive loss of memory and other cognitive functions. A fundamental neuropathological feature of AD is the early and severe brain cholinergic neurodegeneration. Lithium is a monovalent cation classically utilized in the treatment of mood disorders, but recent evidence also advances a beneficial potentiality of this compound in neurodegeneration. Interestingly, lithium acts on several processes whose alterations characterize the brain cholinergic impairment at short and long term. On this basis, the aim of the present research was to evaluate the potential beneficial effects of a chronic lithium treatment in preventing the damage that a basal forebrain cholinergic neurodegeneration provokes, by investigating memory functions and neurodegeneration correlates. Adult male rats were lesioned by bilateral injections of the immunotoxin 192 IgG-Saporin into the basal forebrain. Starting 7 days before the surgery, the animals were exposed to a 30-day lithium treatment, consisting of a 0.24% Li2CO3 diet. Memory functions were investigated by the open field test with objects, the sociability and preference for social novelty test, and the Morris water maze. Hippocampal and neocortical choline acetyltransferase (ChAT) levels and caspase-3 activity were determined. Cholinergic depletion significantly impaired spatial and social recognition memory, decreased hippocampal and neocortical ChAT levels and increased caspase-3 activity. The chronic lithium treatment significantly rescued memory performances but did not modulate ChAT availability and caspase-3 activity. The present findings support the lithium protective effects against the cognitive impairment that characterizes the brain cholinergic depletion.

%B J Alzheimers Dis %V 56 %P 1505-1518 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222508?dopt=Abstract %R 10.3233/JAD-160892 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Chronic Neurodegenerative Illnesses and Epilepsy in Danish Adventists and Baptists: A Nationwide Cohort Study. %A Thygesen, Lau Caspar %A Gimsing, Louise NØrreslet %A Bautz, Andrea %A Hvidt, Niels Christian %A Johansen, Christoffer %X

BACKGROUND: Limited knowledge of the influence of lifestyle risk factors and religious living on chronic neurological diseases exist. Seventh-day Adventists (SDA) do not consume tobacco, alcohol, or pork, and many adhere to lacto-ovo-vegetarian diet, and Baptists discourage excessive use of alcohol and tobacco.

OBJECTIVE: We investigated whether the incidence of four common chronic neurological illnesses: dementia, Alzheimer's disease, Parkinson's disease, and epilepsy in a large cohort of Danish Adventists and Baptists was different compared to the general Danish population. Three of the illnesses are neurodegenerative, whereas epilepsy can occur at any age.

METHODS: We compared hospital admission rates for some major neurological diseases among members of the Danish Religious Societies Health Study comprising 6,532 SDA and 3,720 Baptists with the general Danish population. Standardized incidence rates (SIR) stratified by sex, age, and calendar time were calculated.

RESULTS: SIR of dementia or Alzheimer's disease was significantly decreased for members of both communities (SDA, 0.78; 95% CI, 0.67-#x2013;0.90 and Baptists, 0.59; 0.47-#x2013;0.73). The SIRs of Parkinson's disease and epilepsy were not significantly different compared to the general population.

CONCLUSIONS: We observe reduced incidence for dementia or Alzheimer's disease in a large cohort of members of two religious communities characterized by lifestyle recommendations. More studies are needed to disentangle the interaction between such lifestyle and other components of the religious belief system.

%B J Alzheimers Dis %V 56 %P 1429-1435 %G eng %N 4 %R 10.3233/JAD-160710 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AβPPswe Mice Without Inducing Microhemorrhage. %A Villarreal, Stephanie %A Zhao, Fuqiang %A Hyde, Lynn A %A Holder, Daniel %A Forest, Thomas %A Sondey, Marie %A Chen, Xia %A Sur, Cyrille %A Parker, Eric M %A Kennedy, Matthew E %X

Verubecestat is a potent BACE1 enzyme inhibitor currently being investigated in Phase III trials for the treatment of mild-to-moderate and prodromal Alzheimer's disease. Multiple anti-amyloid immunotherapies have been dose-limited by adverse amyloid related imaging abnormalities such as vasogenic edema (ARIA-E) and microhemorrhage (ARIA-H) observed in human trials and mice. Verubecestat was tested in a 12-week nonclinical study for the potential to exacerbate microhemorrhage (ARIA-H) profiles in 18-22-month-old post-plaque Tg2576-AβPPswe mice. Animals were treated with verubecestat or controls including the anti-Aβ antibody analog of bapineuzumab (3D6) as a positive control for ARIA induction. ARIA-H was measured using in-life longitudinal T2*-MRI and Prussian blue histochemistry at study end. Verubecestat reduced plasma and cerebrospinal fluid Aβ40 and Aβ42 by >90% and 62% to 68%, respectively. The ARIA-H profile of verubecestat-treated mice was not significantly different than controls. Anti-Aβ treatment significantly increased ARIA-H detected by Prussian blue staining; however, anti-Aβ antibody treatment did not impact plaque status. Verubecestat treatment significantly suppressed the accumulation of total levels of brain Aβ40 and Aβ42 and Thioflavin S positive plaque load. Stereological analysis of cortex and hippocampus plaque load similarly revealed significantly reduced area of Aβ immunoreactivity and reduced plaque number in verubecestat-treated animals compared to controls. The absence of elevated ARIA events in verubecestat-treated mice was associated with a significant reduction in the level of accumulated CNS amyloid pathology and brain Aβ peptides; effects consistent with the desired therapeutic mechanism of verubecestat in AD patients. These data will be compared with longitudinal MRI profiles from ongoing clinical trials.

%B J Alzheimers Dis %V 59 %P 1393-1413 %8 2017 %G eng %N 4 %R 10.3233/JAD-170056 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Chronotropic Response and Cognitive Function in a Cohort at Risk for Alzheimer's Disease. %A Law, Lena L %A Schultz, Stephanie A %A Boots, Elizabeth A %A Einerson, Jean A %A Dougherty, Ryan J %A Oh, Jennifer M %A Korcarz, Claudia E %A Edwards, Dorothy F %A Koscik, Rebecca L %A Dowling, N Maritza %A Gallagher, Catherine L %A Bendlin, Barbara B %A Carlsson, Cynthia M %A Asthana, Sanjay %A Hermann, Bruce P %A Sager, Mark A %A Johnson, Sterling C %A Cook, Dane B %A Stein, James H %A Okonkwo, Ozioma C %X

The objective of this study was to examine the association of chronotropic response (CR) and heart rate (HR) recovery- two indices of cardiovascular function within the context of a graded exercise test- with cognitive performance in a cognitively healthy, late-middle-aged cohort at risk for Alzheimer's disease (AD). Ninety participants (age = 63.52±5.86 years; 65.6% female) from the Wisconsin Registry for Alzheimer's Prevention participated in this study. They underwent graded exercise testing and a comprehensive neuropsychological assessment that assessed the following four cognitive domains: Immediate Memory, Verbal & Learning Memory, Working Memory, and Speed & Flexibility. Regression analyses, adjusted for age, sex, and education, were used to examine the association between CR, HR recovery, and cognition. We found significant associations between CR and cognitive performance in the domains of Immediate Memory, Verbal Learning & Memory, and Speed & Flexibility. In contrast, HR recovery was not significantly associated with cognitive function. The association between CR and cognition persisted even after controlling for HR recovery. Together, these findings indicatethat, in a cognitively normal, late-middle-aged cohort, CR is a stronger correlate of cognitive performance than HR recovery. Overall, this study reinforces the idea that cardiovascular health plays an important role in cognitive function, specifically in a cohort at risk for AD; and that interventions that promote vascular health may be a viable pathway to preventing or slowing cognitive decline due to AD.

%B J Alzheimers Dis %V 56 %P 351-359 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911299?dopt=Abstract %R 10.3233/JAD-160642 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Citicholinage Study: Citicoline Plus Cholinesterase Inhibitors in Aged Patients Affected with Alzheimer's Disease Study. %A Gareri, Pietro %A Castagna, Alberto %A Cotroneo, Antonino Maria %A Putignano, Daria %A Conforti, Raffaele %A Santamaria, Francesco %A Marino, Saverio %A Putignano, Salvatore %X

BACKGROUND: Citicoline can have beneficial effects both in degenerative and in vascular cognitive decline in a variety of ways (apoptosis inhibition, neuroplasticity potentiation, phospholipid, and acetylcholine (ACh) synthesis). Acetylcholinesterase inhibitors (AChEIs) have been used for treatment of Alzheimer's disease (AD). When co-administered with cholinergic precursors, they are able to increase the intrasynaptic levels of ACh more than when the single drugs given alone.

OBJECTIVE: The aim of the present study was to show the effectiveness of oral citicoline plus AChEIs in patients affected with AD.

METHODS: This was a retrospective multi-centric case-control study, involving seven Centers for Cognitive Impairment and Dementia in Italy, on 448 consecutive patients aged 65 years old or older affected with AD. 197 patients were treated with an AChEI while 251 were treated with an AchEI + citicoline 1000 mg/day given orally. Cognitive functions were assessed by MMSE, daily life functions by ADL and IADL, behavioral symptoms by NPI, comorbidities by CIRS, and mood by GDS-short form. Tests were administered at baseline (T0), after 3 (T1), and 9 months (T2). The primary outcomes were effects of combined administration versus AChEIs given alone on cognitive functions assessed by MMSE. The secondary outcomes were possible side effects or adverse events of combination therapy versus AChEIs alone.

RESULTS: Patients treated with citicoline plus an AChEI showed a statistically significant increase in MMSE between T0 and T1 (16.88±3.38 versus 17.62±3.64; p = 0.000) and between T1 and T2 (17.62±3.64 versus 17.89±3.54; p = 0.000).

CONCLUSION: The present study encourages the role of combined administration in disease management by slowing disease progression.

%B J Alzheimers Dis %V 56 %P 557-565 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035929?dopt=Abstract %R 10.3233/JAD-160808 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Classification of Alzheimer's Disease and Prediction of Mild Cognitive Impairment Conversion Using Histogram-Based Analysis of Patient-Specific Anatomical Brain Connectivity Networks. %A Beheshti, Iman %A Maikusa, Norihide %A Daneshmand, Morteza %A Matsuda, Hiroshi %A Demirel, Hasan %A Anbarjafari, Gholamreza %X

In this study, we investigated the early detection of Alzheimer's disease (AD) and mild cognitive impairment (MCI) conversion to AD through individual structural connectivity networks using structural magnetic resonance imaging (sMRI) data. In the proposed method, the cortical morphometry of individual gray matter images were used to construct structural connectivity networks. A statistical feature generation approach based on histogram-based feature generation procedure was proposed to represent a statistical-pattern of connectivity networks from a high-dimensional space into low-dimensional feature vectors. The proposed method was evaluated on numerous samples including 61 healthy controls (HC), 42 stable-MCI (sMCI), 45 progressive-MCI (pMCI), and 83 AD subjects at the baseline from the J-ADNI data-set using support vector machine classifier. The proposed method yielded a classification accuracy of 84.17%, 70.38%, and 61.05% in identifying AD/HC, MCIs/HCs, and sMCI/pMCI, respectively. The experimental results show that the proposed method performed in a comparable way to alternative methods using MRI data.

%B J Alzheimers Dis %V 60 %P 295-304 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28800325?dopt=Abstract %R 10.3233/JAD-161080 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Classification of Depression, Cognitive Disorders, and Co-Morbid Depression and Cognitive Disorders with Perfusion SPECT Neuroimaging. %A Amen, Daniel G %A Krishnamani, Pavitra %A Meysami, Somayeh %A Newberg, Andrew %A Raji, Cyrus A %X

BACKGROUND: Depression and cognitive disorders (CDs) are two common co-morbid afflictions that commonly present with overlapping symptoms.

OBJECTIVE: To evaluate if perfusion neuroimaging with brain SPECT can distinguish persons with depression from those with CDs or both conditions.

METHODS: Inclusion criteria were DSM-IV defined depression or CDs (Alzheimer's disease, vascular dementia, dementia not otherwise specified, and amnestic disorders not otherwise specified) including persons with both (total n = 4,541; 847 CDs, 3,269 depression, 425 with both). Perfusion differences between the groups were calculated using two-sampled t-tests corrected for multiple comparisons. Diagnostic separation was determined with discriminant analysis. Feature selection revealed predictive regions in delineating depression from CDs and comorbid cases.

RESULTS: Persons with CDs had lower cerebral perfusion compared to depression. In co-morbid persons, cerebral hypoperfusion was additive, with regions showing lower regional cerebral blood flow compared to either diagnosis alone. Both baseline and concentration SPECT regions yielded correct classification of 86% and leave one out cross-validation of 83%. AUC analysis for SPECT regions showed 86% accuracy, 80% sensitivity and 75% specificity. Discriminant analysis separated depression and CDs from comorbid cases with correct classification of 90.8% and cross validated accuracy of 88.6%. Area under the curve was 83% with sensitivity of 80% and specificity of 70%. Feature selection identified the most predictive regions in left hippocampus, right insula, cerebellar, and frontal lobe regions.

CONCLUSION: Quantitative perfusion SPECT neuroimaging distinguishes depression from dementia and those with both co-morbidities. Perfusion brain SPECT can be utilized clinically to delineate between these two disorders.

%B J Alzheimers Dis %V 57 %P 253-266 %G eng %N 1 %R 10.3233/JAD-161232 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Clinical Effectiveness and Tolerability of Electroconvulsive Therapy in Patients with Neuropsychiatric Symptoms of Dementia. %A Isserles, Moshe %A Daskalakis, Zafiris J %A Kumar, Sanjeev %A Rajji, Tarek K %A Blumberger, Daniel M %X

BACKGROUND: Dementia frequently presents with aggression, agitation, and disorganized behavior for which current treatment is partially effective and is associated with significant adverse effects.

OBJECTIVE: The aim of this study was to retrospectively assess the clinical effectiveness and tolerability of electroconvulsive therapy (ECT) in a sample of patients with neuropsychiatric symptoms of dementia (NPS) and to explore factors associated with response and with cognitive adverse effects.

METHODS: We examined the clinical records of 25 patients with dementia and a pre-existing psychiatric disorder treated with ECT at an academic mental health hospital between April 1, 2010 and January 28, 2016. Twenty-nine acute ECT courses and fifteen maintenance courses were reviewed. We assessed treatment effectiveness and cognitive adverse effects as well as factors associated with response to treatment, including pre-existing psychiatric disorders, concomitant pharmacological treatment and types of dementia.

RESULTS: ECT resulted in a clinically meaningful response in 72% of acute treatment courses. Cognitive adverse effects affecting functioning were reported in 7% of the acute treatment courses. Maintenance treatment was effective in sustaining the response in 87% of treatment courses with two reports of significant cognitive adverse effects. One patient fell and experienced a hip fracture a day after treatment. Use of antipsychotic or antidepressant medications, pre-existing psychiatric disorder, or gender were not associated with response.

CONCLUSION: This study shows meaningful clinical effectiveness and good tolerability of ECT in patients with severe NPS of dementia. Furthermore, maintenance ECT was effective in sustaining treatment response.

%B J Alzheimers Dis %V 57 %P 45-51 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222513?dopt=Abstract %R 10.3233/JAD-161000 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Clinical Response to Donepezil in Mild and Moderate Dementia: Relationship to Drug Plasma Concentration and CYP2D6 and APOE Genetic Polymorphisms. %A Miranda, Luís F J R %A Gomes, Karina B %A Tito, Pedro A L %A Silveira, Josianne N %A Pianetti, Gerson A %A Byrro, Ricardo M D %A Peles, Patrícia R H %A Pereira, Fernando H %A Santos, Thiago R %A Assini, Arthur G %A Ribeiro, Valéria V %A Moraes, Edgar N %A Caramelli, Paulo %X

The clinical response to donepezil in patients with mild and moderate dementia was investigated in relation to the drug plasma concentration and APOE and CYP2D6 polymorphisms. In a prospective naturalistic observational study, 42 patients with Alzheimer's disease (AD) and AD with cerebrovascular disease who took donepezil (10 mg) for 12 months were evaluated. Their DNA was genotyped, and the donepezil plasma concentrations were measured after 3, 6, and 12 months. Good responders scored ≥-1 on the Mini-Mental State Examination at 12 months in comparison to the baseline score. The study results indicated the good response pattern was influenced by the concentration of donepezil, but not by APOE and CYP2D6 polymorphisms.

%B J Alzheimers Dis %V 55 %P 539-549 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716659?dopt=Abstract %R 10.3233/JAD-160164 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Clinical Use of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease Diagnosis: The Italian Selfie. %A Sancesario, Giulia M %A Toniolo, Sofia %A Chiasserini, Davide %A Di Santo, Simona G %A Zegeer, Josh %A Bernardi, Gaetano %A Musicco, Massimo %A Caltagirone, Carlo %A Parnetti, Lucilla %A Bernardini, Sergio %X

Although the use of cerebrospinal fluid (CSF) amyloid β1-42 (Aβ42), tau (T-tau), and phosphorylated tau (p-tau181) gives added diagnostic and prognostic values, the diffusion is still limited in clinical practice and only a restricted number of patients receive an integrated clinico-biological diagnosis. By a survey, we aimed to do a "selfie" of the use and diffusion of CSF biomarkers of dementia in Italy, the standardization of pre-analytical procedures, the harmonization of ranges, and the participation to Quality Control programs. An online questionnaire was sent to the members of SIBioC and SINdem-ITALPLANED and to main neurological clinics all over Italy. In Italy, 25 laboratories provide biomarkers analysis in addition to a network of 15 neighboring hospitals. In sum, 40 neurological centers require CSF analyses. 7/20 regions (35%) lack CSF laboratories. Standardization of pre-analytical procedures is present in 62.02% of the laboratories; only 56.00% of the laboratories participate in International Quality Control. There is no harmonization of cut-offs. In Italy, the use of CSF biomarkers is still limited in clinical practice. Standardization and harmonization of normal ranges are needed. To optimize and expand the use of CSF biomarkers, a cost-benefit analysis should be promoted by scientific societies and national health services.

%B J Alzheimers Dis %V 55 %P 1659-1666 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911328?dopt=Abstract %R 10.3233/JAD-160975 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive and Neuroanatomical Correlates in Early Versus Late Onset Parkinson's Disease Dementia. %A Kim, Younggwang %A Lee, Dongkyun %A Cho, Kyoo Ho %A Lee, Jae Jung %A Ham, Jee Hyun %A Ye, Byoung Seok %A Lee, Seung-Koo %A Lee, Jong-Min %A Sohn, Young H %A Lee, Phil Hyu %X

BACKGROUND: Aging is the most important risk factor of development of dementia in Parkinson's disease (PD), but there are no data on clinical and radiological heterogeneity of PD dementia (PDD) depending on age at onset.

OBJECTIVES: The goal of this study was to examine whether patients with PDD are clinically and radiologically heterogeneous depending on age at onset.

METHODS: A total of 116 patients with PD dementia and 121 age- and sex-matched normal controls were enrolled. The subjects were divided into early-onset (EOPDD; n = 39) and late-onset (LOPDD; n = 77) PDD with the respective age-matched control group based on a cutoff value of 70 years. The effects of diagnosis, age, and their interaction on neuropsychological tests, cortical thickness, and substantia innominata volume were assessed using analysis of covariance.

RESULTS: EOPDD patients had a poorer cognitive performance on digit backward, forward span test (p = 0.011 and 0.05), and visual recognition memory function (p = 0.012) compared with LOPDD patients. Additionally, EOPDD patients exhibited cortical thinning in the left anterior cingulate gyrus and the right inferior temporal gyrus, with significantly decreased normalized substantia innominata volume (p = 0.044).

CONCLUSIONS: Our data demonstrated that EOPDD patients exhibit poorer cognitive performance and more severe atrophy in the cortex and substantia innominata, implying that EOPDD may be a distinct phenotype different from LOPDD.

%B J Alzheimers Dis %V 55 %P 485-495 %G eng %N 2 %R 10.3233/JAD-160597 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Change in Rehabilitation Patients with Dementia: Prevalence and Association with Rehabilitation Success. %A Dutzi, Ilona %A Schwenk, Michael %A Kirchner, Marietta %A Bauer, Jürgen M %A Hauer, Klaus %X

BACKGROUND: Dementia is a frequent diagnosis in geriatric rehabilitation. Studies in patients with dementia on the development of their cognitive status during rehabilitation and its relation to functional outcomes have been scarce.

OBJECTIVES: To describe the changes in cognitive status in patients with dementia during inpatient rehabilitation and to determine its association with patient characteristics and rehabilitation outcome.

METHODS: Cohort study in a geriatric rehabilitation center with data collection at admission and discharge. Outcome measures were change in global and domain-related cognitive functioning and its association with activities of daily living (ADL) and discharge home.

RESULTS: 154 patients (mean age 83.7 years) diagnosed with mild to moderate dementia were included. Cognitive performance significantly improved from admission to discharge for all cognitive variables tested (p < 0.001 to 0.03). Change in global cognitive functioning, executive functions, and episodic memory were positively associated with ADL recovery. Change in global cognitive functioning predicted ADL improvements (β= 0.32; p = 0.006). Only 7.8% of patients, characterized by worse ADL and motor abilities as well as higher frailty scores at admission, deteriorated in global cognitive scores. In comparison to patients with stable or improved cognition, these patients showed least improvements in ADL-scores (4.1 versus 12.5) and a trend for higher institutionalization (50% versus 26.5%).

CONCLUSIONS: The findings highlight the potential of patients with dementia to recover cognitive functioning during rehabilitation. Cognitive change represents an independent rehabilitation outcome and a prognostic factor for successful rehabilitation suggesting that specific interventions are indicated to maintain and enhance cognitive functioning in these highly vulnerable patients.

%B J Alzheimers Dis %V 60 %P 1171-1182 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984597?dopt=Abstract %R 10.3233/JAD-170401 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Composites Domain Scores Related to Neuroimaging Biomarkers within Probable-Amnestic Mild Cognitive Impairment-Storage Subtype. %A Espinosa, Ana %A Alegret, Montserrat %A Pesini, Pedro %A Valero, Sergi %A Lafuente, Asunción %A Buendia, Mar %A San José, Itziar %A Ibarria, Marta %A Tejero, Miguel A %A Giménez, Joan %A Ruiz, Susana %A Hernandez, Isabel %A Pujadas, Francesc %A Martínez-Lage, Pablo %A Munuera, Josep %A Arbizu, Javier %A Tárraga, Lluís %A Hendrix, Suzanne B %A Ruiz, Agustin %A Becker, James T %A Landau, Susan M %A Sotolongo-Grau, Oscar %A Sarasa, Manuel %A Boada, Merce %X

The probable-amnestic (Pr-a) mild cognitive impairment (MCI)-storage subtype is a phenotype with 8.5 times more risk of conversion to dementia, mainly Alzheimer's disease (AD), than the possible non-amnestic (Pss-na) MCI. The aim of this study was to find the optimized cognitive composites (CCs) domain scores most related to neuroimaging biomarkers within Pr-aMCI-storage subtype patients. The Fundació ACE (ACE) study with 20 Pr-aMCI-storage subtype subjects (MCI) were analyzed. All subjects underwent a neuropsychological assessment, a structural MRI, FDG-PET, and PIB-PET. The adjusted hippocampal volume (aHV) on MRI, the standard uptake value ratio (SUVR) on FDG-PET and PIB-PET SUVR measures were analyzed. The construction of the CCs domain scores, and the aHV on MRI and FDG-PET SUVR measures, were replicated in the parental AB255 study database (n = 133 MCI). Partial correlations adjusted by age, gender, and education were calculated with the associated p-value among every CC domain score and the neuroimaging biomarkers. The results were replicated in the "MCI due to AD" with memory storage impairments from ADNI. Delayed Recall CC domain score was significantly correlated with PIB-PET SUVR (β= -0.61, p = 0.003) in the ACE study and also with aHV on MRI (β= 0.27, p = 0.01) and FDG-PET SUVR (β= 0.27, p = 0.01) in the AB255 study. After a median survival time of 20.6 months, 85% from the ACE MCI converted to AD. The replication of our results in the ADNI dataset also confirmed our findings. Delayed Recall is the CC domain score best correlated with neuroimaging biomarkers associated with prodromal AD diagnosis.

%B J Alzheimers Dis %V 57 %P 447-459 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269787?dopt=Abstract %R 10.3233/JAD-161223 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Domain Dispersion Association with Alzheimer's Disease Pathology. %A Malek-Ahmadi, Michael %A Lu, Sophie %A Chan, YanYan %A Perez, Sylvia E %A Chen, Kewei %A Mufson, Elliott J %X

Within neuropsychology, the term dispersion refers to the degree of variation in performance between different cognitive domains for an individual. Previous studies have demonstrated that cognitively normal individuals with higher dispersion are at an increased risk for progressing to mild cognitive impairment (MCI) and Alzheimer's disease (AD). Therefore, we determined 1) whether increased dispersion in older adults was associated with amyloid plaques and neurofibrillary tangles (NFTs) and 2) whether increased cognitive dispersion accurately differentiated MCI and AD from non-cognitively impaired (NCI) individuals. The intra-subject standard deviation (ISD) was used to quantify cognitive dispersion, and receiver operator characteristic (ROC) analysis determined whether ISD differentiated MCI and AD from NCI. Neuropathological scores for diffuse plaques (DPs), neuritic plaques (NPs), and NFTs were used as outcome measures in a series of negative binomial regression models. Regression analyses found that increased ISD was associated with increased NFT pathology (β= 10.93, SE = 3.82, p = 0.004), but not with DPs (β= 1.33, SE = 8.85, p = 0.88) or NPs (β= 14.64, SE = 8.45, p = 0.08) after adjusting for age at death, gender, education, APOE ɛ4 status, and clinical diagnosis. An interaction term of ISD with age at death also showed a significant negative association (β= -0.13, SE = 0.04, p = 0.004), revealing an age-dependent association between ISD with NFTs. The ISD failed to show an acceptable level of diagnostic accuracy for MCI (AUC = 0.60). These findings suggest that increased cognitive dispersion is related to NFT pathology where age significantly affects this association.

%B J Alzheimers Dis %V 58 %P 575-583 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453479?dopt=Abstract %R 10.3233/JAD-161233 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Efficiency in Alzheimer's Disease is Associated with Increased Occipital Connectivity. %A De Marco, Matteo %A Duzzi, Davide %A Meneghello, Francesca %A Venneri, Annalena %X

There are cognitive domains which remain fully functional in a proportion of Alzheimer's disease (AD) patients. It is unknown, however, what distinctive mechanisms sustain such efficient processing. The concept of "cognitive efficiency" was investigated in these patients by operationalizing it as a function of the level of performance shown on the Letter Fluency test, on which, very often, patients in the early stages of AD show unimpaired performance. Forty-five individuals at the prodromal/early stage of AD (diagnosis supported by subsequent clinical follow-ups) and 45 healthy controls completed a battery of neuropsychological tests and an MRI protocol which included resting state acquisitions. The Letter Fluency test was the only task on which no between-group difference in performance was found. Participants were divided into "low-performing" and "high-performing" according to the global median. Dual-regression methods were implemented to compute six patterns of network connectivity. The diagnosis-by-level of performance interaction was inferred on each pattern to determine the network distinctiveness of efficient performance in AD. Significant interactions were found in the anterior default mode network, and in both left and right executive control networks. For all three circuits, high-performing patients showed increased connectivity within the ventral and dorsal part of BA19, as confirmed by post hoc t tests. Peristriate remapping is suggested to play a compensatory role. Since the occipital lobe is the neurophysiological source of long-range cortical connectivity, it is speculated that the physiological mechanisms of functional connectivity might sustain occipital functional remapping in early AD, particularly for those functions which are sustained by areas not excessively affected by the prodromal disease.

%B J Alzheimers Dis %V 57 %P 541-556 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269781?dopt=Abstract %R 10.3233/JAD-161164 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Event-Related Potential, an Early Diagnosis Biomarker in Frail Elderly Subjects: The ERP-MAPT-PLUS Ancillary Study. %A Bennys, Karim %A Gabelle, Audrey %A Berr, Claudine %A De Verbizier, Delphine %A Andrieu, Sandrine %A Vellas, Bruno %A Touchon, Jacques %X

BACKGROUND: By analyzing brain synaptic function, cognitive event-related potentials (ERPs) could provide powerful and innovative tools for early Alzheimer's disease (AD) diagnosis.

OBJECTIVE: We investigated the relevance of the ERP-P300 component as a potential diagnosis marker in elderly subjects at risk of developing AD.

METHODS: ERP-P300 was analyzed on 85 subjects recruited from the Multidomain Alzheimer Preventive Trial (MAPT). PET-AV45 brain imaging was available from 36 subjects.

RESULTS: Two ERP-P300 subgroups were identified according to their PET-AV45 status: PET-Aβ positive (n = 15) and PET-Aβ negative (n = 21). In the amyloid positive group, we observed a highly significant increase in P3b latency in parietal brain regions (p = 0.0052). P3b in parietal regions correctly categorized 69.4% elderly subjects from the P300-PET Aβ positive group. Combined analysis of parietal P3b latencies and category fluency correctly classified 75% subjects from the P300-PET Aβ positive group.

CONCLUSIONS: The P300 ERP presents good predictive measure of brain amyloid load and has the potential to be used as a screening instrument for preclinical AD. The incorporation of P3b latency may be used as an adjunctive tool with neuropsychological assessment (i.e., verbal category fluency) as a specific and sensitive method for preclinical assessment of AD.

%B J Alzheimers Dis %V 58 %P 87-97 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372327?dopt=Abstract %R 10.3233/JAD-161012 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Rehabilitation in Alzheimer's Disease: A Controlled Intervention Trial. %A Brueggen, Katharina %A Kasper, Elisabeth %A Ochmann, Sina %A Pfaff, Henrike %A Webel, Steffi %A Schneider, Wolfgang %A Teipel, Stefan %X

BACKGROUND: Cognitive Rehabilitation for Alzheimer's disease (AD) is an integrative multimodal intervention. It aims to maintain autonomy and quality of life by enhancing the patients' abilities to compensate for decreased cognitive functioning.

OBJECTIVE: We evaluated the feasibility of a group-based Cognitive Rehabilitation approach in mild AD dementia and assessed its effect on activities of daily living (ADL).

METHODS: We included 16 patients with AD dementia in a controlled partial-randomized design. We adapted the manual-guided Cognitive Rehabilitation program (CORDIAL) to a group setting. Over the course of three months, one group received the Cognitive Rehabilitation intervention (n = 8), while the other group received a standardized Cognitive Training as an active control condition (n = 8). ADL-competence was measured as primary outcome. The secondary outcome parameters included cognitive abilities related to daily living, functional cognitive state, and non-cognitive domains, e.g., quality of life. For each scale, we assessed the interaction effect 'intervention by time', i.e., from pre-to post-intervention.

RESULTS: We found no significant interaction effect of intervention by time on the primary outcome ADL-competence. The interaction effect was significant for quality of life (Cohen's d: -1.43), showing an increase in the intervention group compared with the control group.

CONCLUSIONS: Our study demonstrates the feasibility of a group-based Cognitive Rehabilitation program for patients with mild AD dementia. The Cognitive Rehabilitation showed no significant effect on ADL, possibly reflecting a lack of transfer between the therapy setting and real life. However, the group setting enhanced communication skills and coping mechanisms. Effects on ADL may not have reached statistical significance due to a limited sample size. Furthermore, future studies might use an extended duration of the intervention and integrate caregivers to a greater extent to increase transfer to activities of daily living.

%B J Alzheimers Dis %V 57 %P 1315-1324 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372325?dopt=Abstract %R 10.3233/JAD-160771 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Status, Gray Matter Atrophy, and Lower Orthostatic Blood Pressure in Older Adults. %A O'Hare, Celia %A Kenny, Rose-Anne %A Aizenstein, Howard %A Boudreau, Robert %A Newman, Anne %A Launer, Lenore %A Satterfield, Suzanne %A Yaffe, Kristine %A Rosano, Caterina %X

BACKGROUND: Associations between orthostatic blood pressure and cognitive status (CS) have been described with conflicting results.

OBJECTIVE: We hypothesize that long-term exposure to lower orthostatic blood pressure is related to having worse CS later in life and that atrophy of regions involved in central regulation of autonomic function mediate these associations.

METHODS: Three-to-four measures of orthostatic blood pressure were obtained from 1997-2003 in a longitudinal cohort of aging, and average systolic orthostatic blood pressure response (ASOBPR) was computed as % change in systolic blood pressure from sit-to-stand measured at one minute post stand. CS was determined in 2010-2012 by clinician-adjudication (n = 240; age = 87.1±2.6; 59% women; 37% black) with a subsample also undergoing concurrent structural neuroimaging (n = 129). Gray matter volume of regions related to autonomic function was measured. Multinomial regression was used to compare ASOBPR in those who were cognitively intact versus those with a diagnosis of mild cognitive impairment or dementia, controlling for demographics, trajectories of seated blood pressure, incident cardiovascular risk/events and medications measured from 1997 to 2012. Models were repeated in the subsample with neuroimaging, before and after adjustment for regional gray matter volume.

RESULTS: There was an inverse association between ASOBPR and probability of dementia diagnosis (9% lower probability for each % point higher ASOBPR: OR 0.91, CI95%  = 0.85-0.98; p = 0.01). Associations were similar in the subgroup with neuroimaging before and after adjustment for regional gray matter volume.

CONCLUSION: ASOBPR may be an early marker of risk of dementia in older adults living in the community.

%B J Alzheimers Dis %V 57 %P 1239-1250 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28339397?dopt=Abstract %R 10.3233/JAD-161228 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Training Interventions for Patients with Alzheimer's Disease: A Systematic Review. %A Kallio, Eeva-Liisa %A Öhman, Hanna %A Kautiainen, Hannu %A Hietanen, Marja %A Pitkälä, Kaisu %X

BACKGROUND: Cognitive training (CT) refers to guided cognitive exercises designed to improve specific cognitive functions, as well as enhance performance in untrained cognitive tasks. Positive effects of CT on cognitive functions in healthy elderly people and persons with mild cognitive impairment have been reported, but data regarding the effects of CT in patients with dementia is unclear.

OBJECTIVE: We systematically reviewed the current evidence from randomized controlled trials (RCTs) to find out if CT improves or stabilizes cognition and/or everyday functioning in patients with mild and moderate Alzheimer's disease.

RESULTS: Altogether, 31 RCTs with CT as either the primary intervention or part of a broader cognitive or multi-component intervention were found. A positive effect was reported in 24 trials, mainly on global cognition and training-specific tasks, particularly when more intensive or more specific CT programs were used. Little evidence of improved everyday functioning was found.

CONCLUSIONS: Despite some positive findings, the inaccurate definitions of CT, inadequate sample sizes, unclear randomization methods, incomplete datasets at follow-up and multiple testing may have inflated the results in many trials. Future high quality RCTs with appropriate classification and specification of cognitive interventions are necessary to confirm CT as an effective treatment option in Alzheimer's disease.

%B J Alzheimers Dis %V 56 %P 1349-1372 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222505?dopt=Abstract %R 10.3233/JAD-160810 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive-Enhancing Effects of a Polyphenols-Rich Extract from Fruits without Changes in Neuropathology in an Animal Model of Alzheimer's Disease. %A Dal-Pan, Alexandre %A Dudonné, Stéphanie %A Bourassa, Philippe %A Bourdoulous, Morgane %A Tremblay, Cyntia %A Desjardins, Yves %A Calon, Frederic %X

No effective preventive treatment is available for age-related cognitive decline and Alzheimer's disease (AD). Epidemiological studies indicate that a diet rich in fruit is associated with cognitive improvement. It was thus proposed that high polyphenol concentrations found in berries can prevent cognitive impairment associated with aging and AD. Therefore, the Neurophenols project aimed at investigating the effects of a polyphenolic extract from blueberries and grapes (PEBG) in the triple-transgenic (3xTg-AD) mouse model of AD, which develops AD neuropathological markers, including amyloid-β plaques and neurofibrillary tangles, leading to memory deficits. In this study, 12-month-old 3xTg-AD and NonTg mice were fed a diet supplemented with standardized PEBG (500 or 2500 mg/kg) for 4 months (n = 15-20/group). A cognitive evaluation with the novel object recognition test was performed at 15 months of age and mice were sacrificed at 16 months of age. We observed that PEBG supplementation with doses of 500 or 2500 mg/kg prevented the decrease in novel object recognition observed in both 15-month-old 3xTg-AD mice and NonTg mice fed a control diet. Although PEBG treatment did not reduce Aβ and tau pathologies, it prevented the decrease in mature BDNF observed in 16-month-old 3xTg-AD mice. Finally, plasma concentrations of phenolic metabolites, such as dihydroxyphenyl valerolactone, a microbial metabolite of epicatechin, positively correlated with memory performances in supplemented mice. The improvement in object recognition observed in 3xTg-AD mice after PEBG administration supports the consumption of polyphenols-rich extracts to prevent memory impairment associated with age-related disease, without significant effects on classical AD neuropathology.

%B J Alzheimers Dis %V 55 %P 115-135 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662290?dopt=Abstract %R 10.3233/JAD-160281 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Colivelin Ameliorates Impairments in Cognitive Behaviors and Synaptic Plasticity in APP/PS1 Transgenic Mice. %A Wu, Meina %A Shi, Hui %A He, Yexin %A Yuan, Li %A Qu, Xuesong %A Zhang, Jun %A Wang, Zhaojun %A Cai, Hongyan %A Qi, Jinshun %X

Alzheimer's disease (AD) is the most common cause of dementia, and effective therapeutics are lacking. Colivelin (CLN), a novel, strong humanin derivative, is effective in vitro in preventing cell death induced by AD-causative genes and amyloid-β protein (Aβ) even at a low concentration. We recently demonstrated that intrahippocampal injection of CLN prevents Aβ25-35-induced deficits in spatial memory and synaptic plasticity in normal rats. Here, we further observed the effects of chronically intranasally (i.n.) administered CLN on cognitive behaviors and pathological hallmarks in 9-month-old APPswe/PS1dE9 (APP/PS1) AD mice using multiple behavioral tests and immunochemistry. The electrophysiological mechanism of CLN neuroprotection was also investigated by recording in vivo hippocampal long-term potentiation (LTP). CLN pretreatment effectively prevented impairments in new object recognition, working memory, and long-term spatial memory and reversed the depression of in vivo hippocampal LTP in APP/PS1 mice. Additionally, chronic application of CLN obviously reduced Aβ deposition in the hippocampus in APP/PS1 mice. These results indicate that CLN has strong neuroprotective effects on learning and memory behaviors in APP/PS1 mice and that this behavioral improvement is closely associated with the reduction of Aβ deposition and alleviation of LTP suppression in the hippocampus, supporting the potential of CLN for the prevention and treatment of AD.

%B J Alzheimers Dis %V 59 %P 1067-1078 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731445?dopt=Abstract %R 10.3233/JAD-170307 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Co-Localization of Glia Maturation Factor with NLRP3 Inflammasome and Autophagosome Markers in Human Alzheimer's Disease Brain. %A Ahmed, Mohammad Ejaz %A Iyer, Shankar %A Thangavel, Ramasamy %A Kempuraj, Duraisamy %A Selvakumar, Govindhasamy Pushpavathi %A Raikwar, Sudhanshu P %A Zaheer, Smita %A Zaheer, Asgar %X

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the presence of intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated tau, and the extracellular deposition of amyloid plaques (APs) with misfolded amyloid-β (Aβ) peptide. Glia maturation factor (GMF), a highly conserved pro-inflammatory protein, isolated and cloned in our laboratory, has been shown to activate glial cells leading to neuroinflammation and neurodegeneration in AD. We hypothesized that inflammatory reactions promoted by NLRP3-Caspase-1inflammasome pathway trigger dysfunction in autophagy and accumulation of Aβ which is amplified and regulated by GMF in AD. In this study, using immunohistochemical techniques we analyzed components of the NLRP3 inflammasome and autophagy- lysosomal markers in relation to Aβ, p-tau and GMF in human postmortem AD and age-matched non-AD brains. Tissue sections were prepared from the temporal cortex of human postmortem brains. Here, we demonstrate an increased expression of the inflammasome components NLRP3 and Caspase-1 and the products of inflammasome activation IL-1β and IL-18 along with GMF in the temporal cortex of AD brains. These inflammasome components and the pro-inflammatory cytokines co-localized with GMF in the vicinity and periphery of the APs and NFTs. Moreover, using double immunofluorescence staining, AD brain displayed an increase in the autophagy SQSTM1/p62 and LC3 positive vesicles and the lysosomal marker LAMP1 that also co-localized with GMF, Aβ and hyperphosphorylated p-tau. Our results indicate that in AD, the neuroinflammation promoted by the NLRP3 inflammasome may be amplified and regulated by GMF, which further impairs clearance of protein aggregates mediated by the auto-phagosomal pathway.

%B J Alzheimers Dis %V 60 %P 1143-1160 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984607?dopt=Abstract %R 10.3233/JAD-170634 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Combination Therapy with Zonisamide and Antiparkinson Drugs for Parkinson's Disease: A Meta-Analysis. %A Matsunaga, Shinji %A Kishi, Taro %A Iwata, Nakao %X

BACKGROUND: There is uncertainty about the efficacy and tolerability of zonisamide for Parkinson's disease (PD).

OBJECTIVE: We performed a meta-analysis of zonisamide treatment in PD patients who received antiparkinson drugs such as levodopa.

METHODS: The primary outcome measures were the Unified Parkinson's Disease Rating Scale (UPDRS) Part III scores, wearing-off time, and discontinuation rate due to all causes. Secondary outcome measures were UPDRS total and subscale scores; discontinuation rates due to adverse events, inefficacy, and death; and individual adverse events.

RESULTS: Four randomized placebo-controlled trials including 1,068 PD patients were analyzed. All studies were conducted in Japan. UPDRS Part III scores were significantly lower with zonisamide than with placebo (weighted mean difference [WMD], -2.56; 95% confidence interval [CI]; -4.20 to -0.92; p = 0.002). Further, zonisamide significantly decreased the wearing-off time compared with placebo (standardized mean difference, -0.24; 95% CI, -0.39 to -0.09; p = 0.001). Discontinuation rates due to all causes were similar between the zonisamide and placebo groups (risk ratio, 1.29; 95% CI, 0.90 to 1.84; p = 0.16). While zonisamide also decreased both UPDRS Part II (off-time) and UPDRS total scores compared to placebo (UPDRS Part II [off-time] scores: WMD, -0.79; UPDRS total scores: WMD, -2.51), there were no significant differences in other secondary outcomes between the two groups.

CONCLUSIONS: Our results suggested that zonisamide combination therapy was beneficial in treating motor symptoms in PD patients receiving antiparkinson drugs and was well tolerated in Japanese patients. Future studies in populations other than the Japanese are needed.

%B J Alzheimers Dis %V 56 %P 1229-1239 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157097?dopt=Abstract %R 10.3233/JAD-161068 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Combinatorial Treatment Effects in a Cell Culture Model of Alzheimer's Disease. %A Beesley, Stephen %A Olcese, James %A Saunders, Charles %A Bienkiewicz, Ewa A %X

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia, and as its prevalence increases, so does its detrimental impact on society. The currently available therapies have limited efficacy, leaving AD patients on an irrevocably fatal path of this disease.

OBJECTIVE: The purpose of this study was to test efficacy of a novel combinatorial treatment approach to alleviate AD-like pathology.

METHODS: We selected four naturally occurring compounds and used them in different combinations to test their effect on AD-like pathology. Employing a well-established cell culture AD model system, we evaluated levels of several diverse biomarkers associated with a number of cellular pathways associated with AD. The readouts included: amyloid-β peptides, anti-inflammatory and anti-apoptotic proteins, oxidative enzymes, and reactive oxygen species.

RESULTS: Using this approach, we demonstrated that the compounds delivered in combination had higher efficacy than individual treatments. Specifically, we observed significant reduction in levels of the amyloid-β peptides, as well as pro-inflammatory proteins and reactive oxygen species. Similarly, delivery of compounds in combination resulted in an increased expression of anti-apoptotic proteins and anti-oxidative enzymes. Collectively, these modifications in AD pathology biomarkers reflect a promising therapeutic and preventive strategy to combat this disease.

CONCLUSION: The above findings support a novel therapeutic approach to address a currently unmet medical need, which would benefit not only AD patients and their caregivers, but also society as a whole.

%B J Alzheimers Dis %V 55 %P 1155-1166 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27814295?dopt=Abstract %R 10.3233/JAD-160459 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Combined Creutzfeldt-Jakob/ Alzheimer's Disease Cases are Important in Search for Microbes in Alzheimer's Disease. %A Bastian, Frank O %X

The question whether Alzheimer's disease is infectious as brought up in the recent editorial published in the Journal of Alzheimer's Disease is complicated by the controversy whether the causal agent is a microbe or a misfolded host protein (amyloid). The replicating amyloid (prion) theory, based upon data from studies of Creutzfeldt-Jakob disease (CJD) and other transmissible spongiform encephalopathies (TSEs), has been challenged since the prion can be separated from TSE infectivity, and spiroplasma, a wall-less bacterium, has been shown to be involved in the pathogenesis of CJD. Further support for a microbial cause for AD comes from occurrence of mixed CJD/AD cases involving up to 15% of AD brains submitted to brain banks. The association of CJD with AD suggests a common etiology rather than simply being a medical curiosity. A co-infection with the transmissible agent of CJD, which we propose to be a Spiroplasma sp., would explain the diversity of bacteria shown to be associated with cases of AD.

%B J Alzheimers Dis %V 56 %P 867-873 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059790?dopt=Abstract %R 10.3233/JAD-160999 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Combined Dual-Task Gait Training and Aerobic Exercise to Improve Cognition, Mobility, and Vascular Health in Community-Dwelling Older Adults at Risk for Future Cognitive Decline1. %A Gregory, Michael A %A Boa Sorte Silva, Narlon C %A Gill, Dawn P %A McGowan, Cheri L %A Liu-Ambrose, Teresa %A Shoemaker, J Kevin %A Hachinski, Vladimir %A Holmes, Jeff %A Petrella, Robert J %K Aged %K Aged, 80 and over %K Analysis of Variance %K Blood Pressure %K Blood Pressure Monitoring, Ambulatory %K Carotid Intima-Media Thickness %K Cognition Disorders %K Exercise %K Exercise Therapy %K Female %K Follow-Up Studies %K Gait %K Humans %K Independent Living %K Male %K Middle Aged %K Neuropsychological Tests %X

This 6-month experimental case series study investigated the effects of a dual-task gait training and aerobic exercise intervention on cognition, mobility, and cardiovascular health in community-dwelling older adults without dementia. Participants exercised 40 min/day, 3 days/week for 26 weeks on a Biodex GaitTrainer2 treadmill. Participants were assessed at baseline (V0), interim (V1: 12-weeks), intervention endpoint (V2: 26-weeks), and study endpoint (V3: 52-weeks). The study outcomes included: cognition [executive function (EF), processing speed, verbal fluency, and memory]; mobility: usual & dual-task gait (speed, step length, and stride time variability); and vascular health: ambulatory blood pressure, carotid arterial compliance, and intima-media thickness (cIMT). Fifty-six participants [age: 70(6) years; 61% female] were included in this study. Significant improvements following the exercise program (V2) were observed in cognition: EF (p = 0.002), processing speed (p < 0.001), verbal fluency [digit symbol coding (p < 0.001), phonemic verbal fluency (p < 0.001)], and memory [immediate recall (p < 0.001) and delayed recall (p < 0.001)]; mobility: usual & dual-task gait speed (p = 0.002 and p < 0.001, respectively) and step length (p = 0.001 and p = 0.003, respectively); and vascular health: cIMT (p = 0.002). No changes were seen in the remaining outcomes. In conclusion, 26 weeks of dual-task gait training and aerobic exercise improved performance on a number of cognitive outcomes, while increasing usual & dual-task gait speed and step length in a sample of older adults without dementia.

%B J Alzheimers Dis %V 57 %P 747-763 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304305?dopt=Abstract %R 10.3233/JAD-161240 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Combustion-Derived Nanoparticles in Key Brain Target Cells and Organelles in Young Urbanites: Culprit Hidden in Plain Sight in Alzheimer's Disease Development. %A González-Maciel, Angelica %A Reynoso-Robles, Rafael %A Torres-Jardón, Ricardo %A Mukherjee, Partha S %A Calderón-Garcidueñas, Lilian %X

Millions of children and young adults are exposed to fine particulate matter (PM2.5) and ozone, associated with Alzheimer's disease (AD) risk. Mexico City (MC) children exhibit systemic and brain inflammation, low cerebrospinal fluid (CSF) Aβ1-42, breakdown of nasal, olfactory, alveolar-capillary, duodenal, and blood-brain barriers, volumetric and metabolic brain changes, attention and short-term memory deficits, and hallmarks of AD and Parkinson's disease. Airborne iron-rich strongly magnetic combustion-derived nanoparticles (CDNPs) are present in young urbanites' brains. Using transmission electron microscopy, we documented CDNPs in neurons, glia, choroid plexus, and neurovascular units of young MC residents versus matched clean air controls. CDNPs are associated with pathology in mitochondria, endoplasmic reticulum (ER), mitochondria-ER contacts (MERCs), axons,and dendrites. There is a significant difference in size and numbers between spherical CDNPs (>85%) and the angular, euhedral endogenous NPs (<15%). Spherical CDNPs (dogs 21.2±7.1 nm in diameter versus humans 29.1±11.2 nm, p = 0.002) are present in neurons, glia, choroid plexus, endothelium, nasal and olfactory epithelium, and in CSF at significantly higher in numbers in MC residents (p < 0.0001). Degenerated MERCs, abnormal mitochondria, and dilated ER are widespread, and CDNPs in close contact with neurofilaments, glial fibers, and chromatin are a potential source for altered microtubule dynamics, mitochondrial dysfunction, accumulation and aggregation of unfolded proteins, abnormal endosomal systems, altered insulin signaling, calcium homeostasis, apoptotic signaling, autophagy, and epigenetic changes. Highly oxidative, ubiquitous CDNPs constitute a novel path into AD pathogenesis. Exposed children and young adults need early neuroprotection and multidisciplinary prevention efforts to modify the course of AD at early stages.

%B J Alzheimers Dis %V 59 %P 189-208 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598844?dopt=Abstract %R 10.3233/JAD-170012 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Common Variant in the MC1R Gene (p.V92M) is associated with Alzheimer's Disease Risk. %A Tell-Marti, Gemma %A Puig-Butille, Joan Anton %A Potrony, Miriam %A Plana, Estel %A Badenas, Celia %A Antonell, Anna %A Sánchez-Valle, Raquel %A Molinuevo, José L %A Lleo, Alberto %A Alcolea, Daniel %A Fortea, Juan %A Fernández-Santiago, Rubén %A Clarimón, Jordi %A Lladó, Albert %A Puig, Susana %X

Despite the recent identification of some novel risk genes for Alzheimer's disease (AD), the genetic etiology of late-onset Alzheimer's disease (LOAD) remains largely unknown. The inclusion of these novel risk genes to the risk attributable to the APOE gene accounts for roughly half of the total genetic variance in LOAD. The evidence indicates that undiscovered genetic factors may contribute to AD susceptibility. In the present study, we sequenced the MC1R gene in 525 Spanish LOAD patients and in 160 controls. We observed that a common MC1R variant p.V92M (rs2228479), not related to pigmentation traits, was present in 72 (14%) patients and 15 (9%) controls and confers increased risk of developing LOAD (OR: 1.99, 95% CI: 1.08-3.64, p = 0.026), especially in those patients whose genetic risk could not be explained by APOE genotype. This association remains and even increased in the subset of 69 patients with typical AD cerebrospinal fluid profile (OR: 3.40 95% CI: 1.40-8.27, p = 0.007). We did not find an association between p.V92M and age of onset of AD. Further studies are necessary to elucidate the role of MC1R in brain cells through the different MC1R pathways.

%B J Alzheimers Dis %V 56 %P 1065-1074 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059796?dopt=Abstract %R 10.3233/JAD-161113 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains. %A Haddick, Patrick C G %A Larson, Jessica L %A Rathore, Nisha %A Bhangale, Tushar R %A Phung, Qui T %A Srinivasan, Karpagam %A Hansen, David V %A Lill, Jennie R %A Pericak-Vance, Margaret A %A Haines, Jonathan %A Farrer, Lindsay A %A Kauwe, John S %A Schellenberg, Gerard D %A Cruchaga, Carlos %A Goate, Alison M %A Behrens, Timothy W %A Watts, Ryan J %A Graham, Robert R %A Kaminker, Joshua S %A van der Brug, Marcel %X

The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer's disease subjects in an IL6R allele dependent manner. We conducted a screen to identify variants associated with the age of onset of Alzheimer's disease in APOE ɛ4 carriers. Across five datasets, p.D358A had a meta P = 3 ×10-4 and an odds ratio = 1.3, 95% confidence interval 1.12 -1.48. Our study suggests that a common coding region variant of the IL-6 receptor results in neuroinflammatory changes that may influence the age of onset of Alzheimer's disease in APOE ɛ4 carriers.

%B J Alzheimers Dis %V 56 %P 1037-1054 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106546?dopt=Abstract %R 10.3233/JAD-160524 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Comorbidity Analysis between Alzheimer's Disease and Type 2 Diabetes Mellitus (T2DM) Based on Shared Pathways and the Role of T2DM Drugs. %A Karki, Reagon %A Kodamullil, Alpha Tom %A Hofmann-Apitius, Martin %X

BACKGROUND: Various studies suggest a comorbid association between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) indicating that there could be shared underlying pathophysiological mechanisms.

OBJECTIVE: This study aims to systematically model relevant knowledge at the molecular level to find a mechanistic rationale explaining the existing comorbid association between AD and T2DM.

METHOD: We have used a knowledge-based modeling approach to build two network models for AD and T2DM using Biological Expression Language (BEL), which is capable of capturing and representing causal and correlative relationships at both molecular and clinical levels from various knowledge resources.

RESULTS: Using comparative analysis, we have identified several putative "shared pathways". We demonstrate, at a mechanistic level, how the insulin signaling pathway is related to other significant AD pathways such as the neurotrophin signaling pathway, PI3K/AKT signaling, MTOR signaling, and MAPK signaling and how these pathways do cross-talk with each other both in AD and T2DM. In addition, we present a mechanistic hypothesis that explains both favorable and adverse effects of the anti-diabetic drug metformin in AD.

CONCLUSION: The two computable models introduced here provide a powerful framework to identify plausible mechanistic links shared between AD and T2DM and thereby identify targeted pathways for new therapeutics. Our approach can also be used to provide mechanistic answers to the question of why some T2DM treatments seem to increase the risk of AD.

%B J Alzheimers Dis %V 60 %P 721-731 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922161?dopt=Abstract %R 10.3233/JAD-170440 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Comparative Analysis of Cortical Microinfarcts and Microbleeds using 3.0-Tesla Postmortem Magnetic Resonance Images and Histopathology. %A Niwa, Atsushi %A Ii, Yuichiro %A Shindo, Akihiro %A Matsuo, Ko %A Ishikawa, Hidehiro %A Taniguchi, Akira %A Takase, Shinichi %A Maeda, Masayuki %A Sakuma, Hajime %A Akatsu, Hiroyasu %A Hashizume, Yoshio %A Tomimoto, Hidekazu %X

Microvascular lesions including cortical microinfarctions (CMIs) and cerebral lobar microbleeds (CMBs) are usually caused by cerebral amyloid angiopathy (CAA) in the elderly and are correlated with cognitive decline. However, their radiological-histopathological coincidence has not been revealed systematically with widely used 3-Tesla (3T) magnetic resonance imaging (MRI). The purpose of the present study is to delineate the histopathological background corresponding to MR images of these lesions. We examined formalin-fixed 10-mm thick coronal brain blocks from 10 CAA patients (five were also diagnosed with Alzheimer's disease, three with dementia with Lewy bodies, and two with CAA only) with dementia and six non CAA patients with neurodegenerative disease. Using 3T MRI, both 3D-fluid attenuated inversion recovery (FLAIR) and 3D-double inversion recovery (DIR) were examined to identify CMIs, and T2* and susceptibility-weighted images (SWI) were examined to identify CMBs. These blocks were subsequently examined histologically and immunohistochemically. In CAA patients, 48 CMIs and 6 lobar CMBs were invariably observed in close proximity to degenerated Aβ-positive blood vessels. Moreover, 16 CMIs (33%) of 48 were detected with postmortem MRI, but none were seen when the lesion size was smaller than 1 mm. In contrast, only 1 undeniable CMI was founded with MRI and histopathology in 6 non CAA patients. Small, cortical high-intensity lesions seen on 3D-FLAIR and 3D-DIR images likely represent CMIs, and low-intensity lesions in T2* and SWI correspond to CMBs with in vivo MRI. Furthermore, a close association between amyloid-laden vessels and these microvascular lesions indicated the contribution of CAA to their pathogenesis.

%B J Alzheimers Dis %V 59 %P 951-959 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697558?dopt=Abstract %R 10.3233/JAD-161242 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Comparing Approaches to Optimize Cut-off Scores for Short Cognitive Screening Instruments in Mild Cognitive Impairment and Dementia. %A O'Caoimh, Rónán %A Gao, Yang %A Svendovski, Anton %A Gallagher, Paul %A Eustace, Joseph %A Molloy, D William %X

BACKGROUND: Although required to improve the usability of cognitive screening instruments (CSIs), the use of cut-off scores is controversial yet poorly researched.

OBJECTIVE: To explore cut-off scores for two short CSIs: the Standardized Mini-Mental State Examination (SMMSE) and Quick Mild Cognitive Impairment (Qmci) screen, describing adjustments in scores for diagnosis (MCI or dementia), age (≤, >75 years), and education (<, ≥12 years), comparing two methods: the maximal accuracy approach, derived from receiver operating characteristic curves, and Youden's Index.

METHODS: Pooled analysis of assessments from patients attending memory clinics in Canada between 1999-2010 : 766 with mild cognitive impairment (MCI) and 1,746 with dementia, and 875 normal controls.

RESULTS: The Qmci was more accurate than the SMMSE in differentiating controls from MCI or cognitive impairment (MCI and dementia). Employing the maximal accuracy approach, the optimal SMMSE cut-off for cognitive impairment was <28/30 (AUC 0.86, sensitivity 74%, specificity 88%) versus <63/100 for the Qmci (AUC 0.93, sensitivity 85%, specificity 85%). Using Youden's Index, the optimal SMMSE cut-off remained <28/30 but fell slightly to <62/100 for the Qmci (sensitivity 83%, specificity 87%). The optimal cut-off for MCI was <29/30 for the SMMSE and <67/100 for the Qmci, irrespective of technique. The maximal accuracy approach generally produced higher Qmci cut-offs than Youden's Index, both requiring adjustment for age and education. There were no clinically meaningful differences in SMMSE cut-off scores by age and education or method employed.

CONCLUSION: Caution should be exercised selecting cut-offs as these differ by age, education, and method of derivation, with the extent of adjustment varying between CSIs.

%B J Alzheimers Dis %V 57 %P 123-133 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222528?dopt=Abstract %R 10.3233/JAD-161204 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Comparison of Gait Parameters for Predicting Cognitive Decline: The Mayo Clinic Study of Aging. %A Savica, Rodolfo %A Wennberg, Alexandra M V %A Hagen, Clinton %A Edwards, Kelly %A Roberts, Rosebud O %A Hollman, John H %A Knopman, David S %A Boeve, Bradley F %A Machulda, Mary M %A Petersen, Ronald C %A Mielke, Michelle M %X

BACKGROUND: Previous studies reported that slower gait speed might predict cognitive impairment and dementing illnesses, supporting the role of gait speed as a possible subclinical marker of cognitive impairment. However, the predictive value of other gait parameters for cognitive decline is unclear.

OBJECTIVE: To investigate and compare the association with, and prediction of, specific gait parameters for cognition in a population-based sample.

METHODS: The analysis included 3,426 cognitively normal participants enrolled in the Mayo Clinic Study of Aging. At baseline and every 15 months (mean follow-up = 1.93 years), participants had a study coordinator evaluation, neurological examination, and a neuropsychological assessment using nine tests that covered four domains. Gait parameters were assessed with the GAITRite® instrument. General linear mixed effects models were used to compute the annualized rate of change in cognitive domain z-scores, controlling for age, sex, education, depression, comorbidities, body mass index, APOE ɛ4 allele, and visit number, and excluding individuals with a history of stroke, alcoholism, Parkinson's disease, subdural hematoma, and normal pressure hydrocephalus.

RESULTS: Spatial (stride length), temporal (ambulatory time, gait speed, step count, cadence, double support time), and spatiotemporal (cadence) gait parameters, and greater intraindividual variability in stride length, swing time, and stance time were associated with a significant decline in global cognition and in specific domains including memory, executive function, visuospatial, and language.

CONCLUSIONS: Spatial, temporal, and spatiotemporal measures of gait and greater variability of gait parameters were associated with and predictive of both global- and domain-specific cognitive decline.

%B J Alzheimers Dis %V 55 %P 559-567 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662317?dopt=Abstract %R 10.3233/JAD-160697 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Comparison of Model-Based Indices of Cerebral Autoregulation and Vasomotor Reactivity Using Transcranial Doppler versus Near-Infrared Spectroscopy in Patients with Amnestic Mild Cognitive Impairment. %A Marmarelis, Vasilis Z %A Shin, Dae C %A Tarumi, Takashi %A Zhang, Rong %X

We recently introduced model-based "physiomarkers" of dynamic cerebral autoregulation and CO2 vasomotor reactivity as an aid for diagnosis of early-stage Alzheimer's disease (AD) [1], where significant impairment of dynamic vasomotor reactivity (DVR) was observed in early-stage AD patients relative to age-matched controls. Milder impairment of DVR was shown in patients with amnestic mild cognitive impairment (MCI) using the same approach in a subsequent study [2]. The advocated approach utilizes subject-specific data-based models of cerebral hemodynamics to quantify the dynamic effects of resting-state changes in arterial blood pressure and end-tidal CO2 (the putative inputs) upon cerebral blood flow velocity (the putative output) measured at the middle cerebral artery via transcranial Doppler (TCD). The obtained input-output models are then used to compute model-based indices of DCA and DVR from model-predicted responses to an input pressure pulse or an input CO2 pulse, respectively. In this paper, we compare these model-based indices of DVR and DCA in 46 amnestic MCI patients, relative to 20 age-matched controls, using TCD measurements with their counterparts using Near-Infrared Spectroscopy (NIRS) measurements of blood oxygenation at the lateral prefrontal cortex in 43 patients and 22 age-matched controls. The goal of the study is to assess whether NIRS measurements can be used instead of TCD measurements to obtain model-based physiomarkers with comparable diagnostic utility. The results corroborate this view in terms of the ability of either output to yield model-based physiomarkers that can differentiate the group of aMCI patients from age-matched healthy controls.

%B J Alzheimers Dis %V 56 %P 89-105 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911329?dopt=Abstract %R 10.3233/JAD-161004 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Comprehensive Quantitative Profiling of Tau and Phosphorylated Tau Peptides in Cerebrospinal Fluid by Mass Spectrometry Provides New Biomarker Candidates. %A Russell, Claire L %A Mitra, Vikram %A Hansson, Karl %A Blennow, Kaj %A Gobom, Johan %A Zetterberg, Henrik %A Hiltunen, Mikko %A Ward, Malcolm %A Pike, Ian %X

Aberrant tau phosphorylation is a hallmark in Alzheimer's disease (AD), believed to promote formation of paired helical filaments, the main constituent of neurofibrillary tangles in the brain. While cerebrospinal fluid (CSF) levels of total tau and tau phosphorylated at threonine residue 181 (pThr181) are established core biomarkers for AD, the value of alternative phosphorylation sites, which may have more direct relevance to pathology, for early diagnosis is not yet known, largely due to their low levels in CSF and lack of standardized detection methods. To overcome sensitivity limitations for analysis of phosphorylated tau in CSF, we have applied an innovative mass spectrometry (MS) workflow, TMTcalibratortrademark, to enrich and enhance the detection of phosphoproteome components of AD brain tissue in CSF, and enable the quantitation of these analytes. We aimed to identify which tau species present in the AD brain are also detectable in CSF and which, if any, are differentially regulated with disease. Over 75% coverage of full-length (2N4R) tau was detected in the CSF with 47 phosphopeptides covering 31 different phosphorylation sites. Of these, 11 phosphopeptides were upregulated by at least 40%, along with an overall increase in tau levels in the CSF of AD patients relative to controls. Use of the TMTcalibratortrademark workflow dramatically improved our ability to detect tau-derived peptides that are directly related to human AD pathology. Further validation of regulated tau peptides as early biomarkers of AD is warranted and is currently being undertaken.

%B J Alzheimers Dis %V 55 %P 303-313 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636850?dopt=Abstract %R 10.3233/JAD-160633 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Comprehensive Screening for Disease Risk Variants in Early-Onset Alzheimer's Disease Genes in African Americans Identifies Novel PSEN Variants. %A N'Songo, Aurelie %A Carrasquillo, Minerva M %A Wang, Xue %A Nguyen, Thuy %A Asmann, Yan %A Younkin, Steven G %A Allen, Mariet %A Duara, Ranjan %A Custo, Maria T Greig %A Graff-Radford, Neill %A Ertekin-Taner, Nilufer %X

We conducted a comprehensive screening of rare coding variants in an African American cohort to identify novel pathogenic mutations within the early-onset Alzheimer's disease (EOAD) genes (APP, PSEN1, and PSEN2) in this understudied population. Whole-exome sequencing of 238 African American subjects identified 6 rare missense variants within the EOAD genes, which were observed in AD cases but never among controls. These variants were analyzed in an independent cohort of 300 African American subjects in which PSEN2:NM_000447:exon5:c.T331C:p.Phe111Leu and PSEN1-minilin rs777923890 variants were again not observed, indicating that these novel rare variants, may contribute to AD risk in this population.

%B J Alzheimers Dis %V 56 %P 1215-1222 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106563?dopt=Abstract %R 10.3233/JAD-161185 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Computerized Cognitive Screen (CoCoSc): A Self-Administered Computerized Test for Screening for Cognitive Impairment in Community Social Centers. %A Wong, Adrian %A Fong, Ching-Hang %A Mok, Vincent Chung-Tong %A Leung, Kam-Tat %A Tong, Raymond Kai-Yu %X

BACKGROUND: Computerized cognitive tests may serve as a preliminary, low-cost method to identify individuals with suspected cognitive impairment in the community.

OBJECTIVE: To develop a self-administered computerized test, namely the "Computerized Cognitive Screen (CoCoSc), Hong Kong version", for screening of individuals with cognitive impairment (CI) in community settings.

METHODS: The CoCoSc is a 15-min computerized cognitive screen covering memory, executive functions, orientation, attention and working memory, and prospective memory administered on a touchscreen computer. Individuals with CI and cognitively normal controls were administered the CoCoSc and the Montreal Cognitive Assessment (MoCA). Validity of the CoCoSc was assessed based on the relationship with the MoCA using Pearson correlation. Receiver operating characteristic curve (ROC) was used to examine the ability of the CoCoSc to differentiate CI from controls.

RESULTS: Fifty-nine individuals with CI and 101 controls were recruited. Seventy-five (46.9%) participants had ≤6 years of education. Performance on the CoCoSc differed between normal and CI groups in both low and high education subgroups. Total scores of the CoCoSc and MoCA were significantly correlated (r = 0.71, p < 0.001). The area under ROC was 0.78, p < 0.001 for the CoCoSc total score in differentiating the CI group from the cognitively normal group. A cut-off of ≤30 on the CoCoSc was associated with a sensitivity of 0.78 and specificity of 0.69. The CoCoSc was well accepted by attendees of community social centers.

CONCLUSION: The CoCoSc is a promising computerized cognitive screen for self-administration in community social centers. It is feasible for testing individuals with high or low education levels.

%B J Alzheimers Dis %V 59 %P 1299-1306 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731437?dopt=Abstract %R 10.3233/JAD-170196 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Conscientiousness is Negatively Associated with Grey Matter Volume in Young APOE ɛ4-Carriers. %A Kunz, Lukas %A Reuter, Martin %A Axmacher, Nikolai %A Montag, Christian %X

The etiology of late onset Alzheimer's disease (LOAD) depends on multiple factors, among which the APOE ɛ4 allele is the most adverse genetic determinant and conscientiousness represents an influential personality trait. A potential association of both factors with brain structure in young adulthood may constitute a constellation that sets the course toward or against the subtle disease progression of LOAD that starts decades before clinical manifestation. Hence, in the present study, we examined the modulating effects of APOE ɛ4 on the relation between personality dimensions, including conscientiousness, and total grey matter volume (GMV) in young healthy adults using an a priori genotyping design. 105 participants completed an inventory assessing the Five Factor Model of Personality (NEO-FFI) and a structural MRI scan. Total GMV was estimated using both Freesurfer as well as VBM8. Across all participants, total GMV was positively associated with extraversion and negatively related to age. In APOE ɛ4-carriers- but not in APOE ɛ4-non-carriers- conscientiousness was negatively associated with total GMV. In line with the hypothesis of antagonistic pleiotropy of the APOE ɛ4 allele, this result suggests that young APOE ɛ4-carriers with increased total GMV may particularly benefit from cognitive advantages and thus have a lower need to engage in conscientious behavior. In this subset of young APOE ɛ4-carriers, the reduction in conscientiousness could then bring along adverse health behavior in the long run, potentiating the risk for LOAD. Hence, young APOE ɛ4-carriers with increased total GMV may be at a particularly high risk for LOAD.

%B J Alzheimers Dis %V 56 %P 1135-1144 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106551?dopt=Abstract %R 10.3233/JAD-160854 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Consecutive Analysis of BACE1 Function on Developing and Developed Neuronal Cells. %A Kamikubo, Yuji %A Takasugi, Nobumasa %A Niisato, Kazue %A Hashimoto, Yoshie %A Sakurai, Takashi %X

The amyloid-β protein precursor (AβPP) is cleaved by a transmembrane protease termed β-site AβPP cleavage enzyme (BACE1), which is being explored as a target for therapy and prevention of Alzheimer's disease (AD). Although genetic deletion of BACE1 results in abolished amyloid pathology in AD model mice, it also results in neurodevelopmental phenotypes such as hypomyelination and synaptic loss, observed in schizophrenia and autism-like phenotype. These lines of evidence indicate that the inhibition of BACE1 causes adverse side effects during the neurodevelopmental stage. However, the effects of the inhibition of BACE1 activity on already developed neurons remain unclear. Here, we utilized hippocampal slice cultures as an ex vivo model that enabled continuous and long-term analysis for the effect of BACE1 inhibition on neuronal circuits and synapses. Temporal changes in synaptic proteins in hippocampal slices indicated acute synaptic loss, followed by synapse formation and maintenance phases. Long-term BACE1 inhibition in the neurodevelopmental stage caused the loss of synaptic proteins but failed to alter synaptic proteins in the already developed maintenance stage. These data indicate that BACE1 function on synapses is dependent on synaptic developmental stages, and our study provides a useful model to observe the long-term effect of BACE1 activity in the brain, and to evaluate adverse effects of BACE inhibitors.

%B J Alzheimers Dis %V 56 %P 641-653 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035928?dopt=Abstract %R 10.3233/JAD-160806 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Coordinate-Based Meta-Analysis of the Default Mode and Salience Network for Target Identification in Non-Invasive Brain Stimulation of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Networks. %A Pievani, Michela %A Pini, Lorenzo %A Ferrari, Clarissa %A Pizzini, Francesca B %A Boscolo Galazzo, Ilaria %A Cobelli, Chiara %A Cotelli, Maria %A Manenti, Rosa %A Frisoni, Giovanni B %K Alzheimer Disease %K Brain %K Databases, Bibliographic %K Deep Brain Stimulation %K Electroencephalography %K Frontotemporal Dementia %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Models, Neurological %X

BACKGROUND: The accurate choice of the site of non-invasive brain stimulation (NIBS) is an important factor in trial design.

OBJECTIVE: Based on the observation that Alzheimer's disease (AD) and behavioral frontotemporal dementia (bvFTD) affect specific large-scale networks, i.e., the default mode network (DMN) and the salience network (SN), respectively, we aimed to identify population-average coordinates of these networks that could be used as potential targets in NIBS trials aiming to modulate these circuits.

METHODS: A systematic literature search of resting-state functional MRI studies reporting DMN and SN stereotactic coordinates was performed according to PRISMA guidelines. Coordinate-based meta-analyses were conducted to identify consistent nodes of the DMN and SN using GingerALE BrainMap software and the activation likelihood estimation method.

RESULTS: DMN coordinates mapped primarily to mesial areas (posterior cingulate cortex/precuneus [Brodmann Area - BA 23/31] and medial prefrontal cortex [BA 9/10/32]). More superficial areas mapped to the bilateral parietal (angular gyrus [BA 39]), temporal (middle gyrus [BA 21]) and dorsolateral prefrontal (superior gyrus [BA 8]) cortex. SN coordinates mapped primarily to mesial and deep frontal areas (anterior insula, anterior cingulate cortex [BA 24/32]), but more superficial areas mapped to the bilateral parietal (supramarginal gyrus [BA 40]) and the right dorsolateral prefrontal (middle gyrus [BA 9/10]) cortex.

CONCLUSIONS: NIBS should target the bilateral angular, the middle temporal cortex, or superior frontal gyri in AD for DMN modulation, and the right middle frontal or supramarginal gyri in bvFTD for SN modulation.

%B J Alzheimers Dis %V 57 %P 825-843 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304293?dopt=Abstract %R 10.3233/JAD-161105 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Copy Number Variants in Alzheimer's Disease. %A Cuccaro, Denis %A De Marco, Elvira Valeria %A Cittadella, Rita %A Cavallaro, Sebastiano %X

Alzheimer's disease (AD) is a devastating disease mainly afflicting elderly people, characterized by decreased cognition, loss of memory, and eventually death. Although risk and deterministic genes are known, major genetics research programs are underway to gain further insights into the inheritance of AD. In the last years, in particular, new developments in genome-wide scanning methodologies have enabled the association of a number of previously uncharacterized copy number variants (CNVs, gain or loss of DNA) in AD. Because of the exceedingly large number of studies performed, it has become difficult for geneticists as well as clinicians to systematically follow, evaluate, and interpret the growing number of (sometime conflicting) CNVs implicated in AD. In this review, after a brief introduction of this type of structural variation, and a description of available databases, computational analyses, and technologies involved, we provide a systematic review of all published data showing statistical and scientific significance of pathogenic CNVs and discuss the role they might play in AD.

%B J Alzheimers Dis %V 55 %P 37-52 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662298?dopt=Abstract %R 10.3233/JAD-160469 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Correlation between Inflammatory Biomarkers and Polygenic Risk Score in Alzheimer's Disease. %A Morgan, Angharad R %A Touchard, Samuel %A O'Hagan, Caroline %A Sims, Rebecca %A Majounie, Elisa %A Escott-Price, Valentina %A Jones, Lesley %A Williams, Julie %A Morgan, B Paul %X

Plasma biomarkers to aid the early diagnosis of Alzheimer's disease (AD) or to monitor disease progression have long been sought and continue to be widely studied. Biomarkers that correlate with AD polygenic risk score, a measure of the polygenic architecture of the disease and highly predictive of AD status, would be excellent candidates. Therefore, we undertook a preliminary study to assess the association of plasma inflammatory biomarkers with an overall AD polygenic risk score as well as with an inflammation-specific AD polygenic risk score in a sample set of 93 AD cases. We measured five complement biomarkers [complement receptor 1 (CR1), clusterin, complement component 9 (C9), C1 inhibitor (C1inh), terminal complement complex (TCC)] and the benchmark inflammatory marker C-reactive protein (CRP). Plasma clusterin level showed an association with overall AD polygenic risk score, while clusterin, C1inh, and CRP levels each displayed some association with the inflammatory-specific AD polygenic risk score. The results suggest that elevated plasma levels of inflammatory biomarkers, including complement proteins, associate with polygenic risk scores in AD, further strengthening the link between genetic and biomarker disease predictors and indicating a potential role for these markers in disease prediction and patient stratification in AD.

%B J Alzheimers Dis %V 56 %P 25-36 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911318?dopt=Abstract %R 10.3233/JAD-160889 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cortical Cerebral Microinfarcts on 3 Tesla MRI in Patients with Vascular Cognitive Impairment. %A Ferro, Doeschka A %A van Veluw, Susanne J %A Koek, Huiberdina L %A Exalto, Lieza G %A Biessels, Geert Jan %X

BACKGROUND: Cerebral microinfarcts (CMIs) are small ischemic lesions that are a common neuropathological finding in patients with stroke or dementia. CMIs in the cortex can now be detected in vivo on 3 Tesla MRI.

OBJECTIVE: To determine the occurrence of CMIs and associated clinical features in patients with possible vascular cognitive impairment (VCI).

METHOD: 182 memory-clinic patients (mean age 71.4±10.6, 55% male) with vascular injury on brain MRI (i.e., possible VCI) underwent a standardized work-up including 3 Tesla MRI and cognitive assessment. A control group consisted of 70 cognitively normal subjects (mean age 70.6±4.7, 60% male). Cortical CMIs and other neuroimaging markers of vascular brain injury were rated according to established criteria.

RESULT: Occurrence of CMIs was higher (20%) in patients compared to controls (10%). Among patients, the presence of CMIs was associated with male sex, history of stroke, infarcts, and white matter hyperintensities. CMI presence was also associated with a diagnosis of vascular dementia and reduced performance in multiple cognitive domains.

CONCLUSION: CMIs on 3 Tesla MRI are common in patients with possible VCI and co-occur with imaging markers of small and large vessel disease, likely reflecting a heterogeneous etiology. CMIs are associated with worse cognitive performance, independent of other markers of vascular brain injury.

%B J Alzheimers Dis %V 60 %P 1443-1450 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036822?dopt=Abstract %R 10.3233/JAD-170481 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cortical Iron Reflects Severity of Alzheimer's Disease. %A van Duijn, Sara %A Bulk, Marjolein %A van Duinen, Sjoerd G %A Nabuurs, Rob J A %A van Buchem, Mark A %A van der Weerd, Louise %A Natté, Remco %X

Abnormal iron distribution in the isocortex is increasingly recognized as an in vivo marker for Alzheimer's disease (AD). However, the contribution of iron accumulation to the AD pathology is still poorly understood. In this study, we investigated: 1) frontal cortical iron distribution in AD and normal aging and 2) the relation between iron distribution and degree of AD pathology. We used formalin fixed paraffin embedded frontal cortex from 10 AD patients, 10 elder, 10 middle aged, and 10 young controls and visualized iron with a modified Perl's histochemical procedure. AD and elderly subjects were not different with respect to age and sex distribution. Iron distribution in the frontal cortex was not affected by normal aging but was clearly different between AD and controls. AD showed accumulation of iron in plaques, activated microglia, and, in the most severe cases, in the mid-cortical layers along myelinated fibers. The degree of altered iron accumulations was correlated to the amount of amyloid-β plaques and tau pathology in the same block, as well as to Braak stage (p < 0.001). AD and normal aging show different iron and myelin distribution in frontal cortex. These changes appear to occur after the development of the AD pathological hallmarks. These findings may help the interpretation of high resolution in vivo MRI and suggest the potential of using changes in iron-based MRI contrast to indirectly determine the degree of AD pathology in the frontal cortex.

%B J Alzheimers Dis %V 60 %P 1533-1545 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29081415?dopt=Abstract %R 10.3233/JAD-161143 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cortical Metabolic and Cognitive Correlates of Disorientation in Alzheimer's Disease. %A Weissberger, Gali H %A Melrose, Rebecca J %A Fanale, Candace M %A Veliz, Joseph V %A Sultzer, David L %X

Orientation to time, date, and place is commonly utilized in clinical settings to aid in diagnosis, staging, and monitoring of Alzheimer's disease (AD). This study aimed to identify the cerebral metabolic correlates of orientation in patients with AD, and the degree to which regions associated with orientation overlap with memory-related structures. Eighty-five patients with a diagnosis of probable AD underwent fluorodeoxyglucose positron emission tomography (FDG-PET) and neuropsychological testing. Orientation items from the Dementia Rating Scale and recognition performance from the Consortium to Establish a Registry for AD (CERAD) Word List Learning test were correlated with cerebral glucose metabolism. Post-hoc analyses examined neuropsychological predictors of orientation. Better orientation performance related to greater cerebral metabolism in the bilateral middle-inferior temporal lobes, bilateral middle-posterior cingulate, left angular gyrus, and left middle occipital gyrus. In comparison, higher CERAD recognition discriminability score was associated with greater metabolic activity in left medial temporal lobe regions including the hippocampal and parahippocampal gyri, and the left fusiform gyrus. Post-hoc behavioral analyses revealed multiple cognitive functions to be related to orientation, including list learning, recognition memory, visuospatial functioning, attention, and language. Findings from the present study suggest that disorientation in AD results from dysfunction of a network of structures and cognitive abilities commonly found to be implicated in AD. The study supports the notion that memory is necessary but not sufficient for successful orientation.

%B J Alzheimers Dis %V 60 %P 707-719 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869474?dopt=Abstract %R 10.3233/JAD-170420 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cortical Thickness and Depressive Symptoms in Cognitively Normal Individuals: The Mayo Clinic Study of Aging. %A Pink, Anna %A Przybelski, Scott A %A Krell-Roesch, Janina %A Stokin, Gorazd B %A Roberts, Rosebud O %A Mielke, Michelle M %A Knopman, David S %A Jack, Clifford R %A Petersen, Ronald C %A Geda, Yonas E %X

Altered cortical thickness has been observed in aging and various neurodegenerative disorders. Furthermore, reduced hippocampal volume has been reported in late-life depression. Even mild depressive symptoms are common in the elderly. However, little is known about the structural MRI measures of depressive symptoms in normal cognitive aging. Thus we sought to examine the association between depressive symptoms with cortical thickness and hippocampal volume as measured by brain MRI among community-dwelling participants. We conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging, involving cognitively normal participants (N = 1,507) aged≥70 years. We observed that depressive symptoms were associated with lower global cortical thickness and lower thickness in specific prefrontal and temporal cortical regions, labeled by FreeSurfer software, version 5.3. As expected, the strength of correlation was very small, given that participants were community-dwelling with only mild depressive symptoms. We did not observe associations between hippocampal volume and depressive symptoms. These findings may provide insight into the structural correlates of mild depressive symptoms in elderly participants.

%B J Alzheimers Dis %V 58 %P 1273-1281 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550256?dopt=Abstract %R 10.3233/JAD-170041 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cortical Thickness and Microstructural White Matter Changes Detect Amnestic Mild Cognitive Impairment. %A Wang, Zan %A Dai, Zhengjia %A Shu, Hao %A Liu, Duan %A Guo, Qihao %A He, Yong %A Zhang, Zhijun %X

Both the apolipoprotein E (APOE) ɛ4 allele and amnestic mild cognitive impairment (aMCI) are considered to be risk factors for Alzheimer's disease (AD). The primary aim of this study was to determine whether the aMCI-related abnormality in gray matter (GM) cortical thickness and white matter (WM) tracts integrity would be modified by the APOE genotype. A total of 146 older adults, including 64 aMCI patients (28 ɛ4 carriers and 36 non-carriers) and 82 healthy controls (39 ɛ4 carriers and 43 non-carriers), underwent a standardized clinical interview, neuropsychological battery assessment, and multi-modal brain magnetic resonance imaging scans. Compared with control subjects, the patients with aMCI showed significantly reduced cortical thickness bilaterally in the parahippocampal gyrus and disrupted WM integrity in the limbic tracts (e.g., increased mean diffusivity in the right parahippocampal cingulum and bilateral uncinate fasciculus). However, no significant main effects of the APOE genotype and diagnosis-by-genotype interaction on GM thickness and WM integrity were observed. Further, diffusivity measures of the limbic WM tracts were significantly correlated with the parahippocampal atrophy in aMCI. Importantly, the parahippocampal thickness and diffusivity measures of the limbic WM tracts were significantly correlated with the cognitive performance (i.e., episodic memory Z score) in patients with aMCI. These results demonstrate that WM microstructural disruptions in the limbic tracts are present at the early stage of AD in an APOE-independent manner; and this degeneration may occur progressively, in parallel with parahippocampal atrophy, and may specifically contribute to early initial impairment in episodic memory.

%B J Alzheimers Dis %V 56 %P 415-428 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911306?dopt=Abstract %R 10.3233/JAD-160724 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cost-Utility of Using Alzheimer's Disease Biomarkers in Cerebrospinal Fluid to Predict Progression from Mild Cognitive Impairment to Dementia. %A Handels, Ron L H %A Wimo, Anders %A Dodel, Richard %A Kramberger, Milica G %A Visser, Pieter Jelle %A Molinuevo, José Luis %A Verhey, Frans R J %A Winblad, Bengt %X

BACKGROUND: Diagnostic research criteria for Alzheimer's disease support the use of biomarkers in the cerebrospinal fluid (CSF) to improve the accuracy of the prognosis regarding progression to dementia for people with mild cognitive impairment (MCI).

OBJECTIVE: The aim of this study was to estimate the potential incremental cost-effectiveness ratio of adding CSF biomarker testing to the standard diagnostic workup to determine the prognosis for patients with MCI.

METHODS: In an early technology assessment, a mathematical simulation model was built, using available evidence on added prognostic value as well as expert opinion to estimate the incremental costs and quality-adjusted life years (QALYs) of 20,000 virtual MCI patients with (intervention strategy) and without (control strategy) relying on CSF, from a health-care sector perspective and with a 5-year time horizon.

RESULTS: Adding the CSF test improved the accuracy of prognosis by 11%. This resulted in an average QALY gain of 0.046 and € 432 additional costs per patient, representing an incremental cost-effectiveness ratio of € 9,416.

CONCLUSION: The results show the potential of CSF biomarkers in current practice from a health-economics perspective. This result was, however, marked by a high degree of uncertainty, and empirical research is required into the impact of a prognosis on worrying, false-positive/negative prognosis, and stigmatization.

%B J Alzheimers Dis %V 60 %P 1477-1487 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29081416?dopt=Abstract %R 10.3233/JAD-170324 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Critical Assessment of Research on Neurotransmitters in Alzheimer's Disease. %A Reddy, P Hemachandra %X

The purpose of this mini-forum, "Neurotransmitters and Alzheimer's Disease", is to critically assess the current status of neurotransmitters in Alzheimer's disease. Neurotransmitters are essential neurochemicals that maintain synaptic and cognitive functions in mammals, including humans, by sending signals across pre- to post-synaptic neurons. Authorities in the fields of synapses and neurotransmitters of Alzheimer's disease summarize the current status of basic biology of synapses and neurotransmitters, and also update the current status of clinical trials of neurotransmitters in Alzheimer's disease. This article discusses the prevalence, economic impact, and stages of Alzheimer's dementia in humans.

%B J Alzheimers Dis %V 57 %P 969-974 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28409748?dopt=Abstract %R 10.3233/JAD-170256 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cross-Cultural Applicability of the Montreal Cognitive Assessment (MoCA): A Systematic Review. %A O'Driscoll, Ciarán %A Shaikh, Madiha %X

The Montreal Cognitive Assessment (MoCA) is widely used to screen for mild cognitive impairment (MCI). While there are many available versions, the cross-cultural validity of the assessment has not been explored sufficiently. We aimed to interrogate the validity of the MoCA in a cross-cultural context: in differentiating MCI from normal controls (NC); and identifying cut-offs and adjustments for age and education where possible. This review sourced a wide range of studies including case-control studies. In addition, we report findings for differentiating dementias from NC and MCI from dementias, however, these were not considered to be an appropriate use of the MoCA. The subject of the review assumes heterogeneity and therefore meta-analyses was not conducted. Quality ratings, forest plots of validated studies (sensitivity and specificity) with covariates (suggested cut-offs, age, education and country), and summary receiver operating characteristic curve are presented. The results showed a wide range in suggested cutoffs for MCI cross-culturally, with variability in levels of sensitivity and specificity ranging from low to high. Poor methodological rigor appears to have affected reported accuracy and validity of the MoCA. The review highlights the necessity for cross-cultural considerations when using the MoCA, and recognizing it as a screen and not a diagnostic tool. Appropriate cutoffs and point adjustments for education are suggested.

%B J Alzheimers Dis %V 58 %P 789-801 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28482634?dopt=Abstract %R 10.3233/JAD-161042 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cross-Sectional and Longitudinal Cognitive Correlates of FDDNP PET and CSF Amyloid-β and Tau in Parkinson's Disease1. %A Buongiorno, Mariateresa %A Antonelli, Francesca %A Compta, Yaroslau %A Fernandez, Yolanda %A Pavía, Javier %A Lomeña, Francisco %A Ríos, José %A Ramírez, Isabel %A García, José Ramón %A Soler, Marina %A Cámara, Ana %A Fernández, Manel %A Basora, Misericòrdia %A Salazar, Fàtima %A Sanchez-Etayo, Gerard %A Valldeoriola, Francesc %A Barrio, Jorge Raúl %A Marti, Maria Jose %X

Tau and amyloid-β (Aβ) aggregates have been suggested to play a role in the development of dementia in Parkinson's disease (PD). Positron emission tomography (PET) with [18F]FDDNP and the determination of cerebrospinal fluid (CSF) levels of these proteins constitute a means to visualize in vivo Aβ and tau brain accumulation. Information about longitudinal changes of these CSF and PET biomarkers in PD with regard to progression to dementia is lacking. We assessed the cross-sectional and longitudinal associations of CSF and PET biomarkers of tau and Aβ with PD-related cognitive dysfunction in 6 healthy-controls (HC), 16 patients with PD without dementia (PDND), and 8 PD with dementia (PDD). All subjects underwent comprehensive neuropsychological testing, [18F]FDDNP PET, and CSF Aβ-tau determination. After 18 months, the PDND group was re-assessed clinically and by neuropsychological, PET, and CSF determinations. Cross-sectionally, PDD had higher [18F]FDDNP binding in lateral temporal regions and lower levels of CSF Aβ levels compared to PDND, with a congruent correlation between the [18F]FDDNP binding and CSF Aβ levels. Longitudinally, higher baseline lateral temporal [18F]FDDNP binding was associated to longitudinal worsening in cognitive performances and progression to dementia among subjects classified as PDND at baseline, who additionally disclosed at follow-up an increase in lateral-temporal FDDNP binding, as well as a reduction in CSF Aβ and an increase in CSF tau levels. These results confirm the relevance of these CSF and PET biomarkers to PDD, being specifically the first to show [18F]FDDNP PET as a dementia risk biomarker in PD, along with longitudinal CSF and PET changes over time.

%B J Alzheimers Dis %V 55 %P 1261-1272 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27814297?dopt=Abstract %R 10.3233/JAD-160698 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Cross-Validation of FDG- and Amyloid-PET Biomarkers in Mild Cognitive Impairment for the Risk Prediction to Dementia due to Alzheimer's Disease in a Clinical Setting. %A Iaccarino, Leonardo %A Chiotis, Konstantinos %A Alongi, Pierpaolo %A Almkvist, Ove %A Wall, Anders %A Cerami, Chiara %A Bettinardi, Valentino %A Gianolli, Luigi %A Nordberg, Agneta %A Perani, Daniela %X

Assessments of brain glucose metabolism (18F-FDG-PET) and cerebral amyloid burden (11C-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer's disease (ADD). This study investigates, in a clinical setting, the separate and combined values of 18F-FDG-PET and 11C-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for 18F-FDG-PET and of standardized uptake value ratio semiquantification for 11C-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57±7.78 years). Fourteen subjects converted to ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, 18F-FDG-PET and 11C-PiB-PET. 18F-FDG-PET, compared to 11C-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both 18F-FDG-PET and 11C-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings.

%B J Alzheimers Dis %V 59 %P 603-614 %G eng %N 2 %R 10.3233/JAD-170158 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer's Disease. %A Sundaram, Jeyapriya Raja %A Poore, Charlene Priscilla %A Sulaimee, Noor Hazim Bin %A Pareek, Tej %A Cheong, Wei Fun %A Wenk, Markus R %A Pant, Harish C %A Frautschy, Sally A %A Low, Chian-Ming %A Kesavapany, Sashi %X

Several studies have indicated that neuroinflammation is indeed associated with neurodegenerative disease pathology. However, failures of recent clinical trials of anti-inflammatory agents in neurodegenerative disorders have emphasized the need to better understand the complexity of the neuroinflammatory process in order to unravel its link with neurodegeneration. Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer's disease (AD). Recent studies show an association between p25/Cdk5 hyperactivation and robust neuroinflammation. In addition, we recently reported the novel link between the p25/Cdk5 hyperactivation-induced inflammatory responses and neurodegenerative changes using a transgenic mouse that overexpresses p25 (p25Tg). In this study, we aimed to understand the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on p25-mediated neuroinflammation and the progression of neurodegeneration in p25Tg mice. The results from this study showed that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice. Moreover, this curcumin-mediated suppression of neuroinflammation reduced the progression of p25-induced tau/amyloid pathology and in turn ameliorated the p25-induced cognitive impairments. It is widely acknowledged that to treat AD, one must target the early-stage of pathological changes to protect neurons from irreversible damage. In line with this, our results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, our data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases.

%B J Alzheimers Dis %V 60 %P 1429-1442 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036814?dopt=Abstract %R 10.3233/JAD-170093 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Curcumin Inhibits Tau Aggregation and Disintegrates Preformed Tau Filaments in vitro. %A Rane, Jitendra Subhash %A Bhaumik, Prasenjit %A Panda, Dulal %X

The pathological aggregation of tau is a common feature of most of the neuronal disorders including frontotemporal dementia, Parkinson's disease, and Alzheimer's disease. The inhibition of tau aggregation is considered to be one of the important strategies for treating these neurodegenerative diseases. Curcumin, a natural polyphenolic molecule, has been reported to have neuroprotective ability. In this work, curcumin was found to bind to adult tau and fetal tau with a dissociation constant of 3.3±0.4 and 8±1 μM, respectively. Molecular docking studies indicated a putative binding site of curcumin in the microtubule-binding region of tau. Using several complementary techniques, including dynamic light scattering, thioflavin S fluorescence, 90° light scattering, electron microscopy, and atomic force microscopy, curcumin was found to inhibit the aggregation of tau. The dynamic light scattering analysis and atomic force microscopic images revealed that curcumin inhibits the oligomerization of tau. Curcumin also disintegrated preformed tau oligomers. Using Far-UV circular dichroism, curcumin was found to inhibit the β-sheets formation in tau indicating that curcumin inhibits an initial step of tau aggregation. In addition, curcumin inhibited tau fibril formation. Furthermore, the effect of curcumin on the preformed tau filaments was analyzed by atomic force microscopy, transmission electron microscopy, and 90° light scattering. Curcumin treatment disintegrated preformed tau filaments. The results indicated that curcumin inhibited the oligomerization of tau and could disaggregate tau filaments.

%B J Alzheimers Dis %V 60 %P 999-1014 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984591?dopt=Abstract %R 10.3233/JAD-170351 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Current Approaches and Clinician Attitudes to the Use of Cerebrospinal Fluid Biomarkers in Diagnostic Evaluation of Dementia in Europe. %A Miller, Anne-Marie %A Balasa, Mircea %A Blennow, Kaj %A Gardiner, Mary %A Rutkowska, Aleksandra %A Scheltens, Philip %A Teunissen, Charlotte E %A Visser, Pieter Jelle %A Winblad, Bengt %A Waldemar, Gunhild %A Lawlor, Brian %X

BACKGROUND: BIOMARKAPD seeks to diminish the barriers associated with the clinical use of cerebrospinal fluid (CSF) biomarker analysis by reducing variation in CSF laboratory methodologies and generating consensus recommendations on their clinical interpretation and application for dementia diagnosis.

OBJECTIVE: To examine the disparity in practitioner attitudes and clinical practice relating to the use of CSF biomarkers for dementia diagnosis across Europe.

METHODS: Clinical dementia experts were surveyed on the prevalence of national consensus guidelines and analytical reimbursement across Europe, their biomarker platform preferences, lumbar puncture methodologies and application of reference values and cut-offs for CSF analysis.

RESULTS: 74% of respondents (total n = 51) use CSF biomarkers in clinical practice and 69% perform lumbar punctures on an outpatient basis. Most use CSF biomarkers to diagnose atypical (84%) and early-onset cases of cognitive impairment (71%) and for the differential diagnosis of other dementias (69%). 82% state they are sufficiently informed about CSF biomarkers yet 61% report a lack of national consensus guidelines on their use for dementia diagnosis. 48% of countries represented do not reimburse clinical CSF analysis costs. 43% report using normal reference ranges derived from publications.

CONCLUSION: Variations in attitude and practice relating to CSF biomarkers, widely recognised as barriers to their clinical acceptance, remain evident within and between countries across Europe, even in expert centres. These shortcomings must be addressed by developing consensus guidelines on CSF-related methodologies and their clinical application, to further their use for the diagnostic evaluation of dementia.

%B J Alzheimers Dis %V 60 %P 201-210 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826189?dopt=Abstract %R 10.3233/JAD-170502 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cyclic cis-Locked Phospho-Dipeptides Reduce Entry of AβPP into Amyloidogenic Processing Pathway. %A Fisher, Carolyn L %A Resnick, Ross J %A De, Soumya %A Acevedo, Lucila A %A Lu, Kun Ping %A Schroeder, Frank C %A Nicholson, Linda K %X

The cis/trans isomerization of X-Pro peptide bonds in proteins in some instances acts as a molecular switch in biological pathways. Our prior work suggests that the cis isomer of the phospho-Thr668-Pro669 motif, located in the cytoplasmic domain of the amyloid-β protein precursor (AβPP), is correlated with an increase in amyloidogenic processing of AβPP and production of amyloid-beta (Aβ), the neurotoxic peptide fragment in Alzheimer's disease (AD). We designed a 100% cis-locked cyclic dipeptide composed of cyclized phospho-Thr-Pro (pCDP) as a mimic for this putative pathological conformation, and three phosphate-blocked derivatives (pCDP-diBzl, pCDP-Bzl, and pCDP-diPOM). Two H4 neuroglioma cell lines were established as AD cell models for use in testing these compounds: H4-AβPP695 for stable overexpression of wild-type AβPP695, and H4-BACE1 for stable overexpression of β-site AβPP cleaving enzyme-1 (BACE1). The level of the secreted AβPP fragment resulting from BACE1 activity, sAβPPβ, served as a key proxy for amyloidogenic processing, since cleavage of AβPP by BACE1 is a requisite first step in Aβ production. Of the compounds tested, pCDP-diBzl decreased sAβPPβ levels in both cell lines, while pCDP-diPOM decreased sAβPPβ levels in only H4-BACE1 cells, all with similar dose-dependences and patterns of proteolytic AβPP fragments. Enzymatic assays showed that none of the pCDP derivatives directly inhibit BACE1 catalytic activity. These results suggest a model in which pCDP-diBzl and pCDP-diPOM act at a common point to inhibit entry of AβPP into the amyloidogenic AβPP processing pathway but through different targets, and provide important insights for the development of novel AD therapeutics.

%B J Alzheimers Dis %V 55 %P 391-410 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662285?dopt=Abstract %R 10.3233/JAD-160051 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cyclophilin D Promotes Brain Mitochondrial F1FO ATP Synthase Dysfunction in Aging Mice. %A Gauba, Esha %A Guo, Lan %A Du, Heng %X

Brain aging is the known strongest risk factor for Alzheimer's disease (AD). In recent years, mitochondrial deficits have been proposed to be a common mechanism linking brain aging to AD. Therefore, to elucidate the causative mechanisms of mitochondrial dysfunction in aging brains is of paramount importance for our understanding of the pathogenesis of AD, in particular its sporadic form. Cyclophilin D (CypD) is a specific mitochondrial protein. Recent studies have shown that F1FO ATP synthase oligomycin sensitivity conferring protein (OSCP) is a binding partner of CypD. The interaction of CypD with OSCP modulates F1FO ATP synthase function and mediates mitochondrial permeability transition pore (mPTP) opening. Here, we have found that increased CypD expression, enhanced CypD/OSCP interaction, and selective loss of OSCP are prominent brain mitochondrial changes in aging mice. Along with these changes, brain mitochondria from the aging mice demonstrated decreased F1FO ATP synthase activity and defective F1FO complex coupling. In contrast, CypD deficient mice exhibited substantially mitigated brain mitochondrial F1FO ATP synthase dysfunction with relatively preserved mitochondrial function during aging. Interestingly, the aging-related OSCP loss was also dramatically attenuated by CypD depletion. Therefore, the simplest interpretation of this study is that CypD promotes F1FO ATP synthase dysfunction and the resultant mitochondrial deficits in aging brains. In addition, in view of CypD and F1FO ATP synthase alterations seen in AD brains, the results further suggest that CypD-mediated F1FO ATP synthase deregulation is a shared mechanism linking mitochondrial deficits in brain aging and AD.

%B J Alzheimers Dis %V 55 %P 1351-1362 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27834780?dopt=Abstract %R 10.3233/JAD-160822 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Daily Physical Activity Patterns During the Early Stage of Alzheimer's Disease. %A Varma, Vijay R %A Watts, Amber %X

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that results in severe disability. Very few studies have explored changes in daily physical activity patterns during early stages of AD when components of physical function and mobility may be preserved.

OBJECTIVE: Our study explored differences in daily physical activity profiles, independent of the effects of non-cognitive factors including physical function and age, among individuals with mild AD compared to controls.

METHODS: Patients with mild AD and controls (n = 92) recruited from the University of Kansas Alzheimer's Disease Center Registry, wore the Actigraph GT3X+ for seven days, and provided objective physical function (VO2 max) and mobility data. Using multivariate linear regression, we explored whether individuals with mild AD had different daily average and diurnal physical activity patterns compared to controls independent of non-cognitive factors that may affect physical activity, including physical function and mobility.

RESULTS: We found that mild AD was associated with less moderate-intensity physical activity (p < 0.05), lower peak activity (p < 0.01), and lower physical activity complexity (p < 0.05) particularly during the morning. Mild AD was not associated with greater sedentary activity or less lower-intensity physical activity across the day after adjusting for non-cognitive covariates.

CONCLUSIONS: These findings suggest that factors independent of physical capacity and mobility may drive declines in moderate-intensity physical activity, and not lower-intensity or sedentary activity, during the early stage of AD. This underscores the importance of a better mechanistic understanding of how cognitive decline and AD pathology impact physical activity. Findings emphasize the potential value of designing and testing time-of-day specific physical activity interventions targeting individuals in the early stages of AD, prior to significant declines in mobility and physical function.

%B J Alzheimers Dis %V 55 %P 659-667 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716669?dopt=Abstract %R 10.3233/JAD-160582 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Damage to the Frontal Aslant Tract Accounts for Visuo-Constructive Deficits in Alzheimer's Disease. %A Serra, Laura %A Gabrielli, Giulia Bechi %A Tuzzi, Elisa %A Spanò, Barbara %A Giulietti, Giovanni %A Failoni, Virginia %A Marra, Camillo %A Caltagirone, Carlo %A Koch, Giacomo %A Cercignani, Mara %A Bozzali, Marco %X

The frontal aslant tract (FAT) has been described as a bundle connecting the Broca's area to the supplementary motor area (SMA) and the pre-SMA in both hemispheres. The functional properties of this tract and its role in degenerative dementia, such as Alzheimer's disease (AD), still need to be fully clarified. The aim of this study was to explore the microstructural integrity of the FAT in patients with AD and its potential relationship with cognitive functioning. Twenty-three patients with AD and 25 healthy subjects (HS) were enrolled. All subjects underwent cognitive and MRI examination. MRI, including diffusion sequences, was used for probabilistic tractography analysis. We reconstructed individual FATs bilaterally and assessed their microstructural integrity using fractional anisotropy (FA), computed as both mean tract value and voxel-wise using SPM-8. Mean FA values were then used to test for correlations with cognitive measures. Mean tract FA and voxel-wise analyses revealed that patients with AD, compared to HS, had decreased FA in the FAT bilaterally. In addition, positive associations were found between FA in the FATs and patients' performance at tests for constructional praxis and visuospatial logical reasoning. The present results reveal a bilateral damage of FAT in AD patients. The association between FATs' microscopic abnormalities and constructive abilities fits well with the knowledge of a functional involvement of SMA and pre-SMA in movement sequences when executing constructive praxis tasks. The FAT is an associative bundle critically involved in the network sub-serving constructional praxis in patients with AD.

%B J Alzheimers Dis %V 60 %P 1015-1024 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984608?dopt=Abstract %R 10.3233/JAD-170638 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Death of Dementia Patients in Psychiatric Hospitals and Regional Supply of Psychiatric Services: Study of the National Data from 1996 to 2014 in Japan. %A Nakanishi, Miharu %A Niimura, Junko %A Yamasaki, Syudo %A Nishida, Atsushi %X

BACKGROUND: Japan designates psychiatric inpatient care for behavior management of individuals with dementia and for helping dementia patients discharge to home. However, there has been no examination of the effectiveness of this strategy.

OBJECTIVE: The present study investigated the association between dementia and the discharge destination of patients in psychiatric hospitals.

METHODS: Data from the National Patient Survey, which is a nationally representative cross-sectional survey of inpatient care, were used. The 96,420 patients with dementia or other mental illness who were discharged from psychiatric hospitals in September of every 3 years from 1996 to 2014 were included in analyses.

RESULTS: Of the 96,420 discharged patients, 13,823 had dementia as the primary disease. Of the 13,823 dementia patients, 3,865 (28.0%) were discharged to home, 3,870 (28.0%) were admitted to a facility or other care settings, 3,574 (25.9%) were admitted to another hospital, and 2,514 (18.2%) died. Patients were more likely to die in psychiatric hospital if their primary disease was dementia, and they had resided in a region that provided fewer home visits for psychiatric nursing care or had available a larger number of psychiatric hospital beds per capita.

CONCLUSION: Psychiatric inpatient care may be ineffective as a treatment for the challenging behaviors of dementia. A community mental health system for behavior management should be constructed in parallel with a reduction in the number of hospital beds allotted for psychiatric care.

%B J Alzheimers Dis %V 56 %P 817-824 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059786?dopt=Abstract %R 10.3233/JAD-160935 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Decrease of Amyloid-β Levels by Curcumin Derivative via Modulation of Amyloid-β Protein Precursor Trafficking. %A Kotani, Rina %A Urano, Yasuomi %A Sugimoto, Hachiro %A Noguchi, Noriko %X

The abnormal production and deposition of amyloid-β (Aβ) peptides is a pathologic hallmark of Alzheimer's disease. Aβ is generated from amyloid-β protein precursor (AβPP) by two sequential proteolytic cleavage steps involving β- and γ-secretases in the trans-Golgi network and endosomes. Since direct inhibition of secretase could induce undesirable side-effects due to inadvertent inhibition of unrelated secretase substrates, it is important to establish methods for inhibiting Aβ production that do not affect secretase activity. It has been suggested that curcumin may have potent anti-amyloidogenic effect. In the present study, we evaluate the effect of curcumin derivatives on Aβ production in human neuroblastoma SH-SY5Y cells and in CHO cells which stably express human AβPP (CHO-AβPP). We found that the curcumin derivative CU6 was more effective than curcumin itself in reducing Aβ secretion. We further found that in SH-SY5Y cells CU6 inhibited neither β- nor γ-secretase activity, and that increased amounts of immature forms of AβPP accumulated in the endoplasmic reticulum (ER). We also found that CU6 induced expression of the ER chaperone glucose-regulated protein 78 (GRP78), and enhanced formation of the AβPP/GRP78 complex. These results suggest that CU6 downregulates intracellular AβPP trafficking, resulting in suppression of Aβ production independently of secretase activity.

%B J Alzheimers Dis %V 56 %P 529-542 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983550?dopt=Abstract %R 10.3233/JAD-160794 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Decreased Expression of hsa-miR-4274 in Cerebrospinal Fluid of Normal Pressure Hydrocephalus Mimics with Parkinsonian Syndromes. %A Jurjević, Ivana %A Miyajima, Masakazu %A Ogino, Ikuko %A Akiba, Chihiro %A Nakajima, Madoka %A Kondo, Akihide %A Kikkawa, Mika %A Kanai, Mitsuyasu %A Hattori, Nobutaka %A Arai, Hajime %X

BACKGROUND: Patients presenting with the classical idiopathic normal pressure hydrocephalus (iNPH) triad often show additional parkinsonian spectrum signs. Accurate differential diagnosis strongly influences the long-term outcome of cerebrospinal fluid (CSF) shunting.

OBJECTIVE: The aim of this study was to find potential CSF microRNA (miRNA) biomarkers for NPH mimics with parkinsonian syndromes that can reliably distinguish them from iNPH patients.

METHODS: Two cohorts of 81 patients (cohort 1, n = 55; cohort 2, n = 26) with possible iNPH who were treated in two centers between January 2011 and May 2014 were studied. In both cohorts, CSF samples were obtained from patients clinically diagnosed with iNPH (n = 21 and n = 10, respectively), possible iNPH with parkinsonian spectrum (PS) (n = 18, n = 10, respectively), possible iNPH with Alzheimer's disease (AD) (n = 16), and non-affected elderly individuals (NC) (n = 6). A three-step qRT-PCR analysis of the CSF samples was performed to detect miRNAs that were differentially expressed in the groups.

RESULTS: The expression of hsa-miR-4274 in CSF was decreased in both cohorts of PS group patients (cohort 1: p < 0.0001, cohort 2: p < 0.0001), and was able to distinguish PS from iNPH with high accuracy (area under the curve = 0.908). The CSF concentration of hsa-miR-4274 also correlated with the specific binding ratio of ioflupane (123I) dopamine transporter scan (r = -0.494, p = 0.044). By contrast, the level of hsa-miR-4274 was significantly increased in the PS group after CSF diversion.

CONCLUSION: Levels of CSF hsa-miR-4274 can differentiate PS from patients with iNPH, AD, and NC. This may be clinically useful for diagnostic purposes and predicting shunt treatment responses.

%B J Alzheimers Dis %V 56 %P 317-325 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911315?dopt=Abstract %R 10.3233/JAD-160848 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Decreased Glucose Metabolism in Medial Prefrontal Areas is Associated with Nutritional Status in Patients with Prodromal and Early Alzheimer's Disease. %A Sugimoto, Taiki %A Nakamura, Akinori %A Kato, Takashi %A Iwata, Kaori %A Saji, Naoki %A Arahata, Yutaka %A Hattori, Hideyuki %A Bundo, Masahiko %A Ito, Kengo %A Niida, Shumpei %A Sakurai, Takashi %X

BACKGROUND: Weight loss is frequently observed in patients with Alzheimer's disease (AD); however, the underlying mechanisms are not well understood.

OBJECTS: To clarify the associations between nutritional status and AD-related brain changes using Pittsburgh Compound-B (PiB)-PET, fluorodeoxyglucose (FDG)-PET, and structural MRI.

METHODS: The subjects were 34 amyloid-β (Aβ)-positive individuals with mild cognitive impairment or early AD (prodromal/early AD), and 55 Aβ-negative cognitively normal (CN) subjects who attended the Multimodal Neuroimaging for AD Diagnosis (MULNIAD) study. Nutritional status of the subjects was assessed by body mass index and waist to height ratio (waist circumference/height). The associations between nutritional status and brain changes were examined by multiple regression analysis using statistical parametric mapping.

RESULTS: In the prodromal/early AD group, nutritional status was significantly positively correlated with regional cerebral glucose metabolism (rCGM) in the medial prefrontal cortices, while different topographical associations were seen in the CN group, suggesting these changes were AD-specific. Aβ deposition and gray matter volume were not significantly associated with nutritional status. Sub-analysis in the prodromal/early AD group demonstrated that fat mass index, but not fat-free mass index, was positively correlated with rCGM in the medial prefrontal areas.

CONCLUSION: This present study provides preliminary results suggesting that hypometabolism in the medial prefrontal areas is specifically associated with AD-related weight loss, and decrease in fat mass may have a key role.

%B J Alzheimers Dis %V 60 %P 225-233 %G eng %N 1 %R 10.3233/JAD-170257 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Decreased Methylation of the Mitochondrial D-Loop Region in Late-Onset Alzheimer's Disease. %A Stoccoro, Andrea %A Siciliano, Gabriele %A Migliore, Lucia %A Coppedè, Fabio %X

Mitochondrial impairment is a feature of neurodegeneration and many investigators have suggested that epigenetic modifications of the mitochondrial DNA (mtDNA) might be involved in late-onset Alzheimer's disease (LOAD), but evidence in humans is limited. We assessed the methylation levels of the mtDNA D-loop region in blood DNA from 133 LOAD patients and 130 controls, observing a significant 25% reduction of DNA methylation levels in the first group (2.3 versus 3.1%). Overall, the present data indicate that there is a decreased methylation of the D-loop region in LOAD peripheral blood DNA, suggesting that mtDNA epimutations deserve further investigations in AD pathogenesis.

%B J Alzheimers Dis %V 59 %P 559-564 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28655136?dopt=Abstract %R 10.3233/JAD-170139 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Decreased N-Acetyl Aspartate/Myo-Inositol Ratio in the Posterior Cingulate Cortex Shown by Magnetic Resonance Spectroscopy May Be One of the Risk Markers of Preclinical Alzheimer's Disease: A 7-Year Follow-Up Study. %A Waragai, Masaaki %A Moriya, Masaru %A Nojo, Takeshi %X

Although molecular positron emission tomography imaging of amyloid and tau proteins can facilitate the detection of preclinical Alzheimer's disease (AD) pathology, it is not useful in clinical practice. More practical surrogate markers for preclinical AD would provide valuable tools. Thus, we sought to validate the utility of conventional magnetic resonance spectroscopy (MRS) as a screening method for preclinical AD. A total of 289 older participants who were cognitively normal at baseline were clinically followed up for analysis of MRS metabolites, including N-acetyl aspartate (NAA) and myo-inositol (MI) in the posterior cingulate cortex (PCC) for 7 years. The 289 participants were retrospectively divided into five groups 7 years after baseline: 200 (69%) remained cognitively normal; 53 (18%) developed mild cognitive impairment (MCI); 21 (7%) developed AD; eight (2%) developed Parkinson's disease with normal cognition, and seven (2%) developed dementia with Lewy bodies (DLB). The NAA/MI ratios of the PCC in the AD, MCI, and DLB groups were significantly decreased compared with participants who maintained normal cognition from baseline to 7 years after baseline. MMSE scores 7 years after baseline were significantly correlated with MI/Cr and NAA/MI ratios in the PCC. These results suggest that cognitively normal elderly subjects with low NAA/MI ratios in the PCC might be at risk of progression to clinical AD. Thus, the NAA/MI ratio in the PCC measured with conventional 1H MRS should be reconsidered as a possible adjunctive screening marker of preclinical AD in clinical practice.

%B J Alzheimers Dis %V 60 %P 1411-1427 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28968236?dopt=Abstract %R 10.3233/JAD-170450 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Deep Brain Stimulation for Alzheimer's Disease: Ethical Challenges for Clinical Research. %A Siegel, Andrew M %A Barrett, Marna S %A Bhati, Mahendra T %X

Deep brain stimulation (DBS) is an invasive neuromodulation modality that has shown early promise as a novel treatment of Alzheimer's disease (AD). Further clinical research is warranted on the basis of positive results from animal and human studies, as well as the inadequacy of existing treatments in reducing the enormous medical and financial costs of untreated AD. Nevertheless, unique ethical challenges require particular attention to elements of subject enrollment and informed consent. Study protocols should specify robust assessment and regular monitoring of subject decision-making capacity to consent to trial participation. Investigators should also assess for and mitigate therapeutic misconception (the phenomenon whereby a research participant conflates the goals of research with those of clinical treatment) and ensure that all prospective trial participants have adequate post-trial access to treatment and DBS device maintenance. In the following discussion, each issue is summarized and followed by recommendations for proper ethical procedure. We conclude by assimilating relevant ethical considerations into a decision-making algorithm designed to aid future clinical investigators of DBS for AD with the task of ethical subject enrollment.

%B J Alzheimers Dis %V 56 %P 429-439 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983548?dopt=Abstract %R 10.3233/JAD-160356 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Deficit in Central Auditory Processing as a Biomarker of Pre-Clinical Alzheimer's Disease. %A Tuwaig, Miranda %A Savard, Mélissa %A Jutras, Benoît %A Poirier, Judes %A Collins, D Louis %A Rosa-Neto, Pedro %A Fontaine, David %A Breitner, John C S %X

Prevention of dementia due to Alzheimer's disease (d/AD) requires interventions that slow the disease process prior to symptom onset. To develop such interventions, one needs metrics that assess pre-symptomatic disease progression. Familiar measures of progression include cerebrospinal fluid (CSF) biochemical and imaging analyses, as well as cognitive testing. Changes in the latter can sometimes be difficult to distinguish from effects of "normal" aging. A different approach involves testing of "central auditory processing" (CAP), which enables comprehension of auditory stimuli amidst a distracting background (e.g., conversation in a noisy bar or restaurant). Such comprehension is often impaired in d/AD. Similarly, effortful or diminished auditory comprehension is sometimes reported by cognitively healthy elders, raising the possibility that CAP deficit may be a marker of pre-symptomatic AD. In 187 cognitively and physically healthy members of the aging, AD family history-positive PREVENT-AD cohort, we therefore evaluated whether CAP deficits were associated with known markers of AD neurodegeneration. Such markers included CSF tau concentrations and magnetic resonance imaging volumetric and cortical thickness measures in key AD-related regions. Adjusting for age, sex, education, pure-tone hearing, and APOEɛ4 status, we observed a persistent relationship between CAP scores and CSF tau levels, entorhinal and hippocampal cortex volumes, cortical thickness, and deficits in cognition (Repeatable Battery for Assessment of Neuropsychological Status total score, and several of its index scales). These cross-sectional observations suggest that CAP may serve as a novel metric for pre-symptomatic AD pathogenesis. They are therefore being followed up longitudinally with larger samples.

%B J Alzheimers Dis %V 60 %P 1589-1600 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984583?dopt=Abstract %R 10.3233/JAD-170545 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Delayed Recall and Working Memory MMSE Domains Predict Delirium following Cardiac Surgery. %A Price, Catherine C %A Garvan, Cynthia %A Hizel, Loren P %A Lopez, Marcos G %A Billings, Frederic T %X

BACKGROUND: Reduced preoperative cognition is a risk factor for postoperative delirium. The significance for type of preoperative cognitive deficit, however, has yet to be explored and could provide important insights into mechanisms and prediction of delirium.

OBJECTIVE: Our goal was to determine if certain cognitive domains from the general cognitive screener, the Mini-Mental State Exam (MMSE), predict delirium after cardiac surgery.

METHODS: Patients completed a preoperative MMSE prior to undergoing elective cardiac surgery. Following surgery, delirium was assessed throughout ICU stay using the Confusion Assessment Method for ICU delirium and the Richmond Agitation and Sedation Scale.

RESULTS: Cardiac surgery patients who developed delirium (n = 137) had lower total MMSE scores than patients who did not develop delirium (n = 457). In particular, orientation to place, working memory, delayed recall, and language domain scores were lower. Of these, only the working memory and delayed recall domains predicted delirium in a regression model adjusting for history of chronic obstructive pulmonary disease, age, sex, and duration of cardiopulmonary bypass. For each word not recalled on the three-word delayed recall assessment, the odds of delirium increased by 50%. For each item missed on the working memory index, the odds of delirium increased by 36%. Of the patients who developed delirium, 47% had a primary impairment in memory, 21% in working memory, and 33% in both domains. The area under the receiver operating characteristics curve using only the working memory and delayed recall domains was 0.75, compared to 0.76 for total MMSE score.

CONCLUSION: Delirium risk is greater for individuals with reduced MMSE scores on the delayed recall and working memory domains. Research should address why patients with memory and executive vulnerabilities are more prone to postoperative delirium than those with other cognitive limitations.

%B J Alzheimers Dis %V 59 %P 1027-1035 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697572?dopt=Abstract %R 10.3233/JAD-170380 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Deleterious Effect of Butyrylcholinesterase K-Variant in Donepezil Treatment of Mild Cognitive Impairment. %A Sokolow, Sophie %A Li, Xiaohui %A Chen, Lucia %A Taylor, Kent D %A Rotter, Jerome I %A Rissman, Robert A %A Aisen, Paul S %A Apostolova, Liana G %X

BACKGROUND: Donepezil is an acetylcholinesterase inhibitor frequently prescribed for the treatment of mild cognitive impairment (MCI) though not approved by the Food and Drug Administration for this indication. In Alzheimer's disease, butyrylcholinesterase (BChE) activity increases with disease progression and may replace acetylcholinesterase function. The most frequent polymorphism of BChE is the K-variant, which is associated with lower acetylcholine-hydrolyzing activity. BChE-K polymorphism has been studied in Alzheimer's disease progression and donepezil therapy, and has led to contradictory results.

OBJECTIVES: To determine whether BChE-K genotype predicts response to donepezil in MCI.

METHODS: We examined the association between BChE-K genotype and changes in cognitive function using the data collected during the ADCS vitamin E/donepezil clinical trial in MCI.

RESULTS: We found significant interactions between BChE-K genotype and the duration of donepezil treatment, with increased changes in MMSE and CDR-SB scores compared to the common allele in MCI subjects treated during the 3-year trial. We found faster MMSE decline and CDR-SB rise in BChE-K homozygous individuals treated with donepezil compared to the untreated. We observed similar interactions between BChE-K genotype and steeper changes in MMSE and CDR-SB scores in APOE4 carriers treated with donepezil compared to controls.

CONCLUSION: BChE-K polymorphisms are associated with deleterious changes in cognitive decline in MCI patients treated with donepezil for 3 years. This indicates that BChE-K genotyping should be performed to help identify subsets of subjects at risk for donepezil therapy, like those carrying APOE4. BChE-K and APOE4 carriers should not be prescribed off-label donepezil therapy for MCI management.

%B J Alzheimers Dis %V 56 %P 229-237 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911294?dopt=Abstract %R 10.3233/JAD-160562 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dementia and Pressure Ulcers: Is There a Close Pathophysiological Interrelation? %A Jaul, Efraim %A Meiron, Oded %X

The current theoretical investigation aimed to explore common pathophysiological mechanisms underlying dementia and pressure ulcers (PU). Along with the increased longevity, especially in frail elderly patients, there is a higher rate of functional and cognitive impairment with dementia coinciding with immobility, which results in a higher rate of PU. Understanding common etiological paths resulting in pressure ulcers and dementia is likely to produce new treatment strategies that could lead to the prevention of comorbid complications. Data collected from elderly dementia patients indicate a deterioration of several neurophysiological subsystems associated with motor, sensory, autonomic, cognitive, or behavioral pathways, supporting a "close pathophysiological interrelation" perspective linking PU with dementia progression. Overall, the authors' theoretical systemic-model of disease progression and PU comorbidity proposes that increased clinician awareness to PU in mild to moderate dementia may suppress the accelerated development of PU, resulting in less patient suffering, reduced long-term care hospitalization, and hopefully PU prevention.

%B J Alzheimers Dis %V 56 %P 861-866 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035938?dopt=Abstract %R 10.3233/JAD-161134 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dementia Prevalence in a Rural Region of South Africa: A Cross-Sectional Community Study. %A de Jager, Celeste A %A Msemburi, William %A Pepper, Katy %A Combrinck, Marc I %X

BACKGROUND: Dementia is a growing concern for low- and middle-income countries where longevity is increasing and service provision is poor. Global prevalence estimates vary from 2% to 8.5% for those aged 60 years and older. There have been few dementia studies in sub-Saharan Africa, and prevalence data are lacking for South Africa.

OBJECTIVE: To conduct a large dementia prevalence study in a low income rural population in South Africa.

METHODS: 1,394 Xhosa-speaking community dwellers, aged ≥60 y (mean age±sd 71.3±8.3 y), in three clinic catchment areas, were screened at home. Trained community health workers administered the brief Community Screening Instrument for Dementia (CSID) to participants and informants to assess cognitive and functional capacity. Depressive symptoms were assessed with three questions from the EURO-D.

RESULTS: The prevalence estimate using published CSID sensitivity/specificity values was 0.8 (95% CI: 0.06-0.09). Using CSID cut-off scores the estimated prevalence was 0.12 (95% CI: 0.10-0.13), with 161 screen-positives. Both methods gave a rate of 0.11 (95% CI: 0.09-0.13) for those over 65 years (n = 1051). 68.6% of participants were female and 69.8% had less than 7 years of education. Dementia risk was associated with older age and symptoms of depression, but not with sex. The association with education was not significant when controlled for by age.

CONCLUSIONS: Dementia prevalence estimates were higher than expected for this low-income rural community. There is a need for increased dementia awareness and feasible support interventions. We also need further studies of regional prevalences, dementia subtypes, and modifiable risk factors in South Africa.

%B J Alzheimers Dis %V 60 %P 1087-1096 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984589?dopt=Abstract %R 10.3233/JAD-170325 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dementia Pugilistica Revisited. %A Castellani, Rudy J %A Perry, George %X

 Extensive exposure of boxers to neurotrauma in the early 20th century led to the so-called punch drunk syndrome, which was formally recognized in the medical literature in 1928. "Punch drunk" terminology was replaced by the less derisive 'dementia pugilistica' in 1937. In the early case material, the diagnosis of dementia pugilistica required neurological deficits, including slurring dysarthria, ataxia, pyramidal signs, extrapyramidal signs, memory impairment, and personality changes, although the specific clinical substrate has assumed lesser importance in recent years with a shift in focus on molecular pathogenesis. The postmortem neuropathology of dementia pugilistica has also evolved substantially over the past 90 years, from suspected concussion-related hemorrhages to diverse structural and neurofibrillary changes to geographic tauopathy. Progressive neurodegenerative tauopathy is among the prevailing theories for disease pathogenesis currently, although this may be overly simplistic. Careful examination of historical cases reveals both misdiagnoses and a likelihood that dementia pugilistica at that time was caused by cumulative structural brain injury. More recent neuropathological studies indicate subclinical and possibly static tauopathy in some athletes and non-athletes. Indeed, it is unclear from the literature whether retired boxers reach the inflection point that tends toward progressive neurodegeneration in the manner of Alzheimer's disease due to boxing. Even among historical cases with extreme levels of exposure, progressive disease was exceptional.

%B J Alzheimers Dis %V 60 %P 1209-1221 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036831?dopt=Abstract %R 10.3233/JAD-170669 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dementia Screening Accuracy is Robust to Premorbid IQ Variation: Evidence from the Addenbrooke's Cognitive Examination-III and the Test of Premorbid Function. %A Stott, Joshua %A Scior, Katrina %A Mandy, William %A Charlesworth, Georgina %X

BACKGROUND: Scores on cognitive screening tools for dementia are associated with premorbid IQ. It has been suggested that screening scores should be adjusted accordingly. However, no study has examined whether premorbid IQ variation affects screening accuracy.

OBJECTIVE: To investigate whether the screening accuracy of a widely used cognitive screening tool for dementia, the Addenbrooke's cognitive examination-III (ACE-III), is improved by adjusting for premorbid IQ.

METHODS: 171 UK based adults (96 memory service attendees diagnosed with dementia and 75 healthy volunteers over the age of 65 without subjective memory impairments) completed the ACE-III and the Test of Premorbid Function (TOPF). The difference in screening performance between the ACE-III alone and the ACE-III adjusted for TOPF was assessed against a reference standard; the presence or absence of a diagnosis of dementia (Alzheimer's disease, vascular dementia, or others).

RESULTS: Logistic regression and receiver operating curve analyses indicated that the ACE-III has excellent screening accuracy (93% sensitivity, 94% specificity) in distinguishing those with and without a dementia diagnosis. Although ACE-III scores were associated with TOPF scores, TOPF scores may be affected by having dementia and screening accuracy was not improved by accounting for premorbid IQ, age, or years of education.

CONCLUSION: ACE-III screening accuracy is high and screening performance is robust to variation in premorbid IQ, age, and years of education. Adjustment of ACE-III cut-offs for premorbid IQ is not recommended in clinical practice. The analytic strategy used here may be useful to assess the impact of premorbid IQ on other screening tools.

%B J Alzheimers Dis %V 57 %P 1293-1302 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372334?dopt=Abstract %R 10.3233/JAD-161218 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Depressive Symptoms and Tau Accumulation in the Inferior Temporal Lobe and Entorhinal Cortex in Cognitively Normal Older Adults: A Pilot Study. %A Gatchel, Jennifer R %A Donovan, Nancy J %A Locascio, Joseph J %A Schultz, Aaron P %A Becker, J Alex %A Chhatwal, Jasmeer %A Papp, Kathryn V %A Amariglio, Rebecca E %A Rentz, Dorene M %A Blacker, Deborah %A Sperling, Reisa A %A Johnson, Keith A %A Marshall, Gad A %X

BACKGROUND: Depressive symptoms are common in older adults and associated with increased morbidity and cognitive decline. These symptoms occur during preclinical and prodromal stages of Alzheimer's disease (AD), but their relationship to tau, one of the main AD proteinopathies, is poorly understood.

OBJECTIVE: The objective of this study was to investigate the cross-sectional association between depressive symptoms and cerebral tau [18F T807 (also known as 18F-AV-1451) tau positron emission tomography (PET) imaging] in cognitively normal (CN) older adults.

METHODS: We measured depressive symptoms using the Geriatric Depression Scale (GDS), and in vivo cerebral tau using T807 PET in 111 CN older adults. We employed general linear regression models to evaluate the relationship of GDS score regressed on entorhinal cortex (EC) or inferior temporal (IT) tau in separate backward elimination models. Other predictors included age, sex, and in secondary analyses, amyloid (Pittsburgh Compound B PET).

RESULTS: Higher GDS was significantly associated with greater IT tau (partial r = 0.188, p = 0.050) and marginally associated with greater EC tau (partial r = 0.183, p = 0.055). In additional analyses including both linear and quadratic age terms, we found a significant U-shaped relation of GDS to age (p = 0.001).

CONCLUSIONS: Results suggest that IT and EC tau are modestly associated with depressive symptoms in CN older adults. Findings suggest a link between depressive symptoms and tau-mediated neurodegeneration in a region vulnerable in AD. Future longitudinal studies examining the association of more severe depressive symptoms and cerebral tau accumulation are needed to substantiate this finding and to guide prevention and treatment in AD.

%B J Alzheimers Dis %V 59 %P 975-985 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697559?dopt=Abstract %R 10.3233/JAD-170001 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Depressive Symptoms are Associated with Progression to Dementia in Patients with Amyloid-Positive Mild Cognitive Impairment. %A Moon, Byungseung %A Kim, Seongheon %A Park, Young Ho %A Lim, Jae-Sung %A Youn, Young Chul %A Kim, SangYun %A Jang, Jae-Won %X

BACKGROUND: Depressive symptoms are prevalent in patients with mild cognitive impairment (MCI) and are considered to be a risk factor for progression to dementia.

OBJECTIVE: The purpose of this study was to evaluate whether depressive symptoms in MCI promote disease progression in a manner related to amyloid status, and to determine the relationship between depressive symptoms and longitudinal cerebral structural changes.

METHODS: Baseline data for 336 patients with MCI (75 with depression and 261 without) from the Alzheimer's Disease Neuroimaging Initiative study were analyzed. All participants underwent comprehensive cognitive testing, volumetric magnetic resonance imaging (MRI), and [18F]AV45 positron emission tomography amyloid imaging. Depressive symptoms were measured using the Neuropsychiatric Inventory Questionnaire. A voxel-based morphometric analysis using volumetric brain MRI data was used to compare longitudinal structural changes related to depressive symptoms.

RESULTS: The conversion rate to dementia was different between patients with and without depression in amyloid-positive MCI (40.8% versus 19.7%, respectively; p = 0.006). Patients who were amyloid-positive at baseline also exhibited a greater degree of 2-year cognitive decline. Depression in amyloid-positive MCI was associated with longitudinal cortical atrophy in the left cingulate gyrus.

CONCLUSION: Our study indicates that the presence of depressive symptoms in patients with amyloid-positive MCI is associated with higher progression to dementia and longitudinal cortical atrophy.

%B J Alzheimers Dis %V 58 %P 1255-1264 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550264?dopt=Abstract %R 10.3233/JAD-170225 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Detecting At-Risk Alzheimer's Disease Cases. %A Fladby, Tormod %A Pålhaugen, Lene %A Selnes, Per %A Waterloo, Knut %A Bråthen, Geir %A Hessen, Erik %A Almdahl, Ina Selseth %A Arntzen, Kjell-Arne %A Auning, Eirik %A Eliassen, Carl Fredrik %A Espenes, Ragna %A Grambaite, Ramune %A Grøntvedt, Gøril Rolfseng %A Johansen, Krisztina Kunszt %A Johnsen, Stein Harald %A Kalheim, Lisa Flem %A Kirsebom, Bjørn-Eivind %A Müller, Kai Ivar %A Nakling, Arne Exner %A Rongve, Arvid %A Sando, Sigrid Botne %A Siafarikas, Nikias %A Stav, Ane Løvli %A Tecelao, Sandra %A Timon, Santiago %A Bekkelund, Svein Ivar %A Aarsland, Dag %X

While APOEɛ4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aβ42 (pAβ) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAβ and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAβ compared to NC, and cases recruited from memory clinics had higher fractions of pAβ and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAβ enriched, whereas self-referred and NCFD cases more frequently are pAβ negative but at risk (APOEɛ4 positive), suitable for primary intervention.

%B J Alzheimers Dis %V 60 %P 97-105 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826181?dopt=Abstract %R 10.3233/JAD-170231 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Development of a Late-Life Dementia Prediction Index with Supervised Machine Learning in the Population-Based CAIDE Study. %A Pekkala, Timo %A Hall, Anette %A Lötjönen, Jyrki %A Mattila, Jussi %A Soininen, Hilkka %A Ngandu, Tiia %A Laatikainen, Tiina %A Kivipelto, Miia %A Solomon, Alina %X

BACKGROUND AND OBJECTIVE: This study aimed to develop a late-life dementia prediction model using a novel validated supervised machine learning method, the Disease State Index (DSI), in the Finnish population-based CAIDE study.

METHODS: The CAIDE study was based on previous population-based midlife surveys. CAIDE participants were re-examined twice in late-life, and the first late-life re-examination was used as baseline for the present study. The main study population included 709 cognitively normal subjects at first re-examination who returned to the second re-examination up to 10 years later (incident dementia n = 39). An extended population (n = 1009, incident dementia 151) included non-participants/non-survivors (national registers data). DSI was used to develop a dementia index based on first re-examination assessments. Performance in predicting dementia was assessed as area under the ROC curve (AUC).

RESULTS: AUCs for DSI were 0.79 and 0.75 for main and extended populations. Included predictors were cognition, vascular factors, age, subjective memory complaints, and APOE genotype.

CONCLUSION: The supervised machine learning method performed well in identifying comprehensive profiles for predicting dementia development up to 10 years later. DSI could thus be useful for identifying individuals who are most at risk and may benefit from dementia prevention interventions.

%B J Alzheimers Dis %V 55 %P 1055-1067 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802228?dopt=Abstract %R 10.3233/JAD-160560 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Development of Nasal Lipid Nanocarriers Containing Curcumin for Brain Targeting. %A Vaz, Gustavo Richter %A Hädrich, Gabriela %A Bidone, Juliana %A Rodrigues, Jamile Lima %A Falkembach, Mariana Corrêa %A Putaux, Jean-Luc %A Hort, Mariana Appel %A Monserrat, José Maria %A Varela Junior, Antônio Sergio %A Teixeira, Helder Ferreira %A Muccillo-Baisch, Ana Luiza %A Horn, Ana Paula %A Dora, Cristiana Lima %X

BACKGROUND: Curcumin (CUR) has properties that can be useful for the treatment of Alzheimer's disease. Such properties are the inhibition of amyloid-β-protein (Aβ) aggregation, Aβ-induced inflammation, and activities of β-secretase and acetylcholinesterase. However, previous studies have revealed that CUR exhibited low bioavailability and difficulties in reaching the brain.

OBJECTIVE: To overcome such drawbacks, this study aims at developing nasal lipid nanocarriers loaded with CUR to effectively target the brain.

METHODS: The lipid nanocarriers (NE) were prepared using the hot solvent diffusion associated with the phase inversion temperature methods. Physico-chemical and morphological characterizations and in vitro drug release of the nanocarriers were carried out. The CUR permeation/retention was analyzed in Franz-type diffusion cell using porcine nasal mucosa. Confocal laser scan and histopathological studies were also performed.

RESULTS: The results showed that the NE sizes ranged between 18 nm and 44 nm with negative zeta potential. The CUR content ranged from 0.24 to 1.50 mg/mL with an encapsulation efficiency of 99%. The profiles of CUR release indicated a biphasic kinetics. CUR-NE permeation across the porcine nasal mucosa was higher when compared to free CUR. These results have also been validated through an analysis on a confocal microscopy. In addition, no toxicity on the nasal mucosa has been observed in a histopathological analysis.

CONCLUSION: These results suggest that it is possible to develop NEs with a high content of CUR and small particle size. Such an encapsulation increases the potential of CUR permeation across the porcine nasal mucosa.

%B J Alzheimers Dis %V 59 %P 961-974 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731428?dopt=Abstract %R 10.3233/JAD-160355 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Diabetes and Alzheimer's Disease: Can Elevated Free Copper Predict the Risk of the Disease? %A Squitti, Rosanna %A Mendez, Armando J %A Simonelli, Ilaria %A Ricordi, Camillo %X

BACKGROUND: Defective copper regulation, primarily referred to as chelatable redox active Cu(II), has been involved in the etiology of diabetes, and Alzheimer's disease (AD).

OBJECTIVES: However, no study has determined levels of labile copper non-bound to ceruloplasmin (non-Cp Cu, also known as 'free' copper) in the blood of subjects with diabetes compared with that of AD patients.

METHODS: To this aim, values of non-Cp Cu were measured in 25 Type 1 (T1D) and 31 Type 2 (T2D) subjects and in28 healthy controls, along with measurements of C-reactive protein, glycated hemoglobin A1c, cholesterol, and triglycerides. Non-Cp Cu levels were compared with those of an AD group previously studied.

RESULTS: T2D subjects had significantly higher non-Cp Cu levels than Controls and T1D subjects (both p < 0.001 after adjusting for age, sex, and body mass index). A multinomial logistic model revealed that a one unit standard deviation increase of non-Cp Cu increased the relative risk of having T2D by 9.64 with respect to Controls (95% CI: 2.86-32.47). The comparison of non-Cp Cu levels in T2D with those of an AD population previously studied shows rising blood non-Cp Cu copper levels from Controls to T2D and AD.

CONCLUSION: These results suggest the involvement of catalytically-active Cu(II) and glucose dysregulation in oxidative stress reactions leading to tissue damage in both diseases.

%B J Alzheimers Dis %V 56 %P 1055-1064 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983558?dopt=Abstract %R 10.3233/JAD-161033 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Diabetes and Alzheimer's Disease: Can Tea Phytochemicals Play a Role in Prevention? %A Fernando, Warnakulasuriya M A D B %A Somaratne, Geeshani %A Goozee, Kathryn G %A Williams, Shehan %A Singh, Harjinder %A Martins, Ralph N %X

Dementia and diabetes mellitus are prevalent disorders in the elderly population. While recognized as two distinct diseases, diabetes has more recently recognized as a significant contributor to risk for developing dementia, and some studies make reference to type 3 diabetes, a condition resulting from insulin resistance in the brain. Alzheimer's disease, the most common form of dementia, and diabetes, interestingly, share underlying pathological processes, commonality in risk factors, and, importantly, pathways for intervention. Tea has been suggested to possess potent antioxidant properties. It is rich in phytochemicals including, flavonoids, tannins, caffeine, polyphenols, boheic acid, theophylline, theobromine, anthocyanins, gallic acid, and finally epigallocatechin-3-gallate, which is considered to be the most potent active ingredient. Flavonoid phytochemicals, known as catechins, within tea offer potential benefits for reducing the risk of diabetes and Alzheimer's disease by targeting common risk factors, including obesity, hyperlipidemia, hypertension, cardiovascular disease, and stroke. Studies also show that catechins may prevent the formation of amyloid-β plaques and enhance cognitive functions, and thus may be useful in treating patients who have Alzheimer's disease or dementia. Furthermore, other phytochemicals found within tea offer important antioxidant properties along with innate properties capable of modulating intracellular neuronal signal transduction pathways and mitochondrial function.

%B J Alzheimers Dis %V 59 %P 481-501 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582855?dopt=Abstract %R 10.3233/JAD-161200 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Diabetes is Not Associated with Alzheimer's Disease Neuropathology. %A Dos Santos Matioli, Maria Niures Pimentel %A Suemoto, Claudia Kimie %A Rodriguez, Roberta Diehl %A Farias, Daniela Souza %A da Silva, Magnólia Moreira %A Leite, Renata Elaine Paraizo %A Ferretti-Rebustini, Renata Eloah Lucena %A Farfel, José Marcelo %A Pasqualucci, Carlos Augusto %A Jacob Filho, Wilson %A Arvanitakis, Zoe %A Naslavsky, Michel Satya %A Zatz, Mayana %A Grinberg, Lea Tenenholz %A Nitrini, Ricardo %X

BACKGROUND: Previous evidence linking diabetes to Alzheimer's disease (AD) neuropathology is mixed and scant data are available from low- and middle-income countries.

OBJECTIVE: To investigate the association between diabetes and AD neuropathology in a large autopsy study of older Brazilian adults.

METHODS: In this cross-sectional study, diabetes was defined by diagnosis during life or use of antidiabetic medication. A standardized neuropathological examination was performed using immunohistochemistry. The associations of diabetes with Consortium to Establish and Registry for Alzheimer Disease (CERAD) scores for neuritic plaques and Braak-Braak (BB) scores for neurofibrillary tangles were investigated using multivariable ordinal logistic regression. We investigated effect modification of education, race, and APOE on these associations.

RESULTS: Among 1,037 subjects (mean age = 74.4±11.5 y; mean education = 4.0±3.7 y; 48% male, 61% White), diabetes was present in 279 subjects. Diabetes was not associated with BB (OR = 1.12, 95% CI = 0.81-1.54, p = 0.48) or with CERAD (OR = 0.97, 95% CI = 0.68-1.38, p = 0.86) scores on analyses adjusted for sociodemographic and clinical variables. We observed effect modification by the APOE allele ɛ4 on the association between diabetes mellitus and BB scores.

CONCLUSION: No evidence of an association between diabetes and AD neuropathology was found in a large sample of Brazilians; however, certain subgroups, such as APOE allele ɛ4 carriers, had higher odds of accumulation of neurofibrillary tangles.

%B J Alzheimers Dis %V 60 %P 1035-1043 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984587?dopt=Abstract %R 10.3233/JAD-170179 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Diagnostic Accuracy of a Combined Analysis of Cerebrospinal Fluid t-PrP, t-tau, p-tau, and Aβ42 in the Differential Diagnosis of Creutzfeldt-Jakob Disease from Alzheimer's Disease with Emphasis on Atypical Disease Variants. %A Abu Rumeileh, Samir %A Lattanzio, Francesca %A Stanzani Maserati, Michelangelo %A Rizzi, Romana %A Capellari, Sabina %A Parchi, Piero %X

According to recent studies, the determination of cerebrospinal fluid (CSF) total tau (t-tau)/phosphorylated tau (p-tau) ratio and total prion protein (t-PrP) levels significantly improves the accuracy of the diagnosis of Alzheimer's disease (AD) in atypical cases with clinical or laboratory features mimicking Creutzfeldt-Jakob disease (CJD). However, this has neither been validated nor tested in series including atypical CJD variants. Furthermore, the added diagnostic value of amyloid-β (Aβ)42 remains unclear. To address these issues, we measured t-PrP, 14-3-3, t-tau, p-tau, and Aβ 42 CSF levels in 45 typical and 44 atypical/rapidly progressive AD patients, 54 typical and 54 atypical CJD patients, and 33 controls. CJD patients showed significantly lower CSF t-PrP levels than controls and AD patients. Furthermore, atypical CJD was associated with lower t-PrP levels in comparison to typical CJD. T-tau, 14-3-3, or t-PrP alone yielded, respectively, 80.6, 63.0, and 73.0% sensitivity and 75.3, 92.1, and 75% specificity in distinguishing AD from CJD. On receiver operating characteristic (ROC) curve analyses of biomarker combinations, the (t-tau×Aβ 42)/(p-tau×t-PrP) ratio achieved the best accuracy, with 98.1% sensitivity and 97.7% specificity overall, and 96.2% sensitivity and 95.5% specificity for the "atypical" disease groups. Our results show that the combined analysis of CSF t-PrP, t-tau, p-tau, and Aβ 42 is clinically useful in the differential diagnosis between CJD and AD. Furthermore, the finding of reduced CSF t-PrP levels in CJD patients suggest that, likewise Aβ 42 in AD, CSF t-PrP levels reflect the extent of PrPc conversion into abnormal PrP (PrPSc) and the burden of PrPSc deposition in CJD.

%B J Alzheimers Dis %V 55 %P 1471-1480 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27886009?dopt=Abstract %R 10.3233/JAD-160740 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Diagnostic and Prognostic Value of Neuropsychological Assessment in Memory Clinic Patients. %A Jansen, Willemijn J %A Handels, Ron L H %A Visser, Pieter Jelle %A Aalten, Pauline %A Bouwman, Femke %A Claassen, Jurgen %A van Domburg, Peter %A Hoff, Erik %A Hoogmoed, Jan %A Leentjens, Albert F G %A Rikkert, Marcel Olde %A Oleksik, Ania M %A Smid, Machiel %A Scheltens, Philip %A Wolfs, Claire %A Verhey, Frans %A Ramakers, Inez H G B %X

BACKGROUND: Neuropsychological testing has long been embedded in daily clinical practice at memory clinics but the added value of a complete neuropsychological assessment (NPA) to standard clinical evaluation is unknown.

OBJECTIVE: To evaluate the added diagnostic and prognostic value of NPA to clinical evaluation only in memory clinic patients.

METHODS: In 221 memory clinic patients of a prospective cohort study, clinical experts diagnosed clinical syndrome (subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or dementia) and etiology (Alzheimer's disease (AD) or no AD), and provided a prognosis of disease course (decline or no decline) before and after results of NPA were made available. The reference standard was a panel consensus based on all clinical information at baseline and up to 2 follow-up assessments.

RESULTS: With NPA data available, clinicians changed their initial syndromal diagnosis in 22% of patients, and the etiological diagnosis as well as the prognosis in 15%. This led to an increase in correctly classified cases of 18% for syndromal diagnosis, 5% for etiological diagnosis, and 1% for prognosis. NPA data resulted in the largest improvement in patients initially classified as SCI (syndrome: 93.3% (n = 14) correctly reclassified, etiology: net reclassification improvement [NRI] = 0.61, prognosis: NRI = 0.13) or MCI (syndrome: 89.3% (n = 23) correctly reclassified, etiology: NRI = 0.17, prognosis: NRI = 0.14), while there was no improvement in patients with dementia (syndrome: 100% (n = 1) correctly reclassified, etiology: NRI = -0.05, prognosis: NRI = -0.06). Overall, inclusion of NPA in the diagnostic process increased confidence in all diagnoses with 6-7%.

CONCLUSION: Administration of a complete NPA after standard clinical evaluation has added value for diagnosing cognitive syndrome and its underlying etiology in patients regarded as non-demented based on the first clinical impression.

%B J Alzheimers Dis %V 55 %P 679-689 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716658?dopt=Abstract %R 10.3233/JAD-160126 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Diagnostic and Prognostic Value of the Combination of Two Measures of Verbal Memory in Mild Cognitive Impairment due to Alzheimer's Disease. %A Sala, Isabel %A Illán-Gala, Ignacio %A Alcolea, Daniel %A Sánchez-Saudinós, Ma Belén %A Salgado, Sergio Andrés %A Morenas-Rodriguez, Estrella %A Subirana, Andrea %A Videla, Laura %A Clarimón, Jordi %A Carmona-Iragui, María %A Ribosa-Nogué, Roser %A Blesa, Rafael %A Fortea, Juan %A Lleo, Alberto %X

BACKGROUND: Episodic memory impairment is the core feature of typical Alzheimer's disease.

OBJECTIVE: To evaluate the performance of two commonly used verbal memory tests to detect mild cognitive impairment due to Alzheimer's disease (MCI-AD) and to predict progression to Alzheimer's disease dementia (AD-d).

METHODS: Prospective study of MCI patients in a tertiary memory disorder unit. Patients underwent an extensive neuropsychological battery including two tests of declarative verbal memory: The Free and Cued Selective Reminding Test (FCSRT) and the word list learning task from the Consortium to Establish a Registry for Alzheimer's disease (CERAD-WL). Cerebrospinal fluid (CSF) was obtained from all patients and MCI-AD was defined by means of the t-Tau/Aβ1-42 ratio. Logistic regression analyses tested whether the combination of FCSRT and CERAD-WL measures significantly improved the prediction of MCI-AD. Progression to AD-d was analyzed in a Cox regression model.

RESULTS: A total of 202 MCI patients with a mean follow-up of 34.2±24.2 months were included and 98 (48.5%) met the criteria for MCI-AD. The combination of FCSRT and CERAD-WL measures improved MCI-AD classification accuracy based on CSF biomarkers. Both tests yielded similar global predictive values (59.9-65.3% and 59.4-62.8% for FCSRT and CERAD-WL, respectively). MCI-AD patients with deficits in both FCSRT and CERAD-WL had a faster progression to AD-d than patients with deficits in only one test.

CONCLUSIONS: The combination of FCSRT and CERAD-WL improves the classification of MCI-AD and defines different prognostic profiles. These findings have important implications for clinical practice and the design of clinical trials.

%B J Alzheimers Dis %V 58 %P 909-918 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527215?dopt=Abstract %R 10.3233/JAD-170073 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Diagnostic Biomarkers of Alzheimer's Disease as Identified in Saliva using 1H NMR-Based Metabolomics. %A Yilmaz, Ali %A Geddes, Tim %A Han, BeomSoo %A Bahado-Singh, Ray O %A Wilson, George %A Imam, Khaled %A Maddens, Michael %A Graham, Stewart F %X

Using 1H NMR metabolomics, we biochemically profiled saliva samples collected from healthy-controls (n = 12), mild cognitive impairment (MCI) sufferers (n = 8), and Alzheimer's disease (AD) patients (n = 9). We accurately identified significant concentration changes in 22 metabolites in the saliva of MCI and AD patients compared to controls. This pilot study demonstrates the potential for using metabolomics and saliva for the early diagnosis of AD. Given the ease and convenience of collecting saliva, the development of accurate and sensitive salivary biomarkers would be ideal for screening those at greatest risk of developing AD.

%B J Alzheimers Dis %V 58 %P 355-359 %G eng %N 2 %R 10.3233/JAD-161226 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Diagnostic Value of a Tablet-Based Drawing Task for Discrimination of Patients in the Early Course of Alzheimer's Disease from Healthy Individuals. %A Müller, Stephan %A Preische, Oliver %A Heymann, Petra %A Elbing, Ulrich %A Laske, Christoph %X

There is a considerable delay in the diagnosis of dementia, which may reduce the effectiveness of available treatments. Thus, it is of great interest to develop fast and easy to perform, non-invasive and non-expensive diagnostic measures for the early detection of cognitive impairment and dementia. Here we investigate movement kinematics between 20 patients with early dementia due to Alzheimer's disease (eDAT), 30 patients with amnestic mild cognitive impairment (aMCI), and 20 cognitively healthy control (HC) individuals while copying a three-dimensional house using a digitizing tablet. Receiver-operating characteristic (ROC) curves and logistic regression analyzes have been conducted to explore whether alterations in movement kinematics could be used to discriminate patients with aMCI and eDAT from healthy individuals. Time-in-air (i.e., transitioning from one stroke to the next without touching the surface) differed significantly between patients with aMCI, eDAT, and HCs demonstrating an excellent sensitivity and a moderate specificity to discriminate aMCI subjects from normal elderly and an excellent sensitivity and specificity to discriminate patients affected by mild Alzheimer's disease from healthy individuals. Time-on-surface (i.e., time while stylus is touching the surface) differed only between HCs and patients with eDAT but not between HCs and patients with aMCI. Furthermore, total-time (i.e., time-in-air plus time-on-surface) did not differ between patients with aMCI and early dementia due to AD. Modern digitizing devices offer the opportunity to measure a broad range of visuoconstructive abilities that may be used as a fast and easy to perform screening instrument for the early detection of cognitive impairment and dementia in primary care.

%B J Alzheimers Dis %V 55 %P 1463-1469 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858717?dopt=Abstract %R 10.3233/JAD-160921 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Diaschisis-Like Association of Hippocampal Atrophy and Posterior Cingulate Cortex Hypometabolism in Cognitively Normal Elderly Depends on Impaired Integrity of Parahippocampal Cingulum Fibers. %A Fischer, Florian U %A Wolf, Dominik %A Fellgiebel, Andreas %X

Hippocampal atrophy and hypometabolism of the posterior cingulate cortex (PCC), early markers of Alzheimer's disease (AD), have been shown to be associated in late mild cognitive impairment and early AD via atrophy of connecting cingulum fibers. Recently, a direct association of hippocampal atrophy and PCC hypometabolism has been shown in cognitively normal elderly. We aimed to investigate if this association might be modulated by partly non-hippocampogenic alterations of parahippocampal cingulum (PHC) integrity. 45 cognitively healthy elderly aged 59 to 89 years were included from the Alzheimer's Disease Neuroimaging Initiative. Hippocampal volumes and PCC glucose metabolism were measured using MRI and FDG-PET. PHC fibers connecting the hippocampus and the PCC were reconstructed using diffusion weighted MRI and measures of diffusivity were calculated. Using robust linear regression, interaction effects of PHC diffusivity and hippocampal volume on PCC metabolism were calculated. For both hemispheres, significant interaction effects were found for PHC mean diffusivity. Interaction effects were such that the association of hippocampal volume and PCC metabolism was higher in subjects with increased mean diffusivity in PHC fibers. In cognitively normal elderly, compromised integrity of the PHC may increase the risk of PCC hypometabolism due to hippocampal atrophy. Spared PHC fiber integrity may protect against PCC hypometabolism due to hippocampal atrophy.

%B J Alzheimers Dis %V 60 %P 1285-1294 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036815?dopt=Abstract %R 10.3233/JAD-170147 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dickkopf 3 (Dkk3) Improves Amyloid-β Pathology, Cognitive Dysfunction, and Cerebral Glucose Metabolism in a Transgenic Mouse Model of Alzheimer's Disease. %A Zhang, Li %A Sun, Caixian %A Jin, Yaxi %A Gao, Kai %A Shi, Xudong %A Qiu, Wenying %A Ma, Chao %A Zhang, Lianfeng %X

Dysfunctional Wnt signaling is associated with Alzheimer's disease (AD), and activation of the Wnt signaling pathway inhibits AD development. Dickkopf 3 (Dkk3) is a modulator of the Wnt signaling pathway and is physiologically expressed in the brain. The role of Dkk3 in the pathogenesis of AD has not been evaluated. In the present study, we determined that Dkk3 expression was significantly decreased in brain tissue from AD patients and the AD transgenic mouse model APPswe/PS1dE9 (AD mice). Transgenic mice with brain tissue-specific Dkk3 expression were generated or crossed with AD mice to study the effects of Dkk3 on AD. In AD mice, transgenic expression of Dkk3 improved abnormalities in learning, memory, and locomotor activity, reduced the accumulation of amyloid-β, and ameliorated glucose uptake deficits. Furthermore, we determined that Dkk3 downregulated GSK-3β, a central negative regulator in canonical Wnt signaling, and upregulated PKCβ1, a factor implicated in noncanonical Wnt signaling. This indicates that increased activation of GSK-3β and the inhibition of PKCβ1 in AD patients may be responsible for the dysfunctional Wnt signaling in AD. In summary, our data suggest that Dkk3 is an agonist of Wnt signaling, and the ability of transgenic expression of Dkk3 to compensate for the decrease in Dkk3 expression in AD mice, reverse dysfunctional Wnt signaling, and partially inhibit the pathological development of AD suggests that Dkk3 could serve as a therapeutic target for the treatment of AD.

%B J Alzheimers Dis %V 60 %P 733-746 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922151?dopt=Abstract %R 10.3233/JAD-161254 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dietary Lycopene Supplementation Improves Cognitive Performances in Tau Transgenic Mice Expressing P301L Mutation via Inhibiting Oxidative Stress and Tau Hyperphosphorylation. %A Yu, Lixia %A Wang, Weiguang %A Pang, Wei %A Xiao, Zhonghai %A Jiang, Yugang %A Hong, Yan %X

BACKGROUND: Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD) and other tauopathies and participates in their development by promoting hyperphosphorylation of microtubule-associated protein tau. Lycopene, as an effective antioxidant, combined with vitamin E seemed to be additive against oxidative stress.

OBJECTIVE: The present study was undertaken to examine whether lycopene or lycopene/vitamin E could exert protective effects on memory deficit and oxidative stress in tau transgenic mice expressing P301L mutation.

MATERIALS AND METHODS: P301L transgenic mice were assigned to three groups: P301L group (P301L), P301L+lycopene (Lyc), and P301L+lycopene/vitamin E (Lyc+VE). Age-matched C57BL/6J mice as wild type controls (Con) were used in the present study. Spatial memory was assessed by radial arm while passive memories were evaluated by step-down and step-through tests. Levels of tau phosphorylation were detected by western blot. Oxidative stress biomarkers were measured in the serum using biochemical assay kits.

RESULTS: Compared with the control group, P301L mice displayed significant spatial and passive memory impairments, elevated malondialdehyde (MDA) levels and decreased glutathione peroxidase (GSH-Px) activities in serum, and increased tau phosphorylation at Thr231/Ser235, Ser262, and Ser396 in brain. Supplementations of lycopene or lycopene/vitamin E could significantly ameliorate the memory deficits, observably decreased MDA concentrations and increased GSH-Px activities, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites.

CONCLUSIONS: Our findings indicated that the combination of lycopene and vitamin E antioxidants acted in a synergistic fashion to bring significant effects against oxidative stress in tauopathies.

%B J Alzheimers Dis %V 57 %P 475-482 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269786?dopt=Abstract %R 10.3233/JAD-161216 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Differential Hemispheric Predilection of Microstructural White Matter and Functional Connectivity Abnormalities between Respectively Semantic and Behavioral Variant Frontotemporal Dementia. %A Meijboom, Rozanna %A Steketee, Rebecca M E %A Ham, Leontine S %A van der Lugt, Aad %A van Swieten, John C %A Smits, Marion %X

Semantic dementia (SD) and behavioral variant frontotemporal dementia (bvFTD), subtypes of frontotemporal dementia, are characterized by distinct clinical symptoms and neuroimaging features, with predominant left temporal grey matter (GM) atrophy in SD and bilateral or right frontal GM atrophy in bvFTD. Such differential hemispheric predilection may also be reflected by other neuroimaging features, such as brain connectivity. This study investigated white matter (WM) microstructure and functional connectivity differences between SD and bvFTD, focusing on the hemispheric predilection of these differences. Eight SD and 12 bvFTD patients, and 17 controls underwent diffusion tensor imaging and resting state functional MRI at 3T. Whole-brain WM microstructure was assessed to determine distinct WM tracts affected in SD and bvFTD. For these tracts, diffusivity measures and lateralization indices were calculated. Functional connectivity was established for GM regions affected in early stage SD or bvFTD. Results of a direct comparison between SD and bvFTD are reported. Whole-brain WM microstructure abnormalities were more pronounced in the left hemisphere in SD and bilaterally- with a slight predilection for the right- in bvFTD. Lateralization of tract-specific abnormalities was seen in SD only, toward the left hemisphere. Functional connectivity of disease-specific regions was mainly decreased bilaterally in SD and in the right hemisphere in bvFTD. SD and bvFTD show WM microstructure and functional connectivity abnormalities in different regions, that are respectively more pronounced in the left hemisphere in SD and in the right hemisphere in bvFTD. This indicates differential hemispheric predilection of brain connectivity abnormalities between SD and bvFTD.

%B J Alzheimers Dis %V 56 %P 789-804 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059782?dopt=Abstract %R 10.3233/JAD-160564 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Differential Regional Distribution of Juxtacortical White Matter Signal Abnormalities in Aging and Alzheimer's Disease. %A Lindemer, Emily R %A Greve, Douglas N %A Fischl, Bruce %A Augustinack, Jean C %A Salat, David H %X

BACKGROUND: White matter signal abnormalities (WMSA) (also known as 'hyperintensities') on MRI are commonly seen in normal aging and increases have been noted in Alzheimer's disease (AD), but whether there is a spatial specificity to these increases is unknown.

OBJECTIVE: To discern whether or not there is a spatial pattern of WMSA in the brains of individuals with AD that differs from those who exhibit cognitively healthy aging.

METHOD: Structural MRI data from the Alzheimer's Disease Neuroimaging Initiative public database were used to quantify WMSA in 35 regions of interest (ROIs). Regional measures were compared between cognitively healthy older controls (OC; n = 107) and individuals with a clinical diagnosis of AD (n = 127). Regional WMSA volume was also assessed in individuals with mild cognitive impairment (MCI; n = 74) who were 6, 12, and 24 months away from AD conversion.

RESULTS: WMSA volume was significantly greater in AD compared to OC in 24 out of 35 ROIs after controlling for age, and nine were significantly higher after normalizing for total WMSA. Regions with greater WMSA volume in AD included rostral frontal, inferior temporal, and inferior parietal WM. In MCI, frontal and temporal regions demonstrated significantly greater WMSA volume with decreasing time-to-AD-conversion.

DISCUSSION: Individuals with AD have greater regional volume of WMSA compared to OC regardless of age or total WMSA volume. Accumulation of regional WMSA is linked to time to AD conversion in individuals with MCI. These findings indicate WMSA is an important pathological component of AD development.

%B J Alzheimers Dis %V 57 %P 293-303 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222518?dopt=Abstract %R 10.3233/JAD-161057 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Discovery and Confirmation of Diagnostic Serum Lipid Biomarkers for Alzheimer's Disease Using Direct Infusion Mass Spectrometry. %A Anand, Swati %A Barnes, Justin M %A Young, Sydney A %A Garcia, Diana M %A Tolley, H Dennis %A Kauwe, John S K %A Graves, Steven W %X

Alzheimer's disease (AD) is a neurodegenerative disorder lacking early biochemical diagnosis and treatment. Lipids have been implicated in neurodegenerative disorders including AD. A shotgun lipidomic approach was undertaken to determine if lipid biomarkers exist that can discriminate AD cases from controls. The discovery study involved sera from 29 different stage AD cases and 32 controls. Lipid extraction was performed using organic solvent and the samples were directly infused into a time-of-flight mass spectrometer. Differences between AD cases and controls were detected with 87 statistically significant lipid candidate markers found. These potential lipid markers were reevaluated in a second confirmatory study involving 27 cases and 30 controls. Of the 87 candidates from the first study, 35 continued to be statistically significant in the second confirmatory set. Tandem MS studies were performed and almost all confirmed markers were characterized and classified. Using a Bayesian lasso probit regression model on the confirmed markers, a multi-marker set with AUC = 0.886 was developed comparing all stages of AD with controls. Additionally, using confirmed biomarkers, multi-marker sets with AUCs >0.90 were developed for each specific AD Clinical Dementia Rating versus controls, including the earliest stage of AD. More conservative and likely more realistic statistical analyses still found multi-marker sets that appeared useful in diagnosing AD. Finally, using ordinal modeling a set of markers was developed that staged AD accurately 70% of the time, p = 0.0079. These results suggest that these serum lipidomic biomarkers may help diagnose and perhaps even stage AD.

%B J Alzheimers Dis %V 59 %P 277-290 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598845?dopt=Abstract %R 10.3233/JAD-170035 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Discriminative Properties of Hippocampal Hypoperfusion in Marijuana Users Compared to Healthy Controls: Implications for Marijuana Administration in Alzheimer's Dementia. %A Amen, Daniel G %A Darmal, Borhan %A Raji, Cyrus A %A Bao, Weining %A Jorandby, Lantie %A Meysami, Somayeh %A Raghavendra, Cauligi S %X

BACKGROUND: Few studies have evaluated the impact of marijuana use on regional cerebral blood flow.

OBJECTIVE: To determine whether perfusion in specific brain regions on functional neuroimaging, including those affected by Alzheimer's disease pathology, are abnormal in marijuana users compared to controls.

METHOD: Persons with a diagnosis of cannabis use disorder by DSM-IV and DSM-V criteria (n = 982) were compared to controls (n = 92) with perfusion neuroimaging with SPECT at rest and at a concentration task. Perfusion estimates were quantified using a standard atlas. Cerebral perfusion differences were calculated using one-way ANOVA. Diagnostic separation was determined with discriminant analysis of all subjects. Feature selection with a minimum redundancy maximum relevancy (mRMR) identified predictive regions in a subset of marijuana users (n = 436) with reduced psychiatric co-morbidities.

RESULTS: Marijuana users showed lower cerebral perfusion on average (p < 0.05). Discriminant analysis distinguished marijuana users from controls with correct classification of 96% and leave one out cross-validation of 92%. With concentration SPECT regions, there was correct classification of 95% with a leave-one-out cross validation of 90%. AUC analysis for concentration SPECT regions showed 95% accuracy, 90% sensitivity, and 83% specificity. The mRMR analysis showed right hippocampal hypoperfusion on concentration SPECT imaging was the most predictive in separating marijuana subjects from controls.

CONCLUSION: Multiple brain regions show low perfusion on SPECT in marijuana users. The most predictive region distinguishing marijuana users from healthy controls, the hippocampus, is a key target of Alzheimer's disease pathology. This study raises the possibility of deleterious brain effects of marijuana use.

%B J Alzheimers Dis %V 56 %P 261-273 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27886010?dopt=Abstract %R 10.3233/JAD-160833 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Disinhibition in Alzheimer's Disease is Associated with Reduced Right Frontal Pole Cortical Thickness. %A Finger, Elizabeth %A Zhang, Jing %A Dickerson, Bradford %A Bureau, Yves %A Masellis, Mario %X

Neuropsychiatric symptoms in Alzheimer's disease are among the most disabling and difficult aspects for caregivers and treating health professionals to manage. Despite the high prevalence of these behaviors, little is known about the factors which lead some patients to develop florid behavioral symptoms while others may progress to severe dementia without such phenomenon. We examined whether regional brain volumes as measured by cortical thickness would predict the presence or absence of disinhibition in patients with Alzheimer's disease. Using data from the ADNI, we identified 758 patients with caregiver ratings on the Neuropsychiatric Inventory and a volumetric MRI scan with cortical thickness measurements completed in FreeSurfer by the UCSF core. Of these, 177 patients were found to have disinhibition. Logistic regression models demonstrated that reduced cortical thickness in the right frontal pole was associated with the presence of disinhibition even when controlling for age, disease severity, total intracranial volume, gender, and APOE genotype. The results are considered in the context of leading models of the functions of frontopolar cortex.

%B J Alzheimers Dis %V 60 %P 1161-1170 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984590?dopt=Abstract %R 10.3233/JAD-170348 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dissociable Effects of Aging and Mild Cognitive Impairment on Bottom-Up Audiovisual Integration. %A Festa, Elena K %A Katz, Andrew P %A Ott, Brian R %A Tremont, Geoffrey %A Heindel, William C %X

Effective audiovisual sensory integration involves dynamic changes in functional connectivity between superior temporal sulcus and primary sensory areas. This study examined whether disrupted connectivity in early Alzheimer's disease (AD) produces impaired audiovisual integration under conditions requiring greater corticocortical interactions. Audiovisual speech integration was examined in healthy young adult controls (YC), healthy elderly controls (EC), and patients with amnestic mild cognitive impairment (MCI) using McGurk-type stimuli (providing either congruent or incongruent audiovisual speech information) under conditions differing in the strength of bottom-up support and the degree of top-down lexical asymmetry. All groups accurately identified auditory speech under congruent audiovisual conditions, and displayed high levels of visual bias under strong bottom-up incongruent conditions. Under weak bottom-up incongruent conditions, however, EC and amnestic MCI groups displayed opposite patterns of performance, with enhanced visual bias in the EC group and reduced visual bias in the MCI group relative to the YC group. Moreover, there was no overlap between the EC and MCI groups in individual visual bias scores reflecting the change in audiovisual integration from the strong to the weak stimulus conditions. Top-down lexicality influences on visual biasing were observed only in the MCI patients under weaker bottom-up conditions. Results support a deficit in bottom-up audiovisual integration in early AD attributable to disruptions in corticocortical connectivity. Given that this deficit is not simply an exacerbation of changes associated with healthy aging, tests of audiovisual speech integration may serve as sensitive and specific markers of the earliest cognitive change associated with AD.

%B J Alzheimers Dis %V 59 %P 155-167 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598838?dopt=Abstract %R 10.3233/JAD-161062 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dissociating Normal Aging from Alzheimer's Disease: A View from Cognitive Neuroscience. %A Toepper, Max %X

Both normal aging and Alzheimer's disease (AD) are associated with changes in cognition, grey and white matter volume, white matter integrity, neural activation, functional connectivity, and neurotransmission. Obviously, all of these changes are more pronounced in AD and proceed faster providing the basis for an AD diagnosis. Since these differences are quantitative, however, it was hypothesized that AD might simply reflect an accelerated aging process. The present article highlights the different neurocognitive changes associated with normal aging and AD and shows that, next to quantitative differences, there are multiple qualitative differences as well. These differences comprise different neurocognitive dissociations as different cognitive deficit profiles, different weights of grey and white matter atrophy, and different gradients of structural decline. These qualitative differences clearly indicate that AD cannot be simply described as accelerated aging process but on the contrary represents a solid entity.

%B J Alzheimers Dis %V 57 %P 331-352 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269778?dopt=Abstract %R 10.3233/JAD-161099 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Distinction of Amyloid-β Protein Precursor (AβPP) Ratio in Platelet Between Alzheimer's Disease Patients and Controls: A Systematic Review and Meta-Analysis. %A Shi, Yachen %A Gu, Lihua %A Alsharif, Abdul Azeez %A Zhang, Zhijun %X

To systematically assess the clinical significance of platelet amyloid-β protein precursor (AβPP) ratio between Alzheimer's disease (AD) patients and controls. 14 articles were selected in this analysis by search of databases including PubMed and Web of Science up to December 2016. Random effects models were used to calculate the standardized mean difference (SMD). Subgroup analyses were used to detect the cause of heterogeneity. The result showed a significant drop in platelet AβPP ratio in AD patients compared to controls [SMD: -1.871; 95% CI: (-2.33, -1.41); p < 0.001; I2 = 88.0% ]. Subgroup analysis revealed races or the quality of studies may be the cause of high heterogeneity. This meta-analysis concluded that there is a close association between platelet AβPP ratio and AD. It is necessary to design a sizable sample study to further support that platelet AβPP ratio can be a biomarker of AD.

%B J Alzheimers Dis %V 59 %P 1037-1044 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731441?dopt=Abstract %R 10.3233/JAD-170253 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Distribution of Types of Dementia in the First 100 Patients Seen at a Dementia Clinic in India. %A Chandra, Vijay %A Mehta, Veer Singh %X

The aim of our study was to determine if the distribution of types of dementia could explain the reported lower prevalence of dementia in India. The study is an observational study of the first 100 cases of dementia. All patients were evaluated clinically and with blood tests and MRI of the brain. The causes of dementia were: Lewy body dementia (22%), depression (20%), Alzheimer's disease (13%), and mild cognitive impairment (18%). Other dementias were less common. The distribution of dementia types in this series is different from that reported globally. The observation of Lewy body dementia being the most common cause of dementia needs to be verified.

%B J Alzheimers Dis %V 59 %P 797-801 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671125?dopt=Abstract %R 10.3233/JAD-170251 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Diverging Progression of Network Disruption and Atrophy in Alzheimer's Disease and Semantic Dementia. %A Andreotti, Jennifer %A Dierks, Thomas %A Wahlund, Lars-Olof %A Grieder, Matthias %X

The progression of cognitive deficits in Alzheimer's disease and semantic dementia is accompanied by grey matter atrophy and white matter deterioration. The impact of neuronal loss on the structural network connectivity in these dementia subtypes is, however, not well understood. In order to gain a more refined knowledge of the topological organization of white matter alterations in dementia, we used a network-based approach to analyze the brain's structural connectivity network. Diffusion-weighted and anatomical MRI images of groups with eighteen Alzheimer's disease and six semantic dementia patients, as well as twenty-one healthy controls were recorded to reconstruct individual connectivity networks. Additionally, voxel-based morphometry, using grey and white matter volume, served to relate atrophy to altered structural connectivity. The analyses showed that Alzheimer's disease is characterized by decreased connectivity strength in various cortical regions. An overlap with grey matter loss was found only in the inferior frontal and superior temporal areas. In semantic dementia, significantly reduced network strength was found in the temporal lobes, which converged with grey and white matter atrophy. Therefore, this study demonstrated that the structural disconnection in early Alzheimer's disease goes beyond grey matter atrophy and is independent of white matter volume loss, an observation that was not found in semantic dementia.

%B J Alzheimers Dis %V 55 %P 981-993 %G ENG %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802229?dopt=Abstract %R 10.3233/JAD-160571 %0 Journal Article %J J Alzheimers Dis %D 2017 %T DNA Methylation and Tag SNPs of the BDNF Gene in Conversion of Amnestic Mild Cognitive Impairment into Alzheimer's Disease: A Cross-Sectional Cohort Study. %A Xie, Bing %A Liu, Zanchao %A Liu, Wenxuan %A Jiang, Lei %A Zhang, Rui %A Cui, Dongsheng %A Zhang, Qingfu %A Xu, Shunjiang %X

Alzheimer's disease (AD) is a complex multifactorial disease influenced by both genetic and epigenetic factors. This study was aimed to evaluate the interaction between brain-derived neurotrophic factor (BDNF) promoter methylation status and tag single nucleotide polymorphisms (tag SNPs) on amnestic mild cognitive impairment (aMCI) and its conversion to AD. A total of 506 aMCI patients and 728 cognitive normal controls were included in the cross-sectional analysis. Patients (n = 458) from aMCI cohort were selected in the 5-year longitudinal study and classified into two groups: aMCI-stable group (n = 330) and AD-conversion group (n = 128). BDNF promoter methylation was detected by bisulfite-PCR amplification and pyrosequencing. Seven tag SNPs were genotyped by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Elevation of BDNF promoter methylation status was associated with aMCI and AD conversion. The higher methylation levels at CpG5 site showed significant main interactive effects between group and time (F = 8.827, p = 0.005). Genetic analysis revealed rs2030324 and rs6265 were associated with aMCI and rs6265 was associated with AD conversion. The interaction between DNA methylation of CpG5 and AA genotype of rs6265 had a risk role in the development of aMCI (p = 0.019, OR = 1.233, 95% CI: 1.117-1.303) and its progression to AD (p = 0.003, OR = 1.399, 95% CI: 1.198-1.477). The interactions between DNA methylation (CpG5) of the BDNF gene promoter and the tag SNP (rs6265) play important roles in the etiology of aMCI and its conversion to AD.

%B J Alzheimers Dis %V 58 %P 263-274 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387675?dopt=Abstract %R 10.3233/JAD-170007 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Do Cancer Drugs Counteract Neurodegeneration? Repurposing for Alzheimer's Disease. %A Monacelli, Fiammetta %A Cea, Michele %A Borghi, Roberta %A Odetti, Patrizio %A Nencioni, Alessio %X

In spite of in depth investigations in the field of the amyloid cascade hypothesis, so far, no disease modifying therapy has been developed for Alzheimer's disease (AD). The pathophysiology provides some evidence of the inverse correlation between cancer and AD. Both AD and cancer are characterized by abnormal cellular behaviors; trigger factors along with a meta synchronously action is expected to drive cancer or neurodegeneration, supporting, respectively, progressive neuronal loss or uncontrolled cell proliferation in cancer cells. So far, cancer and AD are seemingly two opposite ends of the same biological spectrum. Basic science increasingly indicates shared molecular mechanisms between cancer and AD and gives weight to key relevant biological theories; according to them, the inverse tuning of clustered gene expression, the sharing of mutual independent pathway or the deregulated unfolded proteins system (UPR) may count for this inverse association. Additionally, the common biological background gave credibility to the recent discovery of a repurposing role for cancer drugs in AD. It refers to the development of new uses for existing pharmaceuticals having the same role as the original mechanism or to the discovery of a new drug action with disease modifying effects. The present review summarizes the most important biological theories that link neurodegeneration and cancer and provides an up-to-date revision of the repurposing cancer agents for AD. The review also addresses the gap of knowledge, since drug cancer repositioning holds an important promise but further investigations are warranted to ascertain the clinical relevance of such attractive clinical candidate compounds for AD.

%B J Alzheimers Dis %V 55 %P 1295-1306 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27834781?dopt=Abstract %R 10.3233/JAD-160840 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Do Hearing Aids Influence Behavioral and Psychological Symptoms of Dementia and Quality of Life in Hearing Impaired Alzheimer's Disease Patients and Their Caregivers? %A Adrait, Arnaud %A Perrot, Xavier %A Nguyen, Marie-France %A Gueugnon, Marine %A Petitot, Charles %A Collet, Lionel %A Roux, Adeline %A Bonnefoy, Marc %X

BACKGROUND: It has been suggested that age-related hearing loss (ARHL) and Alzheimer's disease (AD) are commonly associated.

OBJECTIVE: The Alzheimer Disease, Presbycusis and Hearing Aids (ADPHA) clinical trial assessed the influence of hearing aids (HAs) on patients affected by ARHL and AD, as judged by behavioral symptoms and functional abilities, as well as patient and caregiver quality of life (QoL).

METHODS: A multicenter double-blind randomized placebo-controlled trial, with a semi-crossover procedure over 12 months, was conducted from 2006 to 2012. For the first 6 months, the active group was treated with active HAs and the placebo group with inactive HAs. For the last 6 months, HAs in the placebo group were activated. Assessment was conducted at baseline, 6 months, and 12 months. We performed intergroup and intragroup comparisons. Behavioral symptoms were assessed by neuropsychiatric inventory (NPI), functional abilities by instrumental activities of daily living, and QoL by Zarit, Alzheimer's disease related quality of life, and simplified Duke scales.

RESULTS: Fifty-one patients were included and randomized: 22 in active group (mean NPI 17.6; mean age 83±6.2) and 26 in placebo group (mean NPI 25.8; mean age 82.3±7.2) were fitted with HAs. At 6-month follow-up, all scores worsened without significant difference between the two groups. In placebo group, activation of HAs had no effect on the change of these scores.

CONCLUSION: These findings do not provide evidence of improvement in behavioral symptoms, functional status, or QoL of hearing impaired AD patients and their caregivers after 6 months of HA use. However, we cannot exclude that HAs may have a positive effect in patients aged less than 75 years.

%B J Alzheimers Dis %V 58 %P 109-121 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269769?dopt=Abstract %R 10.3233/JAD-160792 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Does Functional Connectivity Provide a Marker for Cognitive Rehabilitation Effects in Alzheimer's Disease? An Interventional Study. %A Ochmann, Sina %A Dyrba, Martin %A Grothe, Michel J %A Kasper, Elisabeth %A Webel, Steffi %A Hauenstein, Karlheinz %A Teipel, Stefan J %X

BACKGROUND: Cognitive rehabilitation (CR) is a cognitive intervention for patients with Alzheimer's disease (AD) that aims to maintain everyday competences. The analysis of functional connectivity (FC) in resting-state functional MRI has been used to investigate the effects of cognitive interventions.

OBJECTIVES: We evaluated the effect of CR on the default mode network FC in a group of patients with mild AD, compared to an active control group.

METHODS: We performed a three-month interventional study including 16 patients with a diagnosis of AD. The intervention group (IG) consisted of eight patients, performing twelve sessions of CR. The active control group (CG) performed a standardized cognitive training. We used a seed region placed in the posterior cingulate cortex (PCC) for FC analysis, comparing scans acquired before and after the intervention. Effects were thresholded at a significance of p < 0.001 (uncorrected) and a minimal cluster size of 50 voxels.

RESULTS: The interaction of group by time showed a higher increase of PCC connectivity in IG compared to CG in the bilateral cerebellar cortex. CG revealed widespread, smaller clusters of higher FC increase compared with IG. Across all participants, an increase in quality of life was associated with connectivity increase over time in the bilateral precuneus.

CONCLUSIONS: CR showed an effect on the FC of the DMN in the IG. These effects need further study in larger samples to confirm if FC analysis may suit as a surrogate marker for the effect of cognitive interventions in AD.

%B J Alzheimers Dis %V 57 %P 1303-1313 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372326?dopt=Abstract %R 10.3233/JAD-160773 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Does the Female Advantage in Verbal Memory Contribute to Underestimating Alzheimer's Disease Pathology in Women versus Men? %A Sundermann, Erin E %A Biegon, Anat %A Rubin, Leah H %A Lipton, Richard B %A Landau, Susan %A Maki, Pauline M %X

There is a growing recognition of sex differences in Alzheimer's disease (AD). Females show an advantage over males on tests of verbal memory, which are used to diagnose AD and its precursor, amnestic mild cognitive impairment (aMCI). Women retain this advantage in aMCI despite reduced hippocampal volume and temporal lobe glucose metabolism. Here we examined whether this female advantage endures despite evidence of AD-specific pathology, cortical amyloid-β (Aβ) deposition measured with [18F]AV45 (florbetapir) positron emission tomography. Participants with normal cognition (N = 304), aMCI (N = 515), and AD dementia (N = 175) were drawn from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Across and within diagnostic groups, we conducted linear regressions to examine the interaction of sex with cortical Aβ burden on immediate and delayed recall on the Rey Auditory Verbal Learning Test (RAVLT) adjusting for age, education, and APOE4. In the overall group, sex by cortical Aβ interaction was significant for delayed recall only. Overall, delayed recall performance was significantly better in women versus men among those with low to moderate Aβ burden, but women and men performed similarly among those with high Aβ burden. In diagnosis-stratified analyses, a significant sex by cortical Aβ interaction was observed for delayed recall in the aMCI group, but not in the normal or AD dementia groups. Thus, women maintain a verbal memory advantage over men in aMCI despite similar levels of AD pathology. Although this advantage may benefit women by delaying verbal memory impairment until more advanced pathology, it may also delay diagnosis of aMCI and treatment intervention.

%B J Alzheimers Dis %V 56 %P 947-957 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106548?dopt=Abstract %R 10.3233/JAD-160716 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer's Disease: The Role of APP. %A Doran, Eric %A Keator, David %A Head, Elizabeth %A Phelan, Michael J %A Kim, Ron %A Totoiu, Minodora %A Barrio, Jorge R %A Small, Gary W %A Potkin, Steven G %A Lott, Ira T %X

Overexpression of the amyloid precursor protein (APP) gene on chromosome 21 in Down syndrome (DS) has been linked to increased brain amyloid levels and early-onset Alzheimer's disease (AD). An elderly man with phenotypic DS and partial trisomy of chromosome 21 (PT21) lacked triplication of APP affording an opportunity to study the role of this gene in the pathogenesis of dementia. Multidisciplinary studies between ages 66-72 years comprised neuropsychological testing, independent neurological exams, amyloid PET imaging with 11C-Pittsburgh compound-B (PiB), plasma amyloid-β (Aβ) measurements, and a brain autopsy examination. The clinical phenotype was typical for DS and his intellectual disability was mild in severity. His serial neuropsychological test scores showed less than a 3% decline as compared to high functioning individuals with DS who developed dementia wherein the scores declined 17-28% per year. No dementia was detected on neurological examinations. On both PiB-PET scans, the patient with PT21 had lower PiB standard uptake values than controls with typical DS or sporadic AD. Plasma Aβ42 was lower than values for demented or non-demented adults with DS. Neuropathological findings showed only a single neuritic plaque and neurofibrillary degeneration consistent with normal aging but not AD. Taken together the findings in this rare patient with PT21 confirm the obligatory role of APP in the clinical, biochemical, and neuropathological findings of AD in DS.

%B J Alzheimers Dis %V 56 %P 459-470 %G eng %N 2 %R 10.3233/JAD-160836 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dual Mechanism of Toxicity for Extracellular Injection of Tau Oligomers versus Monomers in Human Tau Mice. %A Manassero, Giusi %A Guglielmotto, Michela %A Monteleone, Debora %A Vasciaveo, Valeria %A Butenko, Olena %A Tamagno, Elena %A Arancio, Ottavio %A Tabaton, Massimo %X

The mechanism of tau toxicity is still unclear. Here we report that recombinant tau oligomers and monomers, intraventricularly injected in mice with a pure human tau background, foster tau pathology through different mechanisms. Oligomeric forms of tau alter the conformation of tau in a paired helical filament-like manner. This effect occurs without tau hyperphosphorylation as well as activation of specific kinases, suggesting that oligomers of tau induce tau assembly through a nucleation effect. Monomers, in turn, induce neurodegeneration through a calpain-mediated tau cleavage that leads to accumulation of a 17 kDa neurotoxic peptide and induction of apoptotic cell death.

%B J Alzheimers Dis %V 59 %P 743-751 %G eng %N 2 %R 10.3233/JAD-170298 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dynamics of Frailty and Cognition After Age 50: Why It Matters that Cognitive Decline is Mostly Seen in Old Age. %A Godin, Judith %A Armstrong, Joshua J %A Rockwood, Kenneth %A Andrew, Melissa K %X

BACKGROUND: Frailty has been considered an antecedent and, to a lesser extent, an outcome of cognitive impairment. Both frailty and cognitive impairment are multiply determined and each is strongly related to age, making it likely that the two interact, especially as people age. In consequence, understanding their interaction and co-occurrence can offer insight into pathophysiology, prevention, and management.

OBJECTIVE: To examine the nature of the relationship between frailty and cognitive impairment using longitudinal data from the Survey of Health Aging and Retirement in Europe (SHARE), assessing for bidirectionality.

METHODS: We conducted secondary analyses using data from the first two waves of SHARE. The sample (N = 11,941) was randomly split into two halves: one half for model development and one half for model confirmation. We used a 65 deficit Frailty Index and combined 5 cognitive deficits into a global cognitive impairment index. Cross-lagged path analysis within a structural equation modelling framework was used to examine the bi-directional relationship between the two measures.

RESULTS: After controlling for age, sex, social vulnerability, education, and initial cognitive impairment, each 0.10 increase in baseline frailty was associated with a 0.01 increase in cognitive impairment at follow-up (p < 0.001). Likewise, each 0.1 increase in baseline cognitive impairment was associated with a 0.003 increase frailty at follow-up (p < 0.01).

CONCLUSION: Our findings underscore the importance of considering cognitive impairment in the context of overall health. Many people with dementia are likely to have other health problems, which need to be considered in concert to achieve optimal health outcomes.

%B J Alzheimers Dis %V 58 %P 231-242 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387672?dopt=Abstract %R 10.3233/JAD-161280 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dynamics of the Complement, Cytokine, and Chemokine Systems in the Regulation of Synaptic Function and Dysfunction Relevant to Alzheimer's Disease. %A Jiang, Shanya %A Bhaskar, Kiran %X

Alzheimer's disease (AD) is the most common form of dementia affecting nearly 45 million people worldwide. However, the etiology of AD is still unclear. Accumulations of amyloid-β plaques and tau tangles, neuroinflammation, and synaptic and neuronal loss are the major neuropathological hallmarks of AD, with synaptic loss being the strongest correlating factor with memory and cognitive impairment in AD. Many of these pathological hallmarks influence each other during the onset and progression of the disease. Recent genetic evidence suggests the possibility of a causal link between altered immune pathways and synaptic dysfunction in AD. Emerging studies also suggest that immune system-mediated synaptic pruning could initiate early-stage pathogenesis of AD. This comprehensive review is toward understanding the crosstalk of neuron-microglia-astrocyte and dynamics of complement, cytokine, and chemokine systems in the regulation of synaptic function and dysfunction relevant to AD. We start with summarizing several immune pathways, involving complements, MHC-I and CX3CL1, which mediate synaptic elimination during development and in AD. We then will discuss the potential of targeting these molecules as therapeutic interventions or as biomarkers for AD.

%B J Alzheimers Dis %V 57 %P 1123-1135 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372329?dopt=Abstract %R 10.3233/JAD-161123 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Early Detection of Learning Difficulties when Confronted with Novel Information in Preclinical Alzheimer's Disease Stage 1. %A Tort-Merino, Adrià %A Valech, Natalia %A Peñaloza, Claudia %A Grönholm-Nyman, Petra %A León, María %A Olives, Jaume %A Estanga, Ainara %A Ecay-Torres, Mirian %A Fortea, Juan %A Martínez-Lage, Pablo %A Molinuevo, José L %A Laine, Matti %A Rodríguez-Fornells, Antoni %A Rami, Lorena %X

We employed a highly demanding experimental associative learning test (the AFE-T) to explore memory functioning in Preclinical Alzheimer's Disease stage 1 (PreAD-1) and stage 2 (PreAD-2). The task consisted in the learning of unknown object/name pairs and our comprehensive setup allowed the analysis of learning curves, immediate recall, long-term forgetting rates at one week, three months, and six months, and relearning curves. Forty-nine cognitively healthy subjects were included and classified according to the presence or absence of abnormal CSF biomarkers (Control, n = 31; PreAD-1, n = 14; PreAD-2, n = 4). Control and PreAD-1 performances on the experimental test were compared by controlling for age and education. These analyses showed clear learning difficulties in PreAD-1 subjects (F = 6.98; p = 0.01). Between-group differences in long-term forgetting rates were less notable, reaching statistical significance only for the three-month cued forgetting rate (F = 4.83; p = 0.03). Similarly, relearning sessions showed only statistical trends between the groups (F = 3.22; p = 0.08). In the whole sample, significant correlations between CSF Aβ42/tau ratio and the AFE-T were found, both in the total learning score (r = 0.52; p < 0.001) and in the three-month cued forgetting rate (r = -0.38; p < 0.01). Descriptive subanalyses involving PreAD-2 suggested greater learning and recall difficulties in these subjects when compared with the PreAD-1 group. The present results suggest that explicit learning difficulties when binding information could be one of the earliest signs of the future emergence of episodic memory difficulties on the Alzheimer's disease continuum. Our findings indicate that the AFE-T is a sensitive test, capable of detecting subtle memory difficulties in PreAD-1.

%B J Alzheimers Dis %V 58 %P 855-870 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505969?dopt=Abstract %R 10.3233/JAD-161173 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer's Disease. %A Dengler-Crish, Christine M %A Smith, Matthew A %A Wilson, Gina N %X

Reduced bone mineral density (BMD) and its clinical sequelae, osteoporosis, occur at a much greater rate in patients with Alzheimer's disease (AD), often emerging early in the disease before significant cognitive decline is seen. Reduced BMD translates to increased bone fracture risk, decreased quality of life, and increased mortality for AD patients. However, the mechanism responsible for this observation is unclear. We hypothesize that bone loss is an additional component of an AD prodrome-changes that emerge prior to dementia and are mediated by dysfunction of the central serotonergic pathways. We characterized the skeletal phenotype of htau mice that express human forms of the microtubule-associated protein tau that become pathologically hyperphosphorylated in AD. Using radiographic densitometry, we measured BMD in female and male htau mice from 2-6 months of age-time-points prior to the presence of significant tauopathy in the hippocampal/entorhinal regions characteristic of this model. We found a significantly reduced BMD phenotype in htau mice that was most pronounced in males. Using western blotting and immunofluorescence, we showed overall reduced tryptophan hydroxylase (TPH) protein in htau brainstem and a 70% reduction in TPH-positive cells in the dorsal raphe nucleus (DRN)-a pivotal structure in the regulation of the adult skeleton. Elevations of hyperphosphorylated tau (ptau) proteins were also measured in brainstem, and co-labeled immunofluorescence studies showed presence of ptau in TPH-positive cells of the DRN as early as 4 months of age in htau mice. Together, these findings demonstrate that reduced BMD occurs earlier than overt degeneration in a tau-based AD model and that pathological changes in tau phosphorylation occur in the serotonin-producing neurons of the brainstem raphe in these mice. This illuminates a need to define a mechanistic relationship between bone loss and serotonergic deficits in early AD.

%B J Alzheimers Dis %V 55 %P 1605-1619 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27814296?dopt=Abstract %R 10.3233/JAD-160658 %0 Journal Article %J J Alzheimers Dis %D 2017 %T EEG Dominant Frequency Peak Differentiates Between Alzheimer's Disease and Frontotemporal Lobar Degeneration. %A Goossens, Joery %A Laton, Jorne %A Van Schependom, Jeroen %A Gielen, Jeroen %A Struyfs, Hanne %A Van Mossevelde, Sara %A Van den Bossche, Tobi %A Goeman, Johan %A De Deyn, Peter Paul %A Sieben, Anne %A Martin, Jean-Jacques %A Van Broeckhoven, Christine %A van der Zee, Julie %A Engelborghs, Sebastiaan %A Nagels, Guy %X

We investigated the power of EEG as biomarker in differential diagnosis of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). EEG was recorded from 106 patients with AD or FTLD, of which 37 had a definite diagnosis, and 40 controls. Dominant frequency peaks were extracted for all 19 channels, for each subject. The average frequency of the largest dominant frequency peaks (maxpeak) was significantly lower in AD than FTLD patients and controls. Based on ROC analysis, classification could be made with diagnostic accuracy of 78.9%. Our findings show that quantitative analysis of EEG maxpeak frequency is an easy and useful measure for differential dementia diagnosis.

%B J Alzheimers Dis %V 55 %P 53-58 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636837?dopt=Abstract %R 10.3233/JAD-160188 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of a Comprehensive Intervention on Plasma BDNF in Patients with Alzheimer's Disease. %A Balietti, Marta %A Giuli, Cinzia %A Fattoretti, Patrizia %A Fabbietti, Paolo %A Papa, Roberta %A Postacchini, Demetrio %A Conti, Fiorenzo %X

A comprehensive intervention (CI) on patients with Alzheimer's disease was assessed by measuring plasmabrain-derived neurotrophic factor (pBDNF) and ADAS-Cog score (ADAS-Cogscore) before, immediately after (FU1), and 6 (FU2) and 24 months (FU3) after the CI. Baseline pBDNF was higher in patients with moderate AD (but not mild AD) than in healthy controls. At FU1, pBDNF and ADAS-Cogscore decreased significantly. At FU2 and FU3, patients' cognitive status worsened and pBDNF further increased versus baseline, suggesting that CI interruption may be a stress event that prevents return to homeostasis. CI exerted positive short-term effects, but more information is needed on long-term consequences.

%B J Alzheimers Dis %V 57 %P 37-43 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222525?dopt=Abstract %R 10.3233/JAD-161168 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of APOE Genotype on Amyloid Deposition, Brain Volume, and Memory in Cognitively Normal Older Individuals. %A Lim, Yen Ying %A Williamson, Robert %A Laws, Simon M %A Villemagne, Victor L %A Bourgeat, Pierrick %A Fowler, Christopher %A Rainey-Smith, Stephanie %A Salvado, Olivier %A Martins, Ralph N %A Rowe, Christopher C %A Masters, Colin L %A Maruff, Paul %X

BACKGROUND: The association between the apolipoprotein E (APOE) ɛ4 allele and high risk of developing Alzheimer's disease (AD) dementia before the age of 80 has been recognized for over 30 years. However, the timing and mode of action of APOE is not understood, nor has there been a detailed analysis of the effect of APOE genotype on memory, hippocampal volume, and amyloid-β (Aβ) levels in cognitively normal adults.

OBJECTIVE: Examine the effect of APOE allelic genotype on the relationship between Aβ levels, hippocampal volume, and memory in cognitively normal adults.

METHODS: This is a cross-sectional study of 989 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, all of whom underwent APOE genotyping and memory assessment. A subset of this group underwent PET neuroimaging for Aβ (n = 585) and MRI for hippocampal volume (n = 303).

RESULTS: APOEɛ4 homozygotes (ɛ4/ɛ4) showed significantly worse episodic memory and higher Aβ levels than ɛ4 heterozygotes. The relationship between increasing Aβ levels and worse episodic memory was significant for ɛ3 homozygotes (ɛ3/ɛ3), ɛ4 heterozygotes, and strongest for ɛ4 homozygotes. There were no differences in hippocampal volume between APOE groups; the relationship between smaller hippocampal volume and worse episodic memory was significant only for ɛ4 homozygotes.

CONCLUSION: APOE acts in a co-dominant fashion on Aβ levels, episodic memory, and hippocampal volume in cognitively normal older adults. APOEɛ4 is central to the events that lead to AD in cognitively normal older adults, likely through a quantitative role in the disruption of Aβ clearance.

%B J Alzheimers Dis %V 58 %P 1293-1302 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550258?dopt=Abstract %R 10.3233/JAD-170072 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of APOE Genotype on Synaptic Proteins in Earlier Adult Life. %A Sinclair, Lindsey I %A Love, Seth %X

BACKGROUND: Possession of APOEɛ4 is a strong risk factor for late-onset Alzheimer's disease and is associated with loss of synaptic proteins in the elderly even in the absence of Alzheimer's disease.

OBJECTIVE: We hypothesized that ɛ4 allele possession in non-demented adults aged under-75 would also be associated with alterations in the levels of synaptic proteins.

METHODS: We measured synaptophysin, PSD95, drebrin, SNAP-25, and septin 7 by ELISA in hippocampus and superior temporal gyrus from 103 adults aged 

RESULTS: There was no evidence that ɛ4 affected levels of the proteins measured. Instead we found an increase in post-synaptic proteins in the hippocampi of those with an ɛ32 genotype. The evidence was strongest for drebrin (p = 0.011). There was some evidence of increased synaptic protein gene expression in ɛ4 carriers.

CONCLUSIONS: People with an APOEɛ32 genotype have a reduced risk of Alzheimer's disease. It may be relevant that they have a higher level of post-synaptic proteins in the hippocampus even in earlier adulthood.

%B J Alzheimers Dis %V 59 %P 1123-1137 %G eng %N 3 %R 10.3233/JAD-170316 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of APOE ε4 Genotype on Metabolic Biomarkers in Aging and Alzheimer's Disease. %A Morris K, Jill %A Uy, Roxanne Adeline Z %A Vidoni, Eric D %A Wilkins, Heather M %A Archer, Ashley E %A Thyfault, John P %A Miles, John M %A Burns, Jeffrey M %X

Alzheimer's disease (AD) may have heterogeneous pathophysiological underpinnings, with risk factors including apolipoprotein rmvarep4 (APOE4) genotype and insulin resistance. We hypothesized that distinct phenotypes exist within AD. We examined APOE4 and metabolic biomarkers in 338 subjects (n = 213 nondemented (ND), n = 125 AD). We further characterized steady state free fatty acid (FFA) levels in a subset of 45 participants who had also participated in a hyperinsulinemic-euglycemic clamp. Insulin resistance (HOMA-IR) was elevated in AD versus ND (p = 0.04) and in APOE4 noncarriers versus carriers (p < 0.01). This was driven by increased fasting insulin in AD versus ND (p < 0.01) and in APOE4 non-carriers versus carriers (p = 0.01). Fasting glucose was not different. In subjects who underwent a clamp, there was a group x genotype interaction on FFA levels during hyperinsulinemia (p = 0.03). APOE4 non-carriers with AD had higher FFA levels, while APOE4 carriers with AD exhibited lower FFA levels. Metabolic dysfunction is overrepresented in individuals with AD dementia who do not carry the APOE4 allele. This suggests that important subsets of AD phenotypes may exist that diverge metabolically.

%B J Alzheimers Dis %V 58 %P 1129-1135 %G eng %N 4 %R 10.3233/JAD-170148 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of Attention Training in Mild Cognitive Impairment Patients with Subcortical Vascular Changes: The RehAtt Study. %A Pantoni, Leonardo %A Poggesi, Anna %A Diciotti, Stefano %A Valenti, Raffaella %A Orsolini, Stefano %A Della Rocca, Eleonora %A Inzitari, Domenico %A Mascalchi, Mario %A Salvadori, Emilia %X

BACKGROUND AND OBJECTIVE: Mild cognitive impairment (MCI) patients with small vessel disease (SVD) are at high dementia risk. We tested the effects of cognitive rehabilitation in these patients using the Attention Process Training-II (APT-II) program in a single-blinded, randomized clinical trial.

METHODS: Patients were randomized to APT-II or standard care and evaluated at baseline, 6, and 12 months with functional, quality of life, cognitive tests, and resting state functional MRI (rsfMRI).

RESULTS: Forty-six patients were enrolled and 43 (mean±SD age 75.1±6.8) completed the study. No change was seen in functionality and quality of life between treated and non-treated patients. However, the Rey Auditory-Verbal Learning Test immediate recall showed a significant improvement in treated compared to non-treated group (change score 6 versus 12 months: 1.8±4.9 and -1.4±3.8, p = 0.021; baseline versus 12 months: 3.8±6.1 and 0.2±4.4, p = 0.032). A higher proportion of treated patients had stable/better evaluation compared to non-treated group on Visual search test (6 versus 12 months: 95% versus 71%, p = 0.038) and Rey-Osterrieth Complex Figure copy (6 versus 12 months: 95% versus 67%, p = 0.027). RsfMRI, performed in a subsample, showed that the difference between follow-up and baseline in synchronization of activity in cerebellar areas was significantly greater in treated than in non-treated patients.

CONCLUSION: We were unable to show a significant effect in quality of life or functional status in treated patients with MCI and SVD. However, APT-II produces some beneficial effects in focused attention and working memory and seems to increase activity in brain circuits involved in cognitive processes.

%B J Alzheimers Dis %V 60 %P 615-624 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869475?dopt=Abstract %R 10.3233/JAD-170428 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Effect of Escitalopram on Mood and Cognition in Depressive Alzheimer's Disease Subjects. %A An, Hoyoung %A Choi, Booyeol %A Park, Kun-Woo %A Kim, Do-Hoon %A Yang, Dong-Won %A Hong, Chang Hyung %A Kim, Seong Yoon %A Han, Seol-Heui %X

BACKGROUND: Effective treatments to alleviate depression in Alzheimer's disease (AD) have been scarce.

OBJECTIVE: To investigate the efficacy and tolerability of escitalopram in the treatment of depression in AD.

METHODS: In this 12-week randomized, double-blind, placebo-controlled trial with open-label, 12-week extension, AD subjects over 50 years of age, with depression defined by Olin's provisional diagnostic criteria, were enrolled. The Cornell Scale for Depression in Dementia (CSDD), and other measures of depression and cognition were repeated.

RESULTS: 91 subjects were screened, and 84 were randomized into either the study group or placebo group (n = 42 for both groups). Twenty-four subjects (29%) were unable to finish the study, yielding a per protocol population of 60 subjects (study group: n = 27; placebo group: n = 33). At week 12, differences in measures of depression and cognition between the two groups were not statistically significant. However, exploratory analysis suggested that further research on a subset of subjects with 'definite major depression' (baseline CSDD score ≥18) is needed. The number of treatment-related adverse-events (AE) did not differ between groups (p = 0.83) and no serious treatment-related AE were observed.

CONCLUSION: The use of escitalopram was well tolerated in depressive dementia patients. Future studies focusing on subjects with more severe levels of depression, and with more statistical power, will be needed.

%B J Alzheimers Dis %V 55 %P 727-735 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716660?dopt=Abstract %R 10.3233/JAD-160225 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of Spinal Manometers on Cerebrospinal Fluid Amyloid-β Concentration. %A Toombs, Jamie %A Foiani, Martha S %A Paterson, Ross W %A Heslegrave, Amanda %A Wray, Selina %A Schott, Jonathan M %A Fox, Nick C %A Lunn, Michael P %A Blennow, Kaj %A Zetterberg, Henrik %X

The effect of spinal manometers on cerebrospinal fluid (CSF) amyloid-β (Aβ) concentration was investigated. Pooled human CSF samples were divided in two, one half passed through a manometer into a collection tube, the other transferred directly to a collection tube. CSF was analyzed for Aβ38/40/42 using an electrochemiluminescence immunoassay. Relative to control, use of a manometer decreased Aβ38/40/42 concentration by 5.6% (±1.5SE), 4.4% (±1.7SE), and 4.3% (±2.4SE), respectively. The ratios of Aβ42 :40, Aβ42 :38, and Aβ40 :38 were not affected by manometer treatment. Factors which artificially lower CSF Aβ concentrations are relevant to clinical diagnosis for AD and study design.

%B J Alzheimers Dis %V 56 %P 885-891 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059797?dopt=Abstract %R 10.3233/JAD-161126 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Effect of the Association between Donepezil and Choline Alphoscerate on Behavioral Disturbances in Alzheimer's Disease: Interim Results of the ASCOMALVA Trial. %A Carotenuto, Anna %A Rea, Raffaele %A Traini, Enea %A Fasanaro, Angiola Maria %A Ricci, Giovanna %A Manzo, Valentino %A Amenta, Francesco %X

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are a group of psychological reactions, psychiatric symptoms, and behaviors commonly found in Alzheimer's disease (AD). Four clusters of BPSD have been described: mood disorders (depression, anxiety, and apathy), psychotic symptoms (delusions and hallucinations), aberrant motor behaviors (pacing, wandering, and other purposeless behaviors), and inappropriate behaviors (agitation, disinhibition, and euphoria). Most of them are attributed to acetylcholine deficiency.

OBJECTIVE: To evaluate if a higher amount of acetylcholine obtained by associating donepezil and choline alphoscerate might have a favorable effect on BPSD.

METHODS: BPSD were measured at baseline and after 24 months in 113 mild/moderate AD patients, included in the double-blind randomized trial ASCOMALVA, by the Neuropsychiatric Inventory (NPI). Two matched groups were compared: group A treated with donepezil (10 mg/day) plus choline alphoscerate (1200 mg/day), and group B treated with donepezil (10 mg/day) plus placebo.

RESULTS: Data of NPI revealed a significant decrease of BPSD severity and distress of the caregiver in patients of group A compared with group B. Mood disorders (depression, anxiety and apathy) were significantly decreased in subjects treated with donepezil and choline alphoscerate, while their severity and frequency was increased in the other group.

CONCLUSIONS: Patients treated with donepezil plus choline alphoscerate showed a lower level of behavioral disturbances than subjects treated with donepezil only, suggesting that the association can have beneficial effects.

%B J Alzheimers Dis %V 56 %P 805-815 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035924?dopt=Abstract %R 10.3233/JAD-160675 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Effect of Traumatic Brain Injury History with Loss of Consciousness on Rate of Cognitive Decline Among Older Adults with Normal Cognition and Alzheimer's Disease Dementia. %A Tripodis, Yorghos %A Alosco, Michael L %A Zirogiannis, Nikolaos %A Gavett, Brandon E %A Chaisson, Christine %A Martin, Brett %A McClean, Michael D %A Mez, Jesse %A Kowall, Neil %A Stern, Robert A %X

Traumatic brain injury (TBI) is thought to be a risk factor for dementia, including dementia due to Alzheimer's disease (AD). However, the influence of TBI history on the neuropsychological course of AD is unknown and, more broadly, the effect of TBI history on age-related cognitive change is poorly understood. We examined the relationship between history of TBI with loss of consciousness (LOC) history and cognitive change in participants with normal cognition and probable AD, stratified by APOEɛ4 allele status. The sample included 706 participants (432 with normal cognition; 274 probable AD) from the National Alzheimer's Coordinating Center (NACC) dataset that completed the Uniform Data Set evaluation between 2005 and 2014. Normal and probable AD participants with a history of TBI were matched to an equal number of demographically and clinically similar participants without a TBI history. In this dataset, TBI with LOC was defined as brain trauma with brief or extended unconsciousness. For the normal and probable AD cohorts, there was an average of 3.2±1.9 and 1.8±1.1 years of follow-up, respectively. 30.8% of the normal cohort were APOEɛ4 carriers, whereas 70.8% of probable AD participants were carriers. Mixed effects regressions showed TBI with LOC history did not affect rates of cognitive change in APOEɛ4 carriers and non-carriers. Findings from this study suggest that TBI with LOC may not alter the course of cognitive function in older adults with and without probable AD. Future studies that better characterize TBI (e.g., severity, number of TBIs, history of subconconcussive exposure) are needed to clarify the association between TBI and long-term neurocognitive outcomes.

%B J Alzheimers Dis %V 59 %P 251-263 %8 2017 %G eng %N 1 %R 10.3233/JAD-160585 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of Vascular Risk Factors on the Progression of Mild Alzheimer's Disease and Lewy Body Dementia. %A Bergland, Anne Katrine %A Dalen, Ingvild %A Larsen, Alf Inge %A Aarsland, Dag %A Soennesyn, Hogne %X

BACKGROUND: Vascular risk factors (VRF) are associated with an increased risk of neurodegenerative disease.

OBJECTIVE: To examine the association between VRF and cognitive decline in patients with Alzheimer's disease (AD) and Lewy body dementia (LBD).

METHODS: We included consecutive referrals with mild AD or LBD to dementia clinics in western Norway from 2005 to 2013. The Mini-Mental Status Exam (MMSE) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) were administered at baseline and then annually for up to five years. The VRF include diabetes mellitus, hypertension, hypercholesterolemia, overweight and smoking. Generalized Estimating Equations (GEE) were used to examine the potential association between VRF scores and the change in MMSE and CDR-SB scores, adjusting for age, sex, and the apolipoprotein ɛ4 allele (APOE4).

RESULTS: A total of 200 patients were included (113 AD, 87 LBD) (mean age 76 years, mean baseline MMSE 24.0, mean follow-up time 3.5 years). Smoking was the only VRF significantly associated with a more rapid cognitive decline, however only in the AD group. Being overweight at baseline was associated with a slower cognitive decline. Moreover, hypertension at baseline predicted a slower decline in MMSE scores. In the LBD group diabetes mellitus was found to be associated with a slower increase in CDR-SB scores.

CONCLUSION: With the exception of smoking, VRF at time of dementia diagnosis were not associated with a more rapid cognitive decline.

%B J Alzheimers Dis %V 56 %P 575-584 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035932?dopt=Abstract %R 10.3233/JAD-160847 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect Size Analyses of Souvenaid in Patients with Alzheimer's Disease. %A Cummings, Jeffrey %A Scheltens, Philip %A McKeith, Ian %A Blesa, Rafael %A Harrison, John E %A Bertolucci, Paulo H F %A Rockwood, Kenneth %A Wilkinson, David %A Wijker, Wouter %A Bennett, David A %A Shah, Raj C %X

BACKGROUND: Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium), was developed to support the formation and function of neuronal membranes.

OBJECTIVE: To determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm.

METHODS: Data from all three reported randomized controlled trials of Souvenaid in Alzheimer's disease (AD) dementia (Souvenir I, Souvenir II, and S-Connect) and an open-label extension study were included in analyses of effect size for cognitive, functional, and behavioral outcomes. Effect size was determined by calculating Cohen's d statistic (or Cramér's V method for nominal data), number needed to treat and number needed to harm. Statistical calculations were performed for the intent-to-treat populations.

RESULTS: In patients with mild AD, effect sizes were 0.21 (95% confidence intervals: -0.06, 0.49) for the primary outcome in Souvenir II (neuropsychological test battery memory z-score) and 0.20 (0.10, 0.34) for the co-primary outcome of Souvenir I (Wechsler memory scale delayed recall). No effect was shown on cognition in patients with mild-to-moderate AD (S-Connect). The number needed to treat (6 and 21 for Souvenir I and II, respectively) and high number needed to harm values indicate a favorable harm:benefit ratio for Souvenaid versus control in patients with mild AD.

CONCLUSIONS: The favorable safety profile and impact on outcome measures converge to corroborate the putative mode of action and demonstrate that Souvenaid can achieve clinically detectable effects in patients with early AD.

%B J Alzheimers Dis %V 55 %P 1131-1139 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767993?dopt=Abstract %R 10.3233/JAD-160745 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of a DJ-1-Binding Compound on Spatial Learning and Memory Impairment in a Mouse Model of Alzheimer's Disease. %A Kitamura, Yoshihisa %A Inden, Masatoshi %A Kimoto, Yasuto %A Takata, Kazuyuki %A Yanagisawa, Daijiro %A Hijioka, Masanori %A Ashihara, Eishi %A Tooyama, Ikuo %A Shimohama, Shun %A Ariga, Hiroyoshi %X

Previously, DJ-1 modulator UCP0054278/comp-B was identified by virtual screening, where comp-B interacts with DJ-1 to produce antioxidant and neuroprotective responses in Parkinson's disease models. However, the effect of comp-B in an in vivo Alzheimer's disease (AD) model is yet undetermined. Thus, we examined the effect of comp-B on spatial learning, memory, and amyloid-β (Aβ) clearance in a transgenic mouse model of AD. We found that comp-B resolved the cognitive deficits, reduced insoluble Aβ42 levels, and prevented the degeneration of synaptic functions, thereby suggesting that comp-B may become a major compound for AD treatment.

%B J Alzheimers Dis %V 55 %P 67-72 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662308?dopt=Abstract %R 10.3233/JAD-160574 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Alzheimer's Disease-Associated Risk Loci on Amyloid-β Accumulation in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients. %A Laiterä, Tiina %A Paananen, Jussi %A Helisalmi, Seppo %A Sarajärvi, Timo %A Huovinen, Joel %A Laitinen, Marjo %A Rauramaa, Tuomas %A Alafuzoff, Irina %A Remes, Anne M %A Soininen, Hilkka %A Haapasalo, Annakaisa %A Jääskeläinen, Juha E %A Leinonen, Ville %A Hiltunen, Mikko %X

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition featuring characteristic symptoms, ventriculomegaly, and normal or slightly elevated cerebrospinal fluid pressure. In Alzheimer's disease (AD) patients, diffuse aggregates of amyloid-β (Aβ) and neurofibrillary hyperphosphorylated tau are detected in the neocortex of the brain, while similar accumulation of Aβ is also detected in iNPH. Recent genome-wide association studies have identified several novel risk loci for AD, potentially affecting Aβ-related cellular processes. Apart from the apolipoprotein E ɛ4 allele (APOE4), the risk effect of single loci is low, emphasizing the importance of the polygenic risk score approach when assessing the combined effects.

OBJECTIVE: To study the effects of AD-associated individual and polygenic risk score of single nucleotide polymorphisms (SNPs) on the accumulation of Aβ in the brain samples of iNPH patients.

METHODS: A sample set of frontal cortex biopsies from 188 iNPH patients were divided into two groups according to the Aβ pathology. After the genotyping of the AD-associated risk loci, polygenic risk score was calculated for each iNPH patient and subsequently analyzed in relation to Aβ deposition.

RESULTS: Apart from the APOE4, none of the SNPs revealed a statistically significant effect on the accumulation of Aβ in iNPH. Also, the non-APOE4 polygenic risk score did not associate with Aβ deposition.

CONCLUSION: Novel AD-associated risk genes have no significant effect on Aβ accumulation in the brain of iNPH patients. However, APOE4 affects the Aβ deposition in the brain of iNPH and AD patients in a similar manner.

%B J Alzheimers Dis %V 55 %P 995-1003 %G ENG %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802227?dopt=Abstract %R 10.3233/JAD-160554 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Effects of an APOE Promoter Polymorphism on Human White Matter Connectivity during Non-Demented Aging. %A Chang, Peifen %A Li, Xin %A Ma, Chao %A Zhang, Sisi %A Liu, Zhen %A Chen, Kewei %A Ai, Lin %A Chang, Jingling %A Zhang, Zhanjun %X

Polymorphisms of the apolipoprotein E (APOE) promoter rs405509 are related to Alzheimer's disease (AD). The T/T allele of rs405509 decreases the transcription of the APOE gene and leads to impairments in a specific brain structural network in aged individuals; thus, it is an important risk factor for AD. However, it remains unknown whether rs405509 affects white matter networks during aging. Here, we investigated the effect of the rs405509 genotype (T/T versus G-allele) on age-related brain white matter structural networks via construction of the graph theory-based structural connectome using diffusion MRI data in a large cohort. Network communication efficiency was quantified, along with the network's betweenness centrality (Bc), global efficiency, local efficiency, and shortest path length. Regarding cognition, TT carriers had significant negative correlations between age and memory performance and between age and executive functions. A network analysis showed that TT carriers had an accelerated age-related loss of Bc and that regional Bc decreased in the left inferior frontal gyrus pars opercularis, the left posterior cingulate cortex, the right inferior occipital gyrus (IOG.R), and the left angular gyrus (ANG.L). Additional brain-behavior relationship analyses showed that polymorphism of rs405509 and age have strong interaction effects on the association of nodal Bc and cognition, mainly in the IOG.R and ANG.L. These results demonstrate that the rs405509 T/T allele of APOE causes an age-related cognitive decline in non-demented elderly people, possibly by modulating brain network communication efficiency, which may be beneficial for understanding the neural mechanisms of rs405509-related cognitive aging and AD pathogenesis.

%B J Alzheimers Dis %V 55 %P 77-87 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636845?dopt=Abstract %R 10.3233/JAD-160447 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Effects of Cardiotrophin-1 on Early Synaptic Mitochondrial Dysfunction and Synaptic Pathology in APPswe/PS1dE9 Mice. %A Wang, Dongmei %A Liu, Xiaozhuan %A Liu, Yumei %A Li, Sanqiang %A Wang, Chenying %X

The coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Cardiotrophin-1 (CT-1) has been shown to exhibit impressive neuroprotective effects. Previous studies have shown positive effects of CT-1 on brain glucose metabolism and cognition in APPswe/PS1dE9 transgenic mice; however, little is known about the effects of CT-1 on early synaptic mitochondrial dysfunction and resultant synaptic pathology in the brain. In this study, 4-month-old transgenic mice with brain tissue-specific CT-1 expression were used alone or in combination with APPswe/PS1dE9 transgenic mice to evaluate the effect of CT-1 on synaptic mitochondrial dysfunction and resultant synaptic pathology, and cryptic memory deficits in the APPswe/PS1dE9 transgenic mice. The potential mechanism of action of CT-1 was also examined. Young CT-1×APPswe/PS1dE9 transgenic mice exhibited improvements in long-term learning and memory ability and ameliorations of synaptic mitochondrial/synaptic impairments compared to young APPswe/PS1dE9 transgenic mice. Moreover, CT-1 upregulated the expression of AMPAR and increased AMP-activated protein kinase (AMPK) activity in the hippocampus of APPswe/PS1dE9 transgenic mice. However, AMPK inhibition through shRNA knockdown of AMPKα blocked the neuroprotective effects of CT-1 on the expression of AMPAR and mitochondrial/synaptic dysfunction in Aβ-treated mouse neurons. These results suggest that CT-1 may be a potent candidate for the early prevention and treatment of AD.

%B J Alzheimers Dis %V 59 %P 1255-1267 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731433?dopt=Abstract %R 10.3233/JAD-170100 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Effects of Cortical Hypometabolism and Hippocampal Atrophy on Clinical Trajectories in Mild Cognitive Impairment with Suspected Non-Alzheimer's Pathology: A Brief Report. %A Chung, Jun Ku %A Plitman, Eric %A Nakajima, Shinichiro %A Caravaggio, Fernando %A Shinagawa, Shunichiro %A Iwata, Yusuke %A Gerretsen, Philip %A Kim, Julia %A Takeuchi, Hiroyoshi %A Patel, Raihaan %A Chakravarty, M Mallar %A Strafella, Antonio %A Graff-Guerrero, Ariel %X

The clinical and structural trajectories of suspected non-Alzheimer' pathology (SNAP) remain elusive due to its heterogeneous etiology. Baseline and longitudinal clinical (global cognition, daily functioning, symptoms of dementia, and learning memory) and hippocampal volume trajectories over two years were compared between patients with amnestic mild cognitive impairment (aMCI) with SNAP with reduced hippocampal volumes (SNAP+HIPPO) and aMCI patients with SNAP without reduced hippocampal volumes. SNAP+HIPPO showed overall worse baseline cognitive functions. Longitudinally, SNAP+HIPPO showed faster deterioration of clinical symptoms of dementia. Having both hippocampal atrophy and cortical hypometabolism without amyloid pathology may exacerbate symptoms of dementia in aMCI.

%B J Alzheimers Dis %V 60 %P 341-347 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826178?dopt=Abstract %R 10.3233/JAD-170098 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of DHA Supplementation on Hippocampal Volume and Cognitive Function in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized, Double-Blind, Placebo-Controlled Trial. %A Zhang, Yan-Ping %A Miao, Rujuan %A Li, Qing %A Wu, Tianfeng %A Ma, Fei %X

Docosahexaenoic acid (DHA) is important for brain function, and higher DHA intake is inversely correlated with relative risk of Alzheimer's disease. The potential benefits of DHA supplementation in people with mild cognitive impairment (MCI) have not been fully examined. Our study aimed to determine the effect of DHA supplementation on cognitive function and hippocampal atrophy in elderly subjects with MCI. This was a randomized, double-blind, placebo-controlled trial in Tianjin, China. 240 individuals with MCI aged 65 years and over were recruited and equalized randomly allocated to the DHA or the placebo group. Participants received 12-month DHA supplementation (2 g/day) or corn oil as placebo. Both global and specific subdomains of cognitive function and hippocampal volume were measured at baseline, 6 months, and 12 months. Both changes were analyzed by repeated-measure analysis of variance (ANOVA). This trial has been registered: ChiCTR-IOR-15006058. A total of 219 participants (DHA: 110, Placebo: 109) completed the trial. The change in mean serum DHA levels was greater in the intervention group (+3.85%) compared to the control group (+1.06%). Repeated-measures analyses of covariance showed that, over 12 months, there was a significant difference in the Full-Scale Intelligence Quotient (ηp2 = 0.084; p = 0.039), Information (ηp2 = 0.439; p = 0.000), and Digit Span (ηp2 = 0.375; p = 0.000) between DHA-treated versus the placebo group. In addition, there were significant differences in volumes of left hippocampus (ηp2 = 0.121, p = 0.016), right hippocampus (ηp2 = 0.757, p = 0.008), total hippocampus (ηp2 = 0.124, p = 0.023), and global cerebrum (ηp2 = 0.145, p = 0.032) between the two groups. These findings suggest that DHA supplementation (2 g/day) for 12 months in MCI subjects can significantly improve cognitive function and slow the progression of hippocampal atrophy. Larger, longer-term confirmatory studies are warranted.

%B J Alzheimers Dis %V 55 %P 497-507 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716665?dopt=Abstract %R 10.3233/JAD-160439 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Exercise on Cognitive Function in Older People with Dementia: A Randomized Controlled Trial. %A Toots, Annika %A Littbrand, Håkan %A Boström, Gustaf %A Hörnsten, Carl %A Holmberg, Henrik %A Lundin-Olsson, Lillemor %A Lindelöf, Nina %A Nordström, Peter %A Gustafson, Yngve %A Rosendahl, Erik %X

BACKGROUND: Although physical exercise has been suggested to influence cognitive function, previous exercise studies show inconsistent results in people with dementia.

OBJECTIVES: To investigate effects of exercise on cognitive function in people with dementia.

METHOD: The Umeå Dementia and Exercise (UMDEX) study, a cluster-randomized controlled trial, was set in 16 nursing homes in Umeå, Sweden. One hundred-and-forty-one women and 45 men with dementia; mean age of 85 y and mean Mini-Mental State Examination (MMSE) score of 15, were randomized to a High-Intensity Functional Exercise program or a seated attention control activity. Blinded assessors measured global cognitive function using the MMSE and the Alzheimer's disease Assessment Scale - Cognitive subscale (ADAS-Cog), and executive function using Verbal fluency (VF) at baseline and 4 months (directly after intervention completion), and MMSE and VF at 7 months.

RESULTS: Linear mixed models showed no between-group effects in mean difference from baseline (95% confidence intervals, CI) at 4 months in MMSE (-0.27; 95% CI -1.4 to 0.87, p = 0.644), ADAS-Cog (-1.04, 95% CI -4 to 1.92, p = 0.491), or VF (-0.53, 95% CI -1.42 to 0.35, p = 0.241) or at 7 months in MMSE (-1.15, 95% CI -2.32 to 0.03, p = 0.056) or VF (-0.18, 95% CI -1.09 to 0.74, p = 0.707).

CONCLUSION: A 4-month, high-intensity functional exercise program had no superior effects on global cognition or executive function in people with dementia living in nursing homes when compared with an attention control activity.

%B J Alzheimers Dis %V 60 %P 323-332 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28800328?dopt=Abstract %R 10.3233/JAD-170014 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Exercise on Type 2 Diabetes Mellitus-Related Cognitive Impairment and Dementia. %A Callisaya, Michele %A Nosaka, Kazunori %X

Cognitive impairment and dementia are common contributors to institutionalization and loss of quality of life in older people. Both type 2 diabetes mellitus (T2DM) and physical inactivity are prevalent and important modifiable risk factors for developing dementia. Physical activity is recommended in the management of T2DM, and there is growing evidence that exercise, a subgroup of physical activity, is also beneficial for maintaining and improving brain structure and function. This paper reviews the evidence for a benefit of exercise on T2DM related cognitive impairment and dementia. In addition, the type (e.g., aerobic, resistance), intensity, duration, and frequency of exercise are discussed. This review shows that although exercise has known benefits on the mechanisms linking T2DM to dementia, there are very few randomized controlled trials examining whether this is the case. It is concluded that the uptake of exercise for the brain has great potential to improve quality of life and provide significant cost savings, but further research is warranted to clarify the effects of exercise on T2DM and those on dementia.

%B J Alzheimers Dis %V 59 %P 503-513 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598841?dopt=Abstract %R 10.3233/JAD-161154 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Effects of Gene Mutations on Default Mode Network in Familial Alzheimer's Disease. %A Li, Xiaozhen %A Westman, Eric %A Thordardottir, Steinunn %A Ståhlbom, Anne Kinhult %A Almkvist, Ove %A Blennow, Kaj %A Wahlund, Lars-Olof %A Graff, Caroline %X

Familial Alzheimer's disease (FAD) mutations have very high penetrance but age at onset and rate of disease progression differ. Neuroimaging and cerebrospinal fluid (CSF) examinations in mutation carriers (MCs) may provide an opportunity to identify early biomarkers that can be used to track disease progression from presymptomatic to the dementia stages of disease. The default mode network (DMN) is a resting state neuronal network composed of regions known to associate with amyloid deposition in AD. We hypothesized that functional connectivity in the DMN might change at pre-clinical stages in FAD MCs and correlate with changes in CSF biomarkers as a consequence of AD brain pathology. To test the hypothesis, we compared the functional connectivity in DMN between pre-MCs/MCs and non-carriers (NCs). No significant differences between pre-MCs and NCs were observed. When comparing all MCs with NCs, significant decreased functional connectivity in the right inferior parietal lobule, right precuneus, and left posterior cingulate cortex were found. We also found statistically significant correlations between CSF amyloid-β 42 and tau protein levels and average Z-score, a resting-state functional MRI measurement reflecting the degree of the correlation between a given voxel's time courses and the time courses corresponding to DMN, from the region with statistical difference. The observed disruption of DMN and pathological levels of AD CSF-biomarkers in FAD MCs are similar to the changes described in sporadic AD, which give further support that amyloid and tau pathology impairs neuronal and synaptic function.

%B J Alzheimers Dis %V 56 %P 327-334 %G eng %N 1 %R 10.3233/JAD-160730 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Healthy Aging and Mild Cognitive Impairment on a Real-Life Decision-Making Task. %A Pertl, Marie-Theres %A Benke, Thomas %A Zamarian, Laura %A Delazer, Margarete %X

In this study, we investigated the effects of age and of mild cognitive impairment (MCI) on decision making under risk by adopting a task representing real-life health-related situations and involving complex numerical information. Moreover, we assessed the relationship of real-life decision making to other cognitive functions such as number processing, executive functions, language, memory, and attention. For this reason, we compared the performance of 19 healthy, relatively younger adults with that of 18 healthy older adults and the performance of the 18 healthy older adults with that of 17 patients with MCI. Results indicated difficulties in real-life decision making for the healthy older adults compared with the healthy, relatively younger adults. Difficulties of patients with MCI relative to the healthy older adults arose in particular in difficult items requiring processing of frequencies and fractions. Significant effects of age and of MCI in processing frequencies were also evident in a ratio number comparison task. Decision-making performance of healthy participants and of the patient group correlated significantly with number processing. There was a further significant correlation with executive functions for the healthy participants and with reading comprehension for the patients. Our results suggest that healthy older individuals and patients with MCI make less advantageous decisions when the information is complex and high demands are put on executive functions and numerical abilities. Moreover, we show that executive functions and numerical abilities are not only essential in laboratory gambling tasks but also in more realistic and ecological decision situations within the health context.

%B J Alzheimers Dis %V 58 %P 1077-1087 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527216?dopt=Abstract %R 10.3233/JAD-170119 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Effects of LW-AFC on the Hippocampal Transcriptome in Senescence-Accelerated Mouse Prone 8 Strain, a Mouse Model of Alzheimer's Disease. %A Wang, Jianhui %A Liu, Yang %A Cheng, Xiaorui %A Zhang, Xiaorui %A Liu, Feng %A Liu, Gang %A Qiao, Shanyi %A Ni, Ming %A Zhou, Wenxia %A Zhang, Yongxiang %A Li, Fei %X

The senescence-accelerated mouse prone 8 (SAMP8) strain is considered a robust experimental model for developing preventative and therapeutic treatments for Alzheimer's disease (AD), a neurodegenerative disease which cannot be effectively prevented, halted, or cured. Our previous studies showed that LW-AFC, a new formula derived from the classical traditional Chinese medicinal prescription Liuwei Dihuang decoction, ameliorates cognitive deterioration in PrP-hAβPPswe/PS1ΔE9 transgenic mice and SAMP8 mice. This study aims to investigate the mechanism that mediates how LW-AFC improves cognitive deficit on the basis of the transcriptome. We conducted a genome-wide survey of gene expression in the hippocampus in mice from the senescence accelerated mouse resistant 1 (SAMR1) strain, from SAMP8 and from LW-AFC treated SAMP8. The results showed that LW-AFC reversed the transcriptome in the hippocampus of SAMP8 mice. The specific investigation of altered gene expression in subtypes defined by cognitive profiles indicated that the systemic lupus erythematosus pathway, spliceosomes, amyotrophic lateral sclerosis, and the insulin signaling were involved in the improvement of cognitive ability by LW-AFC. The expression of genes Enpp2, Etnk1, Epdr1, and Gm5900 in the hippocampus were correlated with that of LW-AFC's ameliorating cognitive impairment in SAMP8 mice. Because LW-AFC is composed of polysaccharides, glycosides, and oligosaccharides, we infer that LW-AFC has direct or indirect effects on altering gene expressions and regulating pathways in the hippocampus of SAMP8 mice. These data are helpful for the enhanced identification of LW-AFC as new therapeutic modalities to AD.

%B J Alzheimers Dis %V 57 %P 227-240 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222521?dopt=Abstract %R 10.3233/JAD-161079 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Effects of Meditation on Grey Matter Atrophy and Neurodegeneration: A Systematic Review. %A Last, Nicole %A Tufts, Emily %A Auger, Leslie E %X

The present systematic review is based on the premise that a variety of neurodegenerative diseases are accompanied by grey matter atrophy in the brain and meditation may impact this. Given that age is a major risk factor for many of these progressive and neurodegenerative diseases and that the percentage of the population over the age of 65 is quickly increasing, there is an obvious need for prompt treatment and prevention advances in research. As there is currently no cure for Alzheimer's disease and other neurodegenerative diseases, many are seeking non-pharmacological treatment options in attempts to offset the disease-related cognitive and functional declines. On the basis of a growing body of research suggesting that meditation is effective in increasing grey matter volume in healthy participants, this paper systematically reviewed the literature regarding the effects of meditation on restoring grey matter volume in healthy individuals and those affected by neurodegeneration. This review searched PubMed, CINAHL, and APA PsycNET to identify original studies that included MRI imaging to measure grey matter volume in meditators and post-mindfulness-based intervention participants compared to controls. Thirteen studies were considered eligible for review and involved a wide variety of meditation techniques and included participants with and without cognitive impairment. All studies reported significant increases in grey matter volume in the meditators/intervention group, albeit in assorted regions of the brain. Limited research exists on the mechanisms through which meditation affects disease-related neurodegeneration, but preliminary evidence suggests that it may offset grey matter atrophy.

%B J Alzheimers Dis %V 56 %P 275-286 %G eng %N 1 %R 10.3233/JAD-160899 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia. %A Ferrari, Raffaele %A Grassi, Mario %A Graziano, Francesca %A Palluzzi, Fernando %A Archetti, Silvana %A Bonomi, Elisa %A Bruni, Amalia C %A Maletta, Raffaele G %A Bernardi, Livia %A Cupidi, Chiara %A Colao, Rosanna %A Rainero, Innocenzo %A Rubino, Elisa %A Pinessi, Lorenzo %A Galimberti, Daniela %A Scarpini, Elio %A Serpente, Maria %A Nacmias, Benedetta %A Piaceri, Irene %A Bagnoli, Silvia %A Rossi, Giacomina %A Giaccone, Giorgio %A Tagliavini, Fabrizio %A Benussi, Luisa %A Binetti, Giuliano %A Ghidoni, Roberta %A Singleton, Andrew %A Hardy, John %A Momeni, Parastoo %A Padovani, Alessandro %A Borroni, Barbara %X

In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95% CI: -4.64 to -3.07, p < 2×10-16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.

%B J Alzheimers Dis %V 56 %P 1271-1278 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28128768?dopt=Abstract %R 10.3233/JAD-160949 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer's Disease Biomarkers: A Pilot Clinical Trial. %A Craft, Suzanne %A Claxton, Amy %A Baker, Laura D %A Hanson, Angela J %A Cholerton, Brenna %A Trittschuh, Emily H %A Dahl, Deborah %A Caulder, Erin %A Neth, Bryan %A Montine, Thomas J %A Jung, Youngkyoo %A Maldjian, Joseph %A Whitlow, Christopher %A Friedman, Seth %X

BACKGROUND: Long acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). The investigation of longer-term administration is necessary to determine whether benefits persist, whether they are similar to benefits provided by regular insulin, and whether either form of insulin therapy affects AD biomarkers.

OBJECTIVE: The present study aimed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition, daily functioning, and AD biomarkers for adults with MCI or AD.

METHODS: This randomized, double-blind, placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD. Participants received placebo (n = 12), 40 IU of insulin detemir (n = 12), or 40 IU of regular insulin (n = 12) daily for four months, administered with a nasal delivery device. A cognitive battery was administered at baseline and after two and four months of treatment. MRI was administered for all participants and lumbar puncture for a subset (n = 20) at baseline and four months. The primary outcome was change from baseline to four months on a memory composite (sum of Z scores for delayed list and story recall). Secondary outcomes included: global cognition (Alzheimer's Disease Assessment Scale-Cognition), daily functioning (Dementia Severity Rating Scale), MRI volume changes in AD-related regions of interest, and cerebrospinal fluid AD markers.

RESULTS: The regular insulin treated group had better memory after two and four months compared with placebo (p < 0.03). No significant effects were observed for the detemir-assigned group compared with the placebo group, or for daily functioning for either group. Regular insulin treatment was associated with preserved volume on MRI. Regular insulin treatment was also associated with reduction in the tau-P181/Aβ42 ratio.

CONCLUSION: Future research is warranted to examine the mechanistic basis of treatment differences, and to further assess the efficacy and safety of intranasal insulin.

%B J Alzheimers Dis %V 57 %P 1325-1334 %G eng %N 4 %R 10.3233/JAD-161256 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Risperidone and Galantamine Treatment on Alzheimer's Disease Biomarker Levels in Cerebrospinal Fluid. %A Bloniecki, Victor %A Aarsland, Dag %A Blennow, Kaj %A Cummings, Jeffrey %A Falahati, Farshad %A Winblad, Bengt %A Freund-Levi, Yvonne %X

BACKGROUND: Treatment for neuropsychiatric symptoms (NPS) in dementia is insufficient. Antipsychotics and acetylcholinesterase inhibitors are used generating symptomatic improvements in behavior and cognition, but few studies have investigated their effect on Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF).

OBJECTIVE: This is a secondary analysis based on an earlier clinical trial comparing the treatment effects on NPS. The aim of this study was to examine whether treatment with risperidone and galantamine affect levels of the biomarkers T-Tau, P-Tau, Aβ1-42, and Aβ42/40-ratio in CSF. The secondary aim was to test if baseline levels of these biomarkers are associated with the clinical course of NPS.

METHODS: 83 patients (mean + SD 77.9.6±7.7 years) with dementia and NPS were randomized to galantamine (n = 44) or risperidone (n = 39) treatment. CSF samples were collected at baseline and after 12 weeks.

RESULTS: Changes in levels of biomarkers between the two treatment groups did not differ significantly. Low baseline levels of Aβ1 - 42 was significantly associated with reduction of irritability at follow up. Low baseline levels of Aβ1-42, Aβ42/40, and P-Tau were significant correlates of reduction in appetite and eating disorders. CSF Aβ1-42 levels in patients treated with risperidone were significantly decreased at follow up, showing an 8% (40 pg/mL) reduction as compared with baseline (p = 0.03).

CONCLUSIONS: Our results suggest that risperidone may affect the CSF profile of AD biomarkers indicating more amyloid pathology. Treatment with galantamine did not affect the CSF biomarkers in any direction. The AD CSF biomarkers displayed correlations with specific NPS suggesting potential research questions to be pursued.

%B J Alzheimers Dis %V 57 %P 387-393 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269767?dopt=Abstract %R 10.3233/JAD-160758 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Short-Term Exercise Interventions on Behavioral and Psychological Symptoms in Patients with Dementia: A Systematic Review. %A Fleiner, Tim %A Leucht, Stefan %A Förstl, Hans %A Zijlstra, Wiebren %A Haussermann, Peter %X

Observational and interventional studies indicate a direct link between the patients' physical activity and the extent of behavioral and psychological symptoms of dementia (BPSD). At present, there are no evidence-based recommendations for physical exercise in the acute dementia care settings. Hence, this systematic review investigates the effects of short-term exercise trials on BPSD. Trials with a length up to three months investigating the effects of structured exercise interventions on BPSD in acute dementia care settings were included. Five trials, referring to a total of N = 206 patients, met the inclusion criteria. The trial durations ranged from three up to twelve weeks. All trials conducted three sessions per week of 30 to 45 minutes. Three trials reported significant reductions of BPSD and differences in comparison to the pre-test and control groups. Out of the three trials investigating the effects of exercise interventions on depressive symptoms, one reported significant reduction and two reported no differences in pre-post analysis. Exercise represents a potentially worthwhile approach for the treatment of patients suffering from BPSD. Given the scarcity of available studies, more randomized controlled short-term exercise trials in acute dementia care settings are needed to define appropriate exercise recommendations for clinicians treating these patients.

%B J Alzheimers Dis %V 55 %P 1583-1594 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911304?dopt=Abstract %R 10.3233/JAD-160683 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Tooth Loss and the Apolipoprotein E ɛ4 Allele on Mild Memory Impairment in the Fujiwara-kyo Study of Japan: A Nested Case-Control Study. %A Okamoto, Nozomi %A Morikawa, Masayuki %A Amano, Nobuko %A Yanagi, Motokazu %A Takasawa, Shin %A Kurumatani, Norio %X

BACKGROUND: Several studies have suggested that periodontal disease can exacerbate the pro-inflammatory status of the brain. Tooth loss is one of the alternative evaluation indices of periodontal disease. There are few data on the relationship between tooth loss and memory impairment, depending on the apolipoprotein E (APOE) ɛ4 genotype.

OBJECTIVE: To determine if tooth loss is associated with mild memory impairment (MMI) and if this association is modified by the presence of the APOEɛ4 allele.

METHODS: A nested case-control study was conducted from 2007 to 2012 in Japan. Five hundred and thirty-seven Japanese subjects aged 65 years and over who were cognitively intact at baseline were analyzed. MMI at follow-up was evaluated.

RESULTS: The median number of teeth at baseline was significantly lower in MMI participants (n = 179) than in controls (n = 358) (MMI: median 21.0, interquartile range 10.0-25.0 versus controls: 24.0, 14.0-27.0). After adjustment for demographics, vascular risk factors, and APOEɛ4 allele, the multivariate adjusted odds ratio (OR) of ≤8 teeth was 1.97 (95% confidence interval [CI], 1.13-3.44) compared to 25-32 teeth. Participants with both the presence of at least 1 APOEɛ4 allele and ≤8 teeth had a higher risk of MMI compared with those with neither (OR, 2.82; 95% CI, 1.15-6.91). Those with either risk factor alone did not have a higher risk of MMI.

CONCLUSIONS: A lower number of teeth is related to risk of MMI. This may be primarily true for those individuals with an APOEɛ4 allele.

%B J Alzheimers Dis %V 55 %P 575-583 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716671?dopt=Abstract %R 10.3233/JAD-160638 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Efficacy and Safety of Donepezil in Chinese Patients with Severe Alzheimer's Disease: A Randomized Controlled Trial. %A Jia, Jianping %A Wei, Cuibai %A Jia, Longfei %A Tang, Yi %A Liang, Junhua %A Zhou, Aihong %A Li, Fangyu %A Shi, Lu %A Doody, Rachelle S %X

BACKGROUND: Donepezil has been used worldwide for the treatment of severe Alzheimer's disease (AD). Whether it is also appropriate for severe AD in Chinese patients remains unknown.

OBJECTIVE: To determine whether donepezil is effective and tolerable for Chinese patients with severe AD.

METHODS: The present study was a 24-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study conducted at 38 investigational hospitals in China. Patients with severe AD were enrolled in this trial. Patients were randomly assigned in a 1:1 ratio to receive either donepezil or placebo (5 mg for 6 weeks and10 mg for the remaining 18 weeks). The efficacy for donepezil were evaluated by the SIB, the Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC-plus) and the MMSE. Safety parameters were monitored throughout.

RESULTS: A total of 313 patients included the donepezil (n = 157) and the placebo groups (n = 156). Donepezil group improved more in SIB scores (least squares [LS] mean difference: 4.8, 95% CI 1.56 to 8.08, p = 0.004) and CIBIC-plus scores (drug-placebo difference: -0.4, 95% CI -0.66 to 0.03, p = 0.04) than placebo groups at Week 24. The MMSE scores between drug and placebo groups did not differ significantly. Twenty-nine patients with serious adverse events (SAEs) were reported in donepezil (n = 11) and placebo groups (n = 18) (p = 0.08). Most SAEs were not considered drug-related.

CONCLUSION: Donepezil for 24 weeks was more effective than placebo and showed good safety and tolerability in Chinese patients with severe AD. This study supports utility of the drug in severe stages of AD in the Chinese population.

%B J Alzheimers Dis %V 56 %P 1495-1504 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157100?dopt=Abstract %R 10.3233/JAD-161117 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Efficacy and Safety of Plasma Exchange with 5% Albumin to Modify Cerebrospinal Fluid and Plasma Amyloid-β Concentrations and Cognition Outcomes in Alzheimer's Disease Patients: A Multicenter, Randomized, Controlled Clinical Trial. %A Boada, Merce %A Anaya, Fernando %A Ortiz, Pilar %A Olazarán, Javier %A Shua-Haim, Joshua R %A Obisesan, Thomas O %A Hernandez, Isabel %A Muñoz, Joan %A Buendia, Mar %A Alegret, Montserrat %A Lafuente, Asunción %A Tárraga, Lluís %A Núñez, Laura %A Torres, Mireia %A Grifols, Joan Ramon %A Ferrer, Isidre %A Lopez, Oscar L %A Páez, Antonio %X

BACKGROUND: Studies conducted in animal models and humans suggest the presence of a dynamic equilibrium of amyloid-β (Aβ) peptide between cerebrospinal fluid (CSF) and plasma compartments.

OBJECTIVE: To determine whether plasma exchange (PE) with albumin replacement was able to modify Aβ concentrations in CSF and plasma as well as to improve cognition in patients with mild-moderate Alzheimer's disease (AD).

METHODS: In a multicenter, randomized, patient- and rater-blind, controlled, parallel-group, phase II study, 42 AD patients were assigned (1 : 1) to PE treatment or control (sham) groups. Treated patients received a maximum of 18 PE with 5% albumin (Albutein®, Grifols) with three different schedules: two PE/weekly (three weeks), one PE/weekly (six weeks), and one PE/bi- weekly (12 weeks), plus a six-month follow-up period. Plasma and CSF Aβ1-40 and Aβ1-42 levels, as well as cognitive, functional, and behavioral measures were determined.

RESULTS: CSF Aβ1-42 levels after the last PE compared to baseline were marginally higher in PE-treated group versus controls (adjusted means of variation: 75.3 versus -45.5 pg/mL; 95% CI: -19.8, 170.5 versus 135.1, 44.2; p = 0.072). Plasma Aβ1-42 levels were lower in the PE-treated group after each treatment period (p < 0.05). Plasma Aβ1-40 levels showed a saw-tooth pattern variation associated with PE. PE-treated patients scored better in the Boston Naming Test and Semantic Verbal Fluency (p < 0.05) throughout the study. Neuropsychiatric Inventory scores were higher in controls during the PE phase (p < 0.05).

CONCLUSION: PE with human albumin modified CSF and plasma Aβ1-42 levels. Patients treated with PE showed improvement in memory and language functions, which persisted after PE was discontinued.

%B J Alzheimers Dis %V 56 %P 129-143 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911295?dopt=Abstract %R 10.3233/JAD-160565 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Efficacy of Antidepressants for Depression in Alzheimer's Disease: Systematic Review and Meta-Analysis. %A Orgeta, Vasiliki %A Tabet, Naji %A Nilforooshan, Ramin %A Howard, Robert %X

BACKGROUND: Depression is common in people with Alzheimer's disease (AD) affecting overall outcomes and decreasing quality of life. Although depression in AD is primarily treated with antidepressants, there are few randomized controlled trials (RCTs) assessing efficacy and results have been conflicting.

OBJECTIVES: To systematically review evidence on efficacy of antidepressant treatments for depression in AD.

METHODS: Systematic review and meta-analysis of double blind RCTs comparing antidepressants versus placebo for depression in AD. We searched MEDLINE, CINAHL, EMBASE, PsycINFO, the Cochrane Controlled Trials Register and on line national and international registers. Primary outcomes were treatment response and depressive symptoms. Secondary outcomes were cognition, acceptability, and tolerability. Risk of bias was also assessed.

RESULTS: Seven studies met inclusion criteria. Three compared sertraline with placebo; one compared both sertraline and mirtazapine to placebo; imipramine, fluoxetine, and clomipramine were evaluated in one study each. In terms of response to treatment (6 studies, 297 patients treated with antidepressants and 223 with placebo), no statistically significant difference between antidepressants and placebo was found (odds ratio (OR) 1.95, 95% CI 0.97-3.92). We found no significant drug-placebo difference for depressive symptoms (5 studies, 311 patients, SMD -0.13; 95% CI -0.49 to 0.24). Overall quality of the evidence was moderate because of methodological limitations in studies and the small number of trials.

CONCLUSION: Despite the importance of depression in people with AD, few RCTs are available on efficacy of antidepressants, limiting clear conclusions of their potential role. There is a need for further high quality RCTs.

%B J Alzheimers Dis %V 58 %P 725-733 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505970?dopt=Abstract %R 10.3233/JAD-161247 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Efficacy of Emotion Recognition Rehabilitation for People with Alzheimer's Disease. %A García-Casal, J Antonio %A Goñi-Imizcoz, Miguel %A Perea-Bartolomé, M Victoria %A Soto-Pérez, Felipe %A Smith, Sarah Jane %A Calvo-Simal, Sara %A Franco-Martín, Manuel %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Therapy %K Depression %K Emotions %K Female %K Follow-Up Studies %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Outcome Assessment (Health Care) %K Recognition (Psychology) %K Single-Blind Method %K Statistics, Nonparametric %X

BACKGROUND: The ability to recognize emotional expression is essential for social interactions, adapting to the environment, and quality of life. Emotion recognition is impaired in people with Alzheimer's disease (AD), thus rehabilitation of these skills has the potential to elicit significant benefits.

OBJECTIVE: This study sought to establish whether emotion recognition capacity could be rehabilitated in people with AD.

METHODS: Thirty-six participants with AD were assigned to one of three conditions: an experimental group (EG) that received 20 sessions of rehabilitation of emotion recognition and 20 sessions of cognitive stimulation therapy (CST), a control group (CG) that received 40 sessions of CST, and a treatment as usual group (TAU).

RESULTS: A positive treatment effect favoring the EG was found; participants were better able to correctly identify emotions (p = 0.021), made fewer errors of commission (p = 0.002), had greater precision of processing (p = 0.021), and faster processing speed (p = 0.001). Specifically, the EG were better able to identify sadness (p = 0.016), disgust (p = 0.005), and the neutral expression (p = 0.014), with quicker processing speed for disgust (p = 0.002). These gains were maintained at one month follow-up with the exception of processing speed for surprise, which improved.

CONCLUSION: Capacity to recognize facial expressions of emotions can be improved through specific rehabilitation in people with AD, and gains are still present at a one month follow up. These findings have implications for the design of rehabilitation techniques for people with AD that may lead to improved quality of life and social interactions for this population.

%B J Alzheimers Dis %V 57 %P 937-951 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304290?dopt=Abstract %R 10.3233/JAD-160940 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Efficacy of Hearing Aids on the Cognitive Status of Patients with Alzheimer's Disease and Hearing Loss: A Multicenter Controlled Randomized Trial. %A Nguyen, Marie-France %A Bonnefoy, Marc %A Adrait, Arnaud %A Gueugnon, Marine %A Petitot, Charles %A Collet, Lionel %A Roux, Adeline %A Perrot, Xavier %X

BACKGROUND/OBJECTIVE: This study evaluated the cognitive benefit of hearing aids (HA) in older patients with Alzheimer's disease (AD) and hearing loss (HL) after a 6- and 12-month period of utilization.

METHODS: A multicenter double-blind randomized placebo-controlled trial was conducted in patients aged more than 65 years. A group was equipped with active HA for 6 months (active group) and a second group had placebo HA for 6 months (placebo group) followed by a secondary activation phase for a further 6 months (semi crossover procedure). Both groups were retested after a 12-month period. The primary endpoint was the change from baseline of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS Cog) after a 6-month period in both groups and after 6 months of secondary HA activation in the placebo group. A smaller cognitive decline should be obtained with HA use; an increase in ADAS Cog score of less than 6 points was defined a success.

RESULTS: Fifty-one patients aged 68 to 99 years were included; 38 attended the 6-month visit: 18 in the active group and 20 in the placebo group. At 6 months, 14 (82.4%) successes were noticed in the active group, and 15 (88.2%) in the placebo group (p = 1.0); delta ADAS Cog in the active group was 1.8±5.3 and 1.3±5.3 in the placebo group (p = 0.8). In the placebo group, after the secondary HA activation, no significant improvement was observed.

CONCLUSION: No significant effect of HA use was observed after 6 months of follow-up in patients with AD and HL.

%B J Alzheimers Dis %V 58 %P 123-137 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387664?dopt=Abstract %R 10.3233/JAD-160793 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Egocentric versus Allocentric Spatial Memory in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease. %A Tu, Sicong %A Spiers, Hugo J %A Hodges, John R %A Piguet, Olivier %A Hornberger, Michael %X

BACKGROUND: Diagnosis of behavioral variant frontotemporal dementia (bvFTD) can be challenging, in particular when patients present with significant memory problems, which can increase the chance of a misdiagnosis of Alzheimer's disease (AD). Growing evidence suggests spatial orientation is a reliable cognitive marker able to differentiate these two clinical syndromes.

OBJECTIVE: Assess the integrity of egocentric and allocentric heading orientation and memory in bvFTD and AD, and their clinical implications.

METHOD: A cohort of 22 patients with dementia (11 bvFTD; 11 AD) and 14 healthy controls were assessed on the virtual supermarket task of spatial orientation and a battery of standardized neuropsychological measures of visual and verbal memory performance.

RESULTS: Judgements of egocentric and allocentric heading direction were differentially impaired in bvFTD and AD, with AD performing significantly worse on egocentric heading judgements than bvFTD. Both patient cohorts, however, showed similar degree of impaired allocentric spatial representation, and associated hippocampal pathology.

CONCLUSIONS: The findings suggest egocentric heading judgements offer a more sensitive discriminant of bvFTD and AD than allocentric map-based measures of spatial memory.

%B J Alzheimers Dis %V 59 %P 883-892 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697554?dopt=Abstract %R 10.3233/JAD-160592 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Elevated Epstein-Barr Virus Antibody Level is Associated with Cognitive Decline in the Korean Elderly. %A Shim, Sung-Mi %A Cheon, Hyo-Soon %A Jo, Chulman %A Koh, Young Ho %A Song, Jihyun %A Jeon, Jae-Pil %X

Chronic viral infection is implicated in cognitive decline and Alzheimer's disease (AD). Our goal was to identify biomarkers for the development of amnestic mild cognitive impairment (aMCI) from cognitively normal state. To accomplish this, we analyzed plasma IgG levels against Epstein-Barr virus (EBV) and herpes simplex virus 1 (HSV-1) in study subjects with incident aMCI (Converter) and normal cognitive function (NC Control) who did or did not convert from cognitively normal state to aMCI during the 2-year follow-up period, respectively. The Converter group exhibited elevated levels of anti-EBV IgG antibodies in the post-follow-up phase (aMCI state) compared to the pre-follow-up phase (cognitively normal state), but not the NC Control group. In contrast, the total IgG level was not significantly changed over the follow-up period. Moreover, elevated anti-EBV IgG levels were significantly associated with CDR scales and total CERAD scores in the Converter group. These results suggest that EBV infection or its related host immune response is linked to cognitive decline. Thus, an EBV antibody level may be used as a potential biomarker for assessing the risk of aMCI development, implying a role for chronic EBV infection in AD pathogenesis.

%B J Alzheimers Dis %V 55 %P 293-301 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589534?dopt=Abstract %R 10.3233/JAD-160563 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Elevation of Peripheral BDNF Promoter Methylation Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer's Disease: A 5-Year Longitudinal Study. %A Xie, Bing %A Xu, Yao %A Liu, Zanchao %A Liu, Wenxuan %A Jiang, Lei %A Zhang, Rui %A Cui, Dongsheng %A Zhang, Qingfu %A Xu, Shunjiang %X

Epigenetic aberrations have been identified as biomarkers to predict the risk of Alzheimer's disease (AD). This study aimed to evaluate whether altered DNA methylation status of BDNF promoter could be used as potential epigenetic biomarkers for predicting the progression from amnestic mild cognitive impairment (aMCI) to AD. A total of 506 aMCI patients and 728 cognitively normal controls were recruited in the cross-sectional analyses. Patients (n = 458) from aMCI cohort were classified into two groups after 5-year follow-up: aMCI-stable group (n = 330) and AD-conversion group (n = 128). DNA methylation of BDNF promoter was detected by bisulfite-PCR amplification and pyrosequencing. The DNA methylation levels of CpG1 and CpG2 in promoter I and CpG5 and CpG6 in promoter IV of BDNF gene were significantly higher in the aMCI group than in the control group at baseline and also were increased in the conversion group compared with the non-conversion group at 5-year follow up time point. CpG5 in BDNF promoter IV had the highest AUC of 0.910 (95% CI: 0.817-0.983, p < 0.05). Kaplan-Meier analysis showed a significant AD conversion propensity for aMCI patients with high methylation levels of CpG5 (HR = 1.96, 95% CI: 1.07-2.98, p < 0.001). Multivariate Cox regression analysis revealed elevated methylation status of CpG5 was a significant independent predictor for AD conversion (HR = 3.51, p = 0.013). These results suggest that elevation of peripheral BDNF promoter methylation might be used as potential epigenetic biomarkers for predicting the conversion from aMCI to AD.

%B J Alzheimers Dis %V 56 %P 391-401 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27935556?dopt=Abstract %R 10.3233/JAD-160954 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Epidemiological Approaches to Understanding the Link Between Type 2 Diabetes and Dementia. %A Sutherland, Greg T %A Lim, Julia %A Srikanth, Velandai %A Bruce, David G %X

Diabetes and dementia are two diseases that increased dramatically in most societies in direct proportion to increases in average life expectancy. The two conditions are strongly associated and there is much hope that understanding this association will unlock the enigma that is the pathogenesis of dementia. Previous studies suggest that type 2 diabetes is a risk factor for all-cause dementia, vascular dementia and Alzheimer's disease. However these estimates may not necessarily have taken into account the overlap in dementia pathologies or the competing risk of death. Although the link between diabetes and vascular disease is intuitive, it is now becoming clear that type 2 diabetes is also associated with reduced brain volumes and with progression of brain atrophy, apparently independent of its relation with cerebrovascular disease. This raises the possibility that type 2 diabetes may also contribute to neurodegeneration, and particularly tau pathology. Prospective studies that record extensive multimodal in-vivo biomarkers and conduct rigorous postmortem neuropathological examination are certainly required to tease apart these complex pathways. However monitoring cognitive outcomes from current observational studies and randomized clinical trials of new diabetes treatments could be equally valuable in reducing the dementia epidemic.

%B J Alzheimers Dis %V 59 %P 393-403 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372332?dopt=Abstract %R 10.3233/JAD-161194 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Episodic Memory Dysfunction in Behavioral Variant Frontotemporal Dementia: A Clinical And FDG-PET Study. %A Fernández-Matarrubia, Marta %A Matías-Guiu, Jordi A %A Cabrera-Martín, María Nieves %A Moreno-Ramos, Teresa %A Valles-Salgado, María %A Carreras, José Luis %A Matías-Guiu, Jorge %X

BACKGROUND: Episodic memory disturbance is still considered as an exclusion criterion for behavioral variant frontotemporal dementia (bvFTD), but growing evidence suggests that memory can be impaired.

OBJECTIVE: Our main purposes were to assess episodic memory in a group of bvFTD patients comparatively with Alzheimer's disease (AD) patients, and analyze the relationship between episodic memory and brain metabolism measured using positron emission tomography imaging with 18F-fluorodeoxyglucose (FDG-PET).

METHODS: Twenty-six bvFTD, 29 AD, and 24 healthy controls were included. Episodic memory was assessed by the Free and Cued Selective Reminding Test (FCSRT), which controls for effective encoding and measures memory consolidation processing. All participants underwent FDG-PET brain scans to provide data for voxel-based brain mapping analysis.

RESULTS: Half of bvFTD patients had a deficit of total, free delayed, and total free delayed recall as severe as AD patients (amnestic-FTD). The other half had FCSRT scores similar to controls (non-amnestic-FTD). Imaging analyses revealed that amnestic-FTD showed bilateral lower metabolism than non-amnestic-FTD in anterior parahippocampal and inferior temporal gyri. Additionally, FCSRT total and total delayed scores were inversely correlated with parahippocampal metabolism in both bvFTD and AD. Besides, bvFTD showed an inverse association among FCSRT and inferior temporal metabolism.

CONCLUSIONS: Our findings support that bvFTD could present a genuine amnesia affecting storage and consolidation abilities, which involves structures implicated in the Papez circuit, as occurs in AD, and also inferior temporal regions. These results contribute to understanding the mechanisms underpinning memory dysfunction in bvFTD, and may be relevant to further revisions of the current diagnostic criteria.

%B J Alzheimers Dis %V 57 %P 1251-1264 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304289?dopt=Abstract %R 10.3233/JAD-160874 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Estimated Glomerular Filtration Rate is not Associated with Alzheimer's Disease in a Northern Ireland Cohort. %A Paterson, Euan N %A Williams, Michael A %A Passmore, Peter %A Silvestri, Giuliana %A MacGillivray, Tom J %A Maxwell, Alexander P %A McKay, Gareth J %X

BACKGROUND: Alzheimer's disease (AD) prevalence is increasing globally and typically progresses for several years prior to clinical presentation of dementia. Renal dysfunction and vascular disease have been reported in association with dementia in several cross-sectional and longitudinal studies, and may contribute to AD risk. Experimental and observational studies suggest amyloid-β (Aβ) clearance may be impaired in chronic kidney disease (CKD) indicating a mechanism for increased AD risk.

OBJECTIVE: The objective of this study was to compare estimated glomerular filtration rate (eGFR) between individuals with AD and cognitively intact controls, controlling for potential confounding factors.

METHODS: A cross-sectional, case-control study was carried out in 317 cognitively normal participants and 253 cases with a clinical diagnosis of AD in a UK tertiary care dementia clinic. Associations were considered using logistic regression adjusting for confounding variables (age, APOEɛ4 genotype, systolic blood pressure, education (left school at 14), and smoking status).

RESULTS: AD cases were older than cognitively intact controls, had lower MMSE scores, were more likely to have at least one APOEɛ4 allele, had higher rates of smoking, were more likely to be taking aspirin and/or clopidogrel, and had lower blood pressure. We found no significant association between eGFR and AD both before and following adjustment for appropriate confounders.

CONCLUSION: This study failed to find an association between eGFR and AD in a cross-sectional sample study of elderly white individuals.

%B J Alzheimers Dis %V 60 %P 1379-1385 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036821?dopt=Abstract %R 10.3233/JAD-170480 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Estradiol and Cognition in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) Cohort Study. %A Imtiaz, Bushra %A Tolppanen, Anna Maija %A Solomon, Alina %A Soininen, Hilkka %A Kivipelto, Miia %X

Cardiovascular Risk factors, Aging and Dementia (CAIDE) is a Finnish population-based study. 731 cognitively normal women had self-reported hormone therapy (HT) data in 1998 as: no use, use ≤5 years, and >5 years. Information on type of HT was only available from 1995-1998 (Prescription Register). Cognition was assessed in 1998 and 2005-2008. Long-term (>5 years) HT use, especially use of estradiol alone among women having hysterectomy with bilateral oophorectomy, was associated with better episodic memory in 1998, but not in 2005-2008. Although a strong evidence for protective effect of estradiol on cognition was not observed in our study, improved global cognition among long-term users suggests that long-term postmenopausal HT may be beneficial for some cognitive domains.

%B J Alzheimers Dis %V 56 %P 453-458 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983549?dopt=Abstract %R 10.3233/JAD-160643 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Ethical Considerations for Deep Brain Stimulation Trials in Patients with Early-Onset Alzheimer's Disease. %A Viaña, John Noel M %A Bittlinger, Merlin %A Gilbert, Frederic %X

Several studies of deep brain stimulation (DBS) of the fornix or the nucleus basalis of Meynert have been recently conducted in people with Alzheimer's disease, with several recruiting participants <65 and thus have early-onset Alzheimer's disease (EOAD). Although EOAD accounts for less than 5.5% of AD cases, ethical considerations must still be made when performing DBS trials including these participants since a portion of people with EOAD, especially those possessing autosomal-dominant mutations, have an atypical and more aggressive disease progression. These considerations include appropriate patient selection and signing of an informed consent for genetic testing; appropriate study design; potential outcomes that people with EOAD could expect; and accurate interpretation and balanced discussion of trial results. Finally, recommendations for future DBS for AD trials will be made to ensure that EOAD patients will not experience avoidable harms should they be enrolled in these experimental studies.

%B J Alzheimers Dis %V 58 %P 289-301 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28436389?dopt=Abstract %R 10.3233/JAD-161073 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Ethnic Variations in Prognosis of Patients with Dementia: A Prospective Nationwide Registry Linkage Study in The Netherlands. %A Agyemang, Charles %A van de Vorst, Irene E %A Koek, Huiberdina L %A Bots, Michiel L %A Seixas, Azizi %A Norredam, Marie %A Ikram, Umar %A Stronks, Karien %A Vaartjes, Ilonca %X

BACKGROUND: Data on dementia prognosis among ethnic minority groups are limited in Europe.

OBJECTIVE: We assessed differences in short-term (1-year) and long-term (3-year) mortality and readmission risk after a first hospitalization or first ever referral to a day clinic for dementia between ethnic minority groups and the ethnic Dutch population in the NetherlandsMethods: Nationwide prospective cohorts of first hospitalized dementia patients (N = 55,827) from January 1, 2000 to December 31, 2010 were constructed. Differences in short-term and long-term mortality and readmission risk following hospitalization or referral to the day clinic between ethnic minority groups (Surinamese, Turkish, Antilleans, Indonesians) and the ethnic Dutch population were investigated using Cox proportional hazard regression models with adjustment for age, sex, and comorbidities.

RESULTS: Age-sex-adjusted short-term and long-term risks of death following a first hospitalization with dementia were comparable between the ethnic minority groups and the ethnic Dutch. Age- and sex-adjusted risk of admission was higher only in Turkish compared with ethnic Dutch (HR 1.57, 95% CI,1.08-2.29). The difference between Turkish and the Dutch attenuated and was no longer statistically significant after further adjustment for comorbidities. There were no ethnic differences in short-term and long-term risk of death, and risk of readmission among day clinic patients.

CONCLUSION: Compared with Dutch patients with a comparable comorbidity rate, ethnic minority patients with dementia did not have a worse prognosis. Given the poor prognosis of dementia, timely and targeted advance care planning is essential, particularly in ethnic minority groups who are mired by cultural barriers and where uptake of advance care planning is known to be low.

%B J Alzheimers Dis %V 56 %P 205-213 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911320?dopt=Abstract %R 10.3233/JAD-160897 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Evaluation of a DNA Aβ42 Vaccine in Aged NZW Rabbits: Antibody Kinetics and Immune Profile after Intradermal Immunization with Full-Length DNA Aβ42 Trimer. %A Lambracht-Washington, Doris %A Fu, Min %A Wight-Carter, Mary %A Riegel, Matthew %A Rosenberg, Roger N %X

A pathological hallmark of Alzheimer's disease (AD) are amyloid plaques in the brain consisting of aggregated amyloid-β 42 peptide (Aβ42) derived from cellular amyloid-β protein precursor (AβPP). Based on successful experiments in mouse AD models, active immunization with Aβ42 peptide and passive immunizations with anti-Aβ42 antibodies were started in clinical trials. Active Aβ42 peptide immunization in humans had led to an inflammatory autoimmune response, and the trial was stopped. Passive immunizations had shown some effects in slowing AD pathology. Active DNA Aβ42 immunizations administered with the gene gun into the skin elicits a different immune response and is non-inflammatory. While in rodents, good responses had been found for this type of immunization, positive results in larger mammals are missing. We present here results from sixteen New Zealand White Rabbits, which underwent intradermal DNA Aβ42 immunization via gene gun. The humoral immune response was analyzed from blood throughout the study, and cellular immune responses were determined from spleens at the end of the study. A good anti-Aβ antibody response was found in the rabbit model. The T cell response after re-stimulation in cell culture showed no IFNγ producing cells when ELISPOT assays were analyzed from PBMC, but low numbers of IFNγ and IL-17 producing cells were found in ELISPOTS from spleens (both 5 immunizations). Brains from immunized rabbits showed no signs of encephalitis. Based on these results, DNA Aβ42 immunization is highly likely to be safe and effective to test in a possible clinical AD prevention trial in patients.

%B J Alzheimers Dis %V 57 %P 97-112 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222511?dopt=Abstract %R 10.3233/JAD-160947 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Evaluation of the Reliability, Validity, and Predictive Validity of the Subscales of the Perceived Stress Scale in Older Adults. %A Jiang, Julie M %A Seng, Elizabeth K %A Zimmerman, Molly E %A Sliwinski, Martin %A Kim, Mimi %A Lipton, Richard B %X

BACKGROUND: The Perceived Stress Scale (PSS) is made up of two subscales but is typically used as a single summary measure. However, research has shown that the two subscales may have differential properties in older adults.

OBJECTIVE: To evaluate the internal consistency, test-retest reliability, and the concurrent and predictive validity for development of amnestic mild cognitive impairment (aMCI) of the positively-worded (PSS-PW) and negatively-worded (PSS-NW) subscale scores of the PSS in older adults.

METHODS: We recruited community residing older adults free of dementia from the Einstein Aging Study. Reliability of the PSS-PW and PSS-NW was assessed using Cronbach's alpha for internal consistency and intraclass correlation for one year test-retest reliability. Concurrent validity was evaluated by examining the relationship between the PSS subscales and depression, anxiety, neuroticism, and positive and negative affect. Predictive validity was assessed using multivariate Cox regression analyses to examine the relationship between baseline PSS-PW and PSS-NW score and subsequent onset of aMCI.

RESULTS: Both PSS-PW and PSS-NW showed adequate internal consistency and retest reliabilities. Both the PSS-PW and PSS-NW were associated with depression, neuroticism, and negative affect. The PSS-NW was uniquely associated with anxiety while the PSS-PW was uniquely associated with positive affect. Only the PSS-PW was associated with a statistically significant increased risk of incident aMCI (HR = 1.27; 95% CI: 1.06-1.51 for every 5-point increase in PSS-PW).

CONCLUSIONS: Evaluating the separate effects of the two PSS subscales may reveal more information than simply using a single summation score. Future research should investigate the PSS-PW and PSS-NW as separate subscales.

%B J Alzheimers Dis %V 59 %P 987-996 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671128?dopt=Abstract %R 10.3233/JAD-170289 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Everyday Memory in Patients with Alzheimer's Disease: Fragmentary and Distorted. %A Sejunaite, Karolina %A Lanza, Claudia %A Riepe, Matthias W %X

BACKGROUND: Errors of omission are an established hallmark of memory impairment in Alzheimer's disease (AD). Much less is known about other memory errors in AD such as false memories.

OBJECTIVE: We investigated false memories in healthy elderly controls (HC; n = 23) and patients with AD (n = 20) using real-life tasks of watching news and commercials.

METHODS: Participants received a comprehensive neuropsychological assessment and were shown original news and commercials with a subsequent recognition task to assess veridical and false memories.

RESULTS: Subjective estimate of the number of errors were alike in HC and patients with AD. However, memory performance in both the news and the commercials task was significantly worse in patients with AD. Trail-Making Test and Symbol-Span Test were significant predictors of false memories on viewing news and commercials. In patients with AD, levels of Aβ1 - 42, but not levels of tau-protein were correlated with false memories in both tasks.

CONCLUSIONS: Everyday life in patients with AD is impeded not due to the incompleteness of memory but also due to its distortions. Furthermore, it is hindered by the lack of awareness towards these deficits. False memory content in patients with AD is associated with Aβ42 levels in the CSF as a surrogate of the overall extent to which the brain has been affected by AD pathology. Future studies will need to address the impact of this duality of memory failure on everyday life of patients with AD and their proxies in greater detail.

%B J Alzheimers Dis %V 60 %P 1489-1498 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29060940?dopt=Abstract %R 10.3233/JAD-170493 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Evidence of a Cardiovascular Function for Microtubule-Associated Protein Tau. %A Betrie, Ashenafi H %A Ayton, Scott %A Bush, Ashley I %A Angus, James A %A Lei, Peng %A Wright, Christine E %X

Aggregation of tau protein into intracellular deposits is a pathognomonic feature of tauopathies such as Alzheimer's disease (AD) and lowering tau is a prominent therapeutic strategy under development. However, the physiological function of tau protein is not well known, particularly in the periphery. Lowering tau protein risks disrupting its physiological role leading to unwanted effects. In this study, the presence of tau protein in cardiac tissue is confirmed and the functional role in the cardiovascular system and the consequences of its loss were explored. Isolated right and left atria and small mesenteric arteries from wild type and tau deficient (KO) mice of two age groups (13 and 23 months old) were used to assess cardiovascular phenotypes. Tau KO mice showed an increased systolic blood pressure and cardiac hypertrophy at 13 months, which was accompanied by a significantly lower right atrial rate and a subtle decrease in the maximum contractility to calcium, isoprenaline, and electrical sympathetic nerve stimulation. Aging tau KO mice to 23 months resulted in cardiac hypertrophy with significantly attenuated left atrial contractility, increased blood pressure, and sensitivity of isolated mesenteric arteries to angiotensin II contraction and isoprenaline relaxation compared to their younger counterparts. This study supports a functional role of tau in the heart and loss of this protein leads to a deterioration in cardiovascular performance which worsens with age. Taken together, these results provide insight into the peripheral function of tau protein, and give caution to the therapeutic strategy of lowering tau protein.

%B J Alzheimers Dis %V 56 %P 849-860 %8 Jan 2017 %G eng %N 2 %R 10.3233/JAD-161093 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Evidence that the Human Innate Immune Peptide LL-37 may be a Binding Partner of Amyloid-β and Inhibitor of Fibril Assembly. %A De Lorenzi, Ersilia %A Chiari, Marcella %A Colombo, Raffaella %A Cretich, Marina %A Sola, Laura %A Vanna, Renzo %A Gagni, Paola %A Bisceglia, Federica %A Morasso, Carlo %A Lin, Jennifer S %A Lee, Moonhee %A McGeer, Patrick L %A Barron, Annelise E %X

BACKGROUND: Identifying physiologically relevant binding partners of amyloid-β (Aβ) that modulate in vivo fibril formation may yield new insights into Alzheimer's disease (AD) etiology. Human cathelicidin peptide, LL-37, is an innate immune effector and modulator, ubiquitous in human tissues and expressed in myriad cell types.

OBJECTIVE: We present in vitro experimental evidence and discuss findings supporting a novel hypothesis that LL-37 binds to Aβ42 and can modulate Aβ fibril formation.

METHODS: Specific interactions between LL-37 and Aβ (with Aβ in different aggregation states, assessed by capillary electrophoresis) were demonstrated by surface plasmon resonance imaging (SPRi). Morphological and structural changes were investigated by transmission electron microscopy (TEM) and circular dichroism (CD) spectroscopy. Neuroinflammatory and cytotoxic effects of LL-37 alone, Aβ42 alone, and LL-37/Aβ complexes were evaluated in human microglia and neuroblastoma cell lines (SH-SY5Y).

RESULTS: SPRi shows binding specificity between LL-37 and Aβ, while TEM shows that LL-37 inhibits Aβ42 fibril formation, particularly Aβ's ability to form long, straight fibrils characteristic of AD. CD reveals that LL-37 prevents Aβ42 from adopting its typical β-type secondary structure. Microglia-mediated toxicities of LL-37 and Aβ42 to neurons are greatly attenuated when the two peptides are co-incubated prior to addition. We discuss the complementary biophysical characteristics and AD-related biological activities of these two peptides.

CONCLUSION: Based on this body of evidence, we propose that LL-37 and Aβ42 may be natural binding partners, which implies that balanced (or unbalanced) spatiotemporal expression of the two peptides could impact AD initiation and progression.

%B J Alzheimers Dis %V 59 %P 1213-1226 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731438?dopt=Abstract %R 10.3233/JAD-170223 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Exercise Training and Functional Connectivity Changes in Mild Cognitive Impairment and Healthy Elders. %A Chirles, Theresa J %A Reiter, Katherine %A Weiss, Lauren R %A Alfini, Alfonso J %A Nielson, Kristy A %A Smith, J Carson %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Exercise %K Exercise Test %K Female %K Gyrus Cinguli %K Humans %K Image Processing, Computer-Assisted %K Linear Models %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Oxygen %K Psychiatric Status Rating Scales %X

BACKGROUND: Effective interventions are needed to improve brain function in mild cognitive impairment (MCI), an early stage of Alzheimer's disease (AD). The posterior cingulate cortex (PCC)/precuneus is a hub of the default mode network (DMN) and is preferentially vulnerable to disruption of functional connectivity in MCI and AD.

OBJECTIVE: We investigated whether 12 weeks of aerobic exercise could enhance functional connectivity of the PCC/precuneus in MCI and healthy elders.

METHODS: Sixteen MCI and 16 healthy elders (age range = 60-88) engaged in a supervised 12-week walking exercise intervention. Functional MRI was acquired at rest; the PCC/precuneus was used as a seed for correlated brain activity maps.

RESULTS: A linear mixed effects model revealed a significant interaction in the right parietal lobe: the MCI group showed increased connectivity while the healthy elders showed decreased connectivity. In addition, both groups showed increased connectivity with the left postcentral gyrus. Comparing pre to post intervention changes within each group, the MCI group showed increased connectivity in 10 regions spanning frontal, parietal, temporal and insular lobes, and the cerebellum. Healthy elders did not demonstrate any significant connectivity changes.

CONCLUSION: The observed results show increased functional connectivity of the PCC/precuneus in individuals with MCI after 12 weeks of moderate intensity walking exercise training. The protective effects of exercise training on cognition may be realized through the enhancement of neural recruitment mechanisms, which may possibly increase cognitive reserve. Whether these effects of exercise training may delay further cognitive decline in patients diagnosed with MCI remains to be demonstrated.

%B J Alzheimers Dis %V 57 %P 845-856 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304298?dopt=Abstract %R 10.3233/JAD-161151 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Experiences of People with Dementia and Their Caregivers in Dementia Diagnosis. %A Lian, Yan %A Xiao, Lily Dongxia %A Zeng, Fan %A Wu, Xianmu %A Wang, Zhen %A Ren, Hui %X

BACKGROUND: People can live well with dementia if they are diagnosed early and receive early interventions and appropriate dementia management and care. However, dementia is currently under-detected and under-diagnosed. The diagnosis rate is around 50% only in higher-income countries and 5-10% only in low- and middle-income countries. Studies on consumers' experiences in engaging in dementia diagnosis in a socio-cultural context are much needed in order to generate research evidence to inform person-centered dementia care and services.

OBJECTIVE: The aim of the study was to understand the experiences of people with dementia and their caregivers in engaging in dementia diagnosis.

METHODS: An interpretative study design informed by Gadamer's hermeneutic principles was applied to the present study to achieve the aim of the study. The study was strengthened by applying a social ecological framework to the study design. In total, 23 participants contributed to the interviews or focus group. Thematic analysis was applied to data analysis.

RESULTS: Four themes were determined from data and described as: capabilities to detect the memory loss in an early stage, perceptions and beliefs of dementia in the community, different journeys toward the diagnosis and expectations of a smooth journey for others. These findings illuminate a social ecological perspective of improving early detection and timely diagnosis of dementia in the community settings.

CONCLUSION: The findings of this study have implications for policy, resource, and practice development. Consumers expect that government subsidized dementia care services in primary care and specialist care settings are needed in order to enable consumer-driven timely diagnosis and dementia management in home care settings.

%B J Alzheimers Dis %V 59 %P 1203-1211 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731450?dopt=Abstract %R 10.3233/JAD-170370 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Exploring Erythrocytes as Blood Biomarkers for Alzheimer's Disease. %A Stevenson, Anna %A Lopez, Dianne %A Khoo, Paul %A Kalaria, Rajesh N %A Mukaetova-Ladinska, Elizabeta B %X

Peripheral biomarkers for dementia are few and far between. Despite research into blood plasma/serum biomarkers for dementia diagnostics, there is a lack of information on erythrocytes and their vast proteomes as potential biomarkers. This review identifies a number of relevant and potentially promising erythrocyte biomarkers for various subtypes of dementia. These include erythrocyte morphology, oxidative stress, and erythrocyte membrane proteins such as the glucose transporter (GLUT-1), amyloid-β, IgG, Hsp90, calpain-1, and band 3 protein. Of those proteins identified Hsp90, amyloid-β, calpain-1 and band 3 show the most promise as pre-clinical biomarkers. However, the most intriguing aspect of erythrocytes is their changed morphology in dementia. The altered morphology not only could be used as a diagnostic biomarker but may be crucial in early pathogenesis of the disease. Further work must be done to establish the pathological connection between the periphery and central disease processes.

%B J Alzheimers Dis %V 60 %P 845-857 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984593?dopt=Abstract %R 10.3233/JAD-170363 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Exploring Potential Electrophysiological Biomarkers in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Event-Related Potential Studies. %A Gu, Lihua %A Zhang, Zhijun %X

BACKGROUND: Early diagnosis and effective management are pivotal steps in preventing the transition from mild cognitive impairment (MCI) to Alzheimer's disease. Previous investigations indicated that some event-related potential (ERP) components in MCI are sensitive to cognitive decline. However, several comparative analyses of these components in MCI and healthy controls (HC) yielded inconsistent results.

OBJECTIVE: The aim was to perform a systematic review and meta-analysis of ERP studies on MCI patients.

METHODS: We systematically searched on PubMed and Web of Science for MCI-related ERP studies published from April 1986 to August 2016. Standard mean difference estimates of all components were compared between MCI and HC.

RESULTS: Our study showed increased P50 amplitude at the Cz site; reduced N2pc amplitude and delayed P200 latency at the Cz site; N200 latency at the Cz and Pz sites, and P300 latency at the Cz and Pz sites in MCI patients compared to HC.

CONCLUSIONS: In summary, our study indicated that some ERP components, such as P50 and N2pc amplitude, P200, N200, and P300 latency might be potential electrophysiological biomarkers for MCI diagnosis.

%B J Alzheimers Dis %V 58 %P 1283-1292 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550252?dopt=Abstract %R 10.3233/JAD-161286 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction. %A Swanson, Eric %A Breckenridge, Leigham %A McMahon, Lloyd %A Som, Sreemoyee %A McConnell, Ian %A Bloom, George S %X

Aggregates composed of the microtubule associated protein, tau, are a hallmark of Alzheimer's disease and non-Alzheimer's tauopathies. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks over time. There are six splice variants of central nervous system tau, and various oligomeric and fibrillar forms are associated with neurodegeneration in vivo. The particular extracellular forms of tau capable of transferring tau pathology from neuron to neuron remain ill defined, however, as do the consequences of intracellular tau aggregation on neuronal physiology. The present study was undertaken to compare the effects of extracellular tau monomers, oligomers, and filaments comprising various tau isoforms on the behavior of cultured neurons. We found that 2N4R or 2N3R tau oligomers provoked aggregation of endogenous intracellular tau much more effectively than monomers or fibrils, or of oligomers made from other tau isoforms, and that a mixture of all six isoforms most potently provoked intracellular tau accumulation. These effects were associated with invasion of tau into the somatodendritic compartment. Finally, we observed that 2N4R oligomers perturbed fast axonal transport of membranous organelles along microtubules. Intracellular tau accumulation was often accompanied by increases in the run length, run time and instantaneous velocity of membranous cargo. This work indicates that extracellular tau oligomers can disrupt normal neuronal homeostasis by triggering axonal tau accumulation and loss of the polarized distribution of tau, and by impairing fast axonal transport.

%B J Alzheimers Dis %V 58 %P 803-820 %G eng %N 3 %R 10.3233/JAD-170168 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Face-Name Associative Recognition Deficits in Subjective Cognitive Decline and Mild Cognitive Impairment. %A Polcher, Alexandra %A Frommann, Ingo %A Koppara, Alexander %A Wolfsgruber, Steffen %A Jessen, Frank %A Wagner, Michael %X

BACKGROUND: There is a need for more sensitive neuropsychological tests to detect subtle cognitive deficits emerging in the preclinical stage of Alzheimer's disease (AD). Associative memory is a cognitive function supported by the hippocampus and affected early in the process of AD.

OBJECTIVE: We developed a short computerized face-name associative recognition test (FNART) and tested whether it would detect memory impairment in memory clinic patients with mild cognitive impairment (MCI) and subjective cognitive decline (SCD).

METHODS: We recruited 61 elderly patients with either SCD (n = 32) or MCI (n = 29) and 28 healthy controls (HC) and compared performance on FNART, self-reported cognitive deterioration in different domains (ECog-39), and, in a reduced sample (n = 46), performance on the visual Paired Associates Learning of the CANTAB battery.

RESULTS: A significant effect of group on FNART test performance in the total sample was found (p < 0.001). Planned contrasts indicated a significantly lower associative memory performance in the SCD (p = 0.001, d = 0.82) and MCI group (p < 0.001, d = 1.54), as compared to HCs, respectively. The CANTAB-PAL discriminated only between HC and MCI, possibly because of reduced statistical power. Adjusted for depression, performance on FNART was significantly related to ECog-39 Memory in SCD patients (p = 0.024) but not in MCI patients.

CONCLUSIONS: Associative memory is substantially impaired in memory clinic patients with SCD and correlates specifically with memory complaints at this putative preclinical stage of AD. Further studies will need to examine the predictive validity of the FNART in SCD patients with regard to longitudinal (i.e., conversion to MCI/AD) and biomarker outcomes.

%B J Alzheimers Dis %V 56 %P 1185-1196 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106560?dopt=Abstract %R 10.3233/JAD-160637 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Factors Underpinning Caregiver Burden in Frontotemporal Dementia Differ in Spouses and their Children. %A Kaizik, Cassandra %A Caga, Jashelle %A Camino, Julieta %A O'Connor, Claire M %A McKinnon, Colleen %A Oyebode, Jan R %A Piguet, Olivier %A Hodges, John R %A Mioshi, Eneida %X

The objectives of this observational study were to (1) compare spousal and child caregiver burden; (2) compare co-resident and live-out child caregiver burden; and (3) investigate factors influencing spousal and child caregiver burden. Data was collected from 90 caregivers of people with frontotemporal degeneration (FTD) recruited from the Frontotemporal Dementia Research Group (Frontier) at Neuroscience Research, Australia. Of this caregiver group, 43 were spousal caregivers and 47 were child caregivers. Caregiver burden and emotional state were evaluated using the short Zarit Burden Interview and the short version of the Depression, Anxiety and Stress Scale-21. The Social Network Index was applied to ascertain the social network of the caregiver, while the Intimate Bond Measure was used to evaluate the current quality of the relationship between the caregiver and the person with dementia. The Frontotemporal Dementia Rating Scale was used to assess severity of dementia. Spousal and child caregivers experienced similar levels of burden, depression, anxiety, and stress, regardless of disease severity. Co-resident child caregivers had smaller social networks and greater burden than live-out caregivers. Dementia severity was key in spousal caregiver burden, whereas caregiver depression was most important in child caregiver burden. Child and spousal caregivers of individuals with FTD share similar levels of burden, influenced by different factors. Future interventions need to account for these differences.

%B J Alzheimers Dis %V 56 %P 1109-1117 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106550?dopt=Abstract %R 10.3233/JAD-160852 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Failure to Recover from Proactive Semantic Interference and Abnormal Limbic Connectivity in Asymptomatic, Middle-Aged Offspring of Patients with Late-Onset Alzheimer's Disease. %A Sánchez, Stella M %A Abulafia, Carolina %A Duarte-Abritta, Barbara %A de Guevara, M Soledad Ladrón %A Castro, Mariana N %A Drucaroff, Lucas %A Sevlever, Gustavo %A Nemeroff, Charles B %A Vigo, Daniel E %A Loewenstein, David A %A Villarreal, Mirta F %A Guinjoan, Salvador M %X

BACKGROUND: We have obtained previous evidence of limbic dysfunction in middle-aged, asymptomatic offspring of late-onset Alzheimer's disease (LOAD) patients, and failure to recover from proactive semantic interference has been shown to be a sensitive cognitive test in other groups at risk for LOAD.

OBJECTIVE: To assess the effects of specific proactive semantic interference deficits as they relate to functional magnetic resonance imaging (fMRI) neocortical and limbic functional connectivity in middle aged offspring of individuals with LOAD (O-LOAD) and age-equivalent controls.

METHODS: We examined 21 O-LOAD and 20 controls without family history of neurodegenerative disorders (CS) on traditional measures of cognitive functioning and the LASSI-L, a novel semantic interference test uniquely sensitive to the failure to recover from proactive interference (frPSI). Cognitive tests then were correlated to fMRI connectivity of seeds located in entorhinal cortex and anterodorsal thalamic nuclei among O-LOAD and CS participants.

RESULTS: Relative to CS, O-LOAD participants evidenced lower connectivity between entorhinal cortex and orbitofrontal, anterior cingulate, and anterior temporal cortex. In the offspring of LOAD patients, LASSI-L measures of frPSI were inversely associated with connectivity between anterodorsal thalamus and contralateral posterior cingulate. Intrusions on the task related to frPSI were inversely correlated with a widespread connectivity network involving hippocampal, insular, posterior cingulate, and dorsolateral prefrontal cortices, along with precunei and anterior thalamus in this group. Different patterns of connectivity associated with frPSI were observed among controls.

CONCLUSION: The present results suggest that both semantic interference deficits and connectivity abnormalities might reflect limbic circuit dysfunction as a very early clinical signature of LOAD pathology, as previously demonstrated for other limbic phenotypes, such as sleep and circadian alterations.

%B J Alzheimers Dis %V 60 %P 1183-1193 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984601?dopt=Abstract %R 10.3233/JAD-170491 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Family History of Alzheimer's Disease is Associated with Impaired Perceptual Discrimination of Novel Objects. %A Mason, Emily J %A Hussey, Erin P %A Molitor, Robert J %A Ko, Philip C %A Donahue, Manus J %A Ally, Brandon A %K Adult %K Alzheimer Disease %K Cerebral Cortex %K Discrimination (Psychology) %K Family Health %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Perceptual Disorders %K Photic Stimulation %K Recognition (Psychology) %K Signal Detection, Psychological %X

Early detection may be the key to developing therapies that will combat Alzheimer's disease (AD). It has been consistently demonstrated that one of the main pathologies of AD, tau, is present in the brain decades before a clinical diagnosis. Tau pathology follows a stereotypical route through the medial temporal lobe beginning in the entorhinal and perirhinal cortices. If early pathology leads to very subtle changes in behavior, it may be possible to detect these changes in subjects years before a clinical diagnosis can currently be made. We aimed to discover if cognitively normal middle-aged adults (40-60 years old) at increased risk for AD due to family history would have impaired performance on a cognitive task known to challenge the perirhinal cortex. Using an oddity detection task, we found that subjects with a family history of AD had lowered accuracy without demonstrating differences in rate of acquisition. There were no differences between subjects' medial temporal lobe volume or cortical thickness, indicating that the changes in behavior were not due to significant atrophy. These results demonstrate that subtle changes in perceptual processing are detectable years before a typical diagnosis even when there are no differences detectable in structural imaging data. Anatomically-targeted cognitive testing may be useful in identifying subjects in the earliest stages of AD.

%B J Alzheimers Dis %V 57 %P 735-745 %8 2017 %G eng %N 3 %R 10.3233/JAD-160772 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Feasibility of Lumbar Puncture in the Study of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in Subjects with Down Syndrome. %A Carmona-Iragui, María %A Santos, Telma %A Videla, Sebastián %A Fernández, Susana %A Benejam, Bessy %A Videla, Laura %A Alcolea, Daniel %A Blennow, Kaj %A Blesa, Rafael %A Lleo, Alberto %A Fortea, Juan %X

BACKGROUND: Alzheimer's disease (AD) is the main medical problem in older adults with Down syndrome (DS). Studies of cerebrospinal fluid (CSF) AD biomarkers are limited and the feasibility of lumbar puncture (LP) is controversial in this population.

OBJECTIVE: To analyze the frequency of complications after a LP in DS.

METHODS: We collected data from 80 adults with DS that underwent a LP within the Down Alzheimer Barcelona Neuroimaging Initiative. Demographics, cognitive status, headache history, and presence of complications after the LP were recorded in every subject. In 53 of them (active group), this information was collected following a semi-structured and validated protocol that actively looks for complications. Other variables related to the LP procedure were also recorded. A telephone interview to the caregiver was performed 5-7 days after the procedure to ask about complications. Data from 27 subjects (clinical practice group), from whom the presence of complications was obtained in a medical follow-up visit within the three months after the LP, were also included.

RESULTS: There were no adverse events in 90% of our participants. The most frequent complication was headache (6.25%); only one subject reported a typical post-lumbar puncture headache with moderate severity that required analgesic treatment. Dizziness (3.75%) and back pain (1.25%) were also reported. All the participants that reported complications belonged to the active group.

CONCLUSION: LP can be safely performed to study CSF biomarkers in DS. The reported complications are qualitatively similar to the general population, but are less frequently reported, even when actively searched for.

%B J Alzheimers Dis %V 55 %P 1489-1496 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858714?dopt=Abstract %R 10.3233/JAD-160827 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Financial and Health Literacy Predict Incident Alzheimer's Disease Dementia and Pathology. %A Yu, Lei %A Wilson, Robert S %A Schneider, Julie A %A Bennett, David A %A Boyle, Patricia A %X

BACKGROUND: Domain specific literacy is a multidimensional construct that requires multiple resources including cognitive and non-cognitive factors.

OBJECTIVE: We test the hypothesis that domain specific literacy is associated with Alzheimer's disease (AD) dementia and AD pathology after controlling for cognition.

METHODS: Participants were community-based older persons who completed a baseline literacy assessment, underwent annual clinical evaluations for up to 8 years, and agreed to organ donation after death. Financial and health literacy was measured using 32 questions and cognition was measured using 19 tests. Annual diagnosis of AD dementia followed standard criteria. AD pathology was examined postmortem by quantifying plaques and tangles. Cox models examined the association of literacy with incident AD dementia. Performance of model prediction for incident AD dementia was assessed using indices for integrated discrimination improvement and continuous net reclassification improvement. Linear regression models examined the independent association of literacy with AD pathology in autopsied participants.

RESULTS: All 805 participants were free of dementia at baseline and 102 (12.7%) developed AD dementia during the follow-up. Lower literacy was associated with higher risk for incident AD dementia (p < 0.001), and the association persisted after controlling for cognition (hazard ratio = 1.50, p = 0.004). The model including the literacy measure had better predictive performance than the one with demographics and cognition only. Lower literacy also was associated with higher burden of AD pathology after controlling for cognition (β= 0.07, p = 0.035).

CONCLUSION: Literacy predicts incident AD dementia and AD pathology in community-dwelling older persons, and the association is independent of traditional measures of cognition.

%B J Alzheimers Dis %V 56 %P 1485-1493 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157101?dopt=Abstract %R 10.3233/JAD-161132 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Finger-to-Nose Test Findings in Alzheimer's Disease. %A Bergeron, David %A Vermette, Antoine %A De La Sablonnière, Justine %A Cayer, Anne-Marie %A Laforce, Robert %A Bouchard, Rémi W %X

The finger-to-nose test is routinely performed during the clinical assessment of patients with cognitive impairments. Although widely known to screen for cerebellar dysfunction by unmasking appendicular ataxia, we have found that this test could also be interpreted from a cognitive perspective. We describe two typical signs observed at the finger-to-nose test in Alzheimer's disease (AD) patients: the "second finger syndrome" and the "distal pressure sign". By retrospectively reviewing the medical records 461 patients followed at our academic memory clinic, we found that these signs are commonplace in AD, but not in vascular dementia or subjective cognitive impairment.

%B J Alzheimers Dis %V 55 %P 1335-1337 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858718?dopt=Abstract %R 10.3233/JAD-160941 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Five-Year Longitudinal Brain Volume Change in Healthy Elders at Genetic Risk for Alzheimer's Disease. %A Reiter, Katherine %A Nielson, Kristy A %A Durgerian, Sally %A Woodard, John L %A Smith, J Carson %A Seidenberg, Michael %A Kelly, Dana A %A Rao, Stephen M %X

Neuropathological changes associated with Alzheimer's disease (AD) precede symptom onset by more than a decade. Possession of an apolipoprotein E (APOE) ɛ4 allele is the strongest genetic risk factor for late onset AD. Cross-sectional studies of cognitively intact elders have noted smaller hippocampal/medial temporal volumes in ɛ4 carriers (ɛ4+) compared to ɛ4 non-carriers (ɛ4-). Few studies, however, have examined long-term, longitudinal, anatomical brain changes comparing healthy ɛ4+ and ɛ4- individuals. The current five-year study examined global and regional volumes of cortical and subcortical grey and white matter and ventricular size in 42 ɛ4+ and 30 ɛ4- individuals. Cognitively intact participants, ages 65-85 at study entry, underwent repeat anatomical MRI scans on three occasions: baseline, 1.5, and 4.75 years. Results indicated no between-group volumetric differences at baseline. Over the follow-up interval, the ɛ4+ group experienced a greater rate of volume loss in total grey matter, bilateral hippocampi, right hippocampal subfields, bilateral lingual gyri, bilateral parahippocampal gyri, and right lateral orbitofrontal cortex compared to the ɛ4- group. Greater loss in grey matter volumes in ɛ4+ participants were accompanied by greater increases in lateral, third, and fourth ventricular volumes. Rate of change in white matter volumes did not differentiate the groups. The current results indicate that longitudinal measurements of brain atrophy can serve as a sensitive biomarker for identifying neuropathological changes in persons at genetic risk for AD and potentially, for assessing the efficacy of treatments designed to slow or prevent disease progression during the preclinical stage of AD.

%B J Alzheimers Dis %V 55 %P 1363-1377 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27834774?dopt=Abstract %R 10.3233/JAD-160504 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Four Decades of Research in Alzheimer's Disease (1975-2014): A Bibliometric and Scientometric Analysis. %A Serrano-Pozo, Alberto %A Aldridge, Georgina M %A Zhang, Qiang %X

BACKGROUND: Bibliometric and scientometric methods can be applied to the study of a research field.

OBJECTIVE: We hypothesized that a bibliometric and scientometric analysis of the Alzheimer's disease (AD) research field could render trends that provide researchers and funding agencies valuable insight into the history of the field, current tendencies, and potential future directions.

METHODS: We performed searches in publicly available databases including PubMed, Scopus, Web of Science, and Alzheimer's Funding Analyzer for the period 1975-2014, and conducted a curve fitting analysis with non-linear regression.

RESULTS: While the rate and impact of publications continue to increase, the number of patents per year is currently declining after peaking in the late 2000s, and the funding budget has plateaued in the last 5-10 years analyzed. Genetics is the area growing at a fastest pace, whereas pathophysiology and therapy have not grown further in the last decade. Among the targets of pathophysiology research, amyloid-β continues to be the focus of greatest interest, with tau and apolipoprotein E stagnant after a surge in the 1990s. The role of inflammation, microglia, and the synapse are other research topics with growing interest. Regarding preventative strategies, education attainment, diet, and exercise are recently gaining some momentum, whereas NSAIDs and statins have lost the spotlight they once had.

CONCLUSION: Our bibliometric and scientometric analysis provides distinct trends in AD research in the last four decades, including publication and patent output, funding, impact, and topics. Our findings could inform the decision-making of research funding agencies in the near future.

%B J Alzheimers Dis %V 59 %P 763-783 %G eng %N 2 %R 10.3233/JAD-170184 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Framingham Risk Score and the Risk of Progression from Mild Cognitive Impairment to Dementia. %A Viticchi, Giovanna %A Falsetti, Lorenzo %A Buratti, Laura %A Sajeva, Giulia %A Luzzi, Simona %A Bartolini, Marco %A Provinciali, Leandro %A Silvestrini, Mauro %X

BACKGROUND: Mild cognitive impairment (MCI) often represents the clinical manifestation of cognitive deterioration preceding Alzheimer's disease (AD). Currently, there are no reliable approaches for an objective evaluation of the risk of developing AD in MCI patients.

OBJECTIVE: The aim of this study was to verify whether the Framingham cardiovascular risk profile (FCRP) could be useful to identify patients at the highest risk of conversion from MCI to AD.

METHODS: Patients with amnestic MCI (aMCI) were carefully investigated to assess their vascular risk profile. They were also submitted to a comprehensive neuropsychological evaluation. The FCRP was calculated for each patient and the apolipoprotein E (ApoE) genotype was determined from peripheral blood cells. The main outcome was defined as a conversion to AD within 24 months after inclusion.

RESULTS: 385 consecutive aMCI subjects were included. Age, FCRP, and vascular age showed a fairly predictive value on conversion to AD. Selecting the subpopulation of ApoE ɛ4 carriers, we observed that FCRP had an increased performance in predicting the conversion. The rate of conversion increased from 12.5% in the FCRP low-risk group to 43.2% in the high-risk group (p < 0.0001). ApoE ɛ4 carriers had a 3.7-times increased probability of conversion with respect to the other subjects (p < 0.0001).

CONCLUSIONS: FCRP assessment could be considered a reliable approach to predict conversion to AD in aMCI subjects. The presence of ApoE ɛ4 increases significantly the risk of conversion. These data confirm the narrow relationship between genetic and vascular risk factors in influencing the evolution of cognitive impairment.

%B J Alzheimers Dis %V 59 %P 67-75 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582863?dopt=Abstract %R 10.3233/JAD-170160 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Frequency-Dependent Changes in the Amplitude of Low-Frequency Fluctuations in Mild Cognitive Impairment with Mild Depression. %A Li, Yuxia %A Jing, Bin %A Liu, Han %A Li, Yifan %A Gao, Xuan %A Li, Yongqiu %A Mu, Bin %A Yu, Haikuo %A Cheng, Jinbo %A Barker, Peter B %A Wang, Hongxing %A Han, Ying %X

BACKGROUND: Depression is a potential marker of preclinical Alzheimer's disease (AD). However, little is known about the abnormal characteristics revealed by resting-state functional magnetic resonance imaging (rs-fMRI) in mild cognitive impairment (MCI) subjects with depressive symptoms (MCI-d).

OBJECTIVE: The study was to examine whether abnormalities in amplitudes of low-frequency oscillation occurred in MCI-d and tried to find the possible spectrum showed higher recognition ability to the diagnosis by utilizing functional MRI (fMRI).

METHODS: The amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) within full frequency (0.01-0.1 Hz), slow-5 (0.01-0.027 Hz), and slow-4 (0.027-0.073 Hz) were computed using resting-state fMRI data of 27 MCI without depressive symptoms, 19 MCI-d, and 32 well-matched healthy controls (HC). Analysis of covariance was performed on ALFF and fALFF among MCI, MCI-d, and HC groups.

RESULTS: Several brain regions showed significant differences in ALFF and fALFF within full frequency, slow-5, and slow-4 bands among three groups. Importantly, receiver operating characteristic analysis revealed that the ALFF values in the full frequency band in the left parahippocampal gyrus and the left precuneus, Slow 5 value in ALFF in the left inferior frontal gyrus, and Slow 4 value in ALFF in the left precuneus could effectively differentiate MCI-d from MCI patients.

CONCLUSION: In this study, we found that several changes in special brain regions are associated with MCI and MCI-d patients. And the differences depend on the studied frequency bands of rs-fMRI data. The affective network and the default-mode network might be damaged simultaneously in MCI-d patients.

%B J Alzheimers Dis %V 58 %P 1175-1187 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550250?dopt=Abstract %R 10.3233/JAD-161282 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Frontal Lobe Function Correlates with One-Year Incidence of Urinary Incontinence in Elderly with Alzheimer Disease. %A Sugimoto, Taiki %A Yoshida, Masaki %A Ono, Rei %A Murata, Shunsuke %A Saji, Naoki %A Niida, Shumpei %A Toba, Kenji %A Sakurai, Takashi %X

BACKGROUND: Urinary incontinence (UI) is frequently observed in patients with Alzheimer's disease (AD). Although previous works highlight the association between frontal lobe-related function and UI, causal relationship is unclear.

OBJECTS: To clarify the longitudinal association between frontal lobe function and the incidence of UI at 1 year in patients with AD.

METHODS: The subjects were 215 continent AD patients who attended the Memory Clinic of the National Center for Geriatrics and Gerontology of Japan during the period from March 2011 to December 2014. The absence or presence of UI was operationally assigned by the dementia behavior disturbance scale subscale, which was completed by the patients' caregivers. Frontal lobe function was assessed using the Frontal Assessment Battery (FAB). Other confounding factors including demographic data, cognitive status, vitality, mood, physical performance, and use of medication (cholinesterase inhibitors, calcium channel blockers [CCBs], diuretics, alpha blockers and anticholinergic drugs) were assessed.

RESULTS: During 1-year follow up (mean: 377.4±83.7 days), the incidence of UI was 12.1% (n = 26). Patients with UI had significantly lower FAB performance at baseline (no UI versus UI = 9.3±2.8 versus 7.8±2.7). In multivariate analysis, stepwise logistic regression analysis demonstrated that FAB (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.66-0.94) and the use of CCB (OR = 2.72, 95% CI = 1.09-6.77) were significantly associated with UI at 1 year.

CONCLUSION: The results of study indicate that frontal lobe dysfunction is predictor for UI in patients with AD.

%B J Alzheimers Dis %V 56 %P 567-574 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035933?dopt=Abstract %R 10.3233/JAD-160923 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Frontotemporal Dementia due to the Novel GRN Arg161GlyfsX36 Mutation. %A Gazzina, Stefano %A Archetti, Silvana %A Alberici, Antonella %A Bonomi, Elisa %A Cosseddu, Maura %A Di Lorenzo, Diego %A Padovani, Alessandro %A Borroni, Barbara %X

Progranulin is a multifunctional growth factor mainly expressed in neurons and microglia. Loss-of-function mutations in the Granulin (GRN) gene are causative of frontotemporal dementia with TAR DNA-binding protein-43 inclusions. We reported the case of a 51-year-old male patient affected by sporadic agrammatic variant of primary progressive aphasia, in whom we identified a novel heterozygous deletion in the exon 6 (g.10338_39delAG, p.Arg161GlyfsX36). Plasma progranulin levels were significantly reduced and in silico analysis predicted a premature termination codon. This case expands our knowledge on GRN mutations in frontotemporal dementia.

%B J Alzheimers Dis %V 57 %P 1185-1189 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304311?dopt=Abstract %R 10.3233/JAD-170066 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Fully Automatic MRI-Based Hippocampus Volumetry Using FSL-FIRST: Intra-Scanner Test-Retest Stability, Inter-Field Strength Variability, and Performance as Enrichment Biomarker for Clinical Trials Using Prodromal Target Populations at Risk for Alzheimer's %A Cavedo, Enrica %A Suppa, Per %A Lange, Catharina %A Opfer, Roland %A Lista, Simone %A Galluzzi, Samantha %A Schwarz, Adam J %A Spies, Lothar %A Buchert, Ralph %A Hampel, Harald %X

BACKGROUND: MRI-based hippocampus volume is a core clinical biomarker for identification of Alzheimer's disease (AD).

OBJECTIVE: To assess robustness of automatic hippocampus volumetry with the freely available FSL-FIRST software with respect to short-term repeat and across field strength imaging. FSL-FIRST hippocampus volume (FIRST-HV) was also evaluated as enrichment biomarker for mild cognitive impairment (MCI) trials.

METHODS: Robustness of FIRST-HV was assessed in 51 healthy controls (HC), 74 MCI subjects, and 28 patients with AD dementia from ADNI1, each with two pairs of back-to-back scans, one at 1.5T one at 3T. Enrichment performance was tested in a second sample of 287 ADNI MCI subjects.

RESULTS: FSL-FIRST worked properly in all four scans in 147 out of 153 subjects of the first sample (49 HC, 72 MCI, 26 AD). In these subjects, FIRST-HV did not differ between the first and the second scan within an imaging session, neither at 1.5T nor at 3T (p≥0.302). FIRST-HV was on average 0.78% larger at 3T compared to 1.5T (p = 0.012). The variance of the FIRST-HV difference was larger in the inter-field strength setting than in the intra-scanner settings (p < 0.0005). Computer simulations suggested that the additional variability encountered in the inter-field strength scenario does not cause a relevant degradation of FIRST-HV's prognostic performance in MCI. FIRST-HV based enrichment resulted in considerably increased effect size of the 2-years change of cognitive measures.

CONCLUSION: The impact of intra-scanner test-retest and inter-field strength variability of FIRST-HV on clinical tasks is negligible. In addition, FIRST-HV is useful for enrichment in clinical MCI trials.

%B J Alzheimers Dis %V 60 %P 151-164 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28777748?dopt=Abstract %R 10.3233/JAD-161108 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Functional Connectivity in the Default Mode Network is Reduced in Association with Nocturnal Awakening in Mild Cognitive Impairment. %A McKinnon, Andrew C %A Duffy, Shantel L %A Cross, Nathan E %A Terpening, Zoe %A Grunstein, Ron R %A Lagopoulos, Jim %A Batchelor, Jennifer %A Hickie, Ian B %A Lewis, Simon J G %A Shine, James M %A Naismith, Sharon L %X

BACKGROUND: Sleep disturbance is prevalent in MCI, and is a risk factor for cognitive deterioration.

OBJECTIVE: To identify functional connectivity deficits in the default mode network (DMN) in patients with mild cognitive impairment (MCI) and sleep disturbance, relative to MCIs with intact sleep.

METHODS: Participants comprised 47 adults aged 55 years and over, recruited from the Healthy Brain Ageing Clinic at the Brain and Mind Centre, Sydney, Australia. This sample contained 15 controls and 32 participants meeting criteria for MCI. Participants underwent resting-state fMRI and actigraphy, along with comprehensive neuropsychological, medical and psychiatric assessment. MCIs were split into two groups according to average wake after sleep onset (WASO) per night. WASO equal to or greater than 1 standard deviation (SD) above the control mean was deemed to reflect disturbed sleep. There were 11 patients in the MCI sleep-disturbed group, and 21 in the MCI sleep-intact group.

RESULTS: Relative to controls, MCIs demonstrated significant connectivity reductions between parietal and temporoparietal regions, and between temporal regions. Relative to MCIs with intact sleep, MCIs with sleep disturbance demonstrated reductions in functional connectivity between temporal and parietal regions, and between temporal and temporoparietal regions.

CONCLUSIONS: MCIs with nocturnal awakenings demonstrate reductions in DMN connectivity. These reductions comprise brain regions that are crucially involved in sleep and memory processes. These results strengthen our previous findings, which found reduced connectivity in MCIs with self-reported sleep disturbances. Future studies may build on these findings through incorporating complementary neuroimaging techniques and experimental manipulations of sleep.

%B J Alzheimers Dis %V 56 %P 1373-1384 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157095?dopt=Abstract %R 10.3233/JAD-160922 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Functional Disintegration of the Default Mode Network in Prodromal Alzheimer's Disease. %A Dillen, Kim N H %A Jacobs, Heidi I L %A Kukolja, Juraj %A Richter, Nils %A von Reutern, Boris %A Onur, Özgür A %A Langen, Karl-Josef %A Fink, Gereon R %X

Neurodegenerative brain changes can affect the functional connectivity strength between nodes of the default-mode network (DMN), which may underlie changes in cognitive performance. It remains unclear how the functional connectivity strength of DMN nodes differs from healthy to pathological aging and whether these changes are cognitively relevant. We used resting-state functional magnetic resonance imaging to investigate the functional connectivity strength across five DMN nodes in 25 healthy controls (HC), 28 subjective cognitive decline (SCD) participants, and 25 prodromal Alzheimer's disease (AD) patients. After identifying the ventral medial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), retrosplenial cortex (RSC), inferior parietal lobule, and the hippocampus we investigated the functional strength between DMN nodes using temporal network modeling. Functional coupling of the vmPFC and PCC in prodromal AD patients was disrupted. This vmPFC-PCC coupling correlated positively with memory performance in prodromal AD. Furthermore, the hippocampus de-coupled from posterior DMN nodes in SCD and prodromal AD patients. There was no coupling between the hippocampus and the anterior DMN. Additional mediation analyses indicated that the RSC enables communication between the hippocampus and DMN regions in HC but none of the other two groups. These results suggest an anterior-posterior disconnection and a hippocampal de-coupling from posterior DMN nodes with disease progression. Hippocampal de-coupling already occurring in SCD may provide valuable information for the development of a functional biomarker.

%B J Alzheimers Dis %V 59 %P 169-187 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598839?dopt=Abstract %R 10.3233/JAD-161120 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Functional Reserve: Experience Participating in Instrumental Activities of Daily Living is Associated with Gender and Functional Independence in Mild Cognitive Impairment. %A Berezuk, Courtney %A Zakzanis, Konstantine K %A Ramirez, Joel %A Ruocco, Anthony C %A Edwards, Jodi D %A Callahan, Brandy L %A Black, Sandra E %X

BACKGROUND: Gender differences in instrumental activities of daily living (IADLs) in mild cognitive impairment (MCI) and Alzheimer's disease may be explained by gender differences in IADL involvement.

OBJECTIVE: We introduce a novel theoretical construct, termed functional reserve, and empirically examine gender differences in IADL experience as a proxy of this reserve.

METHODS: We cross-sectionally examined men (n = 502) and women (n = 340) with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Demographic factors, depressive symptoms, neuropsychological scores, and IADL experience were included as independent variables and total Functional Activities Questionnaire (FAQ) scores as the dependent variable. Regression analyses were performed on the full cohort and stratified by gender to identify differential predictive relationships for men and women.

RESULTS: Gender was associated with total FAQ (p < 0.05) until adjusting for IADL experience. Furthermore, the combination of cognitive measures accounted for the most variance in functional dependence (12% explained, p < 0.001), although IADL experience was the most important single variable (4.8% explained, p < 0.001). Stratification by gender revealed that IADL experience accounted for 6.6% of the variance in FAQ score in men (p < 0.001) but only 2.4% in women (p = 0.001); however, the interaction between gender and experience was not statistically significant.

DISCUSSION: A small effect of men showing greater functional dependence in MCI may be explained by lower IADL experience. Additionally, IADL experience was associated with superior functioning in all analyses, potentially through increased functional reserve. This concept of functional reserve may have implications for identifying individuals at risk for IADL dependence, preventing or delaying decline, and potentially treating functional impairment.

%B J Alzheimers Dis %V 58 %P 425-434 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453478?dopt=Abstract %R 10.3233/JAD-161227 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Galantamine Response Associates with Agitation and the Prefrontal Cortex in Patients with Alzheimer's Disease. %A Nakayama, Sachiko %A Suda, Akimitsu %A Nakanishi, Atsushi %A Motoi, Yumiko %A Hattori, Nobutaka %X

Behavioral and psychological symptoms of dementia (BPSD) occur in up to 80% of AD patients and represent one of the largest factors contributing to caregiver burden. To analyze the effect of galantamine on BPSD and caregiver burden, we treated a total of 50 patients with mild AD for 12 weeks and evaluated them using the Neuropsychiatric Inventory (NPI) and Japanese version of the Zarit Caregiver Burden Interview (ZBI). We also performed regional cerebral blood flow single photon emission computed tomography (rCBF SPECT) at baseline using three-dimensional sterotatic surface projections. Total NPI and ZBI scores did not significantly change after 12-week galantamine treatment. To identify the characteristics of patients who showed improvement after galantamine treatment, we divided patients into two groups, those with and those without sub-items on the NPI. Patients with aggression showed improvement in ZBI scores (p < 0.05). A comparison of rCBF SPECT between these two groups indicated that patients with aggression exhibited increased rCBF in the right prefrontal cortex compared with those without aggression. In a patient with aggression, 20-month treatment with galantamine inhibited increases in the rCBF area in the right prefrontal lobe. These results suggest that galantamine response may be related to aggression and dysfunction of the prefrontal cortex.

%B J Alzheimers Dis %V 57 %P 267-273 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222509?dopt=Abstract %R 10.3233/JAD-160902 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Gender-Based Cerebral Perfusion Differences in 46,034 Functional Neuroimaging Scans. %A Amen, Daniel G %A Trujillo, Manuel %A Keator, David %A Taylor, Derek V %A Willeumier, Kristen %A Meysami, Somayeh %A Raji, Cyrus A %X

BACKGROUND: Studies have reported that females have widespread increases in regional cerebral blood flow, but the studies were relatively small and inconsistent.

OBJECTIVE: Here we analyzed a healthy and a very large clinical psychiatric population to determine the effect of gender, using single photon emission computed tomography (SPECT).

METHODS: Whole brain and region of interest (ROI) gender differences were analyzed in a total of 46,034 SPECT scans at baseline and concentration. The sample included 119 healthy subjects and 26,683 patients (60.4% male, 39.6% female); a subset of 11,587 patients had complete diagnostic information. A total of 128 regions were analyzed according to the AAL Atlas, using ROI Extract and SPSS statistical software programs, controlling for age, diagnoses, and correcting for multiple comparisons.

RESULTS: Compared to males, healthy females showed significant whole brain (p < 0.01) and ROI increases in 65 baseline and 48 concentration regions (p < 0.01 corrected). Healthy males showed non-significant increases in 9 and 22 regions, respectively. In the clinical group, there were widespread significant increases in females, especially in the prefrontal and limbic regions, and specific increases in males in the inferior occipital lobes, inferior temporal lobes, and lobule 7 and Crus 2 of the cerebellum. These findings were replicated in the subset of 11,587 patients with the effect of diagnoses removed.

CONCLUSIONS: Our results demonstrated significant gender differences in a healthy and clinical population. Understanding these differences is crucial in evaluating functional neuroimaging and may be useful in understanding the epidemiological gender differences among psychiatric disorders.

%B J Alzheimers Dis %V 60 %P 605-614 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28777753?dopt=Abstract %R 10.3233/JAD-170432 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Gender-Specific Degeneration of Dementia-Related Subcortical Structures Throughout the Lifespan. %A Nemeth, Viola Luca %A Must, Anita %A Horvath, Szatmar %A Király, Andras %A Kincses, Zsigmond Tamas %A Vecsei, Laszlo %X

Age-related changes in brain structure are a question of interest to a broad field of research. Structural decline has been consistently, but not unambiguously, linked to functional consequences, including cognitive impairment and dementia. One of the areas considered of crucial importance throughout this process is the medial temporal lobe, and primarily the hippocampal region. Gender also has a considerable effect on volume deterioration of subcortical grey matter (GM) structures, such as the hippocampus. The influence of age×gender interaction on disproportionate GM volume changes might be mediated by hormonal effects on the brain. Hippocampal volume loss appears to become accelerated in the postmenopausal period. This decline might have significant influences on neuroplasticity in the CA1 region of the hippocampus highly vulnerable to pathological influences. Additionally, menopause has been associated with critical pathobiochemical changes involved in neurodegeneration. The micro- and macrostructural alterations and consequent functional deterioration of critical hippocampal regions might result in clinical cognitive impairment-especially if there already is a decline in the cognitive reserve capacity. Several lines of potential vulnerability factors appear to interact in the menopausal period eventually leading to cognitive decline, mild cognitive impairment, or Alzheimer's disease. This focused review aims to delineate the influence of unmodifiable risk factors of neurodegenerative processes, i.e., age and gender, on critical subcortical GM structures in the light of brain derived estrogen effects. The menopausal period appears to be of key importance for the risk of cognitive decline representing a time of special vulnerability for molecular, structural, and functional influences and offering only a narrow window for potential protective effects.

%B J Alzheimers Dis %V 55 %P 865-880 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27792015?dopt=Abstract %R 10.3233/JAD-160812 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Gene Expression and Methylation Analysis of ABCA7 in Patients with Alzheimer's Disease. %A Yamazaki, Kiyohiro %A Yoshino, Yuta %A Mori, Takaaki %A Yoshida, Taku %A Ozaki, Yuki %A Sao, Tomoko %A Mori, Yoko %A Ochi, Shinichiro %A Iga, Jun-Ichi %A Ueno, Shu-Ichi %X

BACKGROUND/OBJECTIVE: The aim of this study was to examine the blood gene expression and methylation of ATP-binding cassette sub-family A member 7 gene (ABCA7) as a biological marker of AD.

METHODS: AD subjects (n = 50; 11 males, 77.7±6.05 years old) and age- and sex-matched healthy controls (n = 50) were recruited. A single nucleotide polymorphism in ABCA7 (rs3764650), methylation rates of CpG sites in the ABCA7 promoter region, and ABCA7 mRNA expression levels in peripheral blood were examined.

RESULTS: The distribution of the rs3764650 polymorphism in AD subjects was not different from that of controls. Although the methylation rates of AD subjects were not significantly different from those of controls, the ABCA7 mRNA expression level in AD subjects was significantly higher than that in controls. Additionally, the ABCA7 mRNA expression level in AD subjects was significantly correlated with Mini-Mental State Examination recall, the Alzheimer's Disease Assessment Scale total score, and the Clinical Dementia Rating score. We also found a significant correlation between the ABCA7 mRNA expression level and duration of illness.

CONCLUSION: The ABCA7 mRNA expression level in peripheral blood may be a marker for early stages of AD and disease progression regardless of rs3764650 and the methylation rate of its promoter.

%B J Alzheimers Dis %V 57 %P 171-181 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222527?dopt=Abstract %R 10.3233/JAD-161195 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Generation and Partial Characterization of Rabbit Monoclonal Antibody to Amyloid-β Peptide 1-37 (Aβ37). %A Mehta, Pankaj D %A Blain, Jean-Francois %A Freeman, Emily A %A Patrick, Bruce A %A Barshatzky, Marc %A Hrdlicka, Lori A %A Mehta, Sangita P %A Frackowiak, Janusz %A Mazur-Kolecka, Bozena %A Wegiel, Jerzy %A Patzke, Holger %A Miller, David L %X

Secreted soluble amyloid-β 1-37 (Aβ37) peptide is one of the prominent Aβ forms next to Aβ40, and is found in cerebrospinal fluid (CSF) and blood. Recent studies have shown the importance of quantitation of CSF Aβ37 levels in combination with Aβ38, Aβ40, and Aβ42 to support the diagnosis of patients with probable Alzheimer's disease (AD), and the value of antibody to Aβ37 to facilitate drug discovery studies. However, the availability of reliable and specific monoclonal antibody to Aβ37 is very limited. Our aims were: 1) to generate and partially characterize rabbit monoclonal antibody (RabmAb) to Aβ37, and 2) to determine whether the antibody detects changes in Aβ37 levels produced by a γ-secretase modulator (GSM). Our generated RabmAb to Aβ37 was found to be specific to Aβ37, since it did not react with Aβ36, Aβ38, Aβ39, Aβ40, and Aβ42 in an ELISA or immunoblotting. The epitope of the antibody was contained in the seven C-terminal residues of Aβ37. The antibody was sensitive enough to measure CSF and plasma Aβ37 levels in ELISA. Immunohistological studies showed the presence of Aβ37-positive deposits in the brain of AD, and Down syndrome persons diagnosed with AD. Our studies also showed that the antibody detected Aβ37 increases in CSF and brains of rodents following treatment with a GSM. Thus, our antibody can be widely applied to AD research, and in a panel based approach it may have potential to support the diagnosis of probable AD, and in testing the effect of GSMs to target AD.

%B J Alzheimers Dis %V 57 %P 135-145 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222530?dopt=Abstract %R 10.3233/JAD-161207 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Genetic Deletion of Tumor Necrosis Factor-α Attenuates Amyloid-β Production and Decreases Amyloid Plaque Formation and Glial Response in the 5XFAD Model of Alzheimer's Disease. %A Paouri, Evi %A Tzara, Ourania %A Zenelak, Sofia %A Georgopoulos, Spiros %X

Increasing evidence suggests that neuroinflammation comprises a major characteristic of Alzheimer's disease (AD). Tumor necrosis factor-α (TNF-α) is a pleiotropic pro-inflammatory cytokine implicated in neurodegenerative diseases including AD, and has been proposed as a potent therapeutic target for AD. Although a number of studies focusing on pharmacological or genetic manipulation of TNF-α and its receptors in AD mice have provided significant knowledge regarding the role of TNF-α signaling pathway in the pathogenesis of AD, the consequences of TNF-α genetic deletion have not been thoroughly examined. Here, we focused on the effect of TNF-α deficiency on the amyloid phenotype of 5XFAD mice. Our analysis revealed that amyloid deposition, amyloid-β (Aβ) levels, and AβPP-carboxyterminal fragments are significantly reduced in the brains of 5XFAD/TNF-α-/- mice compared to the 5XFAD/TNF-α+/+. We found decreased protein levels of β- and α-secretases in the 5XFAD/TNF-α-/- brains, suggesting for an effect of TNF-α on AβPP processing and Aβ generation. We also show for the first time that TNF-α affects PS1in vivo, as 5XFAD mice lacking TNF-α expression display reduced PS1-carboxyterminal fragments implying for diminished PS1 activity. Moreover, TNF-α deficiency decreases microglial and astrocytic activation and significantly restricts the phagocytic activity of macrophages against Aβ, supporting for reduced responsiveness of phagocytes toward Aβ. Overall, our results reveal that TNF-α genetic deletion in 5XFAD mice attenuates amyloid plaque formation by lowering Aβ generation through the reduction of functionally active PS1 and β-secretase rather than promoting Aβ clearance by phagocytic cells. Our data further suggest TNF-α inhibition as a therapeutic approach for AD.

%B J Alzheimers Dis %V 60 %P 165-181 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826177?dopt=Abstract %R 10.3233/JAD-170065 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Genetic Prion Disease Caused by PRNP Q160X Mutation Presenting with an Orbitofrontal Syndrome, Cyclic Diarrhea, and Peripheral Neuropathy. %A Fong, Jamie C %A Rojas, Julio C %A Bang, Jee %A Legati, Andrea %A Rankin, Katherine P %A Forner, Sven %A Miller, Zachary A %A Karydas, Anna M %A Coppola, Giovanni %A Grouse, Carrie K %A Ralph, Jeffrey %A Miller, Bruce L %A Geschwind, Michael D %X

Patients with pathogenic truncating mutations in the prion gene (PRNP) usually present with prolonged disease courses with severe neurofibrillary tangle and cerebral amyloidosis pathology, but more atypical phenotypes also occur, including those with dysautonomia and peripheral neuropathy. We describe the neurological, cognitive, neuroimaging, and electrophysiological features of a 31-year-old man presenting with an orbitofrontal syndrome, gastrointestinal symptoms, and peripheral neuropathy associated with PRNP Q160X nonsense mutation, with symptom onset at age 27. The mutation was also detected in his asymptomatic father and a symptomatic paternal cousin; several members of prior generations died from early onset dementia. This is the first report of a family affected with the nonsense PRNP mutation Q160X displaying clear autosomal dominant disease in multiple family members and reduced penetrance. This case strengthens the evidence suggesting an association between PRNP truncating mutations and prion systemic amyloidosis. PRNP gene testing should be considered in any patient with atypical dementia, especially with early onset and neuropathy, even in the absence of a family history.

%B J Alzheimers Dis %V 55 %P 249-258 %G ENG %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716661?dopt=Abstract %R 10.3233/JAD-160300 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Genetic Risk as a Marker of Amyloid-β and Tau Burden in Cerebrospinal Fluid. %A Voyle, Nicola %A Patel, Hamel %A Folarin, Amos %A Newhouse, Stephen %A Johnston, Caroline %A Visser, Pieter Jelle %A Dobson, Richard J B %A Kiddle, Steven J %X

BACKGROUND: The search for a biomarker of Alzheimer's disease (AD) pathology (amyloid-β (Aβ) and tau) is ongoing, with the best markers currently being measurements of Aβ and tau in cerebrospinal fluid (CSF) and via positron emission tomography (PET) scanning. These methods are relatively invasive, costly, and often have high screening failure rates. Consequently, research is aiming to elucidate blood biomarkers of Aβ and tau.

OBJECTIVE: This study aims to investigate a case/control polygenic risk score (PGRS) as a marker of tau and investigate blood markers of a combined Aβ and tau outcome for the first time. A sub-study also considers plasma tau as markers of Aβ and tau pathology in CSF.

METHODS: We used data from the EDAR*, DESCRIPA**, and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts in a logistic regression analysis to investigate blood markers of Aβ and tau in CSF. In particular, we investigated the extent to which a case/control PGRS is predictive of CSF tau, CSF amyloid, and a combined amyloid and tau outcome. The predictive ability of models was compared to that of age, gender, and APOE genotype ('basic model').

RESULTS: In EDAR and DESCRIPA test data, inclusion of a case/control PGRS was no more predictive of Aβ, and a combined Aβ and tau endpoint than the basic models (accuracies of 66.0%, and 73.3% respectively). The tau model saw a small increase in accuracy compared to basic models (59.6%). ADNI 2 test data also showed a slight increase in accuracy for the Aβ model when compared to the basic models (61.4%).

CONCLUSION: We see some evidence that a case/control PGRS is marginally more predictive of Aβ and tau pathology than the basic models. The search for predictive factors of Aβ and tau pathologies, above and beyond demographic information, is still ongoing. Better understanding of AD risk alleles, development of more sensitive assays, and studies of larger sample size are three avenues that may provide such factors. However, the clinical utility of possible predictors of brain Aβ and tau pathologies must also be investigated.*'Beta amyloid oligomers in the early diagnosis of AD and as marker for treatment response'**'Development of screening guidelines and criteria for pre-dementia Alzheimer's disease'.

%B J Alzheimers Dis %V 55 %P 1417-1427 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27834776?dopt=Abstract %R 10.3233/JAD-160707 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Genetic Stratification to Identify Risk Groups for Alzheimer's Disease. %A Marioni, Riccardo E %A Campbell, Archie %A Hagenaars, Saskia P %A Nagy, Reka %A Amador, Carmen %A Hayward, Caroline %A Porteous, David J %A Visscher, Peter M %A Deary, Ian J %X

Stratification by genetic risk factors for Alzheimer's disease (AD) may help identify groups with the greatest disease risk. Biological changes that cause late-onset AD are likely to occur years, if not decades prior to diagnosis. Here, we select a subset of the Generation Scotland: Scottish Family Health Study cohort in a likely preclinical age-range of 60-70 years (subset n = 3,495 with cognitive and genetic data). We test for cognitive differences by polygenic risk scores for AD. The polygenic scores are constructed using all available SNPs, excluding those within a 500 kb distance of the APOE locus. Additive and multiplicative effects of APOE status on these associations are investigated. Small memory decrements were observed in those with high polygenic risk scores for AD (standardized beta -0.04, p = 0.020). These associations were independent of APOE status. There was no difference in AD polygenic scores across APOE haplotypes (p = 0.72). Individuals with high compared to low polygenic risk scores for AD (top and bottom 5% of the distribution) show cognitive decrements, albeit much smaller than for APOE ɛ4ɛ4 compared to ɛ3ɛ3 individuals (2.3 versus 3.5 fewer points on the processing speed test, and 1.8 versus 2.8 fewer points on the memory test). Polygenic risk scores for AD may help identify older individuals at greatest risk of cognitive decline and preclinical AD.

%B J Alzheimers Dis %V 57 %P 275-283 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222519?dopt=Abstract %R 10.3233/JAD-161070 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Genetically-Predicted Adult Height and Alzheimer's Disease. %A Larsson, Susanna C %A Traylor, Matthew %A Burgess, Stephen %A Markus, Hugh S %X

BACKGROUND: Observational studies have linked increased adult height with better cognitive performance and reduced risk of Alzheimer's disease (AD). It is unclear whether the associations are due to shared biological processes that influence height and AD or due to confounding by early life exposures or environmental factors.

OBJECTIVE: To use a genetic approach to investigate the association between adult height and AD.

METHODS: We selected 682 single nucleotide polymorphisms (SNPs) associated with height at genome-wide significance (p < 5×10-8) in the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary statistics for each of these SNPs on AD were obtained from the International Genomics of Alzheimer's Project (IGAP) of 17,008 individuals with AD and 37,154 controls. The estimate of the association between genetically predicted height and AD was calculated using the inverse-variance weighted method.

RESULTS: The odds ratio of AD was 0.91 (95% confidence interval, 0.86-0.95; p = 9.8×10-5) per one standard deviation increase (about 6.5 cm) in genetically predicted height based on 682 SNPs, which were clustered in 419 loci. In an analysis restricted to one SNP from each height-associated locus (n = 419 SNPs), the corresponding OR was 0.92 (95% confidence interval, 0.86-0.97; p = 4.8×10-3).

CONCLUSIONS: This finding suggests that biological processes that influence adult height may have a role in the etiology of AD.

%B J Alzheimers Dis %V 60 %P 691-698 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869480?dopt=Abstract %R 10.3233/JAD-170528 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Glucose Transporters in Brain: In Health and in Alzheimer's Disease. %A Szablewski, Leszek %X

Neurons need a continuous supply of glucose, the major source of energy for mammalian brain metabolism. The central nervous system is protected by three main physiological cell barriers. Cell membranes are impermeable for glucose, therefore glucose is transferred across the cell membranes by specific transport proteins: sodium-independent glucose transporters (GLUTs), encoded by SLC2 genes, and sodium-dependent glucose transporters (for example SGLTs), encoded by SLC5 genes. Human brain expresses 10 GLUT proteins and 10 proteins encoded by SLC5 genes. In patients with brain diseases, particularly Alzheimer's (AD) and Huntington's diseases, abnormalities in neuronal glucose metabolism have been showed. The levels of GLUT1 and GLUT3, the major brain glucose transporters, are decreased, especially in the cerebral cortex. Therefore, in AD, hypometabolism of glucose and deficits in energy are observed. Production of ATP from glucose metabolism in sporadic AD declines to 50% and the tendency to decline continues throughout the progression of the disease. This decrease is correlated with O-GlcAcetylation and tau hyperphosphorylation, as the compensatory mechanisms in AD are the utilization of endogenous brain substances and drastic increase in GLUT2 levels. The present review focuses on the changes in the expression of glucose transporters due to AD.

%B J Alzheimers Dis %V 55 %P 1307-1320 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858715?dopt=Abstract %R 10.3233/JAD-160841 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Glutathione Conformations and Its Implications for in vivo Magnetic Resonance Spectroscopy. %A Mandal, Pravat K %A Shukla, Deepika %A Govind, Varan %A Boulard, Yves %A Ersland, Lars %X

Glutathione (GSH) is a major antioxidant in humans that is involved in the detoxification of reactive radicals and peroxides. The molecular structural conformations of GSH depend on the surrounding micro-environment, and it has been experimentally evaluated using NMR and Raman spectroscopic techniques as well as by molecular dynamics simulation studies. The converging report indicates that GSH exists mainly in two major conformations, i.e., "extended" and "folded". The NMR-derived information on the GSH conformers is essential to obtain optimal acquisition parameters in in vivo MRS experiments targeted for GSH detection. To further investigate the implications of GSH conformers in in vivo MRS studies and their relative proportions in healthy and pathological conditions, a multi-center clinical research study is necessary with a common protocol for GSH detection and quantification.

%B J Alzheimers Dis %V 59 %P 537-541 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527221?dopt=Abstract %R 10.3233/JAD-170350 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Google Calendar Enhances Prospective Memory in Alzheimer's Disease: A Case Report. %A El Haj, Mohamad %A Gallouj, Karim %A Antoine, Pascal %X

We investigated whether an external memory aid (i.e., Google Calendar) would alleviate prospective memory compromise in a patient with mild Alzheimer's disease. The patient was asked in the baseline phase to perform three prospective targeted events (e.g., attending her weekly bridge game at the community club) and three prospective control events (e.g., buying her weekly magazine). The same six prospective events were assessed in the intervention phase but the targeted-events were cued by Google Calendar while the control-events were not. Results showed less omission of the targeted events in the training phase than in the baseline phase, suggesting a positive effect of Google Calendar. This case report offers a unique view into how smartphone calendars may alleviate prospective memory compromise in patients with mild Alzheimer's disease.

%B J Alzheimers Dis %V 57 %P 285-291 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222535?dopt=Abstract %R 10.3233/JAD-161283 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Growth Arrest Specific 6 Concentration is Increased in the Cerebrospinal Fluid of Patients with Alzheimer's Disease. %A Sainaghi, Pier Paolo %A Bellan, Mattia %A Lombino, Franco %A Alciato, Federica %A Carecchio, Miryam %A Galimberti, Daniela %A Fenoglio, Chiara %A Scarpini, Elio %A Cantello, Roberto %A Pirisi, Mario %A Comi, Cristoforo %X

Growth arrest specific 6 (Gas6) has neurotrophic and neuroinflammatory functions, and may play a role in Alzheimer's disease (AD). In keeping with this hypothesis, we observed that cerebrospinal fluid (CSF) Gas6 is increased in AD patients compared to controls (63 versus 67 subjects; median value 13.3 versus 9.1 ng/ml; p < 0.0001). Thereafter, we assessed whether CSF Gas6 concentration was correlated to the following parameters: disease duration, MMSE score two years after clinical diagnosis, AD CSF biomarkers, and years of formal schooling. We detected an inverse correlation between CSF Gas6 levels at diagnosis and both disease duration (p < 0.0001) and decrease in the MMSE score two years later (p < 0.0001). Conversely, we found no correlation between CSF Gas6 and both AD biomarkers and years of formal schooling. In conclusion, our results suggest that upregulation of CSF Gas6 may be part of a defensive response aimed at counteracting AD progression.

%B J Alzheimers Dis %V 55 %P 59-65 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636849?dopt=Abstract %R 10.3233/JAD-160599 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Gut Microbiota and Alzheimer's Disease. %A Jiang, Chunmei %A Li, Guangning %A Huang, Pengru %A Liu, Zhou %A Zhao, Bin %X

The gut microbiota comprises a complex community of microorganism species that resides in our gastrointestinal ecosystem and whose alterations influence not only various gut disorders but also central nervous system disorders such as Alzheimer's disease (AD). AD, the most common form of dementia, is a neurodegenerative disorder associated with impaired cognition and cerebral accumulation of amyloid-β peptides (Aβ). Most notably, the microbiota-gut-brain axis is a bidirectional communication system that is not fully understood, but includes neural, immune, endocrine, and metabolic pathways. Studies in germ-free animals and in animals exposed to pathogenic microbial infections, antibiotics, probiotics, or fecal microbiota transplantation suggest a role for the gut microbiota in host cognition or AD-related pathogenesis. The increased permeability of the gut and blood-brain barrier induced by microbiota dysbiosis may mediate or affect AD pathogenesis and other neurodegenerative disorders, especially those associated with aging. In addition, bacteria populating the gut microbiota can secrete large amounts of amyloids and lipopolysaccharides, which might contribute to the modulation of signaling pathways and the production of proinflammatory cytokines associated with the pathogenesis of AD. Moreover, imbalances in the gut microbiota can induce inflammation that is associated with the pathogenesis of obesity, type 2 diabetes mellitus, and AD. The purpose of this review is to summarize and discuss the current findings that may elucidate the role of the gut microbiota in the development of AD. Understanding the underlying mechanisms may provide new insights into novel therapeutic strategies for AD.

%B J Alzheimers Dis %V 58 %P 1-15 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372330?dopt=Abstract %R 10.3233/JAD-161141 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Health Advice in a Digital World: Quality and Content of Online Information about the Prevention of Alzheimer's Disease. %A Robillard, Julie M %A Feng, Tanya L %X

BACKGROUND: As the number of older adults turning to the Internet for health information increases, so does the potential for online information to have a substantial impact on the patient-physician relationship and on their health. Inaccurate information may weaken patient-physician relationships or result in increased physician visits and health anxiety, while high quality information may allow Internet users to make better decisions about their health.

OBJECTIVE: To assess the quality and content of available online resources about the prevention of Alzheimer's disease (AD).

METHODS: A sample of 308 articles related to the prevention of AD was collected from the first three pages of location-independent keyword searches on Google.com between September 17-30, 2014. Content analysis was applied to articles that met criteria (n = 298) and a quality evaluation tool was developed to generate a quality score for each of the articles (n = 290).

RESULTS: We found that articles on the high end of the quality spectrum focused on modifiable risk factors and tended to present balanced information, while articles of low quality emphasized nutrition as a method of prevention and were more likely to be in conflict of interest.

CONCLUSION: This study provides the first insight into the content and quality of prevention information for AD currently available online and highlights the importance of future research to better understand the impact of this information on the patient-physician relationship and health decision-making of older adults.

%B J Alzheimers Dis %V 55 %P 219-229 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636852?dopt=Abstract %R 10.3233/JAD-160650 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Heterogeneous Association of Alzheimer's Disease-Linked Amyloid-β and Amyloid-β Protein Precursor with Synapses. %A Willén, Katarina %A Sroka, Agnieszka %A Takahashi, Reisuke H %A Gouras, Gunnar K %X

Alzheimer's disease (AD) is increasingly viewed as a disease of synapses. Loss of synapses correlates better with cognitive decline than amyloid plaques and neurofibrillary tangles, the hallmark neuropathological lesions of AD. Soluble forms of amyloid-β (Aβ) have emerged as mediators of synapse dysfunction. Aβ binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of Aβ and the amyloid-β protein precursor (AβPP) in AD remain poorly understood. In addition, the relative roles of Aβ and AβPP in the development of AD, at pre- versus post-synaptic compartments and axons versus dendrites, respectively, remain unclear. Here we use immunogold electron microscopy and confocal microscopy to provide evidence for heterogeneity in the localization of Aβ/AβPP. We demonstrate that Aβ binds to a subset of synapses in cultured neurons, with preferential binding to glutamatergic compared to GABAergic neurons. We also highlight the challenge of defining pre- versus post-synaptic localization of this binding by confocal microscopy. Further, endogenous Aβ42 accumulates in both glutamatergic and GABAergic AβPP/PS1 transgenic primary neurons, but at varying levels. Moreover, upon knock-out of presenilin 1 or inhibition of γ-secretase AβPP C-terminal fragments accumulate both pre- and post-synaptically; however earlier pre-synaptically, consistent with a higher rate of AβPP processing in axons. A better understanding of the synaptic and anatomical selectivity of Aβ/AβPP in AD can be important for the development of more effective new therapies for this major disease of aging.

%B J Alzheimers Dis %V 60 %P 511-524 %8 2017 %G eng %N 2 %R 10.3233/JAD-170262 %0 Journal Article %J J Alzheimers Dis %D 2017 %T High Sensitivity Cardiac Troponin T and Cognitive Function in the Oldest Old: The Leiden 85-Plus Study. %A Bertens, Anne Suzanne %A Sabayan, Behnam %A de Craen, Anton J M %A Van der Mast, Roos C %A Gussekloo, Jacobijn %X

BACKGROUND: Impaired cardiac function has been related to accelerated cognitive decline in late-life.

OBJECTIVE: To investigate whether higher levels of high sensitivity cardiac troponin T (hs-cTnT), a sensitive marker for myocardial injury, are associated with worse cognitive function in the oldest old.

METHODS: In 455 participants of the population-based Leiden 85-plus Study, hs-cTnT was measured at 86 years. Cognitive function was measured annually during four years with the Mini-Mental State Examination (MMSE).

RESULTS: Participants in the highest gender-specific tertile of hs-cTnT had a 2.0-point lower baseline MMSE score than participants in the lowest tertile (95% confidence interval (CI) (95% CI 0.73-3.3), and had a 0.58-point steeper annual decline in MMSE during follow-up (95% CI 0.06-1.1). The associations remained after adjusting for sociodemographic and cardiovascular risk factors excluding those without a history of overt cardiac disease.

CONCLUSION: In a population-based sample of the oldest old, higher levels of hs-cTnT were associated with worse cognitive function and faster cognitive decline, independently from cardiovascular risk factors and a history of overt cardiac disease.

%B J Alzheimers Dis %V 60 %P 235-242 %G eng %N 1 %R 10.3233/JAD-170171 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A High-Cholesterol Diet Increases 27-Hydroxycholesterol and Modifies Estrogen Receptor Expression and Neurodegeneration in Rabbit Hippocampus. %A Brooks, Sylwia W %A Dykes, Ava C %A Schreurs, Bernard G %X

Hypercholesterolemia has been implicated in numerous health problems from cardiovascular disease to neurodegeneration. High serum cholesterol levels in midlife have been associated with an increased risk of developing Alzheimer's disease (AD) later in life which suggests that the pathways leading to AD pathology might be activated decades before the symptoms of the disease are detected. Cholesterol-fed animals, particularly cholesterol-fed rabbits, exhibit brain pathology similar to the changes found in brains of AD patients. Dietary cholesterol, which cannot pass the blood-brain barrier, is thought to influence central nervous system homeostasis by increased transport of its circulatory breakdown product, 27-hydroxycholesterol (27-OHC), into the brain. 27-OHC is an endogenous selective estrogen receptor modulator. Estrogen-mediated non-reproductive functions require estrogen receptors (ERs) and include modulation of mitochondrial function and structure, as well as regulation of synaptogenesis in the brain. ERs are located in brain areas affected early in AD pathogenesis, including the hippocampus. Here we report that increase in serum cholesterol, induced by feeding rabbits a high-cholesterol diet, is associated with higher levels of 27-OHC in the brain as well as increased levels of neurodegeneration in the hippocampus. Furthermore, these results are accompanied by changes in expression of ERs in the hippocampus as well as a decrease in hippocampal mitochondria. These findings provide an important insight into one of the possible mechanisms involved in the development of AD, and shed light on the processes that may antedate amyloid-β and tau phosphorylation changes currently hypothesized to cause AD symptomology and pathology.

%B J Alzheimers Dis %V 56 %P 185-196 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911307?dopt=Abstract %R 10.3233/JAD-160725 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Higher Peripheral TREM2 mRNA Levels Relate to Cognitive Deficits and Hippocampal Atrophy in Alzheimer's Disease and Amnestic Mild Cognitive Impairment. %A Tan, Yi Jayne %A Ng, Adeline S L %A Vipin, Ashwati %A Lim, Joseph K W %A Chander, Russell J %A Ji, Fang %A Qiu, Yingwei %A Ting, Simon K S %A Hameed, Shahul %A Lee, Tih-Shih %A Zeng, Li %A Kandiah, Nagaendran %A Zhou, Juan %X

BACKGROUND: Variants in triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased Alzheimer's disease (AD) risk. Recent studies have reported inconsistent peripheral TREM2 mRNA expression levels and relationship with cognitive scores in AD and mild cognitive impairment (MCI). Additionally, no study has examined the association of peripheral TREM2 levels with neuroimaging measures in AD and MCI.

OBJECTIVE: To determine peripheral TREM2 mRNA levels in AD, amnestic MCI (aMCI) and healthy controls, and the association with cognitive performance and brain structural changes.

METHODS: We measured peripheral TREM2 mRNA levels in 80 AD, 30 aMCI, and 86 healthy controls using real time polymerase chain reaction. TREM2 levels were correlated with various cognitive performance and brain volumes, correcting for APOE4 status.

RESULTS: TREM2 mRNA levels were significantly higher in AD compared to controls and aMCI. Levels did not differ between aMCI and controls. Corrected for APOE4, higher TREM2 levels correlated with lower Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA) and episodic memory scores, and lower total grey matter and right hippocampal volumes. Whole-brain voxel-based morphometry analysis found negative association between TREM2 mRNA levels and grey matter volumes in temporal, parietal and frontal regions. AD subjects with MoCA scores ≤20 had higher TREM2 levels correlating with smaller total grey matter, left hippocampal and right hippocampal volumes.

CONCLUSION: Peripheral TREM2 mRNA levels are higher in AD and are associated with AD-related cognitive deficits and hippocampal atrophy. Our findings suggest that TREM2 may be a potential non-invasive peripheral biomarker for AD diagnosis.

%B J Alzheimers Dis %V 58 %P 413-423 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453482?dopt=Abstract %R 10.3233/JAD-161277 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Hippocampal and Clinical Trajectories of Mild Cognitive Impairment with Suspected Non-Alzheimer's Disease Pathology. %A Chung, Jun Ku %A Plitman, Eric %A Nakajima, Shinichiro %A Caravaggio, Fernando %A Iwata, Yusuke %A Gerretsen, Philip %A Kim, Julia %A Takeuchi, Hiroyoshi %A Shinagawa, Shunichiro %A Patel, Raihaan %A Chakravarty, M Mallar %A Graff-Guerrero, Ariel %X

Suspected non-Alzheimer's disease pathology (SNAP) characterizes individuals showing neurodegeneration (e.g., hypometabolism) without amyloid-β (Aβ). Findings from previous studies regarding clinical and structural trajectories of SNAP are inconsistent. Using data from the Alzheimer's Disease Neuroimaging Initiative, patients with amnestic mild cognitive impairment (MCI) were categorized into four groups: amyloid positive with hypometabolism (Aβ+ND+), amyloid only (Aβ+ND-), neither amyloid nor hypometabolism (Aβ-ND-), and SNAP (Aβ-ND+). Aβ+ND+(n = 33), Aβ+ND-(n = 32), and Aβ-ND-(n = 36) were matched to SNAP for age, gender, apolipoprotein E4 (apoE4) genotype, and scores on the Montreal Cognitive Assessment. Elderly controls (n = 40) were also matched to SNAP for age, gender, and apoE4 genotype. Longitudinal changes were compared across groups in terms of hippocampal volume, clinical symptoms, daily functioning, and cognitive functioning over a 2-year period. At baseline, no difference in cognition and functioning was observed between SNAP and Aβ+groups. SNAP showed worse clinical symptoms and impaired functioning at baseline compared to Aβ-ND-and controls. Two years of follow-up showed no differences in hippocampal volume changes between SNAP and any of the comparison groups. SNAP showed worse functional deterioration in comparison to Aβ-ND-and controls. However, Aβ+ND+ showed more severe changes in clinical symptoms in comparison to SNAP. Thus, patients with MCI and SNAP showed 1) more severe functional deterioration compared to Aβ-ND-and controls, 2) no differences with Aβ+ND-, and 3) less cognitive deterioration than Aβ+ND+. Future studies should investigate what causes SNAP, which is different from typical AD pathology and biomarker cascades.

%B J Alzheimers Dis %V 58 %P 747-762 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505977?dopt=Abstract %R 10.3233/JAD-170201 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Hippocampus and Basal Forebrain Volumetry for Dementia and Mild Cognitive Impairment Diagnosis: Could It Be Useful in Primary Care? %A Teipel, Stefan J %A Keller, Felix %A Thyrian, Jochen R %A Strohmaier, Urs %A Altiner, Attila %A Hoffmann, Wolfgang %A Kilimann, Ingo %X

BACKGROUND: Once a patient or a knowledgeable informant has noticed decline in memory or other cognitive functions, initiation of early dementia assessment is recommended. Hippocampus and cholinergic basal forebrain (BF) volumetry supports the detection of prodromal and early stages of Alzheimer's disease (AD) dementia in highly selected patient populations.

OBJECTIVE: To compare effect size and diagnostic accuracy of hippocampus and BF volumetry between patients recruited in highly specialized versus primary care and to assess the effect of white matter lesions as a proxy for cerebrovascular comorbidity on diagnostic accuracy.

METHODS: We determined hippocampus and BF volumes and white matter lesion load from MRI scans of 71 participants included in a primary care intervention trial (clinicaltrials.gov identifier: NCT01401582) and matched 71 participants stemming from a memory clinic. Samples included healthy controls and people with mild cognitive impairment (MCI), AD dementia, mixed dementia, and non-AD related dementias.

RESULTS: Volumetric measures reached similar effect sizes and cross-validated levels of accuracy in the primary care and the memory clinic samples for the discrimination of AD and mixed dementia cases from healthy controls. In the primary care MCI cases, volumetric measures reached only random guessing levels of accuracy. White matter lesions had only a modest effect on effect size and diagnostic accuracy.

CONCLUSIONS: Hippocampus and BF volumetry may usefully be employed for the identification of AD and mixed dementia, but the detection of MCI does not benefit from the use of these volumetric markers in a primary care setting.

%B J Alzheimers Dis %V 55 %P 1379-1394 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27834778?dopt=Abstract %R 10.3233/JAD-160778 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Histogram-Based Feature Extraction from Individual Gray Matter Similarity-Matrix for Alzheimer's Disease Classification. %A Beheshti, Iman %A Maikusa, Norihide %A Matsuda, Hiroshi %A Demirel, Hasan %A Anbarjafari, Gholamreza %X

Automatic computer-aided diagnosis (CAD) systems have been widely used in classification of patients who suffer from Alzheimer's disease (AD). This paper presents an automatic CAD system based on histogram feature extraction from single-subject gray matter similarity-matrix for classifying the AD patients from healthy controls (HC) using structural magnetic resonance imaging (MRI) data. The proposed CAD system is composed of five stages. In the first stage, segmentation is employed to perform pre-processing on the MRI images, and segment into gray matter, white matter, and cerebrospinal fluid using the voxel-based morphometric toolbox procedure. In the second stage, gray matter MRI scans are used to construct similarity-matrices. In the third stage, a novel statistical feature-generation process is proposed, utilizing the histogram of the individual similarity-matrix to represent statistical patterns of the respective similarity-matrices of different size and order into fixed-size feature-vectors. In the fourth stage, we propose to combine MRI measures with a neuropsychological test, the Functional Assessment Questionnaire (FAQ), to improve the classification accuracy. Finally, the classification is performed using a support vector machine and evaluated with the 10-fold cross-validation strategy. We evaluated the proposed method on 99 AD and 102 HC subjects from the J-ADNI. The proposed CAD system yields an 84.07% classification accuracy using MRI measures and 97.01% for combining MRI measures with FAQ scores, respectively. The experimental results indicate that the performance of the proposed system is competitive with respect to state-of-the-art techniques reported in the literature.

%B J Alzheimers Dis %V 55 %P 1571-1582 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27886012?dopt=Abstract %R 10.3233/JAD-160850 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Histopathology and Florbetaben PET in Patients Incorrectly Diagnosed with Alzheimer's Disease. %A Sabbagh, Marwan N %A Schäuble, Barbara %A Anand, Keshav %A Richards, Danielle %A Murayama, Shigeo %A Akatsu, Hiroyasu %A Takao, Masaki %A Rowe, Christopher C %A Masters, Colin L %A Barthel, Henryk %A Gertz, Hermann-Josef %A Peters, Oliver %A Rasgon, Natalie %A Jovalekic, Aleksandar %A Sabri, Osama %A Schulz-Schaeffer, Walter J %A Seibyl, John %X

Of 57 individuals diagnosed with Alzheimer's disease (AD) in a phase III study, 13 (23%) had amyloid-β (Aβ) levels on postmortem histopathology that did not explain the dementia. Based on postmortem histopathology, a wide range of different non-AD conditions was identified, including frontotemporal dementia, hippocampal sclerosis, and dementia with Lewy bodies. Of the histopathologically Aβ negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Aβ in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite standardized uptake value ratios. Thus, florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative disorders by reliably excluding Aβ pathology.

%B J Alzheimers Dis %V 56 %P 441-446 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983552?dopt=Abstract %R 10.3233/JAD-160821 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Home-Based Exercise Program Improves Balance and Fear of Falling in Community-Dwelling Older Adults with Mild Alzheimer's Disease: A Pilot Study. %A Padala, Kalpana P %A Padala, Prasad R %A Lensing, Shelly Y %A Dennis, Richard A %A Bopp, Melinda M %A Roberson, Paula K %A Sullivan, Dennis H %X

BACKGROUND/OBJECTIVE: Balance problems are common in older adults with Alzheimer's disease (AD). The objective was to study the effects of a Wii-Fit interactive video-game-led physical exercise program to a walking program on measures of balance in older adults with mild AD.

METHODS: A prospective randomized controlled parallel-group trial (Wii-Fit versus walking) was conducted in thirty community-dwelling older adults (73±6.2 years) with mild AD. Home-based exercises were performed under caregiver supervision for 8 weeks. Primary (Berg Balance Scale, BBS) and secondary outcomes (fear of falls and quality of life) were measured at baseline, 8 weeks (end of intervention), and 16 weeks (8-weeks post-intervention).

RESULTS: At 8 weeks, there was a significantly greater improvement (average inter-group difference [95% CI]) in the Wii-Fit group compared to the walking group in BBS (4.8 [3.3-6.2], p < 0.001), after adjusting for baseline. This improvement was sustained at 16 weeks (3.5 [2.0-5.0], p < 0.001). Analyses of the secondary outcome measures indicated that there was a significantly greater improvement in the Wii-Fit group compared to walking group in Activity-specific Balance Confidence scale (6.5 [3.6-9.4], p < 0.001) and Falls Efficacy Scale (-4.8 [-7.6 to -2.0], p = 0.002) at 8 weeks. However, this effect was not sustained at 16 weeks. Quality of life improved in both groups at 8 weeks; however, there were no inter-group differences (p = 0.445).

CONCLUSION: Home-based, caregiver-supervised Wii-Fit exercises improve balance and may reduce fear of falling in community-dwelling older adults with mild AD.

%B J Alzheimers Dis %V 59 %P 565-574 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28655135?dopt=Abstract %R 10.3233/JAD-170120 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Homocysteine and Real-Space Navigation Performance among Non-Demented Older Adults. %A Pařízková, Martina %A Andel, Ross %A Lerch, Ondřej %A Marková, Hana %A Gažová, Ivana %A Vyhnálek, Martin %A Hort, Jakub %A Laczó, Jan %X

BACKGROUND: High plasma homocysteine (Hcy) level is related to higher risk of Alzheimer's disease (AD) and lower cognitive performance in older adults.

OBJECTIVE: To assess the association between plasma Hcy level and real-space navigation performance and the role of vascular risk and protective factors, APOE status, and white matter lesions (WML) on this association.

METHODS: Ninety-two non-demented older adults (29 with amnestic mild cognitive impairment, 46 with subjective cognitive decline, and 17 cognitively normal older adults) underwent spatial navigation testing of egocentric, allocentric, and mixed navigation in a real-space analogue of the Morris water maze, neuropsychological examination, blood collection, and MRI brain scan with evaluation of WML.

RESULTS: In the regression analyses controlling for age, gender, education, and depressive symptoms, higher plasma Hcy level was related to worse mixed and egocentric (β= 0.31; p = 0.003 and β= 0.23; p = 0.017) but not allocentric (p > 0.05) navigation performance. Additional controlling for vascular risk and protective factors, WML, and APOE status did not modify the results. High total cholesterol and low vitamin B12 and folate levels increased the adverse effect of Hcy on egocentric and mixed navigation. WML did not explain the association between plasma Hcy level and navigation performance.

CONCLUSION: Elevated plasma Hcy level may affect real-space navigation performance above and beyond vascular brain changes. This association may be magnified in the presence of high total cholesterol and low folate or vitamin B12 levels. Attention to the level of plasma Hcy may be a viable intervention strategy to prevent decline in spatial navigation in non-demented older adults.

%B J Alzheimers Dis %V 55 %P 951-964 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802238?dopt=Abstract %R 10.3233/JAD-160667 %0 Journal Article %J J Alzheimers Dis %D 2017 %T How Different are Quality of Life Ratings for People with Dementia Reported by Their Family Caregivers from Those Reported by the Patients Themselves? %A Jacob, Louis %A Han, Ji Won %A Kim, Tae Hui %A Park, Joon Hyuk %A Lee, Seok Bum %A Lee, Jung Jae %A Ryu, Seung-Ho %A Kim, Shin-Kyeom %A Yoon, Jong Chul %A Jhoo, Jin Hyeong %A Kim, Jeong Lan %A Kwak, Kyung Phil %A Moon, Seok Woo %A Kim, Bong Jo %A Lee, Dong Young %A Kim, Ki Woong %X

BACKGROUND: Measurements of patient quality of life (QoL) play a major role in the management of dementia.

OBJECTIVE: We investigated the self-proxy discrepancy of QoL ratings in the elderly and the impact of dementia severity on the discrepancy.

METHODS: QoL of 718 patients with dementia and 651 non-demented elderly were rated by themselves and their caregivers (CG) using the Quality of Life-Alzheimer's Disease (QoL-AD). The impact of the rater on the total and item scores of QoL-AD was analyzed using repeated measures ANOVA and differential response patterns between self and proxy were analyzed using differential item functioning (DIF) analysis.

RESULTS: Self-rated scores were higher than CG-rated scores in all diagnostic groups. The interaction between rater and diagnostic group was significant in total QoL-AD score and 5 item scores ('memory', 'marriage', 'chores around the house', 'do things for fun', and 'life as a whole'). The strength of the DIF increased with advancing dementia in these items.

CONCLUSION: Self-proxy rating discrepancy of QoL was influenced by the presence and severity of dementia only in five items.

%B J Alzheimers Dis %V 55 %P 259-267 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662302?dopt=Abstract %R 10.3233/JAD-160538 %0 Journal Article %J J Alzheimers Dis %D 2017 %T How Does Exercise Reduce the Rate of Age-Associated Cognitive Decline? A Review of Potential Mechanisms. %A Kennedy, Greg %A Hardman, Roy J %A Macpherson, Helen %A Scholey, Andrew B %A Pipingas, Andrew %X

The rate of age-associated cognitive decline varies considerably between individuals. It is important, both on a societal and individual level, to investigate factors that underlie these differences in order to identify those which might realistically slow cognitive decline. Physical activity is one such factor with substantial support in the literature. Regular exercise can positively influence cognitive ability, reduce the rate of cognitive aging, and even reduce the risk of Alzheimer's disease (AD) and other dementias. However, while there is substantial evidence in the extant literature for the effect of exercise on cognition, the processes that mediate this relationship are less clear. This review examines cardiovascular health, production of brain derived neurotrophic factor (BDNF), insulin sensitivity, stress, and inflammation as potential pathways, via which exercise may maintain or improve cognitive functioning, and may be particularly pertinent in the context of the aging brain. A greater understanding of these mechanisms and their potential relationships with exercise and cognition will be invaluable in providing biomarkers for investigating the efficacy of differing exercise regimes on cognitive outcomes.

%B J Alzheimers Dis %V 55 %P 1-18 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636853?dopt=Abstract %R 10.3233/JAD-160665 %0 Journal Article %J J Alzheimers Dis %D 2017 %T How Studies of the Serotonin System in Macaque Models of Menopause Relate to Alzheimer's Disease1. %A Bethea, Cynthia L %A Reddy, Arubala P %A Christian, Fernanda Lima %X

Serotonin plays a key role in mood or affect, and dysfunction of the serotonin system has been linked to depression in humans and animal models. Depression appears prior to or coincident with overt symptoms of Alzheimer's disease (AD) in about 50% of patients, and some experts consider it a risk factor for the development of AD. In addition, AD is more prevalent in women, who also show increased incidence of depression. Indeed, it has been proposed that mechanisms underlying depression overlap the mechanisms thought to hasten AD. Women undergo ovarian failure and cessation of ovarian steroid production in middle age and the postmenopausal period correlates with an increase in the onset of depression and AD. This laboratory has examined the many actions of ovarian steroids in the serotonin system of non-human primates using a rhesus macaque model of surgical menopause with short or long-term estradiol (E) or estradiol plus progesterone (E+P) replacement therapy. In this mini-review, we present a brief synopsis of the relevant literature concerning AD, depression, and serotonin. We also present some of our data on serotonin neuron viability, the involvement of the caspase-independent pathway, and apoptosis-inducing factor in serotonin-neuron viability, as well as gene expression related to neurodegeneration and neuron viability in serotonin neurons from adult and aged surgical menopausal macaques. We show that ovarian steroids, particularly E, are crucial for serotonin neuron function and health. In the absence of E, serotonin neurons are endangered and deteriorating toward apoptosis. The possibility that this scenario may proceed or accompany AD in postmenopausal women seems likely.

%B J Alzheimers Dis %V 57 %P 1001-1015 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662311?dopt=Abstract %R 10.3233/JAD-160601 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Humanin Specifically Interacts with Amyloid-β Oligomers and Counteracts Their in vivo Toxicity. %A Romeo, Margherita %A Stravalaci, Matteo %A Beeg, Marten %A Rossi, Alessandro %A Fiordaliso, Fabio %A Corbelli, Alessandro %A Salmona, Mario %A Gobbi, Marco %A Cagnotto, Alfredo %A Diomede, Luisa %K Amyloid beta-Peptides %K Animals %K Animals, Genetically Modified %K Caenorhabditis elegans %K Caenorhabditis elegans Proteins %K Circular Dichroism %K Disease Models, Animal %K Dose-Response Relationship, Drug %K Gene Expression Regulation %K Humans %K Intracellular Signaling Peptides and Proteins %K Microscopy, Atomic Force %K Microscopy, Electron, Transmission %K Neprilysin %K Paralysis %K Peptide Fragments %K Surface Plasmon Resonance %X

The 24-residue peptide humanin (HN) has been proposed as a peptide-based inhibitor able to interact directly with amyloid-β (Aβ) oligomers and interfere with the formation and/or biological properties of toxic Aβ species. When administered exogenously, HN, or its synthetic S14G-derivative (HNG), exerted multiple cytoprotective effects, counteracting the Aβ-induced toxicity. Whether these peptides interact directly with Aβ, particularly with the soluble oligomeric assemblies, remains largely unknown. We here investigated the ability of HN and HNG to interact directly with highly aggregating Aβ42, and interfere with the formation and toxicity of its oligomers. Experiments were run in cell-free conditions and in vivo in a transgenic C. elegans strain in which the Aβ toxicity was specifically due to oligomeric species. Thioflavin-T assay indicated that both HN and HNG delay the formation and reduce the final amount of Aβ42 fibrils. In vitro surface plasmon resonance studies indicated that they interact with Aβ42 oligomers favoring the formation of amorphous larger assemblies, observed with turbidity and electron microscopy. In vivo studies indicated that both HN and HNG decrease the relative abundance of A11-positive prefibrillar oligomers as well as OC-positive fibrillar oligomers and had similar protective effects. However, while HN possibly decreased the oligomers by promoting their assembly into larger aggregates, the reduction of oligomers caused by HNG can be ascribed to a marked decrease of the total Aβ levels, likely the consequence of the HNG-induced overexpression of the Aβ-degrading enzyme neprilysin. These findings provide information on the mechanisms underlying the anti-oligomeric effects of HN and HNG and illustrate the role of S14G substitution in regulating the in vivo mechanism of action.

%B J Alzheimers Dis %V 57 %P 857-871 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28282805?dopt=Abstract %R 10.3233/JAD-160951 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits. %A Fried, Peter J %A Schilberg, Lukas %A Brem, Anna-Katharine %A Saxena, Sadhvi %A Wong, Bonnie %A Cypess, Aaron M %A Horton, Edward S %A Pascual-Leone, Alvaro %X

BACKGROUND: Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer's disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed.

OBJECTIVE: Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition.

METHODS: A prospective cross-sectional cohort study was conducted on 21 adults with T2DM and 15 demographically-similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores.

RESULTS: In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance.

CONCLUSION: Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions.

%B J Alzheimers Dis %V 55 %P 89-100 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636847?dopt=Abstract %R 10.3233/JAD-160505 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Identification of Circulating miR-125b as a Potential Biomarker of Alzheimer's Disease in APP/PS1 Transgenic Mouse. %A Hong, Honghai %A Li, Yang %A Su, Baochang %X

Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive decline in cognitive abilities of the affected individuals. Biological markers are essential to identify individuals at early stages of the disease for timely therapeutic intervention. Currently, pathological biomarkers are detected either through cerebrospinal fluid analysis or brain imaging, or postmortem, all of which are expensive, invasive, or time consuming. Recently, some studies have shown that circulating miR-125b, miR-181c, miR-9, miR-191-5p, miR-26b-3p, and miR-28-3p may be biomarkers of AD. However, those potential biomarkers are not validated in an AD mouse model. In the current study, we found that circulating miR-125b, miR-9, and miR-191-5p are downregulated, and miR-28-3p is upregulated in an APP/PS1 transgenic mouse model of AD. Furthermore, the correlation analysis shows a positive correlation between the expression of miR-125b and cognitive function of the APP/PS1 transgenic mouse. Moreover, we also determined that the level of serum miR-125b, miR-9, and miR-191-5p were reversed in EGCG-treated APP/PS1 transgenic mouse models. Finally, the expression of miR-125b was significantly downregulated in EGCG-treated SH-SY5Y cells.

%B J Alzheimers Dis %V 59 %P 1449-1458 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731435?dopt=Abstract %R 10.3233/JAD-170156 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Identification of Fungal Species in Brain Tissue from Alzheimer's Disease by Next-Generation Sequencing. %A Alonso, Ruth %A Pisa, Diana %A Aguado, Begoña %A Carrasco, Luis %X

The possibility that patients diagnosed with Alzheimer's disease (AD) have disseminated fungal infection has been recently advanced by the demonstration of fungal proteins and DNA in nervous tissue from AD patients. In the present study, next-generation sequencing (NGS) was used to identify fungal species present in the central nervous system (CNS) of AD patients. Initially, DNA was extracted from frozen tissue from four different CNS regions of one AD patient and the fungi in each region were identified by NGS. Notably, whereas a great variety of species were identified using the Illumina platform, Botrytis cinerea and Cryptococcus curvatus were common to all four CNS regions analyzed. Further analysis of entorhinal/cortex hippocampus samples from an additional eight AD patients revealed a variety of fungal species, although some were more prominent than others. Five genera were common to all nine patients: Alternaria, Botrytis, Candida, Cladosporium, and Malassezia. These observations could be used to guide targeted antifungal therapy for AD patients. Moreover, the differences found between the fungal species in each patient may constitute a basis to understand the evolution and severity of clinical symptoms in AD.

%B J Alzheimers Dis %V 58 %P 55-67 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387676?dopt=Abstract %R 10.3233/JAD-170058 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Identification of Successful Cognitive Aging in the Alzheimer's Disease Neuroimaging Initiative Study. %A Lin, Feng V %A Wang, Xixi %A Wu, Rachel %A Rebok, George W %A Chapman, Benjamin P %X

The present prospective observational study aimed to identify the existence of successful cognitive agers among a group of well-defined cognitively healthy older adults (n = 354, mean age = 75 years), and to examine baseline individual-level predictors and associated health outcomes over time. Episodic memory (EM) and executive function (EF) composite scores and multiple health outcomes were obtained annually over 5 years. Potential individual-level predictors that were related to Alzheimer's disease pathology or genetic risk, neurodegeneration, and vascular risks were collected at baseline. Three latent classes with matched age and education were identified using growth mixture modeling: a group of participants who exhibited high, stable EM and EF (40.7% of the sample, "successful agers"); a group who had initial high cognitive performance that declined over time (21.2%, "declining agers"); and a group who had normal (EM) or poor (EF) but stable cognitive performance over time (38.1%, "low stable agers"). The group classification predicted significant differences in the incidence of global cognitive impairment, the development of at least one depressive symptom, and everyday functional impairment. Sex, apolipoprotein E allele 4, amyloid-β1-42, and t-tau significantly contributed to the difference in cognitive trajectories between the successful agers and the other two groups. Characterizing successful cognitive agers who are relatively resistant to both tau and amyloid pathology provides potential pathways for promoting successful cognitive aging and preventing cognitive decline.

%B J Alzheimers Dis %V 59 %P 101-111 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582857?dopt=Abstract %R 10.3233/JAD-161278 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Impact of Alzheimer's Disease on the Resting State Functional Connectivity of Brain Regions Modulating Pain: A Cross Sectional Study. %A Monroe, Todd B %A Beach, Paul A %A Bruehl, Stephen P %A Dietrich, Mary S %A Rogers, Baxter P %A Gore, John C %A Atalla, Sebastian W %A Cowan, Ronald L %X

BACKGROUND: It is currently unknown why people with Alzheimer's disease (AD) receive less pain medication and report pain less frequently.

OBJECTIVE: The purpose of this study was to determine the impact of AD on thermal psychophysics and resting-state functional connectivity (RSFC) among sensory, affective, descending modulatory, and default mode structures.

METHODS: Controls (n = 23, 13 = female) and age-matched people with AD (n = 23, 13 = females) underwent psychophysical testing to rate perceptions of warmth, mild, and moderate pain and then completed resting-state fMRI. Between groups analysis in psychophysics and RSFC were conducted among pre-defined regions of interest implicated in sensory and affective dimensions of pain, descending pain modulation, and the default mode network.

RESULTS: People with AD displayed higher thermal thresholds for warmth and mild pain but similar moderate pain thresholds to controls. No between-group differences were found for unpleasantness at any percept. Relative to controls, people with AD demonstrated reduced RSFC between the right posterior insula and left anterior cingulate and also between right amygdala and right secondary somatosensory cortex. Moderate pain unpleasantness reports were associated with increased RSFC between right dorsolateral prefrontal cortex and left ACC in controls only.

CONCLUSIONS: While AD had little effect on unpleasantness, people with AD had increased thermal thresholds, altered RSFC, and no association of psychophysics with RSFC in pain regions. Findings begin to elucidate that in people with AD, altered integration of pain sensation, affect, and descending modulation may, in part, contribute to decreased verbal pain reports and thus decreased analgesic administration.

%B J Alzheimers Dis %V 57 %P 71-83 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222526?dopt=Abstract %R 10.3233/JAD-161187 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Impact of Recruitment Methods in Subjective Cognitive Decline. %A Abdelnour, Carla %A Rodríguez-Gómez, Octavio %A Alegret, Montserrat %A Valero, Sergi %A Moreno-Grau, Sonia %A Sanabria, Ángela %A Hernandez, Isabel %A Rosende-Roca, Maitee %A Vargas, Liliana %A Mauleón, Ana %A Sánchez, Domingo %A Espinosa, Ana %A Ortega, Gemma %A Pérez-Cordón, Alba %A Diego, Susana %A Gailhajanet, Anna %A Guitart, Marina %A Sotolongo-Grau, Oscar %A Ruiz, Agustin %A Tárraga, Lluís %A Boada, Merce %X

BACKGROUND: Recruitment methods can determine sample characteristics in mild cognitive impairment and Alzheimer's disease dementia, but little is known about its influence in subjective cognitive decline (SCD).

OBJECTIVE: To determine the influence of two types of recruitment methods in the characteristics of individuals with SCD.

METHODS: We select and compare clinical and neuropsychological features, and frequency of APOE ɛ4 allele of 326 subjects with SCD from two cohorts: Open House Initiative (OHI) versus Memory Unit (MU). A logistic regression analysis (LRA), using gender and years of education as covariates, was used to examine the neuropsychological variables.

RESULTS: The OHI sample were mostly women (75.9% versus 64.5%, p < 0.05), with higher educational level (12.15 [3.71] versus 10.70 [3.80] years, p = 0.001), and more family history of dementia (138 [62.7%] versus 44 [41.5%], p < 0.001) than the MU sample. Also, the OHI sample showed better overall neuropsychological performance than the MU sample, and after a LRA, this trend continued in automatic response inhibition capacity, abstract reasoning, and recognition memory. We did not find differences in age, depression history, and/or APOE ɛ4 allele frequency.

CONCLUSION: SCD subjects showed different demographic and neuropsychological characteristics depending on the recruitment method, which should be taken into account in the design of research studies with this target population.

%B J Alzheimers Dis %V 57 %P 625-632 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269773?dopt=Abstract %R 10.3233/JAD-160915 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Impact of the Relationship of Stress and the Immune System in the Appearance of Alzheimer's Disease. %A de la Rubia Ortí, Jose Enrique %A Sancho Castillo, Sandra %A Benlloch, Maria %A Julián Rochina, Mariano %A Corchón Arreche, Silvia %A García-Pardo, María Pilar %X

The understanding of how the immune system works, as well as its relationship with the stress level, seems to be important at the start of the Alzheimer's disease (AD). To analyze this, immunoglobulin A (IgA) and cortisol in saliva were measured using ELISA in patients with mild AD and healthy volunteers, and the production of both biomarkers was compared and correlated. In participants without AD, IgA was higher when cortisol was lower, and the opposite happened in participants with AD, with the quantification in saliva being a suitable method to determine it.

%B J Alzheimers Dis %V 55 %P 899-903 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767997?dopt=Abstract %R 10.3233/JAD-160903 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Impaired Center-Surround Suppression in Patients with Alzheimer's Disease. %A Zhuang, Xianbo %A Chen, Yanxiu %A Zhuang, Xianpeng %A Xing, Tao %A Chen, Tuanzhi %A Jiang, Guisheng %A Yang, Xiafeng %X

Alzheimer's disease (AD) is often associated with declined visual processing abilities. Here we tested whether the functions of center-surround suppression- a hallmark property in the visual system- are altered by AD. To this end, we recruited three groups of participants (AD, elderly, and young) in a motion direction discrimination task, in which we measured the temporal duration threshold of a  drifting Gabor with varying stimulus sizes. We first replicated the phenomena of center-surround suppression that the required duration for discriminating a high contrast grating decreases with increasing stimulus size. We then showed that the magnitudes of suppression varied among the three groups. There was progressive reduction of suppression in the elderly and AD groups compared with the young group. Interestingly, we found that the levels of suppression can predict the severity of dementia in the AD group. Our results suggest that AD is associated with impaired center-surround functions in the visual motion processing pathway.

%B J Alzheimers Dis %V 55 %P 1101-1108 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767987?dopt=Abstract %R 10.3233/JAD-160603 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Impaired Processing of Serial Order Determines Working Memory Impairments in Alzheimer's Disease. %A De Belder, Maya %A Santens, Patrick %A Sieben, Anne %A Fias, Wim %X

BACKGROUND: Working memory (WM) problems are commonly observed in Alzheimer's disease (AD), but the affected mechanisms leading to impaired WM are still insufficiently understood. The ability to efficiently process serial order in WM has been demonstrated to be fundamental to fluent daily life functioning. The decreased capability to mentally process serial position in WM has been put forward as the underlying explanation for generally compromised WM performance.

OBJECTIVE: Determine which mechanisms, such as order processing, are responsible for deficient WM functioning in AD.

METHOD: A group of AD patients (n = 32) and their partners (n = 25), assigned to the control group, were submitted to an extensive battery of neuropsychological and experimental tasks, assessing general cognitive state and functioning of several aspects related to serial order WM.

RESULTS: The results revealed an impaired ability to bind item information to serial position within WM in AD patients compared to controls. It was additionally observed that AD patients experienced specific difficulties with directing spatial attention when searching for item information stored in WM.

CONCLUSION: The processing of serial order and the allocation of attentional resources are both disrupted, explaining the generally reduced WM functioning in AD patients. Further studies should now clarify whether this observation could explain disease-related problems for other cognitive functions such as verbal expression, auditory comprehension, or planning.

%B J Alzheimers Dis %V 59 %P 1171-1186 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731436?dopt=Abstract %R 10.3233/JAD-170193 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Implication of the APP Gene in Intellectual Abilities. %A Myrum, Craig %A Nikolaienko, Oleksii %A Bramham, Clive R %A Haavik, Jan %A Zayats, Tetyana %X

BACKGROUND: Cognitive functions are highly heritable and polygenic, though the source of this genetic influence is unclear. On the neurobiological level, these functions rely on effective neuroplasticity, in which the activity-regulated cytoskeleton associated protein (ARC) plays an essential role.

OBJECTIVES: To examine whether the ARC gene complex may contribute to the genetic components of intellectual function given the crucial role of ARC in brain plasticity and memory formation.

METHODS: The ARC complex was tested for association with intelligence (IQ) in children from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 5,165). As Alzheimer's disease (AD) shares genetics with cognitive functioning, the association was followed up in an AD sample (17,008 cases, 37,154 controls).

RESULTS: The ARC complex revealed association with verbal and total IQ (empirical p = 0.027 and 0.041, respectively) in the ALSPAC. The strongest single variant signal (rs2830077; empirical p = 0.018), within the APP gene, was confirmed in the AD sample (p = 2.76E-03). Functional analyses of this variant showed its preferential binding to the transcription factor CP2.

DISCUSSION: This study implicates APP in childhood IQ. While follow-up studies are needed, this observation could help elucidate the etiology of disorders associated with cognitive dysfunction, such as AD.

%B J Alzheimers Dis %V 59 %P 723-735 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671113?dopt=Abstract %R 10.3233/JAD-170049 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Improved Brain Insulin/IGF Signaling and Reduced Neuroinflammation with T3D-959 in an Experimental Model of Sporadic Alzheimer's Disease. %A de la Monte, Suzanne M %A Tong, Ming %A Schiano, Irio %A Didsbury, John %X

BACKGROUND: Alzheimer's disease (AD) is associated with progressive impairments in brain insulin, insulin-like growth factor (IGF), and insulin receptor substrate (IRS) signaling through Akt pathways that regulate neuronal growth, survival, metabolism, and plasticity. The intracerebral streptozotocin (i.c. STZ) model replicates the full range of abnormalities in sporadic AD. T3D-959, an orally active PPAR-delta/gamma agonist remediates neurocognitive deficits and AD neuropathology in the i.c. STZ model.

OBJECTIVE: This study characterizes the effects of T3D-959 on AD biomarkers, insulin/IGF/IRS signaling through Akt pathways, and neuroinflammation in an i.c. STZ model.

METHODS: Long Evans rats were treated with i.c. STZ or saline, followed by daily oral doses of T3D-959 (1 mg/kg) or saline initiated 1 day (T3D-959-E) or 7 days (T3D-959-L) later through Experimental Day 28. Protein and phospho-protein expression and pro-inflammatory cytokine activation were measured in temporal lobe homogenates by duplex or multiplex bead-based ELISAs.

RESULTS: i.c. STZ treatments caused neurodegeneration with increased pTau, AβPP, Aβ42, ubiquitin, and SNAP-25, and reduced levels of synaptophysin, IGF-1 receptor (R), IRS-1, Akt, p70S6K, mTOR, and S9-GSK-3β. i.c. STZ also broadly increased neuroinflammation. T3D-959 abrogated or reduced most of the AD neuropathological and biomarker abnormalities, increased/normalized IGF-1R, IRS-1, Akt, p70S6K, and S9-GSK-3β, and decreased expression of multiple pro-inflammatory cytokines. T3D-959-E or -L effectively restored insulin/IGF signaling, whereas T3D-959-L more broadly resolved neuroinflammation.

CONCLUSION: AD remediating effects of T3D-959 are potentially due to enhanced expression of key insulin/IGF signaling proteins and inhibition of GSK-3β and neuroinflammation. These effects lead to reduced neurodegeneration, cognitive impairment, and AD biomarker levels in the brain.

%B J Alzheimers Dis %V 55 %P 849-864 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802237?dopt=Abstract %R 10.3233/JAD-160656 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes. %A van Waalwijk van Doorn, Linda J C %A Gispert, Juan D %A Kuiperij, H Bea %A Claassen, Jurgen A H R %A Arighi, Andrea %A Baldeiras, Ines %A Blennow, Kaj %A Bozzali, Marco %A Castelo-Branco, Miguel %A Cavedo, Enrica %A Emek-Savaş, Derya D %A Eren, Erden %A Eusebi, Paolo %A Farotti, Lucia %A Fenoglio, Chiara %A Ormaechea, Juan Fortea %A Freund-Levi, Yvonne %A Frisoni, Giovanni B %A Galimberti, Daniela %A Genc, Sermin %A Greco, Viviana %A Hampel, Harald %A Herukka, Sanna-Kaisa %A Liu, Yawu %A Lladó, Albert %A Lleo, Alberto %A Nobili, Flavio M %A Oguz, Kader K %A Parnetti, Lucilla %A Pereira, João %A Picco, Agnese %A Pikkarainen, Maria %A de Oliveira, Catarina Resende %A Saka, Esen %A Salvadori, Nicola %A Sánchez-Valle, Raquel %A Santana, Isabel %A Scarpini, Elio %A Scheltens, Philip %A Soininen, Hilkka %A Tarducci, Roberto %A Teunissen, Charlotte %A Tsolaki, Magda %A Urbani, Andrea %A Vilaplana, Eduard %A Visser, Pieter Jelle %A Wallin, Asa K %A Yener, Görsev %A Molinuevo, José L %A Meulenbroek, Olga %A Verbeek, Marcel M %X

Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r = -0.28; p < 0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r = -0.15; p-tau: r = -0.13; both p < 0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aβ42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.

%B J Alzheimers Dis %V 56 %P 543-555 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059783?dopt=Abstract %R 10.3233/JAD-160668 %0 Journal Article %J J Alzheimers Dis %D 2017 %T An Improved Drugs Screening System Reveals that Baicalein Ameliorates the Aβ/AMPA/NMDA-Induced Depolarization of Neurons. %A Lin, Tian-Syuan %A Tsai, Han-Jung %A Lee, Chih-Han %A Song, Yan-Qing %A Huang, Rih-Sheng %A Hsieh-Li, Hsiu-Mei %A Liang, Mei-Chih %A Lin, Yenshou %X

The presence of amyloid-β (Aβ) plaque and tau protein hyperphosphorylation in brain tissue is the pathological hallmark of Alzheimer's disease (AD). At least some Aβ neurotoxicity is caused by the presence of excess glutamate that has been induced by Aβ accumulation. Memantine is currently the only NMDA receptor inhibitor approved for treating moderate-to-severe AD patients. We utilized primary cortical neurons and DiBAC4(3), a slow-response voltage sensitive fluorescence dye, to create a novel system for screening herbal medicines that allows the identification of pure compounds able to ameliorate Aβ-induced abnormal depolarization. The intensity of DiBAC4(3) fluorescence was increased when primary neurons were stimulated by Aβ; furthermore, pre-treatment with memantine abolished this change. Using this system, we identified six crude extracts made from herbal medicines that effectively alleviated this Aβ-induced abnormal depolarization. Among these herbal medicines, one pure compound, baicalein, which was known to be present in Scutellaria baricalensis and is known to improve memory using an AD mouse model, was identified by our assay. However, the compound's molecular mechanism remained unknown. We found that baicalein, in addition to inhibiting Aβ-induced depolarization, possibly functions as an antagonist of AMPA and NMDA receptors. Taken together, we have established a system/platform to identify herbal medicines that ameliorate Aβ-induced depolarization of neurons. Equally important, baicalein is a candidate drug with great potential for the treatment of AD patients.

%B J Alzheimers Dis %V 56 %P 959-976 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106556?dopt=Abstract %R 10.3233/JAD-160898 %0 Journal Article %J J Alzheimers Dis %D 2017 %T In Vivo Detection of Gray Matter Neuropathology in the 3xTg Mouse Model of Alzheimer's Disease with Diffusion Tensor Imaging. %A Snow, Wanda M %A Dale, Ryan %A O'Brien-Moran, Zoe %A Buist, Richard %A Peirson, Danial %A Martin, Melanie %A Albensi, Benedict C %X

A diagnosis of Alzheimer's disease (AD), a neurodegenerative disorder accompanied by severe functional and cognitive decline, is based on clinical findings, with final confirmation of the disease at autopsy by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles. Given that microstructural brain alterations occur years prior to clinical symptoms, efforts to detect brain changes early could significantly enhance our ability to diagnose AD sooner. Diffusion tensor imaging (DTI), a type of MRI that characterizes the magnitude, orientation, and anisotropy of the diffusion of water in tissues, has been used to infer neuropathological changes in vivo. Its utility in AD, however, is still under investigation. The current study used DTI to examine brain regions susceptible to AD-related pathology; the cerebral cortex, entorhinal cortex, and hippocampus, in 12-14-month-old 3xTg AD mice that possess both Aβ plaques and neurofibrillary tangles. Mean diffusivity did not differ between 3xTg and control mice in any region. Decreased fractional anisotropy (p < 0.01) and axial diffusivity (p < 0.05) were detected only in the hippocampus, in which both congophilic Aβ plaques and hyperphosphorylated tau accumulation, consistent with neurofibrillary tangle formation, were detected. Pathological tau accumulation was seen in the cortex. The entorhinal cortex was largely spared from AD-related neuropathology. This is the first study to demonstrate DTI abnormalities in gray matter in a mouse model of AD in which both pathological hallmarks are present, suggesting the feasibility of DTI as a non-invasive means of detecting brain pathology in vivo in early-stage AD.

%B J Alzheimers Dis %V 58 %P 841-853 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505976?dopt=Abstract %R 10.3233/JAD-170136 %0 Journal Article %J J Alzheimers Dis %D 2017 %T In vivo Patterns of Tau Pathology, Amyloid-β Burden, and Neuronal Dysfunction in Clinical Variants of Alzheimer's Disease. %A Dronse, Julian %A Fliessbach, Klaus %A Bischof, Gérard N %A von Reutern, Boris %A Faber, Jennifer %A Hammes, Jochen %A Kuhnert, Georg %A Neumaier, Bernd %A Onur, Oezguer A %A Kukolja, Juraj %A van Eimeren, Thilo %A Jessen, Frank %A Fink, Gereon R %A Klockgether, Thomas %A Drzezga, Alexander %X

The clinical heterogeneity of Alzheimer's disease is not reflected in the rather diffuse cortical deposition of amyloid-β. We assessed the relationship between clinical symptoms, in vivo tau pathology, amyloid distribution, and hypometabolism in variants of Alzheimer's disease using novel multimodal PET imaging techniques. Tau pathology was primarily observed in brain regions related to clinical symptoms and overlapped with areas of hypometabolism. In contrast, amyloid-β deposition was diffusely distributed over the entire cortex. Tau PET imaging may thus serve as a valuable biomarker for the localization of neuronal injury in vivo and may help to validate atypical subtypes of Alzheimer's disease.

%B J Alzheimers Dis %V 55 %P 465-471 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802224?dopt=Abstract %R 10.3233/JAD-160316 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Incident Cerebral Microbleeds Detected by Susceptibility Weight-Imaging Help to Identify Patients with Mild Cognitive Impairment Progressing to Alzheimer's Disease. %A Basselerie, Hubert %A Bracoud, Luc %A Zeestraten, Eva %A Bouguen, Eva %A Kiyasova, Vera %A Pueyo, Maria %A Cognard, Christophe %A Dumas, Hervé %A Gramada, Raluca %A Ousset, Pierre Jean %A Vellas, Bruno %A Bonneville, Fabrice %X

BACKGROUND: The relationship between cerebral microbleeds (CMB) and Alzheimer's disease (AD) has not yet been clearly determined, particularly with susceptibility weight-imaging (SWI).

OBJECTIVE: To evaluate the SWI sequence using 3T MRI for the detection of CMB, and its ability to differentiate elderly control subjects (CS), stable mild cognitive impairment patients (MCI-s), MCI patients progressing to AD (MCI-p), and AD patients.

METHODS: It was a prospective, monocentric, observational study that took place in Toulouse, France. Participants were 65 years and older, enrolled in three groups: CS, MCI, and AD. Based on the longitudinal analysis of cognitive decline, MCI subjects were retrospectively classified as MCI-s or MCI-p. Each patient had a 4-year follow-up with MRI at baseline (MRI#1) and during the fourth year (MRI#3). CMB were counted on native SWI images juxtaposed to minIP reformatted images.

RESULTS: 150 patients were enrolled: 48 CS, 25 MCI-s, 18 MCI-p, 59 AD. At MRI#1 and at MRI#3, there was no significant difference in the prevalence of CMB between groups (p = 0.75 and p = 0.87). In the MCI-p + AD group, significantly more subjects had≥4 incident CMB compared to the CS + MCI-s group (p = 0.016). In the MCI-p + AD group, the prevalence of patients with >4 CMB was significantly higher at MRI#3 than at MRI#1 (p = 0.008).

CONCLUSION: Using SWI, AD and MCI-p patients had developed significantly more new CMB than CS and MCI-s patients during the follow-up. Incident CMB might be suggested as a potential imaging marker of AD progression.

%B J Alzheimers Dis %V 60 %P 253-262 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826188?dopt=Abstract %R 10.3233/JAD-170470 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Increased Carbohydrate Intake is Associated with Poorer Performance in Verbal Memory and Attention in an APOE Genotype-Dependent Manner. %A Gardener, Samantha L %A Rainey-Smith, Stephanie R %A Sohrabi, Hamid R %A Weinborn, Michael %A Verdile, Giuseppe %A Fernando, W M A D Binosha %A Lim, Yen Ying %A Harrington, Karra %A Burnham, Samantha %A Taddei, Kevin %A Masters, Colin L %A Macaulay, Stuart L %A Rowe, Christopher C %A Ames, David %A Maruff, Paul %A Martins, Ralph N %X

Evidence suggests that a diet low in carbohydrates can impact on cognitive performance among those with Alzheimer's disease (AD). However, there is a lack of data assessing this relationship among cognitively normal (CN) older adults at increased future risk of developing AD due to carriage of the apolipoprotein E (APOE) ɛ4 allele. We assessed the cross-sectional association between carbohydrate intake, cognitive performance, and cerebral amyloid-β (Aβ) load in CN older adults, genotyped for APOEɛ4 allele carrier status. Greater carbohydrate intake was associated with poorer performance in verbal memory in APOEɛ4 allele non-carriers, and poorer performance in attention in APOEɛ4 allele carriers. There were no associations between carbohydrate intake and cerebral Aβ load. These results provide support to the idea that decreasing carbohydrate intake may offer neurocognitive benefits, with specific cognitive domains affected in an APOE genotype-dependent manner. These findings warrant further investigation utilizing a longitudinal study design.

%B J Alzheimers Dis %V 58 %P 193-201 %G eng %N 1 %R 10.3233/JAD-161158 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Increased PCSK9 Cerebrospinal Fluid Concentrations in Alzheimer's Disease. %A Zimetti, Francesca %A Caffarra, Paolo %A Ronda, Nicoletta %A Favari, Elda %A Adorni, Maria Pia %A Zanotti, Ilaria %A Bernini, Franco %A Barocco, Federica %A Spallazzi, Marco %A Galimberti, Daniela %A Ricci, Chiara %A Ruscica, Massimiliano %A Corsini, Alberto %A Ferri, Nicola %X

BACKGROUND: Alzheimer's disease (AD) has been associated with dysregulation of brain cholesterol trafficking and abnormal production of apolipoprotein E isoform 4 (apoE4). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein present in serum and cerebrospinal fluid (CSF) degrading the low-density lipoprotein receptor (LDLr) and other apoE-binding receptors involved in neuron cholesterol uptake. The role of PCSK9 in AD is controversial.

OBJECTIVE: We compared PCSK9 levels in CSF of AD patients and non-AD controls and looked at correlations with CSF total apoE and apoE4.

METHODS: CSF from AD (n = 30) and from age and sex-matched non-AD patients (n = 30) was collected by lumbar puncture for routine diagnosis. CSF PCSK9, total apoE, and apoE4 levels were measured by ELISA. AD patients showed the typical CSF neurobiomarker pattern (decreased Aβ42 and increased tau and phospho-tau) and impaired cognitive performances, as indicated by the scores of the Mini-Mental State Examination test.

RESULTS: PCSK9 levels in CSF were higher in AD than in non-AD subjects (+1.45 fold; p = 0.0049). CSF total apoE concentrations did not differ between the two groups, while apoE4 levels were higher in AD subjects (+3.34 fold; p = 0.0068). Considering all samples, a significant positive correlation was found between PCSK9 and apoE4 (r = 0.4409; p = 0.0006). PCSK9 levels were higher in APOE ɛ4 carriers, reaching statistical significance in the AD group (+1.45 fold; p = 0.0454).

CONCLUSION: These results report for the first time an alteration of CSF PCSK9 levels in AD and suggest a pathophysiological link between PCSK9, apoE4, and AD.

%B J Alzheimers Dis %V 55 %P 315-320 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662294?dopt=Abstract %R 10.3233/JAD-160411 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Increased Plasma Homocysteine Level is Associated with Executive Dysfunction in Type 2 Diabetic Patients with Mild Cognitive Impairment. %A Tian, Sai %A Han, Jing %A Huang, Rong %A Sun, Jie %A Cai, Rongrong %A Shen, Yanjue %A Wang, Shaohua %X

BACKGROUND: Homocysteine (Hcy) is involved in the pathogenesis of type 2 diabetes mellitus (T2DM) and Alzheimer's disease.

OBJECTIVE: We aimed to investigate the role of Hcy in T2DM patients with mild cognitive impairment (MCI), and to determine whether methylene tetrahydrofolate reductase (MTHFR) C677T or cystathionine beta-synthase (CBS) 844ins68 polymorphism is related to T2DM-associated MCI.

METHODS: We recruited 285 T2DM patients and divided them into two groups, 140 patients with MCI, and 145 healthy-cognition controls, on the basis of Montreal Cognitive Assessment (MoCA) scores. Demographic characteristics, clinical parameters, and neuropsychological tests were assessed. MTHFR C677T and CBS 844ins68 polymorphisms were analyzed.

RESULTS: The MCI group exhibited significantly higher plasma total Hcy (tHcy) levels than control group (p < 0.001). Plasma tHcy level was negatively correlated with MoCA scores (p = 0.002), but positively associated with Trail Making Test A and B scores (p = 0.044; p = 0.005, respectively). Multivariable logistic regression model showed that high tHcy level was an independent factor for MCI in T2DM patients. No significant difference was observed in the genotype or allele distributions of MTHFR and CBS between MCI and control groups. We did not find significant MCI risks in MTHFR T allele compared with C allele, and in CBS I allele compared with D allele (OR = 1.361, p = 0.067; OR = 1.048, p = 0.909, respectively).

CONCLUSION: Increased plasma tHcy level was significantly related to T2DM-associated MCI, especially executive dysfunction. Further investigation with a large population size should be conducted to confirm these findings.

%B J Alzheimers Dis %V 58 %P 1163-1173 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550262?dopt=Abstract %R 10.3233/JAD-170162 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Increased Release of Apolipoprotein E in Extracellular Vesicles Following Amyloid-β Protofibril Exposure of Neuroglial Co-Cultures. %A Nikitidou, Elisabeth %A Khoonsari, Payam Emami %A Shevchenko, Ganna %A Ingelsson, Martin %A Kultima, Kim %A Erlandsson, Anna %X

Extracellular vesicles (EVs), including exosomes and larger microvesicles, have been implicated to play a role in several conditions, including Alzheimer's disease (AD). Since the EV content mirrors the intracellular environment, it could contribute with important information about ongoing pathological processes and may be a useful source for biomarkers, reflecting the disease progression. The aim of the present study was to analyze the protein content of EVs specifically released from a mixed co-culture of primary astrocytes, neurons, and oligodendrocytes treated with synthetic amyloid-β (Aβ42) protofibrils. The EV isolation was performed by ultracentrifugation and validated by transmission electron microscopy. Mass spectrometry analysis of the EV content revealed a total of 807 unique proteins, of which five displayed altered levels in Aβ42 protofibril exposed cultures. The most prominent protein was apolipoprotein E (apoE), and by western blot analysis we could confirm a threefold increase of apoE in EVs from Aβ42 protofibril exposed cells, compared to unexposed cells. Moreover, immunoprecipitation studies demonstrated that apoE was primarily situated inside the EVs, whereas immunocytochemistry indicated that the EVs most likely derived from the astrocytes and the neurons in the culture. The identified Aβ-induced sorting of apoE into EVs from cultured neuroglial cells suggests a possible role for intercellular transfer of apoE in AD pathology and encourage future studies to fully elucidate the clinical relevance of this event.

%B J Alzheimers Dis %V 60 %P 305-321 %G eng %N 1 %R 10.3233/JAD-170278 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Increased Serum miR-206 Level Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer's Disease: A 5-Year Follow-up Study. %A Xie, Bing %A Liu, Zanchao %A Jiang, Lei %A Liu, Wei %A Song, Mei %A Zhang, Qingfu %A Zhang, Rui %A Cui, Dongsheng %A Wang, Xueyi %A Xu, Shunjiang %X

Evidence suggests that individuals with amnestic mild cognitive impairment (aMCI) tend to progress to probable Alzheimer's disease (AD) with aging. This study was performed to examine whether circulating miRNAs could be potential predictors for the progression of aMCI to AD. A total of 458 patients with aMCI were included in this study, and the clinical data were collected at two time points: the baseline and the follow-up assessment. These aMCI patients were classified into two groups after 5 years: aMCI-stable group (n = 330) and AD-conversion group (n = 128). The expression of miR-206 and miR-132 and the levels of BDNF and SIRT1 in serum were detected using a quantitative real-time RT-PCR (qPCR) and the ELISA method, respectively. Kaplan-Meier method (Log-rank test) was used for univariate survival analysis. Cox proportional hazard model was used to estimate the prognostic value of miRNAs in conversion from aMCI to AD. At the baseline, serum levels of miR-206 in aMCI-AD group were significantly elevated compared to aMCI-aMCI group and the same trend was found at 5-year follow-up time point as well. There were no significant differences in serum levels of miR-132 between the conversion and non-conversion group at both time points. Kaplan-Meier analysis showed significant correlation between AD conversion and higher serum levels of miR-206 for aMCI patients (HR = 3.60, 95% CI: 2.51- 5.36, p < 0.001). Multivariate Cox regression analysis revealed that serum miR-206 and its target BDNF were significant independent predictors for AD conversion (HR = 4.22, p < 0.001). These results suggested that increased serum miR-206 level might be a potential predictor of conversion from aMCI to AD.

%B J Alzheimers Dis %V 55 %P 509-520 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662297?dopt=Abstract %R 10.3233/JAD-160468 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Increased Transforming Growth Factor β2 in the Neocortex of Alzheimer's Disease and Dementia with Lewy Bodies is Correlated with Disease Severity and Soluble Aβ42 Load. %A Chong, Joyce R %A Chai, Yuek Ling %A Lee, Jasinda H %A Howlett, David %A Attems, Johannes %A Ballard, Clive G %A Aarsland, Dag %A Francis, Paul T %A Chen, Christopher P %A Lai, Mitchell K P %X

BACKGROUND: Of the three transforming growth factor (TGF)-β isoforms known, TGFβ1 deficits have been widely reported in Alzheimer's disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGFβ2, which has been shown to mediate amyloid-β (Aβ)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden.

OBJECTIVE: To measure neocortical TGFβ2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), known to manifest relatively high and low Aβ plaque burden, respectively.

METHODS: Postmortem samples from temporal cortex (BA21) were measured for TGFβ2 using a Luminex-based platform, and correlated with scores for neuritic plaques, neurofibrillary tangles, α-synuclein pathology, dementia severity (as measured by annual decline of Mini-Mental State Examination scores) as well as soluble and total fractions of brain Aβ42.

RESULTS: TGFβ2 was significantly increased in AD and DLB, but not in PDD. TGFβ2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble Aβ42 concentration, but not with neuritic plaque scores, total Aβ42, or monomeric α-synuclein immunoreactivity.

CONCLUSIONS: TGFβ2 is increased in the temporal cortex of AD and DLB, and its correlations with neuropathological and clinical markers of disease severity as well as with soluble Aβ42 load suggest a potential pathogenic role in mediating the neurotoxicity of non-fibrillar Aβ. Our study also indicates the potential utility of targeting TGFβ2 in pharmacotherapeutic approaches to AD and DLB.

%B J Alzheimers Dis %V 56 %P 157-166 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911312?dopt=Abstract %R 10.3233/JAD-160781 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Increasing Body Mass Index at Midlife is Associated with Increased Cortical Thinning in Alzheimer's Disease-Vulnerable Regions. %A Shaw, Marnie E %A Abhayaratna, Walter P %A Anstey, Kaarin J %A Cherbuin, Nicolas %X

Higher body mass index (BMI) at midlife is associated with greater decreases in cognitive function at older age as well as increased Alzheimer's disease (AD) risk, compared to those with normal BMI. Here, we tested whether BMI at midlife was associated with cortical thinning in brain regions known to be affected in early AD. We examined a large sample (n = 404) of midlife individuals (44-49 years) from the PATH population-based study. Individuals were scanned with magnetic resonance imaging (1.5T) on up to three occasions over eight years. Change in cortical thickness was modeled as a linear function of BMI and change in BMI longitudinally. Being obese was associated with thinner right frontal cortex at baseline (44-49 years). Across all individuals, increasing BMI over the 8-year study period was associated with increased cortical thinning in posterior cingulate bilaterally, as well as right lingual gyrus, anterior cingulate, and the peri-calcarine sulcus. Accelerated age-related cortical atrophy at midlife, particularly in posterior cingulate, is consistent with increased risk of AD in individuals with high BMI at this age. The findings suggest that management of body weight at midlife could reduce the risk of AD.

%B J Alzheimers Dis %V 59 %P 113-120 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550257?dopt=Abstract %R 10.3233/JAD-170055 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Individual Correspondence of Amyloid-β and Intrinsic Connectivity in the Posterior Default Mode Network Across Stages of Alzheimer's Disease. %A Pasquini, Lorenzo %A Benson, Gloria %A Grothe, Michel J %A Utz, Lukas %A Myers, Nicholas E %A Yakushev, Igor %A Grimmer, Timo %A Scherr, Martin %A Sorg, Christian %X

In Alzheimer's disease (AD), amyloid-β (Aβ) pathology and intrinsic functional connectivity (iFC) interact. Across stages of AD, we expected individual spatial correspondence of Aβ and iFC to reveal both Aβ accumulation and its detrimental effects on iFC. We used resting-state functional magnetic imaging and Aβ imaging in a cross-sectional sample of 90 subjects across stages of AD and healthy older adults. Global and local correspondence of Aβ and iFC were assessed within the posterior default mode network (pDMN) by within-subject voxel-wise correlations. Beginning at preclinical stages, global Aβ-iFC correspondence was positive for the whole pDMN, showing that Aβ accumulates in areas of high connectivity, and reached a plateau at prodromal stages. Starting at preclinical stages, local correspondence was negative in network centers, indicating that Aβ reduces connectivity of the pDMN as a function of local plaque concentration, and peaked at prodromal stages. Positive global correspondence suggests that Aβ accumulation progresses along iFC, with this effect starting in preclinical stages, and being constant along clinical periods. Negative local correspondence suggests detrimental effects of Aβ on iFC in network centers, starting at preclinical stages, and peaking when first symptoms appear. Data reveal a complex trajectory of Aβ and iFC correspondence, affecting both Aβ accumulation and iFC impairments.

%B J Alzheimers Dis %V 58 %P 763-773 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28482640?dopt=Abstract %R 10.3233/JAD-170096 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Inflammation, Amyloid, and Atrophy in The Aging Brain: Relationships with Longitudinal Changes in Cognition. %A Sala-Llonch, Roser %A Idland, Ane-Victoria %A Borza, Tom %A Watne, Leiv Otto %A Wyller, Torgeir Bruun %A Brækhus, Anne %A Zetterberg, Henrik %A Blennow, Kaj %A Walhovd, Kristine Beate %A Fjell, Anders Martin %X

Amyloid deposition occurs in aging, even in individuals free from cognitive symptoms, and is often interpreted as preclinical Alzheimer's disease (AD) pathophysiology. YKL-40 is a marker of neuroinflammation, being increased in AD, and hypothesized to interact with amyloid-β (Aβ) in causing cognitive decline early in the cascade of AD pathophysiology. Whether and how Aβ and YKL-40 affect brain and cognitive changes in cognitively healthy older adults is still unknown. We studied 89 participants (mean age: 73.1 years) with cerebrospinal fluid samples at baseline, and both MRI and cognitive assessments from two time-points separated by two years. We tested how baseline levels of Aβ42 and YKL-40 correlated with changes in cortical thickness and cognition. Thickness change correlated with Aβ42 only in Aβ42+ participants (<600 pg/mL, n = 27) in the left motor and premotor cortices. Aβ42 was unrelated to cognitive change. Increased YKL-40 was associated with less preservation of scores on the animal naming test in the total sample (r = -0.28, p = 0.012) and less preservation of a score reflecting global cognitive function for Aβ42+ participants (r = -0.58, p = 0.004). Our results suggest a role for inflammation in brain atrophy and cognitive changes in cognitively normal older adults, which partly depended on Aβ accumulation.

%B J Alzheimers Dis %V 58 %P 829-840 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505968?dopt=Abstract %R 10.3233/JAD-161146 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Inflection Point in Course of Mild Cognitive Impairment: Increased Functional Connectivity of Default Mode Network. %A Tao, Wuhai %A Li, Xin %A Zhang, Junying %A Chen, Yaojing %A Ma, Chao %A Liu, Zhen %A Yang, Caishui %A Wang, Wenxiao %A Chen, Kewei %A Wang, Jun %A Zhang, Zhanjun %X

The alteration of the default mode network (DMN) functional connectivity (FC) has been reported in patients with amnestic mild cognitive impairment (aMCI) as a predictor of Alzheimer's disease (AD). However, no studies exist that examined stage-dependent DMN FC changes throughout the course of aMCI. The present study aims to characterize patterns of DMN FC over three aMCI stages as first defined. Utilizing the extreme groups approach on the performance of memory tasks, aMCI subjects were divided into mild, moderate, and severe stages. Independent component analysis was used to assess DMN for individual patients in each of the three cross-sectionally defined stages. Instead of finding that continued monotonic decline was the case for the hippocampus volume, which we also investigated in this study, we observed an increase in DMN functional connectivity from mild aMCI to moderate aMCI and a decrease to severe aMCI, mainly in the left precuneus and superior parietal lobe. Moreover, the FC was significantly associated with cognitive performance. Though a longitudinal study is needed to confirm these results, our cross-sectional finding is that non-linear FC changes in DMN could be a characteristic of prodromal early disease development.

%B J Alzheimers Dis %V 60 %P 679-690 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869465?dopt=Abstract %R 10.3233/JAD-170252 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Information and Communication Technologies for the Activities of Daily Living in Older Patients with Dementia: A Systematic Review. %A D'Onofrio, Grazia %A Sancarlo, Daniele %A Ricciardi, Francesco %A Panza, Francesco %A Seripa, Davide %A Cavallo, Filippo %A Giuliani, Francesco %A Greco, Antonio %K Activities of Daily Living %K Aging %K Databases, Bibliographic %K Dementia %K Humans %K Medical Informatics %K Self-Help Devices %X

BACKGROUND: Significant innovations have been introduced in recent years in the application of information and communication technologies (ICTs) to support healthcare for patients with dementia.

OBJECTIVE: In the present systematic review, our goal is to keep track of ICT concepts and approaches to support the range of activities of daily living for people with dementia and to provide a snapshot of the effect that technology is having on patients' self-reliance.

METHODS: We reviewed the literature and identified systematic reviews of cohort studies and other authoritative reports. Our selection criteria included: (1) activities of daily living, (2) ICT, and (3) dementia.

RESULTS: We identified 56 studies published between 2000 and 2015, of which 26 met inclusion criteria. The present systematic review revealed many ICT systems that could purportedly support the range of activities of daily living for patients with dementia. The results showed five research bodies: 1) technologies used by patients with dementia, 2) technologies used by caregivers, 3) monitoring systems, 4) ambient assistive living with ICTs, and 5) tracking and wayfinding.

CONCLUSIONS: There is a potential for ICTs to support dementia care at home and to improve quality of life for caregivers, reducing healthcare costs and premature institutional care for these patients.

%B J Alzheimers Dis %V 57 %P 927-935 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304297?dopt=Abstract %R 10.3233/JAD-161145 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Initial Heart Rate Reactivity to Socioemotional Pictures in Early-Onset Alzheimer's Disease. %A Joshi, Aditi %A Jimenez, Elvira %A Mendez, Mario F %X

Patients with Alzheimer's disease (AD) often have generalized anxiety, particularly in early-onset AD (EOAD) or the first stages of their disease. This increased anxiety could be associated with decreased sensorimotor gating with increased attention to significant stimuli from AD pathology in the entorhinal cortex. We investigated whether widening initial attention to socioemotional stimuli was association with anxiety among 16 patients with first stage EOAD compared to 19 normal controls (NCs). The participants underwent assessment of their initial heart rate deceleration ("orienting response"; OR), a measure of attentional refocusing, to pictures (International Affective Picture Stimuli) varying in pleasant-unpleasant valence and social-nonsocial content. The results showed group differences; the EOAD patients had significantly larger ORs than the NCs across conditions, with larger ORs in each valence and social condition. In addition, the EOAD patients, but not the NCs, showed ORs to normally less threatening stimuli, particularly pleasant, but also less significantly, social stimuli. On the Neuropsychiatric Inventory, the ORs among the EOAD patients significantly correlated with anxiety scores. Together, these findings suggest that anxiety in mild EOAD may be associated with widening attentional refocusing to socioemotional stimuli, possibly reflecting decreased sensorimotor gating in the entorhinal cortex. This finding could be a potential biomarker for the first stages of AD.

%B J Alzheimers Dis %V 60 %P 1325-1332 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036817?dopt=Abstract %R 10.3233/JAD-170319 %0 Journal Article %J J Alzheimers Dis %D 2017 %T INPP5D mRNA Expression and Cognitive Decline in Japanese Alzheimer's Disease Subjects. %A Yoshino, Yuta %A Yamazaki, Kiyohiro %A Ozaki, Yuki %A Sao, Tomoko %A Yoshida, Taku %A Mori, Takaaki %A Mori, Yoko %A Ochi, Shinichiro %A Iga, Jun-Ichi %A Ueno, Shu-Ichi %X

Microglial dysfunction and inflammation have recently been shown to be related to the development of Alzheimer's disease (AD). Inositol polyphosphate-5-phosphatase (INPP5D) functions broadly as a negative regulator of immune signaling, and its locus was associated with development of AD in a large-scale genome-wide association study. Thus, we examined INPP5D mRNA expression and methylation rates of the CpG sites in the upstream region of INPP5D exon 1 in peripheral leukocytes in 50 AD and age- and sex-matched control subjects. INPP5D mRNA expression in AD subjects was significantly higher than that in control subjects (1.16±0.39 versus 1.0±0.23, p = 0.049) and was correlated with the Mini-Mental State Examination score (p = 0.002, r = 0.426) and the total score of the Alzheimer's Disease Assessment Scale (p < 0.001, r = -0.697). Methylation rates in the upstream region of INPP5D exon 1 were not significantly different between AD and control subjects (average rate: 3.5±3.0 versus 2.8±1.3, p = 0.551). Our results suggested that INPP5D mRNA expression was elevated in the early stage and decreased with cognitive decline in AD. INPP5D mRNA expression in leukocytes may be a useful biomarker for the early stage of AD.

%B J Alzheimers Dis %V 58 %P 687-694 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28482637?dopt=Abstract %R 10.3233/JAD-161211 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Insula and Inferior Frontal Gyrus' Activities Protect Memory Performance Against Alzheimer's Disease Pathology in Old Age. %A Lin, Feng %A Ren, Ping %A Lo, Raymond Y %A Chapman, Benjamin P %A Jacobs, Alanna %A Baran, Timothy M %A Porsteinsson, Anton P %A Foxe, John J %X

Apolipoprotein E (APOE) ɛ4 carriers and patients with amnestic mild cognitive impairment (MCI) have high risk of developing Alzheimer's disease (AD). The Scaffolding Theory of Aging and Cognition proposes that recruitment of additional frontal brain regions can protect cognition against aging. This thesis has yet to be fully tested in older adults at high risk for AD. In the present study, 75 older participants (mean age: 74 years) were included. Applying a voxel-wise approach, fractional amplitude of low-frequency fluctuations (fALFF) in resting-state functional neuroimaging data were analyzed as a function of APOEɛ4 status (carrier versus noncarrier) and clinical status (healthy control [HC] versus MCI) using a 2×2 analysis of covariance (ANCOVA). Measures of cognition and cerebrospinal fluid levels of amyloid- β were also obtained. Three frontal regions were identified with significant interaction effects using ANCOVA (corrected p < 0.01): left-insula, left-inferior frontal gyrus (IFG), and right-precentral gyrus. The HC/APOEɛ4 carrier group had significantly higher fALFF in all three regions than other groups. In the entire sample, for two regions (left insula and left IFG), a significant positive relationship between amyloid-β and memory was only observed among individuals with low fALFF. Our results suggest higher activity in frontal regions may explain being cognitively normal among a subgroup of APOEɛ4 carriers and protect against the negative impact of AD-associated pathology on memory. This is an observation with potential implications for AD therapeutics.

%B J Alzheimers Dis %V 55 %P 669-678 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716674?dopt=Abstract %R 10.3233/JAD-160715 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Insulin Resistance and Future Cognitive Performance and Cognitive Decline in Elderly Patients with Cardiovascular Disease. %A Lutski, Miri %A Weinstein, Galit %A Goldbourt, Uri %A Tanne, David %X

BACKGROUND: The role of insulin resistance (IR) in the pathogenesis of cognitive performance is not yet clear.

OBJECTIVE: To examine the associations between IR and cognitive performance and change in cognitive functions two decades later in individuals with cardiovascular disease with and without diabetes.

METHODS: A subset of 489 surviving patients (mean age at baseline 57.7±6.5 y) with coronary heart disease who previously participated in the secondary prevention Bezafibrate Infarction Prevention (BIP trial; 1990-1997), were included in the current neurocognitive study. Biochemical parameters including IR (using the homeostasis model of assessment; HOMA-IR) were measured at baseline. During 2004-2008, computerized cognitive assessment and atherosclerosis parameters were measured (T1; n = 558; mean age 72.6±6.4 years). A second cognitive assessment was performed during 2011-2013 (T2; n = 351; mean age 77.2±6.4 years). Cognitive function, overall and in specific domains, was assessed. We used linear regression models and linear mixed models to evaluate the differences in cognitive performance and decline, respectively.

RESULTS: Controlling for potential confounders, IR (top HOMA-IR quartile versus others) was associated with subsequent poorer cognitive performance overall (β= -4.45±Standard Error (SE) 1.54; p = 0.004) and on tests of memory and executive function among non-diabetic patients (β= -7.16±2.38; p = 0.003 and β= -3.33±1.84; p = 0.073, respectively). Moreover, among non-diabetic patients, IR was related to a greater decline overall (β= -0.17±0.06; p = 0.008), and in memory (β= -0.22±0.10; p = 0.024) and executive function (β= -0.19±0.08; p = 0.012). The observed associations did not differ after excluding subjects with prevalent stroke or dementia.

CONCLUSION: IR is related to subsequent poorer cognitive performance and greater cognitive decline among patients with cardiovascular disease with and without diabetes.

%B J Alzheimers Dis %V 57 %P 633-643 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304291?dopt=Abstract %R 10.3233/JAD-161016 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Integration of Multilocus Genetic Risk into the Default Mode Network Longitudinal Trajectory during the Alzheimer's Disease Process. %A Su, Fan %A Shu, Hao %A Ye, Qing %A Xie, Chunming %A Yuan, Baoyu %A Zhang, Zhijun %A Bai, Feng %X

The aim of the study was to investigate the cognitive significance of the changes in default mode network (DMN) during the process of Alzheimer's disease (AD) and the genetic basis that drives the alteration. Eighty-seven subjects with mild cognitive impairment (MCI) and 131 healthy controls (HC) were employed at baseline, and they had the genetic risk scores (GRS) based on the GWAS-validated AD-related top loci. Eleven MCIs who converted to AD (c-MCIs), 32 subjects who remained stable (nc-MCIs), and 56 HCs participated in the follow-up analyses after an average of 35 months. Decreased functional connectivity (FC) within temporal cortex was identified for MCIs at baseline, which was partially determined by the GRS; moreover, compensations may occur within the frontal-parietal brain to maintain relatively intact cognition. During the follow-ups, c-MCIs exhibited more FC declines within the prefrontal-parietal lobes and parahippocampal gyrus/hippocampus than the HCs and nc-MCIs. The GRS did not significantly vary among the three groups, whereas associations were identified at risky alleles and FC declines in all AD spectra. Interestingly, the influence of APOEɛ4 varied as the disease progressed; APOEɛ4 was associated with longitudinal FC decreases only for HCs in the single variance-based analyses and deteriorated DMN integration in nc-MCIs by combining the effects of other loci. However, the GRS without APOEɛ4 predicted FC decline for converters. It is suggested that the integration of multilocus genetic risk predicted the longitudinal trajectory of DMN and may be used as a clinical strategy to track AD progression.

%B J Alzheimers Dis %V 56 %P 491-507 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035927?dopt=Abstract %R 10.3233/JAD-160787 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Intelligent Assistive Technology for Alzheimer's Disease and Other Dementias: A Systematic Review. %A Ienca, Marcello %A Fabrice, Jotterand %A Elger, Bernice %A Caon, Maurizio %A Pappagallo, Alessandro Scoccia %A Kressig, Reto W %A Wangmo, Tenzin %X

Intelligent assistive technologies (IATs) have the potential of offering innovative solutions to mitigate the global burden of dementia and provide new tools for dementia care. While technological opportunities multiply rapidly, clinical applications are rare as the technological potential of IATs remains inadequately translated into dementia care. In this article, the authors present the results of a systematic review and the resulting comprehensive technology index of IATs with application in dementia care. Computer science, engineering, and medical databases were extensively searched and the retrieved items were systematically reviewed. For each IAT, the authors examined their technological type, application, target population, model of development, and evidence of clinical validation. The findings reveal that the IAT spectrum is expanding rapidly in volume and variety over time, and encompasses intelligent systems supporting various assistive tasks and clinical uses. At the same time, the results confirm the persistence of structural limitations to successful adoption including partial lack of clinical validation and insufficient focus on patients' needs. This index is designed to orient clinicians and relevant stakeholders involved in the implementation and management of dementia care across the current capabilities, applications, and limitations of IATs and to facilitate the translation of medical engineering research into clinical practice. In addition, a discussion of the major methodological challenges and policy implications for the successful and ethically responsible implementation of IAT into dementia care is provided.

%B J Alzheimers Dis %V 56 %P 1301-1340 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222516?dopt=Abstract %R 10.3233/JAD-161037 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Intensive 'Brain Training' Intervention Fails to Reduce Amyloid Pathologies or Cognitive Deficits in Transgenic Mouse Models of Alzheimer's Disease. %A Anderson, Maria %A Xu, Feng %A Ou-Yang, Ming-Hsuan %A Davis, Judianne %A Van Nostrand, William E %A Robinson, John K %X

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia in the elderly. Amyloid-β protein (Aβ) depositions in both the brain parenchyma and the cerebral vasculature are recognized as important pathological components that contribute to the cognitive impairments found in individuals with AD. Because pharmacological options have been minimally effective in treating cognitive impairment to date, interest in the development of preventative lifestyle intervention strategies has increased in the field. One controversial strategy, cognitive-specific stimulation, has been studied previously in human participants and has been widely commercialized in the form of 'brain-training games.' In the present study, we developed a highly controlled, isolated cognitive training intervention program for mice. Two transgenic mouse lines, one that develops Aβ deposition largely in brain parenchyma, and another in the cerebral microvasculature, progressed through a series of domain-specific tasks for an average of 4 months. Despite the high intensity and duration of the intervention, we found little evidence of positive benefits for AD amyloid pathologies and post-training cognitive testing in these two models. Taken together, these results support the current evidence in human studies that cognitive-specific stimulation does not lead to a measurable reduction in AD pathology or an improvement in general brain health.

%B J Alzheimers Dis %V 55 %P 1109-1121 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767989?dopt=Abstract %R 10.3233/JAD-160674 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Interactive Effects of Dementia Severity and Comorbidities on Medicare Expenditures. %A Zhu, Carolyn W %A Cosentino, Stephanie %A Ornstein, Katherine A %A Gu, Yian %A Andrews, Howard %A Stern, Yaakov %X

BACKGROUND: Few studies have examined how dementia and comorbidities may interact to affect healthcare expenditures.

OBJECTIVE: To examine whether effects of dementia severity on Medicare expenditures differed for individuals with different levels of comorbidities.

METHODS: Data are drawn from the Washington Heights-Inwood Columbia Aging Project (WHICAP). Comprehensive clinical assessments of dementia severity were systematically carried out at ∼18 month intervals. Dementia severity was measured by Clinical Dementia Rating (CDR). Comorbidities were measured by a modified Elixhauser comorbidities index. Generalized linear models examined effects of dementia severity, comorbidities, and their interactions on Medicare expenditures (1999-2010).

RESULTS: At baseline, 1,280 subjects were dementia free (CDR = 0, 66.4%), 490 had very mild dementia (CDR = 0.5, 25.4%), 108 had mild dementia (CDR = 1, 5.6%), and 49 had moderate/severe dementia (CDR = 2/3, 2.5%). Average annual Medicare expenditures for individuals with moderate/severe dementia were more than twice as high as those who were dementia free (CDR = 0: $9,108, CDR = 0.5/1: $11,664, CDR≥2: $19,604, p < 0.01). Expenditures were approximately 10 times higher among those with≥3 comorbidities than among those with no comorbidities ($2,612 for those with no comorbidities, to $6,109 for those with 1, $10,656 for those with 2, and $30,244 for those with≥3 comorbidities, p < 0.001). Dementia severity was associated with higher expenditures, but comorbidities were the most important predictor of expenditures. We did not find strong interaction effects between number of comorbidities and dementia severity.

CONCLUSIONS: Increasing dementia severity and higher comorbidities are associated with higher Medicare expenditures. Care of individuals with dementia should focus on management of comorbidities.

%B J Alzheimers Dis %V 57 %P 305-315 %G eng %N 1 %R 10.3233/JAD-161077 %0 Journal Article %J J Alzheimers Dis %D 2017 %T An International Comparative Study on Driving Regulations on People with Dementia. %A Kim, You Joung %A An, Hoyoung %A Kim, Binna %A Park, Young Shin %A Kim, Ki Woong %X

Over 40% of people with dementia drive, with a two to five times greater accident risk than controls. This has fueled public concerns about the risk of traffic accidents by drivers with dementia (DWD). We compared driving regulations on seniors and DWD between ten European and Asia-Pacific countries to identify key implications for national strategies. Moderate to severe dementia was a reason for driver's license revocation in all countries. However, regulations on mild dementia varied considerably, with most basing their decisions on severity, rather than simply the presence of dementia. Most used validated assessments, but responsibility for triggering the administrative process fell on drivers in some countries and on physicians in others. Administrations should consider the following when developing driving policies: 1) ideal regulations on DWD should ensure that restrictions are implemented only when needed; 2) fitness to drive should be assessed using validated instruments; 3) the use of processes that automatically initiate driving competency examinations following a diagnosis of dementia should be explored; and 4) restrictions should be delicately tailored to a range of driving competence levels, and assistive incentives compensating for lost driving privileges should be provided.

%B J Alzheimers Dis %V 56 %P 1007-1014 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059784?dopt=Abstract %R 10.3233/JAD-160762 %0 Journal Article %J J Alzheimers Dis %D 2017 %T An Intracellular Amyloid-β/AβPP Epitope Correlates with Neurodegeneration in those Neuronal Populations Early Involved in Alzheimer's Disease. %A Esquerda-Canals, Gisela %A Martí-Clúa, Joaquim %A Roda, Alejandro R %A Villegas, Sandra %X

The main histopathological hallmarks of Alzheimer's disease (AD) are the extracellular deposition of neuritic amyloid plaques, composed of amyloid-β (Aβ) peptide, and the intracellular accumulation of neurofibrillary tangles, composed of hyperphosphorylated tau. Both traits are emulated in the 3xTg-AD mouse model. Because the relevance of this model in the bibliography and the main role of Aβ in neuronal impairment, here we have detailed the brain Aβ/AβPP distribution to subsequently quantify cellular density and intracellular burden for specific neuronal populations in the early stages of the disease. 6E10 immunoreactivity was evident in the deep layers of the cerebral cortex, in the pyramidal cell layer of the hippocampus, in the basolateral amygdala nucleus, and in the deep cerebellar nuclei macroneurons; whereas the specific neuronal populations with decreased cellular density were the large pyramidal neurons from the layers V-VI in the cerebral cortex, the pyramidal neurons from the CA2-3 region in the hippocampus, and the large neurons from the basolateral nucleus in the amygdala, apart from the already reported deep cerebellar nuclei. Interestingly, we found a strong correlation between intracellular Aβ/AβPP burden and cellular density in all these populations. In addition, behavioral testing showed the functional consequences of such a neuronal depletion. Concretely, anxious-like behavior is manifested in the corner and open-field tests, as well as cognitive functions shown to be impaired in the novel object recognition test and Morris water maze paradigm. To our knowledge, this is the first deep characterization of the specific neuronal populations affected in the 3xTg-AD mouse model.

%B J Alzheimers Dis %V 59 %P 1079-1096 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697564?dopt=Abstract %R 10.3233/JAD-170218 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Intracerebroventricular Streptozotocin Induces Obesity and Dementia in Lewis Rats. %A Bloch, Konstantin %A Gil-Ad, Irit %A Vanichkin, Alexey %A Hornfeld, Shay Henry %A Koroukhov, Nickolay %A Taler, Michal %A Vardi, Pnina %A Weizman, Abraham %X

BACKGROUND: Animal models of dementia associated with metabolic abnormalities play an important role in understanding the bidirectional relationships between these pathologies. Rodent strains develop cognitive dysfunctions without alteration of peripheral metabolism following intracerebroventricular administration of streptozotocin (icv-STZ).

OBJECTIVE: We aimed to estimate the effect of icv-STZ on cognitive functions and peripheral metabolism in Lewis rats, which are rarely used for the induction of cognitive abnormalities.

METHODS: Inbred adult Lewis rats were treated with single icv-STZ (3 mg/kg). Cognitive functions were assessed using Morris water maze (MWM) test and locomotion by the Open Field test. Metabolic alterations were studied using histological and biochemical analysis of brain and peripheral tissues.

RESULTS: The icv-STZ induced rapid weight decline during the first two weeks. Thereafter, the rats showed an accelerated weight gain. Three months after the icv-STZ treatment, the rats were severely obese and revealed fatty liver, pancreatic islet hypertrophy, significantly elevated levels of blood insulin, leptin, and adiponectin, but intact peripheral glucose homeostasis. The icv-STZ rats expressed amyloid-β deposits in blood vessels of leptomeningeal area, microgliosis, astrogliosis, and spongiosis in fimbria-fornix area of hippocampus. Locomotor activities of icv-STZ treated and sham-operated rats were similar. In the MWM test, the icv-STZ treated rats demonstrated severely impaired spatial learning during both acquisition and reversal phases.

CONCLUSIONS: Icv-STZ treated Lewis rats develop severe dementia associated with obesity and peripheral metabolic abnormalities. This animal model may be useful for exploring the pathophysiological relationship between obesity and dementia and provides a new tool for development of effective therapy.

%B J Alzheimers Dis %V 60 %P 121-136 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28800326?dopt=Abstract %R 10.3233/JAD-161289 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Intracranial Arterial 4D Flow in Individuals with Mild Cognitive Impairment is Associated with Cognitive Performance and Amyloid Positivity. %A Berman, Sara E %A Clark, Lindsay R %A Rivera-Rivera, Leonardo A %A Norton, Derek %A Racine, Annie M %A Rowley, Howard A %A Bendlin, Barbara B %A Blennow, Kaj %A Zetterberg, Henrik %A Carlsson, Cynthia M %A Asthana, Sanjay %A Turski, Patrick %A Wieben, Oliver %A Johnson, Sterling C %X

It is becoming increasingly recognized that cerebrovascular disease is a contributing factor in the pathogenesis of Alzheimer's disease (AD). A unique 4D-Flow magnetic resonance imaging (MRI) technique, phase contrast vastly undersampled isotropic projection imaging (PC VIPR), enables examination of angiographic and quantitative metrics of blood flow in the arteries of the Circle of Willis within a single MRI acquisition. Thirty-eight participants with mild cognitive impairment (MCI) underwent a comprehensive neuroimaging protocol (including 4D-Flow imaging) and a standard neuropsychological battery. A subset of participants (n = 22) also underwent lumbar puncture and had cerebrospinal fluid (CSF) assayed for AD biomarkers. Cut-offs for biomarker positivity in CSF resulting from a receiver operating characteristic curve analysis of AD cases and controls from the larger Wisconsin Alzheimer's Disease Research Center cohort were used to classify MCI participants as biomarker positive or negative on amyloid-β (Aβ42), total-tau and total-tau/Aβ42 ratio. Internal carotid artery (ICA) and middle cerebral artery (MCA) mean flow were associated with executive functioning performance, with lower mean flow corresponding to worse performance. MCI participants who were biomarker positive for Aβ42 had lower ICA mean flow than did those who were Aβ42 negative. In sum, mean ICA and MCA arterial flow was associated with cognitive performance in participants with MCI and lower flow in the ICA was associated with amyloid positivity. This provides further evidence for vascular health as a contributing factor in the etiopathogenesis of AD, and could represent a point to intervene in the disease process.

%B J Alzheimers Dis %V 60 %P 243-252 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826187?dopt=Abstract %R 10.3233/JAD-170402 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Intrahippocampal Pathways Involved in Learning/Memory Mechanisms are Affected by Intracerebral Infusions of Amyloid-β25-35 Peptide and Hydrated Fullerene C60 in Rats. %A Gordon, Rita %A Podolski, Igor %A Makarova, Ekaterina %A Deev, Alexander %A Mugantseva, Ekaterina %A Khutsyan, Sergey %A Sengpiel, Frank %A Murashev, Arkady %A Vorobyov, Vasily %X

Primary memory impairments associated with increased level of amyloid-β (Aβ) in the brain have been shown to be linked, partially, with early pathological changes in the entorhinal cortex (EC) which spread on the whole limbic system. While the hippocampus is known to play a key role in learning and memory mechanisms, it is as yet unclear how its structures are involved in the EC pathology. In this study, changes in memory and neuronal morphology in male Wistar rats intrahippocampally injected with Aβ25-35 were correlated on days 14 and 45 after the injection to reveal specific cognitive-structural associations. The main focus was on the dentate gyrus (DG) and hippocampal areas of CA1 and CA3 because of their involvement in afferent flows from EC to the hippocampus through tri-synaptic (EC → DG → CA3 → CA1) and/or mono-synaptic (EC → CA1) pathways. Evident memory impairments were observed at both time points after Aβ25-35 injection. However, on day 14, populations of morphological intact neurons were decreased in CA3 and, drastically, in CA1, and the DG supramedial bundle was significantly damaged. On day 45, this bundle largely and CA1 neurons partially recovered, whereas CA3 neurons remained damaged. We suggest that Aβ25-35 primarily affects the tri-synaptic pathway, destroying the granular cells in the DG supramedial area and neurons in CA3 and, through the Schaffer collaterals, in CA1. Intrahippocampal pretreatment with hydrated fullerene C60 allows the neurons and their connections to survive the amyloidosis, thus supporting the memory mechanisms.

%B J Alzheimers Dis %V 58 %P 711-724 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28482636?dopt=Abstract %R 10.3233/JAD-161182 %0 Journal Article %J J Alzheimers Dis %D 2017 %T An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APPSwe Transgenic Mouse Model of Alzheimer's Disease. %A Rodríguez Cruz, Yamila %A Strehaiano, Manon %A Rodríguez Obaya, Teresita %A García Rodríguez, Julío César %A Maurice, Tangui %X

Erythropoietin (EPO) is a cytokine known to have effective cytoprotective action in the brain, particularly in ischemic, traumatic, inflammatory, and neurodegenerative conditions. We previously reported the neuroprotective effect of a low sialic form of EPO, Neuro-EPO, applied intranasally in rodent models of stroke or cerebellar ataxia and in a non-transgenic mouse model of Alzheimer's disease (AD). Here we analyzed the protective effect of Neuro-EPO in APPSwe mice, a reference transgenic mouse model of AD. Mice were administered 3 times a day, 3 days in the week with Neuro-EPO (125, 250 μg/kg) intranasally, between 12 and 14 months of age. Motor responses, general activity, and memory responses were analyzed during and after treatment. The deficits in spontaneous alternation, place learning in the water-maze, and novel object recognition observed in APPSwe mice were alleviated by the low dose of Neuro-EPO. Oxidative stress, neuroinflammation, trophic factor levels, and a synaptic marker were analyzed in the hippocampus or cortex of the animals. The increases in lipid peroxidation or in GFAP and Iba-1 contents in APPSwe mice were significantly reduced after Neuro-EPO. Activation of intrinsic and extrinsic apoptotic pathways was analyzed. The increases in Bax/Bcl-2 ratio, TNFα, or Fas ligand levels observed in APPSwe mice were reduced by Neuro-EPO. Finally, immunohistochemical and ELISA analyses of Aβ1-42 levels in the APPSwe mouse cortex and hippocampus showed a marked reduction in Aβ deposits and in soluble and insoluble Aβ1-42 forms. This study therefore confirmed the neuroprotective activity of EPO, particularly for an intranasally deliverable formulation, devoid of erythropoietic side effects, in a transgenic mouse model of AD. Neuro-EPO alleviated memory alterations, oxidative stress, neuroinflammation, apoptosis induction, and amyloid load in 14-month-old APPSwe mice.

%B J Alzheimers Dis %V 55 %P 231-248 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662300?dopt=Abstract %R 10.3233/JAD-160500 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Intranasal Insulin Transport is Preserved in Aged SAMP8 Mice and is Altered by Albumin and Insulin Receptor Inhibition. %A Rhea, Elizabeth M %A Humann, Samantha R %A Nirkhe, Surabhi %A Farr, Susan A %A Morley, John E %A Banks, William A %X

Insulin delivered to the level of the cribriform plate (intranasal insulin) is being investigated for its ability to enhance memory in people with Alzheimer's disease (AD). Recent work has shown intranasal insulin can be detected in young CD-1 mice within 5 min and is still present 60 min after injection. The current study determined whether intranasal insulin transport and the subsequent brain distribution of insulin varies in young, healthy mice (CD-1) compared to those with an AD-like phenotype (aged SAMP8) or those pre-disposed to develop such a phenotype (young SAMP8). We showed transport does not vary among these three mouse cohorts, suggesting that intranasal uptake and brain pharmacokinetics do not differ with AD-like signs or the genetic predisposition to developing them. We found that co-administration with bovine serum albumin increased levels of insulin in most brain regions. In addition, the insulin receptor inhibitor, S961, decreases the amount of insulin transported throughout the brain after intranasal injection. These results show insulin delivery to the brain by intranasal administration can be modified with agents such as albumin, may be dependent on the insulin receptor, and is not affected by an AD-like phenotype as presented by the SAMP8 mouse.

%B J Alzheimers Dis %V 57 %P 241-252 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222522?dopt=Abstract %R 10.3233/JAD-161095 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Investigating Simulated Driving Errors in Amnestic Single- and Multiple-Domain Mild Cognitive Impairment. %A Hird, Megan A %A Vesely, Kristin A %A Fischer, Corinne E %A Graham, Simon J %A Naglie, Gary %A Schweizer, Tom A %X

The areas of driving impairment characteristic of mild cognitive impairment (MCI) remain unclear. This study compared the simulated driving performance of 24 individuals with MCI, including amnestic single-domain (sd-MCI, n = 11) and amnestic multiple-domain MCI (md-MCI, n = 13), and 20 age-matched controls. Individuals with MCI committed over twice as many driving errors (20.0 versus 9.9), demonstrated difficulty with lane maintenance, and committed more errors during left turns with traffic compared to healthy controls. Specifically, individuals with md-MCI demonstrated greater driving difficulty compared to healthy controls, relative to those with sd-MCI. Differentiating between different subtypes of MCI may be important when evaluating driving safety.

%B J Alzheimers Dis %V 56 %P 447-452 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983557?dopt=Abstract %R 10.3233/JAD-160995 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Investigation on the Role of BDNF in the Benefits of Blueberry Extracts for the Improvement of Learning and Memory in Alzheimer's Disease Mouse Model. %A Tan, Long %A Yang, Hongpeng %A Pang, Wei %A Li, Haiqiang %A Liu, Wei %A Sun, Shoudan %A Song, Nan %A Zhang, Wanqi %A Jiang, Yugang %X

BACKGROUND: Blueberry (BB) can provide a wide range of antioxidant benefits for AD. There is evidence that BB extracts could improve brain functions. However, the details are still unknown.

OBJECTIVE: In the present study, we aimed to investigate the possible mechanism involved in the improvement of learning and memory capacity from BB extracts in AD.

METHODS: APP/PS1 transgenic mice were fed BB extracts for 16 weeks. The capacity of learning and memory was assessed by Morris water maze (MWM) test, and long-term potentiation (LTP) was determined to evaluate hippocampal neuronal plasticity at the end of administration. Pathological changes in the brain were observed, and the expressions of brain-derived neurotrophic factor (BDNF) and extracellular signal-related kinase (ERK1/2) were determined to explore the mechanism of BB extract-induced benefits.

RESULTS: AD mice exhibited more difficulties to learn and remember the exact position of the platform in the MWM test. The data showed that AD mice lacked effective learning in the platform search. In contrast, AD mice exhibited better performance both in the training phase and probe test of MWM after the BB treatment. Moreover, LTP was enhanced and the neuron loss was alleviated with BB treatment, while we did not find any obvious effect on the elimination of amyloid-β. In the AD mice, the expression of ERK1/2 was significantly increased (p < 0.05), while the level of BDNF was decreased (p < 0.05).

CONCLUSIONS: BB treatment was beneficial for the improvement of learning and memory of AD, and these effects might be related to the regulation of BDNF.

%B J Alzheimers Dis %V 56 %P 629-640 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035919?dopt=Abstract %R 10.3233/JAD-151108 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Investigations into Retinal Pathology in the Early Stages of a Mouse Model of Alzheimer's Disease. %A Chidlow, Glyn %A Wood, John P M %A Manavis, Jim %A Finnie, John %A Casson, Robert J %X

There is increasing recognition that visual performance is impaired in early stages of Alzheimer's disease (AD); however, no consensus exists as to the mechanisms underlying this visual dysfunction, in particular regarding the timing, nature, and extent of retinal versus cortical pathology. If retinal pathology presents sufficiently early, it offers great potential as a source of novel biomarkers for disease diagnosis. The current project utilized an array of immunochemical and molecular tools to perform a characterization of retinal pathology in the early stages of disease progression using a well-validated mouse model of AD (APPSWE/PS1ΔE9). Analytical endpoints included examination of aberrant amyloid and tau in the retina, quantification of any neuronal degeneration, delineation of cellular stress responses of neurons and particularly glial cells, and investigation of oxidative stress. Brain, eyes, and optic nerves were taken from transgenic and wild-type mice of 3 to 12 months of age and processed for immunohistochemistry, qPCR, or western immunoblotting. The results revealed robust expression of the human APP transgene in the retinas of transgenic mice, but a lack of identifiable retinal pathology during the period when amyloid deposits were dramatically escalating in the brain. We were unable to demonstrate the presence of amyloid plaques, dystrophic neurites, neuronal loss, macro- or micro-gliosis, aberrant cell cycle re-entry, oxidative stress, tau hyperphosphorylation, or upregulations of proinflammatory cytokines or stress signaling molecules in the retina. The overall results do not support the hypothesis that detectable retinal pathology occurs concurrently with escalating amyloid deposition in the brains of APPSWE/PS1ΔE9 mice.

%B J Alzheimers Dis %V 56 %P 655-675 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035930?dopt=Abstract %R 10.3233/JAD-160823 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Iron Concentration in Deep Gray Matter Structures is Associated with Worse Visual Memory Performance in Healthy Young Adults. %A Darnai, Gergely %A Nagy, Szilvia Anett %A Horváth, Réka %A Ács, Péter %A Perlaki, Gábor %A Orsi, Gergely %A Kovács, Norbert %A Altbäcker, Anna %A Plózer, Enikő %A Tényi, Dalma %A Weintraut, Rita %A Schwarcz, Attila %A John, Flóra %A Varga, Eszter %A Bereczkei, Tamás %A Clemens, Zsófia %A Komoly, Sámuel %A Janszky, József %X

Abnormally high deposition of iron can contribute to neurodegenerative disorders with cognitive impairment. Since previous studies investigating cognition-brain iron accumulation relationships focused on elderly people, our aim was to explore the association between iron concentration in subcortical nuclei and two types of memory performances in a healthy young population. Gender difference was found only in the globus pallidus. Our results showed that iron load characterized by R2* value on the MRI in the caudate and putamen was related to visual memory, while verbal memory was unrelated to iron concentration.

%B J Alzheimers Dis %V 59 %P 675-681 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671115?dopt=Abstract %R 10.3233/JAD-170118 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Job Loss After Diagnosis of Early-Onset Dementia: A Matched Cohort Study. %A Sakata, Nobuo %A Okumura, Yasuyuki %X

Early-onset dementia (EOD) affects the employment of patients and family members. To demonstrate how likely employees are to leave their jobs after an EOD diagnosis for themselves or a family member, we conducted a matched cohort study of 143 employees and 77 family members diagnosed with EOD using a claims database. We matched these participants to 5 controls each, and followed them for approximately 600 days. In the employee cohort, patients with EOD were more likely to leave their jobs than were controls (hazard ratio: 2.26). This suggests that healthcare providers should offer employment support to patients just after diagnosis.

%B J Alzheimers Dis %V 60 %P 1231-1235 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036820?dopt=Abstract %R 10.3233/JAD-170478 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Kidins220 Correlates with Tau in Alzheimer's Disease Brain and Cerebrospinal Fluid. %A Gamir-Morralla, Andrea %A Belbin, Olivia %A Fortea, Juan %A Alcolea, Daniel %A Ferrer, Isidro %A Lleo, Alberto %A Iglesias, Teresa %X

Identification of neurodegeneration-monitoring biomarkers would be of great clinical value for Alzheimer's disease (AD) diagnosis. Using N- or C-terminal antibodies, we studied the pro-survival synaptic effector, Kidins220, in the brain and cerebrospinal fluid (CSF) of controls and AD patients. Only the N-terminal antibody showed a positive correlation between Kidins220 and phosphorylated tau in AD brains. Using this antibody, Kidins220 was detected in CSF from AD patients where it positively correlated with CSF phosphorylated tau and tau. This study highlights the potential of Kidins220 as a CSF biomarker in AD.

%B J Alzheimers Dis %V 55 %P 1327-1333 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858709?dopt=Abstract %R 10.3233/JAD-160639 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Kynurenine Pathway Metabolites in Alzheimer's Disease. %A Giil, Lasse Melvaer %A Midttun, Øivind %A Refsum, Helga %A Ulvik, Arve %A Advani, Rajiv %A Smith, A David %A Ueland, Per Magne %X

BACKGROUND: Metabolites of tryptophan, produced via the kynurenine pathway (kynurenines), have been linked to Alzheimer's disease (AD) in small cohorts with conflicting results.

OBJECTIVE: To compare differences in plasma kynurenine levels between AD and controls and identify potential associations with cognition.

METHODS: The study included 65 histopathologically-confirmed AD patients and 65 cognitively-screened controls from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. Cognition was assessed using the Cambridge Cognitive Examination (CamCog). Tryptophan, kynurenines, neopterin, and vitamin B6 forms were measured in plasma by liquid chromatography-tandem mass spectrometry. Non-parametric statistics, logistic regression and standardized robust regressions were applied with a false discovery rate of 0.05.

RESULTS: Tryptophan, xanthurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid were lower in AD (Odds ratios (ORs) 0.24 -0.47; p-values <0.001 -0.01). Pyridoxal 5'phosphate did not differ between AD and controls. Kynurenine, anthranilic acid, quinolinic acid, and markers of immune activation (neopterin, kynurenine/tryptophan ratio, and the PAr index (Pyridoxic acid/(Pyridoxal 5'phosphate + Pyridoxal)) increased with age (β 0.31 -0.51; p-values <0.001 -0.006). Xanthurenic acid decreased with age (β: -0.42, p < 0.001). Elderly AD patients with high quinolinic acid performed worse on the CamCog test, indicated by a significant age*quinolinic acid interaction (β 0.21, p < 0.001).

CONCLUSION: Plasma concentrations of several kynurenines were lower in patients with AD compared to controls. Low xanthurenic acid occurred in both AD and with aging. Inflammation-related markers were associated with age, but not AD. However, elevated QA was associated with poor cognition in older AD patients.

%B J Alzheimers Dis %V 60 %P 495-504 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869479?dopt=Abstract %R 10.3233/JAD-170485 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Late Onset Alzheimer's Disease Risk Variants in Cognitive Decline: The PATH Through Life Study. %A Andrews, Shea J %A Das, Debjani %A Anstey, Kaarin J %A Easteal, Simon %X

Recent genome wide association studies have identified a number of single nucleotide polymorphisms associated with late onset Alzheimer's disease (LOAD). We examined the associations of 24 LOAD risk loci, individually and collectively as a genetic risk score, with cognitive function. We used data from 1,626 non-demented older Australians of European ancestry who were examined up to four times over 12 years on tests assessing episodic memory, working memory, vocabulary, and information processing speed. Linear mixed models were generated to examine associations between genetic factors and cognitive performance. Twelve SNPs were significantly associated with baseline cognitive performance (ABCA7, MS4A4E, SORL1), linear rate of change (APOE, ABCA7, INPP5D, ZCWPW1, CELF1), or quadratic rate of change (APOE, CLU, EPHA1, HLA-DRB5, INPP5D, FERMT2). In addition, a weighted genetic risk score was associated with linear rate of change in episodic memory and information processing speed. Our results suggest that a minority of AD related SNPs may be associated with non-clinical cognitive decline. Further research is required to verify these results and to examine the effect of preclinical AD in genetic association studies of cognitive decline. The identification of LOAD risk loci associated with non-clinical cognitive performance may help in screening for individuals at greater risk of cognitive decline.

%B J Alzheimers Dis %V 57 %P 423-436 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269768?dopt=Abstract %R 10.3233/JAD-160774 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Left Frontal Hub Connectivity during Memory Performance Supports Reserve in Aging and Mild Cognitive Impairment. %A Franzmeier, Nicolai %A Hartmann, Julia C %A Taylor, Alexander N W %A Araque Caballero, Miguel Á %A Simon-Vermot, Lee %A Buerger, Katharina %A Kambeitz-Ilankovic, Lana M %A Ertl-Wagner, Birgit %A Mueller, Claudia %A Catak, Cihan %A Janowitz, Daniel %A Stahl, Robert %A Dichgans, Martin %A Duering, Marco %A Ewers, Michael %X

Reserve in aging and Alzheimer's disease (AD) is defined as maintaining cognition at a relatively high level in the presence of neurodegeneration, an ability often associated with higher education among other life factors. Recent evidence suggests that higher resting-state functional connectivity within the frontoparietal control network, specifically the left frontal cortex (LFC) hub, contributes to higher reserve. Following up these previous resting-state fMRI findings, we probed memory-task related functional connectivity of the LFC hub as a neural substrate of reserve. In elderly controls (CN, n = 37) and patients with mild cognitive impairment (MCI, n = 17), we assessed global connectivity of the LFC hub during successful face-name association learning, using generalized psychophysiological interaction analyses. Reserve was quantified as residualized memory performance, accounted for gender and proxies of neurodegeneration (age, hippocampus atrophy, and APOE genotype). We found that greater education was associated with higher LFC-connectivity in both CN and MCI during successful memory. Furthermore, higher LFC-connectivity predicted higher residualized memory (i.e., reserve). These results suggest that higher LFC-connectivity contributes to reserve in both healthy and pathological aging.

%B J Alzheimers Dis %V 59 %P 1381-1392 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731448?dopt=Abstract %R 10.3233/JAD-170360 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Left Ventricular Hypertrophy and Cognitive Decline in Old Age. %A Mahinrad, Simin %A Vriend, Annelotte E %A Jukema, J Wouter %A van Heemst, Diana %A Sattar, Naveed %A Blauw, Gerard Jan %A Macfarlane, Peter W %A Clark, Elaine N %A de Craen, Anton J M %A Sabayan, Behnam %X

BACKGROUND: Patients with advanced heart failure run a greater risk of dementia. Whether early cardiac structural changes also associate with cognitive decline is yet to be determined.

OBJECTIVE: We tested whether left ventricular hypertrophy (LVH) derived from electrocardiogram associates with cognitive decline in older subjects at risk of cardiovascular disease.

METHODS: We included 4,233 participants (mean age 75.2 years, 47.8% male) from PROSPER (PROspective Study of Pravastatin in the Elderly at Risk). LVH was assessed from baseline electrocardiograms by measuring the Sokolow-Lyon index. Higher levels of Sokolow-Lyon index indicate higher degrees of LVH. Cognitive domains involving selective attention, processing speed, and immediate and delayed memory were measured at baseline and repeated during a mean follow-up of 3.2 years.

RESULTS: At baseline, LVH was not associated with worse cognitive function. During follow-up, participants with higher levels of LVH had a steeper decline in cognitive function including in selective attention (p = 0.009), processing speed (p = 0.010), immediate memory (p < 0.001), and delayed memory (p = 0.002). These associations were independent of cardiovascular risk factors, co-morbidities, and medications.

CONCLUSION: LVH assessed by electrocardiogram associates with steeper decline in cognitive function of older subjects independent of cardiovascular risk factors and co-morbidities. This study provides further evidence on the link between subclinical cardiac structural changes and cognitive decline in older subjects.

%B J Alzheimers Dis %V 58 %P 275-283 %G eng %N 1 %R 10.3233/JAD-161150 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The level of 24-Hydroxycholesteryl Esters is an Early Marker of Alzheimer's Disease. %A Benussi, Luisa %A Ghidoni, Roberta %A Dal Piaz, Fabrizio %A Binetti, Giuliano %A Di Iorio, Giuseppe %A Abrescia, Paolo %X

Cholesterol (C) brain accumulation seems to play a role in the Alzheimer's disease (AD) pathogenesis. 24(S)-hydroxycholesterol (24OH-C) is the predominant metabolite of brain C and its synthesis is believed to represent a way to remove excess C from neurons. Previous studies showed that 24OH-C level is altered in patients with neurodegenerative diseases, including AD. Only one study demonstrated that 24OH-C esterification is altered in neurodegenerative diseases, i.e., amyotrophic lateral sclerosis. Herein we analyzed the level of 24OH-C esters (% 24OH-CE) in i) cerebrospinal fluid (CSF) and homologous serum of AD (n = 13) and controls (n = 8); ii) plasma from AD (n = 30), controls (n = 30), mild cognitive impairment (MCI) converting to AD (n = 34), and stable MCI (n = 40). The % 24OH-CE in CSF positively correlated with that in homologous serum and was lower in both CSF and blood from AD patients as compared to controls; moreover, the plasma value of % 24OH-CE was lower in MCI conv-AD than in non-converters. Kaplan Meier Survival curves revealed a significant anticipation of the disease onset in AD and MCI conv-AD subjects with the lowest % 24OH-CE values. In conclusion, the reduction of % 24OH-CE in AD and MCI conv-AD, as well as the anticipation of the disease in patients with the lowest % 24OH-CE, support a role of the cholesterol/lecithin-cholesterol acyltransferase axis in AD onset/progression. Thus, targeting brain cholesterol metabolism could be a valuable strategy to prevent AD associated cognitive decline.

%B J Alzheimers Dis %V 56 %P 825-833 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983556?dopt=Abstract %R 10.3233/JAD-160930 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Levetiracetam Alters Oscillatory Connectivity in Alzheimer's Disease. %A Musaeus, Christian S %A Shafi, Mouhsin M %A Santarnecchi, Emiliano %A Herman, Susan T %A Press, Daniel Z %X

Seizures occur at a higher frequency in people with Alzheimer's disease (AD) but overt, clinically obvious events are infrequent. Evidence from animal models and studies in mild cognitive impairment suggest that subclinical epileptic discharges may play a role in the clinical and pathophysiological manifestations of AD. In this feasibility study, the neurophysiological and cognitive effects of acute administration of levetiracetam (LEV) are measured in patients with mild AD to test whether it could have a therapeutic benefit. AD participants were administered low dose LEV (2.5 mg/kg), higher dose LEV (7.5 mg/kg), or placebo in a double-blind, within-subject repeated measures study with EEG recorded at rest before and after administration. After administration of higher dose of LEV, we found significant decreases in coherence in the delta band (1-3.99 Hz) and increases in the low beta (13-17.99 Hz) and the high beta band (24-29.99 Hz). Furthermore, we found trends toward increased power in the frontal and central regions in the high beta band (24-29.99 Hz). However, there were no significant changes in cognitive performance after this single dose administration. The pattern of decreased coherence in the lower frequency bands and increased coherence in the higher frequency bands suggests a beneficial effect of LEV for patients with AD. Larger longitudinal studies and studies with healthy age-matched controls are needed to determine whether this represents a relative normalization of EEG patterns, whether it is unique to AD as compared to normal aging, and whether longer term administration is associated with a beneficial clinical effect.

%B J Alzheimers Dis %V 58 %P 1065-1076 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527204?dopt=Abstract %R 10.3233/JAD-160742 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-β, Amylin, and Tau Proteins. %A Bharadwaj, Prashant %A Wijesekara, Nadeeja %A Liyanapathirana, Milindu %A Newsholme, Philip %A Ittner, Lars %A Fraser, Paul %A Verdile, Giuseppe %X

A wealth of evidence indicates a strong link between type 2 diabetes (T2D) and neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanism remains unclear, T2D can exacerbate neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism, and central nervous system insulin resistance are features of both AD and T2D. The T2D phenotype (glucose dyshomeostasis, insulin resistance, impaired insulin signaling) also promotes AD pathology, namely accumulation of amyloid-β (Aβ) and hyperphosphorylated tau and can induce other aspects of neuronal degeneration including inflammatory and oxidative processes. Aβ and hyperphosphorylated tau may also have roles in pancreatic β-cell dysfunction and in reducing insulin sensitivity and glucose uptake by peripheral tissues such as liver, skeletal muscle, and adipose tissue. This suggests a role for these AD-related proteins in promoting T2D. The accumulation of the islet amyloid polypeptide (IAPP, or amylin) within islet β-cells is a major pathological feature of the pancreas in patients with chronic T2D. Co-secreted with insulin, amylin accumulates over time and contributes to β-cell toxicity, ultimately leading to reduced insulin secretion and onset of overt (insulin dependent) diabetes. Recent evidence also suggests that this protein accumulates in the brain of AD patients and may interact with Aβ to exacerbate the neurodegenerative process. In this review, we highlight evidence indicating T2D in promoting Aβ and tau mediated neurodegeneration and the potential contributions of Aβ and tau in promoting a diabetic phenotype that could further exacerbate neurodegeneration. We also discuss underlying mechanisms by which amylin can contribute to the neurodegenerative processes.

%B J Alzheimers Dis %V 59 %P 421-432 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269785?dopt=Abstract %R 10.3233/JAD-161192 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Lipid Peroxidation Markers in Coronary Artery Disease Patients with Possible Vascular Mild Cognitive Impairment. %A Suridjan, Ivonne %A Herrmann, Nathan %A Adibfar, Alex %A Saleem, Mahwesh %A Andreazza, Ana %A Oh, Paul I %A Lanctôt, Krista L %X

This study examined associations between lipid peroxidation markers and cognition, and associations between these markers and cognitive response to an exercise intervention program, in adults with coronary artery disease at risk of dementia. Lipid peroxidation products were measured in serum in 118 patients (29 possible vascular mild cognitive impairment and 89 controls). Ratios of early- (lipid hydroperoxides, LPH) to late-stage (8-isoprostane, 8-ISO; 4-hydroxy-2-nonenal, 4-HNE) lipid peroxidation products were calculated. Cognitive performance was assessed before and at completion of a 24-week exercise intervention program. A global effect of group on lipid peroxidation markers was observed, adjusting for sex, years of education, and cardiopulmonary fitness (main effect of group F (3,102) = 2.957, p = 0.036). Lower lipid peroxidation at baseline, as determined by lower 8-ISO concentration, was associated with greater improvement in verbal memory (F (1, 64) = 4.738, p = 0.03) and executive function (F (1, 64) = 5.219, p = 0.026) performance. Similarly, higher ratios of 8-ISO/LPH (F (1, 65) = 6.592, p = 0.013) and (8-ISO+4-HNE) to LPH (F (1, 65) = 3.857, p = 0.054), were associated with less improvement in executive function performance over a 24-week exercise intervention. Lipid peroxidation may be a biomarker of early vascular cognitive impairment, and elevated lipid peroxidation might limit the cognitive benefits of exercise in this high-risk population.

%B J Alzheimers Dis %V 58 %P 885-896 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505971?dopt=Abstract %R 10.3233/JAD-161248 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Lipidomic Profiles in Diabetes and Dementia. %A Huynh, Kevin %A Martins, Ralph N %A Meikle, Peter J %X

Lipids are a diverse class of hydrophobic and amphiphilic molecules which make up the bulk of most biological systems and are essential for human life. The role of lipids in health and disease has been recognized for many decades, as evidenced by the early identification of cholesterol as an important risk factor of heart disease and the development and introduction of statins as a one of the most successful therapeutic interventions to date. While several studies have demonstrated an increased risk of dementia, including Alzheimer's disease (AD), in those with diabetes mellitus, the nature of this risk is not well understood. Recent developments in the field of lipidomics, driven primarily by technological advances in high pressure liquid chromatography and particularly mass spectrometry, have enabled the detailed characterization of the many hundreds of individual lipid species in mammalian systems and their association with disease states. Diabetes mellitus and AD have received particular attention due to their prominence in Western societies as a result of the ongoing obesity epidemic and the aging populations. In this review, we examine how these lipidomic studies are informing on the relationship between lipid metabolism with diabetes and AD and how this may inform on the common pathological pathways that link diabetes risk with dementia.

%B J Alzheimers Dis %V 59 %P 433-444 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582856?dopt=Abstract %R 10.3233/JAD-161215 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Lipidomics Approach to Assess the Association Between Plasma Sphingolipids and Verbal Memory Performance in Coronary Artery Disease Patients Undertaking Cardiac Rehabilitation: A C18:0 Signature for Cognitive Response to Exercise. %A Saleem, Mahwesh %A Herrmann, Nathan %A Dinoff, Adam %A Mielke, Michelle M %A Oh, Paul I %A Shammi, Prathiba %A Cao, Xingshan %A Venkata, Swarajya Lakshmi Vattem %A Haughey, Norman J %A Lanctôt, Krista L %X

BACKGROUND: Early subtle deficits in verbal memory, which may indicate early neural risk, are common in patients with coronary artery disease (CAD). While exercise can improve cognition, cognitive response to exercise is heterogeneous. Sphingolipids have been associated with the development and progression of CAD, and impairments in sphingolipid metabolism may play roles in neurodegeneration and in the neural adaptation response to exercise.

OBJECTIVE: In this study, change in plasma concentrations of sphingolipids was assessed in relation to change in verbal memory performance and in other cognitive domains among CAD subjects undertaking a 6-month cardiac rehabilitation (CR) program.

METHODS: Patients with CAD (n = 120, mean age = 64±6 y, 84% male, years of education = 16±3) underwent CR with neuropsychological assessments and blood collected at baseline, 3-, and 6-months. Z-scores based on age, gender, and education were combined for verbal memory, visuospatial memory, processing speed, executive function, and global cognition tasks to calculate cognitive domain Z-scores. Plasma sphingolipid concentrations were measured from fasting blood samples using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Mixed models were used to identify sphingolipids significantly associated with performance in verbal memory and other cognitive domains, adjusting for potential confounders.

RESULTS: A decrease in ceramide C18:0 concentration was significantly associated with improvement in verbal memory performance (b[SE] = -0.51 [0.25], p = 0.04), visuospatial memory (b[SE] = -0.44 [0.22], p = 0.05), processing speed (b[SE] = -0.89 [0.32], p = 0.007), and global cognition (b[SE] = -1.47 [0.59], p = 0.01) over 6 months of CR.

CONCLUSIONS: Plasma ceramide C18:0 concentrations may be a sensitive marker of cognitive response to exercise in patients with CAD.

%B J Alzheimers Dis %V 60 %P 829-841 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598843?dopt=Abstract %R 10.3233/JAD-161292 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Living Alone with Alzheimer's Disease: Data from SveDem, the Swedish Dementia Registry. %A Cermakova, Pavla %A Nelson, Maja %A Secnik, Juraj %A Garcia-Ptacek, Sara %A Johnell, Kristina %A Fastbom, Johan %A Kilander, Lena %A Winblad, Bengt %A Eriksdotter, Maria %A Religa, Dorota %X

BACKGROUND: Many people with Alzheimer's disease (AD) live alone in their own homes. There is a lack of knowledge about whether these individuals receive the same quality of diagnostics and treatment for AD as patients who are cohabiting.

OBJECTIVES: To investigate the diagnostic work-up and treatment of community-dwelling AD patients who live alone.

METHODS: We performed a cross-sectional cohort study based on data from the Swedish Dementia Registry (SveDem). We studied patients diagnosed with AD between 2007 and 2015 (n = 26,163). Information about drugs and comorbidities was acquired from the Swedish Prescribed Drug Register and the Swedish Patient Register.

RESULTS: 11,878 (46%) patients lived alone, primarily older women. After adjusting for confounders, living alone was inversely associated with receiving computed tomography (OR 0.90; 95% CI 0.82-0.99), magnetic resonance imaging (OR 0.91; 95% CI 0.83-0.99), and lumbar puncture (OR 0.86; 95% CI 0.80-0.92). Living alone was also negatively associated with the use of cholinesterase inhibitors (OR 0.81; 95% CI 0.76; 0.87), memantine (OR 0.77; 95% CI 0.72; 0.83), and cardiovascular medication (OR 0.92; 0.86; 0.99). On the other hand, living alone was positively associated with the use of antidepressants (OR 1.15; 95% CI 1.08; 1.22), antipsychotics (OR 1.41; 95% CI 1.25; 1.58), and hypnotics and sedatives (OR 1.09; 95% CI 1.02; 1.17).

CONCLUSIONS: Solitary living AD patients do not receive the same extent of care as those who are cohabiting.

%B J Alzheimers Dis %V 58 %P 1265-1272 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550260?dopt=Abstract %R 10.3233/JAD-170102 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes. %A Del Prete, Dolores %A Suski, Jan M %A Oulès, Bénédicte %A Debayle, Delphine %A Gay, Anne Sophie %A Lacas-Gervais, Sandra %A Bussiere, Renaud %A Bauer, Charlotte %A Pinton, Paolo %A Paterlini-Bréchot, Patrizia %A Wieckowski, Mariusz R %A Checler, Frédéric %A Chami, Mounia %X

Alteration of mitochondria-associated membranes (MAMs) has been proposed to contribute to the pathogenesis of Alzheimer's disease (AD). We studied herein the subcellular distribution, the processing, and the protein interactome of the amyloid-β protein precursor (AβPP) and its proteolytic products in MAMs. We reveal that AβPP and its catabolites are present in MAMs in cellular models overexpressing wild type AβPP or AβPP harboring the double Swedish or London familial AD mutations, and in brains of transgenic mice model of AD. Furthermore, we evidenced that both β- and γ-secretases are present and harbor AβPP processing activities in MAMs. Interestingly, cells overexpressing APPswe show increased ER-mitochondria contact sites. We also document increased neutral lipid accumulation linked to Aβ production and reversed by inhibiting β- or γ-secretases. Using a proteomic approach, we show that AβPP and its catabolites interact with key proteins of MAMs controlling mitochondria and ER functions. These data highlight the role of AβPP processing and proteomic interactome in MAMs deregulation taking place in AD.

%B J Alzheimers Dis %V 55 %P 1549-1570 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911326?dopt=Abstract %R 10.3233/JAD-160953 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Logopenic Aphasia due to a Strategic Stroke: New Evidence from a Single Case. %A Riancho, Javier %A Pozueta, Ana %A Santos, Miguel %A Lage, Carmen %A Carril, José M %A Banzo, Ignacio %A Martínez-Rodriguez, Isabel %A Gorno-Tempini, Marilu %A Sánchez-Juan, Pascual %K Aphasia %K Atrophy %K Brain %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Stroke %X

Among primary progressive aphasias (PPAs), logopenic variant PPA (lv-PPA) is usually related to Alzheimer's disease. Although it has been widely clinically and pathologically evaluated, the topography in LPA is still controversial. We report a patient presenting with a logopenic syndrome due to a strategic lesion located in the superior and middle temporal gyrus and compare our findings with those of a PiB-PET positive lv-PPA patient matched by age, gender, and education. We consider that our study provides new anatomical clues to better understand the cognitive mechanisms underlying the logopenic syndrome.

%B J Alzheimers Dis %V 57 %P 717-721 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304307?dopt=Abstract %R 10.3233/JAD-161267 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Longer-Term Investigation of the Value of 18F-FDG-PET and Magnetic Resonance Imaging for Predicting the Conversion of Mild Cognitive Impairment to Alzheimer's Disease: A Multicenter Study. %A Inui, Yoshitaka %A Ito, Kengo %A Kato, Takashi %X

BACKGROUND: The value of fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) and magnetic resonance imaging (MRI) for predicting conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD) in longer-term is unclear.

OBJECTIVE: To evaluate longer-term prediction of MCI to AD conversion using 18F-FDG-PET and MRI in a multicenter study.

METHODS: One-hundred and fourteen patients with MCI were followed for 5 years. They underwent clinical and neuropsychological examinations, 18F-FDG-PET, and MRI at baseline. PET images were visually classified into predefined dementia patterns. PET scores were calculated as a semi quantitative index. For structural MRI, z-scores in medial temporal area were calculated by automated volume-based morphometry (VBM).

RESULTS: Overall, 72% patients with amnestic MCI progressed to AD during the 5-year follow-up. The diagnostic accuracy of PET scores over 5 years was 60% with 53% sensitivity and 84% specificity. Visual interpretation of PET images predicted conversion to AD with an overall 82% diagnostic accuracy, 94% sensitivity, and 53% specificity. The accuracy of VBM analysis presented little fluctuation through 5 years and it was highest (73%) at the 5-year follow-up, with 79% sensitivity and 63% specificity. The best performance (87.9% diagnostic accuracy, 89.8% sensitivity, and 82.4% specificity) was with a combination identified using multivariate logistic regression analysis that included PET visual interpretation, educational level, and neuropsychological tests as predictors.

CONCLUSION: 18F-FDG-PET visual assessment showed high performance for predicting conversion to AD from MCI, particularly in combination with neuropsychological tests. PET scores showed high diagnostic specificity. Structural MRI focused on the medial temporal area showed stable predictive value throughout the 5-year course.

%B J Alzheimers Dis %V 60 %P 877-887 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922157?dopt=Abstract %R 10.3233/JAD-170395 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Longitudinal Characterization of [18F]-FDG and [18F]-AV45 Uptake in the Double Transgenic TASTPM Mouse Model. %A Waldron, Ann-Marie %A Wyffels, Leonie %A Verhaeghe, Jeroen %A Richardson, Jill C %A Schmidt, Mark %A Stroobants, Sigrid %A Langlois, Xavier %A Staelens, Steven %X

We aimed to monitor the timing of amyloid-β deposition in relation to changes in brain function using in vivo imaging with [18F]-AV45 and [18F]-FDG in a mouse model of Alzheimer's disease. TASTPM transgenic mice and wild-type controls were scanned longitudinally with [18F]-AV45 and [18F]-FDG before (3 months of age) and at multiple time points after the onset of amyloid deposition (6, 9, 12, and 15 months of age). As expected with increasing amyloidosis, TASTPM mice demonstrated progressive age-dependent increases in [18F]-AV45 uptake that were significantly higher than for WT from 9 months onwards and correlated to ex vivo measures of amyloid burden. The metabolism of [18F]-AV45 produces several brain penetrant radiometabolites and normalization to a reference region helps to negate this non-specific binding and improve the sensitivity of [18F]-AV45. The observed trajectory of [18F]-FDG alterations deviated from our proposed hypothesis of gradual decreases with worsening amyloidosis. While [18F]-FDG uptake in TASTPM mice was significantly lower than that of WT at 9 months, reduced [18F]-FDG was not associated with aging in TASTPM mice. Moreover, [18F]-FDG uptake did not correlate to measures of ex vivo amyloid burden. Our findings suggest that while amyloid-β is sufficient to induce hypometabolism, these pathologies are not linked in a dose-dependent manner in TASTPM mice.

%B J Alzheimers Dis %V 55 %P 1537-1548 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911309?dopt=Abstract %R 10.3233/JAD-160760 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Longitudinal Study on Resting State Functional Connectivity in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease. %A Hafkemeijer, Anne %A Möller, Christiane %A Dopper, Elise G P %A Jiskoot, Lize C %A van den Berg-Huysmans, Annette A %A van Swieten, John C %A van der Flier, Wiesje M %A Vrenken, Hugo %A Pijnenburg, Yolande A L %A Barkhof, Frederik %A Scheltens, Philip %A van der Grond, Jeroen %A Rombouts, Serge A R B %X

BACKGROUND/OBJECTIVE: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. We applied longitudinal resting state functional magnetic resonance imaging (fMRI) to delineate functional brain connections relevant for disease progression and diagnostic accuracy.

METHODS: We used two-center resting state fMRI data of 20 AD patients (65.1±8.0 years), 12 bvFTD patients (64.7±5.4 years), and 22 control subjects (63.8±5.0 years) at baseline and 1.8-year follow-up. We used whole-network and voxel-based network-to-region analyses to study group differences in functional connectivity at baseline and follow-up, and longitudinal changes in connectivity within and between groups.

RESULTS: At baseline, connectivity between paracingulate gyrus and executive control network, between cuneal cortex and medial visual network, and between paracingulate gyrus and salience network was higher in AD compared with controls. These differences were also present after 1.8 years. At follow-up, connectivity between angular gyrus and right frontoparietal network, and between paracingulate gyrus and default mode network was lower in bvFTD compared with controls, and lower compared with AD between anterior cingulate gyrus and executive control network, and between lateral occipital cortex and medial visual network. Over time, connectivity decreased in AD between precuneus and right frontoparietal network and in bvFTD between inferior frontal gyrus and left frontoparietal network. Longitudinal changes in connectivity between supramarginal gyrus and right frontoparietal network differ between both patient groups and controls.

CONCLUSION: We found disease-specific brain regions with longitudinal connectivity changes. This suggests the potential of longitudinal resting state fMRI to delineate regions relevant for disease progression and for diagnostic accuracy, although no group differences in longitudinal changes in the direct comparison of AD and bvFTD were found.

%B J Alzheimers Dis %V 55 %P 521-537 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662284?dopt=Abstract %R 10.3233/JAD-150695 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Long-Term Cognitive Decline in Dementia with Lewy Bodies in a Large Multicenter, International Cohort. %A Kramberger, Milica G %A Auestad, Bjørn %A Garcia-Ptacek, Sara %A Abdelnour, Carla %A Olmo, Josep Garre %A Walker, Zuzana %A Lemstra, Afina W %A Londos, Elisabet %A Blanc, Frédéric %A Bonanni, Laura %A McKeith, Ian %A Winblad, Bengt %A de Jong, Frank Jan %A Nobili, Flavio %A Stefanova, Elka %A Petrova, Maria %A Falup-Pecurariu, Cristian %A Rektorova, Irena %A Bostantjopoulou, Sevasti %A Biundo, Roberta %A Weintraub, Daniel %A Aarsland, Dag %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cognition Disorders %K Cohort Studies %K Female %K Humans %K International Cooperation %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %X

BACKGROUND/OBJECTIVE: The aim of this study was to describe the rate and clinical predictors of cognitive decline in dementia with Lewy bodies (DLB), and compare the findings with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) patients.

METHODS: Longitudinal scores for the Mini-Mental State Examination (MMSE) in 1,290 patients (835 DLB, 198 PDD, and 257 AD) were available from 18 centers with up to three years longitudinal data. Linear mixed effects analyses with appropriate covariates were used to model MMSE decline over time. Several subgroup analyses were performed, defined by anti-dementia medication use, baseline MMSE score, and DLB core features.

RESULTS: The mean annual decline in MMSE score was 2.1 points in DLB, compared to 1.6 in AD (p = 0.07 compared to DLB) and 1.8 in PDD (p = 0.19). Rates of decline were significantly higher in DLB compared to AD and PDD when baseline MMSE score was included as a covariate, and when only those DLB patients with an abnormal dopamine transporter SPECT scan were included. Decline was not predicted by sex, baseline MMSE score, or presence of specific DLB core features.

CONCLUSIONS: The average annual decline in MMSE score in DLB is approximately two points. Although in the overall analyses there were no differences in the rate of decline between the three neurodegenerative disorders, there were indications of a more rapid decline in DLB than in AD and PDD. Further studies are needed to understand the predictors and mechanisms of cognitive decline in DLB.

%B J Alzheimers Dis %V 57 %P 787-795 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304294?dopt=Abstract %R 10.3233/JAD-161109 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Long-Term Maintenance of Executive-Related Oculomotor Improvements in Older Adults with Self-Reported Cognitive Complaints Following a 24-Week Multiple Modality Exercise Program. %A Shellington, Erin M %A Heath, Matthew %A Gill, Dawn P %A Petrella, Robert J %X

Adults (≥55 years) with self-reported cognitive complaints (sCC) were randomized to: multiple-modality exercise (M2), or multiple-modality plus mind-motor exercise (M4), for 24-weeks. Participants (n = 58) were assessed on antisaccade reaction time (RT) to examine executive-related oculomotor control and self-reported physical activity (PA) at pre-intervention (V0), post-intervention (V1), and 52-weeks follow-up (V2). We previously reported significant improvements in antisaccade RT of 23 ms at V1, in both groups. We now report maintenance of antisaccade RT improvement from V1 to V2, t(57) = 0.8, p = 0.45, and improved PA from V1 to V2, t(56) = -2.4, p = 0.02. Improvements in executive-related oculomotor control attained at V1 were maintained at V2.

%B J Alzheimers Dis %V 58 %P 17-22 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28409744?dopt=Abstract %R 10.3233/JAD-161190 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Low Arousal Positive Emotional Stimuli Attenuate Aberrant Working Memory Processing in Persons with Mild Cognitive Impairment. %A Broster, Lucas S %A Jenkins, Shonna L %A Holmes, Sarah D %A Jicha, Gregory A %A Jiang, Yang %X

Emotional enhancement effects on memory have been reported to mitigate the pathophysiology of Alzheimer's disease (AD). However, relative to their manifestation in persons without pathologic aging, these effects may be reduced in magnitude or even deleterious, especially in tasks that more closely model ecologic memory performance. Based upon a synthesis of such reports, we hypothesized that in persons with AD low arousal positive stimuli would evoke relatively intact emotional enhancement effects, but that high arousal negative stimuli would evoke disordered emotional enhancement effects. To assess this, participants with and without mild cognitive impairment (MCI) presumed to be due to AD performed an emotionally-valenced short-term memory task while encephalography was recorded. Results indicated that for persons with MCI, high arousal negative stimuli led to working memory processing patterns previously associated with MCI presumed due to AD and dementia of the Alzheimer-type. In contrast, low arousal positive stimuli evoked a processing pattern similar to MCI participants' unaffected spouses. Our current findings suggest that low arousal positive stimuli attenuate working memory deficits of MCI due to AD.

%B J Alzheimers Dis %V 60 %P 1333-1349 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29060938?dopt=Abstract %R 10.3233/JAD-170233 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Low Cognitive Awareness, but Not Complaint, is a Good Marker of Preclinical Alzheimer's Disease. %A Cacciamani, Federica %A Tandetnik, Caroline %A Gagliardi, Geoffroy %A Bertin, Hugo %A Habert, Marie-Odile %A Hampel, Harald %A Boukadida, Laurie %A Révillon, Marie %A Epelbaum, Stéphane %A Dubois, Bruno %X

BACKGROUND: Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer's disease (AD).

OBJECTIVE: In this study, we searched for a specific pattern of SCD in asymptomatic individuals at risk for AD.

METHODS: Cognitively normal older adults (N = 318) reporting SCD and their informants were enrolled in the INSIGHT-PreAD cohort. We examined the relationship between six SCD measures and both cognitive scores and AD neuroimaging markers (amyloid burden, hippocampal atrophy and brain hypometabolism). An awareness of cognitive decline index (ACDI) has been introduced based on the subject-informant discrepancy in a questionnaire of SCD and participants with low versus high awareness were compared.

RESULTS: Scores in the INSIGHT-PreAD SCD questionnaires did not correlate with AD neuroimaging markers. As well, no correlation has been found between SCD measures and cognitive scores. Comparing subjects with a low (n = 19) and high (n = 86) level of awareness, no significant difference in terms of demography, neuropsychiatric symptoms, autonomy, quality of life, cognition, and hippocampal volume was found. However, the "low awareness" group showed greater amyloid burden and lower cortical metabolism, compared to the "high awareness" group.

CONCLUSION: This study provided additional evidence that reporting SCD by itself is not a specific symptom of preclinical AD. Conversely, a low cognitive awareness (namely, when subjects report fewer difficulties than their relatives do) may represent a very early form of anosognosia and serve as a specific indicator of preclinical AD. This finding is of key importance as an enrichment factor to consider in both clinical practice and research trials.

%B J Alzheimers Dis %V 59 %P 753-762 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671134?dopt=Abstract %R 10.3233/JAD-170399 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Low Erythrocyte Levels of Proteasome and Acyl-Peptide Hydrolase (APEH) Activities in Alzheimer's Disease: A Sign of Defective Proteostasis? %A Palmieri, Gianna %A Cocca, Ennio %A Gogliettino, Marta %A Valentino, Roberta %A Ruvo, Menotti %A Cristofano, Gloria %A Angiolillo, Antonella %A Balestrieri, Marco %A Rossi, Mosè %A Di Costanzo, Alfonso %X

Alzheimer's disease (AD) is a progressive, multifactorial neurodegenerative disorder that is the main cause of dementia. To date, there are no definitive diagnostic tests that can predict or assess onset and progression of the disease. Blood biomarkers for AD are being sought for many years but their identification remains a challenging task. In this study, we investigated the potential relationship between AD and levels of acyl-peptide hydrolase (APEH) and proteasome in erythrocyte samples of 52 participants (26 AD and 26 cognitively healthy controls). A statistically significant decrease in proteasome and exopeptidase/endopeptidase APEH activities was found in AD samples compared to those of healthy controls. Moreover, in contrast to what was observed for proteasome transcripts, APEH activities reduction in AD patients was unrelated to its gene expression levels, suggesting the occurrence of posttranslational modifications or the expression of endogenous inhibitors that might impair enzyme activity. These preliminary data further support a relationship between the APEH-proteasome system and AD molecular players, providing the first evidence of its potential use as a novel blood-based indicator for the routine detection of AD.

%B J Alzheimers Dis %V 60 %P 1097-1106 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984596?dopt=Abstract %R 10.3233/JAD-170389 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Low Florbetapir PET Uptake and Normal Aβ1-42 Cerebrospinal Fluid in an APP Ala713Thr Mutation Carrier. %A Lombardi, Gemma %A Berti, Valentina %A Tedde, Andrea %A Bagnoli, Silvia %A Piaceri, Irene %A Polito, Cristina %A Lucidi, Giulia %A Ferrari, Camilla %A Ginestroni, Andrea %A Moretti, Marco %A Pupi, Alberto %A Nacmias, Benedetta %A Sorbi, Sandro %K Alanine %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Aniline Compounds %K Brain %K Ethylene Glycols %K Humans %K Male %K Middle Aged %K Mutation %K Peptide Fragments %K Positron-Emission Tomography %K Threonine %X

According to the literature, the APP Ala713Thr mutation is associated with Alzheimer's disease and cerebral amyloid angiopathy. We describe a case of dementia clinically compatible with frontotemporal dementia in an APP Ala713Thr mutation carrier in which both [18F]Florbetapir PET uptake and Aβ1-42 cerebrospinal fluid levels were normal. Further evidences are required to establish if this association is only incidental.

%B J Alzheimers Dis %V 57 %P 697-703 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304299?dopt=Abstract %R 10.3233/JAD-161170 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Low Prevalence and Clinical Effect of Vascular Risk Factors in Early-Onset Alzheimer's Disease. %A Chen, Yaohua %A Sillaire, Adeline Rollin %A Dallongeville, Jean %A Skrobala, Emilie %A Wallon, David %A Dubois, Bruno %A Hannequin, Didier %A Pasquier, Florence %X

BACKGROUND: Determinants of early-onset Alzheimer's disease (EOAD) are not well known. In late-onset AD, vascular risk factors (VRFs) are associated with earlier clinical manifestation.

OBJECTIVE: The objective of this study was to assess the putative association between VRFs and EOAD.

METHODS: We studied participants with dementia meeting criteria for EOAD (recruited into the French CoMAJ prospective cohort study from 1 June 2009 to 28 February 2014) and age-, gender-matched controls (ratio 1:3, drawn randomly from the French MONA-LISA population-based survey between 2005 and 2007). Demographic data, VRFs, comorbidities, treatments, and APOE genotypes were compared in multivariable logistic regression analyses.

RESULTS: We studied 102 participants with dementia (mean±standard deviation age: 59.5±3.8; women: 59.8%) and 306 controls. Compared with controls, EOAD participants had spent less time in formal education (9.9±2.9 versus 11.7±3.8 y; p < 0.0001), were less likely to be regular alcohol consumers (p < 0.0001), had a lower body mass index (-2 kg/m2; p < 0.0004), and a lower mean systolic blood pressure (-6.2 mmHg; p = 0.0036). The prevalence of APOE ɛ4 allele was higher in participants with dementia than in controls (50% versus 29.4%; p = 0.0002), as was the prevalence of depression (48% versus 32%; p < 0.001). Similar results were observed in multivariable analysis. Compared with EOAD participants lacking VRFs, EOAD participants with at least one VRF had a higher prevalence of depression (29.6% versus 53.3%, respectively; p = 0.03).

CONCLUSION: The prevalence of VRFs is not elevated in EOAD patients (in contrast to older AD patients). Extensive genetic testing should be considered more frequently in the context of EOAD.

%B J Alzheimers Dis %V 60 %P 1045-1054 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984595?dopt=Abstract %R 10.3233/JAD-170367 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Macrophage Migration Inhibitory Factor is Associated with Biomarkers of Alzheimer's Disease Pathology and Predicts Cognitive Decline in Mild Cognitive Impairment and Mild Dementia. %A Oikonomidi, Aikaterini %A Tautvydaitė, Domilė %A Gholamrezaee, Mehdi M %A Henry, Hugues %A Bacher, Michael %A Popp, Julius %X

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory protein playing a regulatory role in the immune response. First evidence from in vitro and animal studies suggests that MIF may be involved in the development of Alzheimer's disease (AD) pathology.

OBJECTIVE: To address in older subjects (i) the relationships between AD pathology and MIF plasma and cerebrospinal fluid (CSF) levels; and (ii) to investigate whether increased MIF-related systemic and CNS inflammation is associated with clinical disease progression.

METHODS: CSF and plasma concentrations of MIF as well as biomarkers of amyloid, neuronal injury, and tau hyperphosphorylation (CSF Aβ1-42, tau, and ptau, respectively) were assessed in 97 subjects with MCI or mild dementia (cognitive impairment, CI) and 52 healthy volunteers with normal cognition. Clinical and neuropsychological evaluations were performed at inclusion and at follow up visits.

RESULTS: CSF MIF levels were higher in participants with CI with an AD CSF biomarker profile, but not in CI with a non-AD profile, compared to the healthy controls. Higher MIF CSF levels were associated with higher CSF tau and ptau and lower CSF Aβ1-42 after adjusting for potential confounders. In CI, MIF CSF independently predicted cognitive decline at a follow-up visit after controlling for potential confounders including CSF Aβ1-42 and tau levels.

CONCLUSION: Our study provides evidence that MIF-related inflammation is related to amyloid pathology, tau hyperphosphorylation, and neuronal injury at the early clinical stages of AD. Higher MIF CSF levels are associated with accelerated cognitive decline in MCI and mild dementia.

%B J Alzheimers Dis %V 60 %P 273-281 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826184?dopt=Abstract %R 10.3233/JAD-170335 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Magnetic Resonance Imaging and Anatomical Correlation of Human Temporal Lobe Landmarks, in 3D Euclidean Space: A Study of Control and Alzheimer's Disease Subjects. %A Delgado-González, José-Carlos %A Florensa-Vila, José %A Mansilla-Legorburo, Francisco %A Insausti, Ricardo %A Artacho-Pérula, Emilio %X

BACKGROUND: The medial temporal lobe (MTL), and in particular the hippocampal formation, is essential in the processing and consolidation of declarative memory. The 3D environment of the anatomical structures contained in the MTL is an important issue.

OBJECTIVE: Our aim was to explore the spatial relationship of the anatomical structures of the MTL and changes in aging and/or Alzheimer's disease (AD).

METHODS: MTL anatomical landmarks are identified and registered to create a 3D network. The brain network is quantitatively described as a plane, rostrocaudally-oriented, and presenting Euclidean/real distances. Correspondence between 1.5T RM, 3T RM, and histological sections were assessed to determine the most important recognizable changes in AD, based on statistical significance.

RESULTS: In both 1.5T and 3T RM images and histology, inter-rater reliability was high. Sex and hemisphere had no influence on network pattern. Minor changes were found in relation to aging. Distances from the temporal pole to the dentate gyrus showed the most significant differences when comparing control and AD groups. The best discriminative distance between control and AD cases was found in the temporal pole/dentate gyrus rostrocaudal length in histological sections. Moreover, more distances between landmarks were required to obtain 100% discrimination between control (divided into <65 years or >65 years) and AD cases.

DISCUSSION: Changes in the distance between MTL anatomical landmarks can successfully be detected by using measurements of 3D network patterns in control and AD cases.

%B J Alzheimers Dis %V 57 %P 461-473 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269774?dopt=Abstract %R 10.3233/JAD-160944 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Mechanisms of Action of Curcumin in Alzheimer's Disease. %A Tang, Mengxi %A Taghibiglou, Changiz %X

Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly. As the prevalence of AD rises in the 21st century, there is an urgent need for the development of effective pharmacotherapies. Currently, drug treatments target the symptoms of the disease and do not modify or halt the disease progress. Thus, natural compounds have been investigated for their ability to treat AD. This review examines the efficacy of curcumin, a polyphenol derived from turmeric herb, to treat AD. We summarize the in vivo and in vitro research describing the mechanisms of action in which curcumin modifies AD pathology: curcumin inhibits the formation and promotes the disaggregation of amyloid-β plaques, attenuates the hyperphosphorylation of tau and enhances its clearance, binds copper, lowers cholesterol, modifies microglial activity, inhibits acetylcholinesterase, mediates the insulin signaling pathway, and is an antioxidant. In conclusion, curcumin has the potential to be more efficacious than current treatments. However, its usefulness as a therapeutic agent may be hindered by its low bioavailability. If the challenge of low bioavailability is overcome, curcumin-based medications for AD may be in the horizon.

%B J Alzheimers Dis %V 58 %P 1003-1016 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527218?dopt=Abstract %R 10.3233/JAD-170188 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Meditation and Music Improve Memory and Cognitive Function in Adults with Subjective Cognitive Decline: A Pilot Randomized Controlled Trial. %A Innes, Kim E %A Selfe, Terry Kit %A Khalsa, Dharma Singh %A Kandati, Sahiti %X

BACKGROUND: While effective therapies for preventing or slowing cognitive decline in at-risk populations remain elusive, evidence suggests mind-body interventions may hold promise.

OBJECTIVES: In this study, we assessed the effects of Kirtan Kriya meditation (KK) and music listening (ML) on cognitive outcomes in adults experiencing subjective cognitive decline (SCD), a strong predictor of Alzheimer's disease.

METHODS: Sixty participants with SCD were randomized to a KK or ML program and asked to practice 12 minutes/day for 3 months, then at their discretion for the ensuing 3 months. At baseline, 3 months, and 6 months we measured memory and cognitive functioning [Memory Functioning Questionnaire (MFQ), Trail-making Test (TMT-A/B), and Digit-Symbol Substitution Test (DSST)].

RESULTS: The 6-month study was completed by 53 participants (88%). Participants performed an average of 93% (91% KK, 94% ML) of sessions in the first 3 months, and 71% (68% KK, 74% ML) during the 3-month, practice-optional, follow-up period. Both groups showed marked and significant improvements at 3 months in memory and cognitive performance (MFQ, DSST, TMT-A/B; p's≤0.04). At 6 months, overall gains were maintained or improved (p's≤0.006), with effect sizes ranging from medium (DSST, ML group) to large (DSST, KK group; TMT-A/B, MFQ). Changes were unrelated to treatment expectancies and did not differ by age, gender, baseline cognition scores, or other factors.

CONCLUSIONS: Findings of this preliminary randomized controlled trial suggest practice of meditation or ML can significantly enhance both subjective memory function and objective cognitive performance in adults with SCD, and may offer promise for improving outcomes in this population.

%B J Alzheimers Dis %V 56 %P 899-916 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106552?dopt=Abstract %R 10.3233/JAD-160867 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Memantine for Alzheimer's Disease: An Updated Systematic Review and Meta-analysis. %A Kishi, Taro %A Matsunaga, Shinji %A Oya, Kazuto %A Nomura, Ikuo %A Ikuta, Toshikazu %A Iwata, Nakao %X

BACKGROUND: The clinical benefit of memantine for Alzheimer's disease (AD) remains inconclusive.

OBJECTIVE: We performed an updated systematic review and meta-analysis of the efficacy/safety of memantine in AD.

METHODS: We included randomized trials of memantine for AD patients. Cognitive function scores (CF), behavioral disturbances scores (BD), and all-cause discontinuation were used as primary measures. Effect size based on a random-effects model was evaluated in the meta-analyses.

RESULTS: Thirty studies (n = 7,567; memantine versus placebo: N = 11, n = 3,298; memantine + cholinesterase inhibitors (M+ChEIs) versus ChEIs: N = 17, n = 4,175) were identified. Memantine showed a significant improvement in CF [standardized mean difference (SMD) = -0.24, 95% confidence intervals (95% CIs) = -0.34, -0.15, p < 0.00001, I2 = 35% ] and BD (SMD = -0.16, 95% CIs = -0.29, -0.04, p = 0.01, I2 = 52%) compared with placebo. In the sensitivity analysis including only patients with moderate-severe AD, memantine was superior to the placebo in reducing BD without considerable heterogeneity (SMD = -0.20, 95% CIs = -0.34, -0.07, p = 0.003, I2 = 36%). Compared with ChEIs, M+ChEIs showed a greater reduction in BD (SMD = -0.20, 95% CIs = -0.36, -0.03, p = 0.02, I2 = 77%) and a trend of CF improvement (SMD = -0.11, 95% CIs = -0.22, 0.01, p = 0.06, I2 = 56%). However, in the sensitivity analysis of double-blind, placebo-controlled studies only, M+ChEIs showed a significant reduction in BD compared with ChEIs without considerable heterogeneity (SMD = -0.11, 95% CIs = -0.21, -0.01, p = 0.04, I2 = 40%). When performing the sensitivity analysis of donepezil studies only, M+ChEIs was superior to ChEIs in improving CF without considerable heterogeneity (SMD = -0.18, 95% CIs = -0.31, -0.05, p = 0.006, I2 = 49%). No differences were detected in all-cause discontinuation between the groups.

CONCLUSIONS: The meta-analyses suggest the credible efficacy and safety of memantine in treating AD when used alone or in combination with ChEIs.

%B J Alzheimers Dis %V 60 %P 401-425 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922160?dopt=Abstract %R 10.3233/JAD-170424 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Memory Complaints and Cognitive Decline: Data from the GUIDAGE Study1. %A Dardenne, Sophie %A Delrieu, Julien %A Sourdet, Sandrine %A Cantet, Christelle %A Andrieu, Sandrine %A Mathiex-Fortunet, Hélène %A Fougère, Bertrand %A Vellas, Bruno %X

BACKGROUND: Subjective cognitive decline (SCD) may be a very early symptom of Alzheimer's disease (AD) and may be associated with a cognitive decline in a cognitively normal population. The McNair and Kahn Scale was used to assess memory complaints in the GuidAge study.

OBJECTIVE: Our objectives were to examine if the McNair and Kahn Scale can predict cognitive decline and to screen which (if any) of the question(s) of this scale would better predict this cognitive decline.

METHODS: The GuidAge study was a phase III, multicenter, randomized, double blind, placebo-controlled study. Individuals aged 70 years and older, without cognitive impairment (Clinical Dementia Rate (CDR = 0)) at baseline who had spontaneously reported SCD were included in this study. The 20-item version of the McNair and Kahn Scale was used to assess SCD and a standardized neuropsychological assessment was used to assess the cognitive status.

RESULTS: 1,307 patients with SCD and with CDR = 0 at baseline were included. During the 5 years of follow-up, 519 patients showed cognitive decline. Incidence of aggravation score of CDR was 13.40% person years (95% CI [12.24-14.56]). Results showed a significant relationship between the McNair and Kahn Scale score and decline in cognitive performance (HR 1.012; 95% CI [1.002-1.021]; p = 0.0156). Among the 20 items, 5 were statistically significant to predict cognitive decline after adjustment.

CONCLUSION: SCD is a promising indicator of memory impairment. Our study found that using the McNair and Kahn scale can predict cognitive decline. A 5-item version of this scale could be used to screen patients in clinical practice and in clinical research.

%B J Alzheimers Dis %V 60 %P 1567-1578 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984580?dopt=Abstract %R 10.3233/JAD-170229 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Memory Correlates of Alzheimer's Disease Cerebrospinal Fluid Markers: A Longitudinal Cohort Study. %A Reijs, Babette L R %A Ramakers, Inez H G B %A Köhler, Sebastian %A Teunissen, Charlotte E %A Koel-Simmelink, Marleen %A Nathan, Pradeep J %A Tsolaki, Magda %A Wahlund, Lars-Olof %A Waldemar, Gunhild %A Hausner, Lucrezia %A Vandenberghe, Rik %A Johannsen, Peter %A Blackwell, Andrew %A Vanderstichele, Hugo %A Verhey, Frans %A Visser, Pieter Jelle %X

BACKGROUND: Performance on episodic, semantic, and working memory tests is impaired in Alzheimer's disease (AD)-type dementia, but it is unclear which type of memory test is most strongly associated with early AD biomarkers in cerebrospinal fluid (CSF), and most useful for monitoring disease progression.

OBJECTIVE: To examine the association between amyloid-β 1-42 (Aβ42) and tau in CSF with performance on different memory domains at baseline, and how these CSF markers are related with memory decline.

METHODS: We included 263 individuals with normal cognition, mild cognitive impairment, AD-type dementia, and non-AD dementia from the European EDAR study. Assessment included CSF Aβ42 and t-tau analyses with INNO-BIA AlzBio3 Luminex assay, the CERAD wordlist learning and delayed recall, animal fluency test, and the CANTAB Paired Associates Learning (PAL) and Spatial Working Memory tasks. Follow-up assessments were performed within 3 years after baseline.

RESULTS: At baseline, decreased CSF Aβ42 correlated most strongly with the PAL total errors adjusted and the wordlist delayed recall and increased CSF t-tau with the wordlist delayed recall. Over time, decreased CSF Aβ42 was associated with decline on the wordlist learning, whereas increased CSF t-tau were associated with decline in scores on the wordlist learning, wordlist delayed recall, and animal fluency. Associations were independent of baseline diagnosis.

CONCLUSION: Tests assessing episodic verbal and visuospatial memory are most useful for detection of AD pathology. Tests for episodic verbal memory and semantic memory are most useful for tracking memory decline.

%B J Alzheimers Dis %V 60 %P 1119-1128 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984585?dopt=Abstract %R 10.3233/JAD-160766 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Memory is Not Enough: The Neurobiological Substrates of Dynamic Cognitive Reserve. %A Serra, Laura %A Bruschini, Michela %A Di Domenico, Carlotta %A Gabrielli, Giulia Bechi %A Marra, Camillo %A Caltagirone, Carlo %A Cercignani, Mara %A Bozzali, Marco %X

Changes in the residual memory variance are considered as a dynamic aspect of cognitive reserve (d-CR). We aimed to investigate for the first time the neural substrate associated with changes in the residual memory variance overtime in patients with amnestic mild cognitive impairment (aMCI). Thirty-four aMCI patients followed-up for 36 months and 48 healthy elderly individuals (HE) were recruited. All participants underwent 3T MRI, collecting T1-weighted images for voxel-based morphometry (VBM). They underwent an extensive neuropsychological battery, including six episodic memory tests. In patients and controls, factor analyses were used on the episodic memory scores to obtain a composite memory score (C-MS). Partial Least Square analyses were used to decompose the variance of C-MS in latent variables (LT scores), accounting for demographic variables and for the general cognitive efficiency level; linear regressions were applied on LT scores, striping off any contribution of general cognitive abilities, to obtain the residual value of memory variance, considered as an index of d-CR. LT scores and d-CR were used in discriminant analysis, in patients only. Finally, LT scores and d-CR were used as variable of interest in VBM analysis. The d-CR score was not able to correctly classify patients. In both aMCI patients and HE, LT1st and d-CR scores showed correlations with grey matter volumes in common and in specific brain areas. Using CR measures limited to assess memory function is likely less sensitive to detect the cognitive decline and predict the evolution of Alzheimer's disease. In conclusion, d-CR needs a measure of general cognition to identify conversion to Alzheimer's disease efficiently.

%B J Alzheimers Dis %V 58 %P 171-184 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387678?dopt=Abstract %R 10.3233/JAD-170086 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Meta-Analysis of Memantine for Depression. %A Kishi, Taro %A Matsunaga, Shinji %A Iwata, Nakao %X

We conducted a systematic review and meta-analysis on whether memantine was beneficial for the treatment of depressive symptoms in major depressive disorder (MDD) and bipolar disorder (BD). The analysis included double-blind, randomized, placebo-controlled trials of memantine in MDD and BD. The primary outcome measures for efficacy and safety were response rate and all-cause discontinuation, respectively. Risk ratio (RR) and standardized mean difference with 95% confidence intervals (95% CI) were calculated. We identified six trials including 451 patients: MDD, four trials (n = 189), three of which studied memantine augmentation for antidepressants; BD, two trials (n = 262), both on memantine augmentation for mood stabilizers. The mean study duration was 8.33 weeks, and the mean age of patients was 39.9 years. Memantine was not superior to placebo with regard to response rate (RR = 0.92, 95% CI = 0.70-1.20, I2 = 72%), remission rate, improvement of depressive symptoms scale score, all-cause discontinuation (RR = 0.84, 95% CI = 0.60-1.18, I2 = 0%), discontinuation due to inefficacy and adverse events, or incidence of individual adverse events including decreased appetite, dizziness, nausea, and sedation. Although we conducted sensitivity analyses of the response rate to determine the reasons for the heterogeneity (diagnosis, age of patients, memantine dose, memantine augmentation, geographical region, and statistical population), we did not seek confounding factors. Memantine did not improve the treatment efficacy for depressive symptoms in MDD and BD patients. Long-term study of memantine for depression is required.

%B J Alzheimers Dis %V 57 %P 113-121 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222534?dopt=Abstract %R 10.3233/JAD-161251 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Meta-Analysis of Parkinson's Disease and Alzheimer's Disease Revealed Commonly Impaired Pathways and Dysregulation of NRF2-Dependent Genes. %A Wang, Qian %A Li, Wen-Xing %A Dai, Shao-Xing %A Guo, Yi-Cheng %A Han, Fei-Fei %A Zheng, Jun-Juan %A Li, Gong-Hua %A Huang, Jing-Fei %X

Many lines of evidence suggest that Parkinson's disease (PD) and Alzheimer's disease (AD) have common characteristics, such as mitochondrial dysfunction and oxidative stress. As the underlying molecular mechanisms are unclear, we perform a meta-analysis with 9 microarray datasets of PD studies and 7 of AD studies to explore it. Functional enrichment analysis revealed that PD and AD both showed dysfunction in the synaptic vesicle cycle, GABAergic synapses, phagosomes, oxidative phosphorylation, and TCA cycle pathways, and AD had more enriched genes. Comparing the differentially expressed genes between AD and PD, we identified 54 common genes shared by more than six tissues. Among them, 31 downregulated genes contained the antioxidant response element (ARE) consensus sequence bound by NRF2. NRF2 is a transcription factor, which protects cells against oxidative stress through coordinated upregulation of ARE-driven genes. To our surprise, although NRF2 was upregulated, its target genes were all downregulated. Further exploration found that MAFF was upregulated in all tissues and significantly negatively correlated with the 31 NRF2-dependent genes in diseased conditions. Previous studies have demonstrated over-expressed small MAFs can form homodimers and act as transcriptional repressors. Therefore, MAFF might play an important role in dysfunction of NRF2 regulatory network in PD and AD.

%B J Alzheimers Dis %V 56 %P 1525-1539 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222515?dopt=Abstract %R 10.3233/JAD-161032 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Metabolic and Growth Rate Alterations in Lymphoblastic Cell Lines Discriminate Between Down Syndrome and Alzheimer's Disease. %A Coskun, Pinar %A Helguera, Pablo %A Nemati, Zahra %A Bohannan, Ryan C %A Thomas, Jean %A Samuel, Schriner E %A Argueta, Jocelyn %A Doran, Eric %A Wallace, Douglas C %A Lott, Ira T %A Busciglio, Jorge %X

BACKGROUND: Deficits in mitochondrial function and oxidative stress play pivotal roles in Down syndrome (DS) and Alzheimer's disease (AD) and these alterations in mitochondria occur systemically in both conditions.

OBJECTIVE: We hypothesized that peripheral cells of elder subjects with DS exhibit disease-specific and dementia-specific metabolic features. To test this, we performed a comprehensive analysis of energy metabolism in lymphoblastic-cell-lines (LCLs) derived from subjects belonging to four groups: DS-with-dementia (DSAD), DS-without-dementia (DS), sporadic AD, and age-matched controls.

METHODS: LCLs were studied under regular or minimal feeding regimes with galactose or glucose as primary carbohydrate sources. We assessed metabolism under glycolysis or oxidative phosphorylation by quantifying cell viability, oxidative stress, ATP levels, mitochondrial membrane potential (MMP), mitochondrial calcium uptake, and autophagy.

RESULTS: DS and DSAD LCLs showed slower growth rates under minimal feeding. DS LCLs mainly dependent on mitochondrial respiration exhibited significantly slower growth and higher levels of oxidative stress compared to other groups. While ATP levels (under mitochondrial inhibitors) and mitochondrial calcium uptake were significantly reduced in DSAD and AD cells, MMP was decreased in DS, DSAD, and AD LCLs. Finally, DS LCLs showed markedly reduced levels of the autophagy marker LC3-II, underscoring the close association between metabolic dysfunction and impaired autophagy in DS.

CONCLUSION: There are significant mitochondrial functional changes in LCLs derived from DS, DSAD, and AD patients. Several parameters analyzed were consistently different between DS, DSAD, and AD lines suggesting that metabolic indicators between LCL groups may be utilized as biomarkers of disease progression and/or treatment outcomes.

%B J Alzheimers Dis %V 55 %P 737-748 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802222?dopt=Abstract %R 10.3233/JAD-160278 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Metal-Free Method for Producing MRI Contrast at Amyloid-β. %A Hilt, Silvia %A Tang, Tang %A Walton, Jeffrey H %A Budamagunta, Madhu %A Maezawa, Izumi %A Kálai, Tamás %A Hideg, Kálmán %A Singh, Vikrant %A Wulff, Heike %A Gong, Qizhi %A Jin, Lee-Way %A Louie, Angelique %A Voss, John C %X

Alzheimer's disease (AD) is characterized by depositions of the amyloid-β (Aβ) peptide in the brain. The disease process develops over decades, with substantial neurological loss occurring before a clinical diagnosis of dementia can be rendered. It is therefore imperative to develop methods that permit early detection and monitoring of disease progression. In addition, the multifactorial pathogenesis of AD has identified several potential avenues for AD intervention. Thus, evaluation of therapeutic candidates over lengthy trial periods also demands a practical, noninvasive method for measuring Aβ in the brain. Magnetic resonance imaging (MRI) is the obvious choice for such measurements, but contrast enhancement for Aβ has only been achieved using Gd(III)-based agents. There is great interest in gadolinium-free methods to image the brain. In this study, we provide the first demonstration that a nitroxide-based small-molecule produces MRI contrast in brain specimens with elevated levels of Aβ. The molecule is comprised of a  fluorene (a molecule with high affinity for Aβ) and a nitroxide spin label (a paramagnetic MRI contrast species). Labeling of brain specimens with the spin-labeled fluorene produces negative contrast in samples from AD model mice whereas no negative contrast is seen in specimens harvested from wild-type mice. Injection of spin-labeled fluorene into live mice resulted in good brain penetration, with the compound able to generate contrast 24-h post injection. These results provide a proof of concept method that can be used for early, noninvasive, gadolinium-free detection of amyloid plaques by MRI.

%B J Alzheimers Dis %V 55 %P 1667-1681 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911291?dopt=Abstract %R 10.3233/JAD-160279 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Methionine Sulfoxide Reductase-B3 (MsrB3) Protein Associates with Synaptic Vesicles and its Expression Changes in the Hippocampi of Alzheimer's Disease Patients. %A Adams, Stephanie L %A Benayoun, Laurent %A Tilton, Kathy %A Chavez, Olivia R %A Himali, Jayandra J %A Blusztajn, Jan Krzysztof %A Seshadri, Sudha %A Delalle, Ivana %X

Genome-wide association studies (GWAS) identified susceptibility loci associated with decreased hippocampal volume, and found hippocampal subfield-specific effects at MSRB3 (methionine sulfoxide reductase-B3). The MSRB3 locus was also linked to increased risk for late onset Alzheimer's disease (AD). In this study, we uncovered novel sites of MsrB3 expression in CA pyramidal layer and arteriolar walls by using automated immunohistochemistry on hippocampal sections from 23 individuals accompanied by neuropathology reports and clinical dementia rating scores. Controls, cognitively intact subjects with no hippocampal neurofibrillary tangles, exhibited MsrB3 signal as distinct but rare puncta in CA1 pyramidal neuronal somata. In CA3, however, MsrB3-immunoreactivity was strongest in the neuropil of the pyramidal layer. These patterns were replicated in rodent hippocampi where ultrastructural and immunohistofluorescence analysis revealed MsrB3 signal associated with synaptic vesicles and colocalized with mossy fiber terminals. In AD subjects, the number of CA1 pyramidal neurons with frequent, rather than rare, MsrB3-immunoreactive somatic puncta increased in comparison to controls. This change in CA1 phenotype correlated with the occurrence of AD pathological hallmarks. Moreover, the intensity of MsrB3 signal in the neuropil of CA3 pyramidal layer correlated with the signal pattern in neurons of CA1 pyramidal layer that was characteristic of cognitively intact individuals. Finally, MsrB3 signal in the arteriolar walls in the hippocampal white matter decreased in AD patients. This characterization of GWAS-implicated MSRB3 protein expression in human hippocampus suggests that patterns of neuronal and vascular MsrB3 protein expression reflect or underlie pathology associated with AD.

%B J Alzheimers Dis %V 60 %P 43-56 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28777754?dopt=Abstract %R 10.3233/JAD-170459 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Method for Diagnosing Alzheimer's Disease Based on Salivary Amyloid-β Protein 42 Levels. %A Lee, Moonhee %A Guo, Jian-Ping %A Kennedy, Krista %A McGeer, Edith G %A McGeer, Patrick L %X

We have developed a non-invasive method of diagnosing Alzheimer's disease (AD), which can also predict the risk of its future onset. It is based on measuring salivary levels of amyloid-β protein terminating at position 42 (Aβ42). Brain deposits of this peptide are characteristic of AD. Biomarker studies indicate that such brain deposits commence a decade or more prior to clinical onset of the disease. We report here that Aβ42 is produced in all peripheral organs tested, thus establishing the generality of its production. We used this information to develop simple and sensitive tests to determine salivary Aβ42 levels. The levels were first stabilized by adding thioflavin S as an anti-aggregation agent and sodium azide as an anti-bacterial agent. We then quantitated the Aβ42 in a series of samples with ELISA type tests. Control cases showed almost identical levels of salivary Aβ42 regardless of sex or age. All AD cases secreted levels of Aβ42 more than double those of controls. Individuals at elevated risk of developing AD secreted levels comparable to the AD cases. The results establish that salivary Aβ42 levels can be used to diagnose AD as well as to predict the risk of its future onset.

%B J Alzheimers Dis %V 55 %P 1175-1182 %G eng %N 3 %R 10.3233/JAD-160748 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Methylene Blue (Tetramethylthionine Chloride) Influences the Mobility of Adult Neural Stem Cells: A Potentially Novel Therapeutic Mechanism of a Therapeutic Approach in the Treatment of Alzheimer's Disease. %A van der Ven, Amelie T %A Pape, Julius C %A Hermann, Dirk %A Schloesser, Robert %A Genius, Just %A Fischer, Nadine %A Mößner, Rainald %A Scherbaum, Norbert %A Wiltfang, Jens %A Rujescu, Dan %A Benninghoff, Jens %X

An interest in neurogenesis in the adult human brain as a relevant and targetable process has emerged as a potential treatment option for Alzheimer's disease and other neurodegenerative conditions. The aim of this study was to investigate the effects of tetramethylthionine chloride (methylene blue, MB) on properties of adult murine neural stem cells. Based on recent clinical studies, MB has increasingly been discussed as a potential treatment for Alzheimer's disease. While no differences in the proliferative capacity were identified, a general potential of MB in modulating the migratory capacity of adult neural stem cells was indicated in a cell mobility assay. To our knowledge, this is the first time that MB could be associated with neural mobility. The results of this study add insight to the spectrum of features of MB within the central nervous system and may be helpful for understanding the molecular mechanisms underlying a potential therapeutic effect of MB.

%B J Alzheimers Dis %V 57 %P 531-540 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269766?dopt=Abstract %R 10.3233/JAD-160755 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Methylenetetrahydrofolate Reductase C677T Polymorphism and Risk for Late-Onset Alzheimer's disease: Further Evidence in an Italian Multicenter Study. %A Stoccoro, Andrea %A Tannorella, Pierpaola %A Salluzzo, Maria Grazia %A Ferri, Raffaele %A Romano, Corrado %A Nacmias, Benedetta %A Siciliano, Gabriele %A Migliore, Lucia %A Coppedè, Fabio %X

BACKGROUND: A functional polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, namely C677T (rs1801133), results in increased Hcy levels and has been associated with risk of late-onset Alzheimer's disease (LOAD). Many investigators reported association between rs1801133 and LOAD risk in Asian populations and in carriers of the apolipoprotein E (APOE) ɛ4 allele, but recent meta-analyses suggest a contribution also in other populations, including Caucasians and/or northern Africans.

OBJECTIVE: To further address this issue, we performed a relatively large case-control study, including 581 LOAD patients and 468 matched controls of Italian origin. APOE data were available for a subgroup of almost 600 subjects.

METHODS: Genotyping for rs1801133 was performed with PCR-RFLP techniques.

RESULTS: In the total population, the MTHFR 677T allele (OR = 1.20; 95% CI = 1.01-1.43) and carriers of the MTHFR 677T allele (CT+TT versus CC: OR = 1.34; 95% CI = 1.03-1.73) resulted in increased LOAD risk. Similarly, in APOEɛ4 carriers, we observed an increased frequency of MTHFR 677CT carriers (CT versus CC: OR = 2.82; 95% CI = 1.25-6.32). Very interestingly, also in non-APOEɛ4 carriers, both MTHFR 677T allele (OR = 1.38; 95% CI = 1.03-1.85) and MTHFR 677TT genotype (OR = 2.08; 95% CI = 1.11-3.90) were associated with LOAD. All these associations survived after corrections for age, gender, and multiple testing.

CONCLUSIONS: The present results suggest that the MTHFR C677T polymorphism is likely a LOAD risk factor in our cohort, either in APOEɛ4 or in non-APOEɛ4 carriers.

%B J Alzheimers Dis %V 56 %P 1451-1457 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28211809?dopt=Abstract %R 10.3233/JAD-161081 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Microglial and Neuronal TDP-43 Pathology in Anti-IgLON5-Related Tauopathy. %A Cagnin, Annachiara %A Mariotto, Sara %A Fiorini, Michele %A Gaule, Marina %A Bonetto, Nicola %A Tagliapietra, Matteo %A Buratti, Emanuele %A Zanusso, Gianluigi %A Ferrari, Sergio %A Monaco, Salvatore %X

A novel neuronal tauopathy, mainly confined to hypothalamus and brainstem tegmentum, has recently been reported in patients with autoantibodies to the neuronal cell-adhesion molecule IgLON5. We describe a patient with anti-IgLON5 syndrome, who presented with dysautonomia and sleep disorder, followed by subacute dementia. Postmortem brain examination disclosed neuronal tau pathology prevailing in the hippocampus, amygdala, and locus coeruleus, in addition to microglial/neuronal TDP-43 pathology, with overexpression of aberrantly phosphorylated forms and neurotoxic truncated fragments, in basal ganglia, nucleus basalis, thalamus, and midbrain. These findings suggest that neurodegeneration in anti-IgLON5 syndrome might also occur via a microglia-triggered non-cell autonomous pathway.

%B J Alzheimers Dis %V 59 %P 13-20 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550263?dopt=Abstract %R 10.3233/JAD-170189 %0 Journal Article %J J Alzheimers Dis %D 2017 %T MicroRNA Profile in Patients with Alzheimer's Disease: Analysis of miR-9-5p and miR-598 in Raw and Exosome Enriched Cerebrospinal Fluid Samples. %A Riancho, Javier %A Vázquez-Higuera, José Luis %A Pozueta, Ana %A Lage, Carmen %A Kazimierczak, Martha %A Bravo, María %A Calero, Miguel %A Gonalezález, Andrea %A Rodríguez, Eloy %A Lleo, Alberto %A Sánchez-Juan, Pascual %X

BACKGROUND: MicroRNAs have been postulated as potential biomarkers for Alzheimer's disease (AD). Exosomes are nanovesicles which transport microRNAs, proteins, and other cargos. It has been hypothesized that the exosome traffic might be increased in neurodegenerative disorders.

OBJECTIVE: i) To assess the cerebrospinal fluid (CSF) microRNA profile in a group of AD patients and control subjects and to validate a group of microRNAs previously reported by other authors. ii) To compare microRNA levels in whole CSF and in the exosome-enriched fraction in AD patients.

METHODS: A panel of 760 microRNAs was analyzed in the CSF of 10 AD patients and 10 healthy subjects. Among microRNAs differently expressed, we selected those that had been previously reported by other authors. Candidates were validated in a larger group by individual qPCR assays. MicroRNA expression was also evaluated in exosome-enriched CSF samples of patients with AD and controls.

RESULTS: Fifteen microRNAs were differently expressed in AD. MiR-9-5p, miR-134, and miR-598 were selected as candidates for further analysis. MiR-9-5p and miR-598 were detected in 50 and 75% of control CSF samples, respectively, while they were not detected in any AD CSF samples. We observed an opposite pattern when we evaluated the microRNA expression in the exosome-enriched CSF AD samples. No pattern variations were noted among healthy subjects.

CONCLUSION: These data propose miR-9-5p and miR-598 as potential biomarkers for AD. Further studies in plasma and other body fluids will confirm their potential role as easily accessible biomarkers. In addition, our data suggest that exosome trafficking is different between AD and control subjects raising the need to take this phenomenon into consideration in future studies of AD biomarkers.

%B J Alzheimers Dis %V 57 %P 483-491 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269782?dopt=Abstract %R 10.3233/JAD-161179 %0 Journal Article %J J Alzheimers Dis %D 2017 %T MicroRNAs in Human Cerebrospinal Fluid as Biomarkers for Alzheimer's Disease. %A Lusardi, Theresa A %A Phillips, Jay I %A Wiedrick, Jack T %A Harrington, Christina A %A Lind, Babett %A Lapidus, Jodi A %A Quinn, Joseph F %A Saugstad, Julie A %X

BACKGROUND: Currently available biomarkers of Alzheimer's disease (AD) include cerebrospinal fluid (CSF) protein analysis and amyloid PET imaging, each of which has limitations. The discovery of extracellular microRNAs (miRNAs) in CSF raises the possibility that miRNA may serve as novel biomarkers of AD.

OBJECTIVE: Investigate miRNAs in CSF obtained from living donors as biomarkers for AD.

METHODS: We profiled miRNAs in CSF from 50 AD patients and 49 controls using TaqMan® arrays. Replicate studies performed on a subset of 32 of the original CSF samples verified 20 high confidence miRNAs. Stringent data analysis using a four-step statistical selection process including log-rank and receiver operating characteristic (ROC) tests, followed by random forest tests, identified 16 additional miRNAs that discriminate AD from controls. Multimarker modeling evaluated linear combinations of these miRNAs via best-subsets logistic regression, and computed area under the ROC (AUC) curve ascertained classification performance. The influence of ApoE genotype on miRNA biomarker performance was also evaluated.

RESULTS: We discovered 36 miRNAs that discriminate AD from control CSF. 20 of these retested in replicate studies verified differential expression between AD and controls. Stringent statistical analysis also identified these 20 miRNAs, and 16 additional miRNA candidates. Top-performing linear combinations of 3 and 4 miRNAs have AUC of 0.80-0.82. Addition of ApoE genotype to the model improved performance, i.e., AUC of 3 miRNA plus ApoE4 improves to 0.84.

CONCLUSIONS: CSF miRNAs can discriminate AD from controls. Combining miRNAs improves sensitivity and specificity of biomarker performance, and adding ApoE genotype improves classification.

%B J Alzheimers Dis %V 55 %P 1223-1233 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27814298?dopt=Abstract %R 10.3233/JAD-160835 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Midlife Metabolic Profile and the Risk of Late-Life Cognitive Decline. %A Tortelli, Rosanna %A Lozupone, Madia %A Guerra, Vito %A Barulli, Maria Rosaria %A Imbimbo, Bruno P %A Capozzo, Rosa %A Grasso, Alessandra %A Tursi, Marianna %A Di Dio, Cristina %A Sardone, Rodolfo %A Giannelli, Gianluigi %A Seripa, Davide %A Misciagna, Giovanni %A Panza, Francesco %A Logroscino, Giancarlo %X

Among metabolic syndrome components, the effects of higher plasma glucose levels on cognitive decline (CD) have been considered in few studies. We evaluated the associations among midlife glycemia, total cholesterol, high-density lipoprotein cholesterol, triglycerides, midlife insulin resistance [homeostasis model assessment for insulin resistance (HOMA-index)], and CD in the older subjects of the population-based MICOL Study (Castellana Grotte, Italy) at baseline (M1) and at follow-ups seven (M2) and twenty years later (M3). At M1, a dementia risk score and a composite cardiovascular risk score for dementia were calculated. For 797 subjects out of 833, we obtained a Mini-Mental State Examination (MMSE) score at M3, subdividing these subjects in three cognitive functioning subgroups: normal cognition, mild CD, and moderate-severe CD. Mean fasting glycemia at baseline was significantly higher in moderate-severe CD subgroup (114.6±71.4 mg/dl) than in the normal cognition subgroup (101.2±20.6). Adjusting for gender, age, and other metabolic components, higher fasting glycemia values both at M1 [odds ratio (OR) = 1.31; 95% confidence interval (CI): 1.08-1.59] and M2 (OR = 1.26; 95% CI: 1.01-1.57) were associated with an increased risk of moderate-severe CD. Mean HOMA index value was significantly higher in the moderate-severe CD subgroup (5.7±9.4) compared to the normal cognition subgroup (2.9±1.4) at M1. The dementia risk probability (MMSE < 24) increased moving through higher categories of the dementia risk score and decreased as long as the cardiovascular score increased. The present findings highlighted the indication to control blood glucose levels, regardless of a diagnosis of diabetes mellitus, as early as midlife for prevention of late-life dementia.

%B J Alzheimers Dis %V 59 %P 121-130 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582862?dopt=Abstract %R 10.3233/JAD-170153 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Mild Behavioral Impairment Checklist (MBI-C): A Rating Scale for Neuropsychiatric Symptoms in Pre-Dementia Populations. %A Ismail, Zahinoor %A Agüera-Ortiz, Luis %A Brodaty, Henry %A Cieslak, Alicja %A Cummings, Jeffrey %A Fischer, Corinne E %A Gauthier, Serge %A Geda, Yonas E %A Herrmann, Nathan %A Kanji, Jamila %A Lanctôt, Krista L %A Miller, David S %A Mortby, Moyra E %A Onyike, Chiadi U %A Rosenberg, Paul B %A Smith, Eric E %A Smith, Gwenn S %A Sultzer, David L %A Lyketsos, Constantine %X

BACKGROUND: Mild behavioral impairment (MBI) is a construct that describes the emergence at ≥50 years of age of sustained and impactful neuropsychiatric symptoms (NPS), as a precursor to cognitive decline and dementia. MBI describes NPS of any severity, which are not captured by traditional psychiatric nosology, persist for at least 6 months, and occur in advance of or in concert with mild cognitive impairment. While the detection and description of MBI has been operationalized in the International Society to Advance Alzheimer's Research and Treatment - Alzheimer's Association (ISTAART-AA) research diagnostic criteria, there is no instrument that accurately reflects MBI as described.

OBJECTIVE: To develop an instrument based on ISTAART-AA MBI criteria.

METHODS: Eighteen subject matter experts participated in development using a modified Delphi process. An iterative process ensured items reflected the five MBI domains of 1) decreased motivation; 2) emotional dysregulation; 3) impulse dyscontrol; 4) social inappropriateness; and 5) abnormal perception or thought content. Instrument language was developed a priori to pertain to non-demented functionally independent older adults.

RESULTS: We present the Mild Behavioral Impairment Checklist (MBI-C), a 34-item instrument, which can easily be completed by a patient, close informant, or clinician.

CONCLUSION: The MBI-C provides the first measure specifically developed to assess the MBI construct as explicitly described in the criteria. Its utility lies in MBI case detection, and monitoring the emergence of MBI symptoms and domains over time. Studies are required to determine the prognostic value of MBI for dementia development, and for predicting different dementia subtypes.

%B J Alzheimers Dis %V 56 %P 929-938 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059789?dopt=Abstract %R 10.3233/JAD-160979 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Mitochondria in Excitatory and Inhibitory Synapses have Similar Susceptibility to Amyloid-β Peptides Modeling Alzheimer's Disease. %A Amorim, João A %A Canas, Paula M %A Tomé, Angelo R %A Rolo, Anabela P %A Agostinho, Paula %A Palmeira, Carlos M %A Cunha, Rodrigo A %X

Mitochondrial dysfunction is proposed to trigger memory deficits and synaptic damage at the onset of Alzheimer's disease (AD). However, it is unknown how mitochondria dysfunction might trigger synaptotoxicity and if a differential susceptibility of mitochondria located in synapses underlies the greater glutamatergic than GABAergic synaptotoxicity in early AD. Hippocampal synaptosomes (purified synapses) of a rat model of early AD, typified by selective memory deficits two weeks after intracerebroventricular injection of amyloid-β peptides (Aβ1-42, 2 nmol), simultaneously displayed three mitochondria-associated deleterious alterations: 1) hampered metabolism (decreased MTT reduction); 2) increased oxygen radical production (increased hydrogen peroxide production); 3) increased caspase-3 activity. The direct exposure of hippocampal synaptosomes to Aβ1-42 (500 nM) similarly decreased mitochondrial membrane potential (TMRM+ fluorescence) and increased mitochondria-derived oxygen radicals (MitoTraker®red-CM-H2Xros fluorescence) in individual glutamatergic (vesicular glutamate transporter-immunopositive) and GABAergic (vesicular GABA transporter-immunopositive) synaptosomes. However, significantly more glutamatergic than GABAergic synaptosomes were endowed with mitochondria (Tom20-immunopositive). These results indicate that dysfunctional mitochondria located in synapses can trigger synaptotoxicity through multifaceted mechanisms and that it is not the susceptibility of mitochondria to Aβ but more likely a different impact of dysfunctional mitochondria that underlies the greater sensitivity to synaptotoxicity of glutamatergic than GABA synapses in early AD.

%B J Alzheimers Dis %V 60 %P 525-536 %8 2017 %G eng %N 2 %R 10.3233/JAD-170356 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Mitochondria-Division Inhibitor 1 Protects Against Amyloid-β induced Mitochondrial Fragmentation and Synaptic Damage in Alzheimer's Disease. %A Reddy, P Hemachandra %A Manczak, Maria %A Yin, XiangLing %X

The purpose our study was to determine the protective effects of mitochondria division inhibitor 1 (Mdivi1) in Alzheimer's disease (AD). Mdivi1 is hypothesized to reduce excessive fragmentation of mitochondria and mitochondrial dysfunction in AD neurons. Very little is known about whether Mdivi1 can confer protective effects in AD. In the present study, we sought to determine the protective effects of Mdivi1 against amyloid-β (Aβ)- and mitochondrial fission protein, dynamin-related protein 1 (Drp1)-induced excessive fragmentation of mitochondria in AD progression. We also studied preventive (Mdivi1+Aβ42) and intervention (Aβ42+Mdivi1) effects against Aβ42 in N2a cells. Using real-time RT-PCR and immunoblotting analysis, we measured mRNA and protein levels of mitochondrial dynamics, mitochondrial biogenesis, and synaptic genes. We also assessed mitochondrial function by measuring H2O2, lipid peroxidation, cytochrome oxidase activity, and mitochondrial ATP. MTT assays were used to assess the cell viability. Aβ42 was found to impair mitochondrial dynamics, lower mitochondrial biogenesis, lower synaptic activity, and lower mitochondrial function. On the contrary, Mdivi1 enhanced mitochondrial fusion activity, lowered fission machinery, and increased biogenesis and synaptic proteins. Mitochondrial function and cell viability were elevated in Mdivi1-treated cells. Interestingly, Mdivi1 pre- and post-treated cells treated with Aβ showed reduced mitochondrial dysfunction, and maintained cell viability, mitochondrial dynamics, mitochondrial biogenesis, and synaptic activity. The protective effects of Mdivi1 were stronger in N2a+Aβ42 pre-treated with Mdivi1, than in N2a+Aβ42 cells than Mdivi1 post-treated cells, indicating that Mdivi1 works better in prevention than treatment in AD like neurons.

%B J Alzheimers Dis %V 58 %P 147-162 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28409745?dopt=Abstract %R 10.3233/JAD-170051 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Mitochondrial Abnormalities and Synaptic Loss Underlie Memory Deficits Seen in Mouse Models of Obesity and Alzheimer's Disease. %A Martins, Isaura V A %A Rivers-Auty, Jack %A Allan, Stuart M %A Lawrence, Catherine B %X

Obesity is associated with impaired memory in humans, and obesity induced by high-fat diets leads to cognitive deficits in rodents and in mouse models of Alzheimer's disease (AD). However, it remains unclear how high-fat diets contribute to memory impairment. Therefore, we tested the effect of a high-fat diet on memory in male and female control non-transgenic (Non-Tg) and triple-transgenic AD (3xTgAD) mice and determined if a high-fat diet caused similar ultrastructural abnormalities to those observed in AD. Behavior was assessed in mice on control or high-fat diet at 4, 8, or 14 months of age and ultrastructural analysis at 8 months of age. A high-fat diet increased body weight, fat weight, and insulin levels with some differences in these metabolic responses observed between Non-Tg and 3xTgAD mice. In both sexes, high-fat feeding caused memory impairments in Non-Tg mice and accelerated memory deficits in 3xTgAD mice. In 3xTgAD mice, changes in hippocampal mitochondrial morphology were observed in capillaries and brain neuropil that were accompanied by a reduction in synapse number. A high-fat diet also caused mitochondria abnormalities and a reduction in synapse number in Non-Tg mice, but did not exacerbate the changes seen in 3xTgAD mice. Our data demonstrate that a high-fat diet affected memory in Non-Tg mice and produced similar impairments in mitochondrial morphology and synapse number comparable to those seen in AD mice, suggesting that the detrimental effects of a high-fat diet on memory might be due to changes in mitochondrial morphology leading to a reduction in synaptic number.

%B J Alzheimers Dis %V 55 %P 915-932 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802235?dopt=Abstract %R 10.3233/JAD-160640 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Mitochondrial Aspects of Synaptic Dysfunction in Alzheimer's Disease. %A Cai, Qian %A Tammineni, Prasad %X

Alzheimer's disease (AD) is characterized by brain deposition of amyloid plaques and tau neurofibrillary tangles along with steady cognitive decline. Synaptic damage, an early pathological event, correlates strongly with cognitive deficits and memory loss. Mitochondria are essential organelles for synaptic function. Neurons utilize specialized mechanisms to drive mitochondrial trafficking to synapses in which mitochondria buffer Ca2+ and serve as local energy sources by supplying ATP to sustain neurotransmitter release. Mitochondrial abnormalities are one of the earliest and prominent features in AD patient brains. Amyloid-β (Aβ) and tau both trigger mitochondrial alterations. Accumulating evidence suggests that mitochondrial perturbation acts as a key factor that is involved in synaptic failure and degeneration in AD. The importance of mitochondria in supporting synaptic function has made them a promising target of new therapeutic strategies for AD. Here, we review the molecular mechanisms regulating mitochondrial function at synapses, highlight recent findings on the disturbance of mitochondrial dynamics and transport in AD, and discuss how these alterations impact synaptic vesicle release and thus contribute to synaptic pathology associated with AD.

%B J Alzheimers Dis %V 57 %P 1087-1103 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767992?dopt=Abstract %R 10.3233/JAD-160726 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Mitochondrial Biomarker-Based Study of S-Equol in Alzheimer's Disease Subjects: Results of a Single-Arm, Pilot Trial. %A Wilkins, Heather M %A Mahnken, Jonathan D %A Welch, Paul %A Bothwell, Rebecca %A Koppel, Scott %A Jackson, Richard L %A Burns, Jeffrey M %A Swerdlow, Russell H %X

Reductions in bioenergetic fluxes, mitochondrial enzyme activities, and mitochondrial number are observed in Alzheimer's disease (AD). Preclinical work indicates estrogen pathway signaling by either estrogen or selective β estrogen receptor (ERβ) agonists benefits these parameters. To assess whether an ERβ agonist could improve mitochondrial function in actual AD subjects, we administered S-equol (10 mg twice daily) to 15 women with AD and determined the platelet mitochondria cytochrome oxidase (COX) activity before initiating S-equol (lead-in), after two weeks of S-equol (active treatment), and two weeks after stopping S-equol (wash-out). Because the intra-individual variation of this enzyme across samples taken at different times was unknown we used a nonparametric, single-arm, dichotomous endpoint that classified subjects whose active treatment COX activity exceeded the average of their lead-in and wash-out measures as positive responders. Eleven positive responses were observed (p < 0.06). The implications of this finding on our null hypothesis (that S-equol does not influence platelet mitochondria COX activity) are discussed. To our knowledge, this is the first time a direct mitochondrial target engagement biomarker has been utilized in an AD clinical study.

%B J Alzheimers Dis %V 59 %P 291-300 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598847?dopt=Abstract %R 10.3233/JAD-170077 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer's Disease. %A Guo, Lan %A Tian, Jing %A Du, Heng %X

Alzheimer's disease (AD) is a chronic neurodegenerative disorder, in which multiple risk factors converge. Despite the complexity of the etiology of the disease, synaptic failure is the pathological basis of cognitive impairment, the cardinal sign of AD. Decreased synaptic density, compromised synaptic transmission, and defected synaptic plasticity are hallmark synaptic pathologies accompanying AD. However, the mechanisms by which synapses are injured in AD-related conditions have not been fully elucidated. Mitochondria are a critical organelle in neurons. The pivotal role of mitochondria in supporting synaptic function and the concomitant occurrence of mitochondrial dysfunction with synaptic stress in postmortem AD brains as well as AD animal models seem to lend the credibility to the hypothesis that mitochondrial defects underlie synaptic failure in AD. This concept is further strengthened by the protective effect of mitochondrial medicine on synaptic function against the toxicity of amyloid-β, a key player in the pathogenesis of AD. In this review, we focus on the association between mitochondrial dysfunction and synaptic transmission deficits in AD. Impaired mitochondrial energy production, deregulated mitochondrial calcium handling, excess mitochondrial reactive oxygen species generation and release play a crucial role in mediating synaptic transmission deregulation in AD. The understanding of the role of mitochondrial dysfunction in synaptic stress may lead to novel therapeutic strategies for the treatment of AD through the protection of synaptic transmission by targeting to mitochondrial deficits.

%B J Alzheimers Dis %V 57 %P 1071-1086 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662318?dopt=Abstract %R 10.3233/JAD-160702 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Mitochondrial Dysfunction Triggers Synaptic Deficits via Activation of p38 MAP Kinase Signaling in Differentiated Alzheimer's Disease Trans-Mitochondrial Cybrid Cells. %A Yu, Qing %A Du, Fang %A Douglas, Justin T %A Yu, Haiyang %A Yan, Shirley ShiDu %A Yan, Shi Fang %X

Loss of synapse and synaptic dysfunction contribute importantly to cognitive impairment in Alzheimer's disease (AD). Mitochondrial dysfunction and oxidative stress are early pathological features in AD-affected brain. However, the effect of AD mitochondria on synaptogenesis remains to be determined. Using human trans-mitochondrial "cybrid" (cytoplasmic hybrid) neuronal cells whose mitochondria were transferred from platelets of patients with sporadic AD or age-matched non-AD subjects with relatively normal cognition, we provide the first evidence of mitochondrial dysfunction compromises synaptic development and formation of synapse in AD cybrid cells in response to chemical-induced neuronal differentiation. Compared to non-AD control cybrids, AD cybrid cells showed synaptic loss which was evidenced by a significant reduction in expression of two synaptic marker proteins: synaptophysin (presynaptic marker) and postsynaptic density protein-95, and neuronal proteins (MAP-2 and NeuN) upon neuronal differentiation. In parallel, AD-mediated synaptic deficits correlate to mitochondrial dysfunction and oxidative stress as well as activation of p38 MAP kinase. Notably, inhibition of p38 MAP kinase by pharmacological specific p38 inhibitor significantly increased synaptic density, improved mitochondrial function, and reduced oxidative stress. These results suggest that activation of p38 MAP kinase signaling pathway contributes to AD-mediated impairment in neurogenesis, possibly by inhibiting the neuronal differentiation. Our results provide new insight into the crosstalk of dysfunctional AD mitochondria to synaptic formation and maturation via activation of p38 MAP kinase. Therefore, blockade of p38 MAP kinase signal transduction could be a potential therapeutic strategy for AD by alleviating loss of synapses.

%B J Alzheimers Dis %V 59 %P 223-239 %G eng %N 1 %R 10.3233/JAD-170283 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Mitochondrial Repair Effects of Oxygen Treatment on Alzheimer's Disease Model Mice Revealed by Quantitative Proteomics. %A Wang, Hao %A Hong, Xiaoyu %A Wang, Yong %X

Mitochondrial dysfunction plays a pivotal role in Alzheimer's disease (AD), even before signs of AD pathology are evident. Our previous research has shown that oxygen treatment can improve cognitive function in AD model mice. To address whether oxygen treatment is beneficial to mitochondrial biology, we analyzed differential expressions of hippocampal mitochondrial proteins in AD model mice given supplementary oxygen. Numerous respiratory chain, Kreb's cycle, and glycolysis proteins were upregulated significantly after oxygen treatment, suggesting that oxygen therapy can alleviate mitochondrial damage. Furthermore, the treatment was associated with decreased expressions of some AD biomarkers, suggesting oxygen treatment to be a potential therapy for AD.

%B J Alzheimers Dis %V 56 %P 875-883 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059791?dopt=Abstract %R 10.3233/JAD-161010 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Modeling the Distress of Spousal Caregivers of People with Dementia. %A Wawrziczny, Emilie %A Berna, Guillaume %A Ducharme, Francine %A Kergoat, Marie-Jeanne %A Pasquier, Florence %A Antoine, Pascal %X

BACKGROUND: The progressive mobilization of spouse caregivers who take care of a person with dementia (PWD) can lead to situations of distress.

OBJECTIVE: The current study sought to investigate the influence of the characteristics of the caregiving context on spousal caregiver distress.

METHODS: 125 spousal caregivers participated in this study. The characteristics of the caregiving context were assessed using questionnaires. We examined a moderated-mediator model (Step 1) in which we hypothesized that PWD and caregiver characteristics and dyadic determinants contribute to spousal caregiver distress. This model was compared based on the age at onset of the disease and the gender of the caregiver (Step 2).

RESULTS: The model revealed that poor self-rated health and a lack of family support accentuated spousal caregiver distress, whereas the feeling of being prepared and level of confidence decreased spousal caregiver distress. Moreover, the quality of couple adjustment affected spousal caregiver distress, and this effect was mediated by the severity of the PWD's symptoms. Regarding the age at onset of the disease, the path between Couple Adjustment and the Care recipient's impairments was more important for caregivers of person with early-onset dementia (PEOD). Female caregivers who reported poor self-rated health experienced greater distress.

CONCLUSIONS: It would be interesting to create a support program that would incorporate these three areas of intervention regarding the progression of the disease: first, "preparedness modules"; second, "dyadic modules" (especially for caregivers of PEOD); and third, "family modules". Specific attention should be given to female caregivers who report poor self-rated health.

%B J Alzheimers Dis %V 55 %P 703-716 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716667?dopt=Abstract %R 10.3233/JAD-160558 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Modeling the Relationships Among Late-Life Body Mass Index, Cerebrovascular Disease, and Alzheimer's Disease Neuropathology in an Autopsy Sample of 1,421 Subjects from the National Alzheimer's Coordinating Center Data Set. %A Alosco, Michael L %A Duskin, Jonathan %A Besser, Lilah M %A Martin, Brett %A Chaisson, Christine E %A Gunstad, John %A Kowall, Neil W %A McKee, Ann C %A Stern, Robert A %A Tripodis, Yorghos %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Autopsy %K Body Mass Index %K Cerebrovascular Disorders %K Datasets as Topic %K Female %K Humans %K Male %K National Institute on Aging (U.S.) %K Neuropathology %K Neuropsychological Tests %K Retrospective Studies %K United States %X

The relationship between late-life body mass index (BMI) and Alzheimer's disease (AD) is poorly understood due to the lack of research in samples with autopsy-confirmed AD neuropathology (ADNP). The role of cerebrovascular disease (CVD) in the interplay between late-life BMI and ADNP is unclear. We conducted a retrospective longitudinal investigation and used joint modeling of linear mixed effects to investigate causal relationships among repeated antemortem BMI measurements, CVD (quantified neuropathologically), and ADNP in an autopsy sample of subjects across the AD clinical continuum. The sample included 1,421 subjects from the National Alzheimer's Coordinating Center's Uniform Data Set and Neuropathology Data Set with diagnoses of normal cognition (NC; n = 234), mild cognitive impairment (MCI; n = 201), or AD dementia (n = 986). ADNP was defined as moderate to frequent neuritic plaques and Braak stageIII-VI. Ischemic Injury Scale (IIS) operationalized CVD. Joint modeling examined relationships among BMI, IIS, and ADNP in the overall sample and stratified by initial visit Clinical Dementia Rating score. Subject-specific random intercept for BMI was the predictor for ADNP due to minimal BMI change (p = 0.3028). Analyses controlling for demographic variables and APOE ɛ4 showed lower late-life BMI predicted increased odds of ADNP in the overall sample (p < 0.001), and in subjects with CDR of 0 (p = 0.0021) and 0.5 (p = 0.0012), but not ≥1.0 (p = 0.2012). Although higher IIS predicted greater odds of ADNP (p < 0.0001), BMI did not predict IIS (p = 0.2814). The current findings confirm lower late-life BMI confers increased odds for ADNP. Lower late-life BMI may be a preclinical indicator of underlying ADNP.

%B J Alzheimers Dis %V 57 %P 953-968 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304301?dopt=Abstract %R 10.3233/JAD-161205 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Moderate Physical Activity is Associated with Cerebral Glucose Metabolism in Adults at Risk for Alzheimer's Disease. %A Dougherty, Ryan J %A Schultz, Stephanie A %A Kirby, Taylor K %A Boots, Elizabeth A %A Oh, Jennifer M %A Edwards, Dorothy %A Gallagher, Catherine L %A Carlsson, Cynthia M %A Bendlin, Barbara B %A Asthana, Sanjay %A Sager, Mark A %A Hermann, Bruce P %A Christian, Bradley T %A Johnson, Sterling C %A Cook, Dane B %A Okonkwo, Ozioma C %X

The objective of this study was to investigate the relationship between accelerometer-measured physical activity (PA) and glucose metabolism in asymptomatic late-middle-aged adults. Ninety-three cognitively healthy late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention participated in this cross-sectional study. They underwent 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging and wore an accelerometer (ActiGraph GT3X+) to measure free-living PA. Accelerometer data yielded measures of light (LPA), moderate (MPA), and vigorous (VPA) intensity PA. FDG-PET images were scaled to the cerebellum and pons, and cerebral glucose metabolic rate was extracted from specific regions of interest (ROIs) known to be hypometabolic in AD, i.e., hippocampus, posterior cingulate, inferior temporal cortex, and angular gyrus. Regression analyses were utilized to examine the association between PA and glucose metabolism, while adjusting for potential confounds. There were associations between MPA and glucose metabolism in all ROIs examined. In contrast, LPA was not associated with glucose uptake in any ROI and VPA was only associated with hippocampal FDG uptake. Secondary analyses did not reveal associations between sedentary time and glucose metabolism in any of the ROIs. Exploratory voxel-wise analysis identified additional regions where MPA was significantly associated with glucose metabolism including the precuneus, supramarginal gyrus, amygdala, and middle frontal gyrus. These findings suggest that the intensity of PA is an important contributor to neuronal function in a late-middle-aged cohort, with MPA being the most salient. Prospective studies are necessary for fully elucidating the link between midlife engagement in PA and later life development of AD.

%B J Alzheimers Dis %V 58 %P 1089-1097 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527205?dopt=Abstract %R 10.3233/JAD-161067 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Modifiable Risk Factors for Prevention of Dementia in Midlife, Late Life and the Oldest-Old: Validation of the LIBRA Index. %A Vos, Stephanie J B %A van Boxtel, Martin P J %A Schiepers, Olga J G %A Deckers, Kay %A de Vugt, Marjolein %A Carrière, Isabelle %A Dartigues, Jean-François %A Pérès, Karine %A Artero, Sylvaine %A Ritchie, Karen %A Galluzzo, Lucia %A Scafato, Emanuele %A Frisoni, Giovanni B %A Huisman, Martijn %A Comijs, Hannie C %A Sacuiu, Simona F %A Skoog, Ingmar %A Irving, Kate %A O'Donnell, Catherine A %A Verhey, Frans R J %A Visser, Pieter Jelle %A Köhler, Sebastian %X

BACKGROUND: Recently, the LIfestyle for BRAin health (LIBRA) index was developed to assess an individual's prevention potential for dementia.

OBJECTIVE: We investigated the predictive validity of the LIBRA index for incident dementia in midlife, late life, and the oldest-old.

METHODS: 9,387 non-demented individuals were recruited from the European population-based DESCRIPA study. An individual's LIBRA index was calculated solely based on modifiable risk factors: depression, diabetes, physical activity, hypertension, obesity, smoking, hypercholesterolemia, coronary heart disease, and mild/moderate alcohol use. Cox regression was used to test the predictive validity of LIBRA for dementia at follow-up (mean 7.2 y, range 1-16).

RESULTS: In midlife (55-69 y, n = 3,256) and late life (70-79 y, n = 4,320), the risk for dementia increased with higher LIBRA scores. Individuals in the intermediate- and high-risk groups had a higher risk of dementia than those in the low-risk group. In the oldest-old (80-97 y, n = 1,811), higher LIBRA scores did not increase the risk for dementia.

CONCLUSION: LIBRA might be a useful tool to identify individuals for primary prevention interventions of dementia in midlife, and maybe in late life, but not in the oldest-old.

%B J Alzheimers Dis %V 58 %P 537-547 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453475?dopt=Abstract %R 10.3233/JAD-161208 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Modified Frontal Behavioral Inventory (FBI-mod) for Patients with Frontotemporal Lobar Degeneration, Alzheimer's Disease, and Mild Cognitive Impairment. %A Suhonen, Noora-Maria %A Hallikainen, Ilona %A Hänninen, Tuomo %A Jokelainen, Jari %A Krüger, Johanna %A Hall, Anette %A Pikkarainen, Maria %A Soininen, Hilkka %A Remes, Anne M %X

While behavioral symptoms are both early and prevalent features of behavioral variant frontotemporal dementia (bvFTD), they can be present in other types of dementia as well, including Alzheimer's disease (AD) and even mild cognitive impairment (MCI). The Frontal Behavioral Inventory (FBI) was specifically developed to capture the behavioral and personality changes in bvFTD; it has also been modified into a self-administered caregiver questionnaire (FBI-mod). We examined the utility of the FBI-mod in differentiating bvFTD (n = 26), primary progressive aphasia (PPA) (n = 7), AD (n = 53), and MCI (n = 50) patients, and investigated how the FBI-mod may be associated with neuropsychological measures. The bvFTD patients scored significantly higher as compared to all other patient groups on the FBI-mod Total (p < 0.005), Negative (p < 0.005), and Positive (p < 0.01) scores. The cut-off point for the FBI-mod Total score that best discriminated the bvFTD and AD patients in our sample was 16, thus substantially lower than reported for the original FBI. For the bvFTD group, only mild correlations emerged between the FBI-mod and the cognitive measures. However, significant correlations between the FBI-mod and depressive symptoms as measured by the BDI-II were found for bvFTD. This suggests that while behavioral symptoms appear independent from cognitive deficits in bvFTD, they may nevertheless be interrelated with depressive symptoms. We conclude that the FBI-mod is an easily administered behavioral scale that can aid in differential diagnosis of bvFTD and should be used in clinical practice. The FBI-mod may further be considered as an outcome measure in clinical trials.

%B J Alzheimers Dis %V 56 %P 1241-1251 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106561?dopt=Abstract %R 10.3233/JAD-160983 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Modulating the Balance of Synaptic and Extrasynaptic NMDA Receptors Shows Positive Effects against Amyloid-β-Induced Neurotoxicity. %A Huang, Yan %A Shen, Wei %A Su, Jie %A Cheng, Bin %A Li, Dong %A Liu, Gang %A Zhou, Wen-Xia %A Zhang, Yong-Xiang %K Amyloid beta-Peptides %K Animals %K Antimetabolites %K Cycloserine %K Disease Models, Animal %K Excitatory Amino Acid Antagonists %K Excitatory Postsynaptic Potentials %K Hippocampus %K Locomotion %K Male %K Maze Learning %K N-Methylaspartate %K Nesting Behavior %K Neurotoxicity Syndromes %K Peptide Fragments %K Piperidines %K Rats %K Rats, Wistar %K Receptors, N-Methyl-D-Aspartate %K Recognition (Psychology) %K Signal Transduction %K Synapses %X

Alzheimer's disease (AD) patients suffer a disturbance in the balance between synaptic (GluN2A, mediating the protective pathway) and extrasynaptic NMDA receptors (NMDARs) (GluN2B, mediating the excitotoxic pathway), and, therefore, restoring the balance of GluN2A and GluN2B should be beneficial for AD. In this study, the GluN2B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effect on amyloid-β (Aβ)-induced long-term potentiation deficits. Enhancing the activity of GluN2A had a protective effect against Aβ, and specific activation of GluN2A and inhibition of GluN2B showed a better protective effect. In Aβ ICV-injected animals, the combination of ifenprodil and D-cycloserine (a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests (nest building, novel object recognition, and Morris water maze) than ifenprodil (Morris water maze) or D-cycloserine (nest building) alone. Signal pathway analysis showed that Aβ disturbed the GluN2A/GluN2B-related pathway. The ratio of GluN2A to GluN2B decreased in Aβ-treated animals, and TORC dephosphorylation and ERK1/2 activation, which could be initiated by GluN2A, also decreased in the hippocampal tissues of Aβ-treated animals. As a result, the activation of CREB and the content of brain-derived BDNF decreased. The combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone, indicating that Aβ-induced toxicology was mediated both by functionally inhibiting GluN2A and enhancing GluN2B. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Aβ-induced neurotoxicity, suggesting that modulation of the balance between GluN2A and GluN2B could be a potential strategy for AD drug development and therapy.

%B J Alzheimers Dis %V 57 %P 885-897 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269783?dopt=Abstract %R 10.3233/JAD-161186 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Modulation of AβPP and GSK3β by Endoplasmic Reticulum Stress and Involvement in Alzheimer's Disease. %A Liu, Xin-Jun %A Wei, Jun %A Shang, Ying-Hui %A Huang, Han-Chang %A Lao, Feng-Xue %X

Alzheimer's disease (AD) is a dementia disease with neuronal loss and synaptic impairment. This impairment is caused, at least partly, by the generation of two main AD hallmarks, namely the hyperphosphorylated tau protein comprising neurofibrillary tangles and senile plaques containing amyloid-β (Aβ) peptides. The amyloid-β protein precursor (AβPP) and glycogen synthase kinase-3β (GSK3β) are two main proteins associated with AD and are closely correlated with these hallmarks. Recently, both of the proteins were reported to be modulated by endoplasmic reticulum stress (ERS) and are involved in the pathogenesis of AD. The mechanism of ERS plus the modulation of AβPP processing and GSK3β activity by ERS in AD are summarized and explored in this review.

%B J Alzheimers Dis %V 57 %P 1157-1170 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28339396?dopt=Abstract %R 10.3233/JAD-161111 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Modulation of Immune Responses to Herpes Simplex Virus Type 1 by IFNL3 and IRF7 Polymorphisms: A Study in Alzheimer's Disease. %A Costa, Andrea Saul %A Agostini, Simone %A Guerini, Franca Rosa %A Mancuso, Roberta %A Zanzottera, Milena %A Ripamonti, Enrico %A Racca, Vittorio %A Nemni, Raffaello %A Clerici, Mario %X

Herpes simplex virus type 1 (HSV-1) has long been suspected to play a role in Alzheimer's disease (AD), the most common form of dementia. IFN-lambda (IFN-λ) is one of the key cytokine in innate antiviral defenses and, in particular, has an appreciable antiviral activity against HSV-1 infection. IFN-λ expression is regulated by the interaction between two different proteins: Mediator Complex 23 (MED23) and Interferon-Responsive Transcription Factor 7 (IRF7); single nucleotide polymorphisms (SNPs) in these genes as well as in IFNL3 were shown to be differently distributed in AD patients. In this study, allelic discrimination analysis for IFNL3 rs12979860, MED23 rs3756784, and IRF7 rs6598008, as well as IFN-λ serum concentration and anti-HSV-1 antibody (Ab) titers were performed in 79 AD patients, 57 mild cognitive impairment (MCI) individuals, and 81 healthy controls (HC) who were HSV-1-seropositive. Results showed that INF-λ serum concentration was increased in AD and MCI carrying the IFNL3 T allele compared to HC (AD versus HC: p = 0.014; MCI versus HC: p = 0.029), with the highest anti-HSV-1 Ab titers seen in AD patients carrying the IFNL3 CC genotype (p = 0.012 versus HC). Notably, anti-HSV-1 Ab titers were higher in AD and MCI individuals carrying the IRF7 AA genotype compared to HC (p = 0.018 for both). MED23 polymorphisms did not show any statistical association either with serum IFN-λ or with anti-HSV-1 Ab. Data herein suggest that the IFNL3 rs12979860 and IRF7 rs6598008 polymorphisms modulate immune responses against HSV-1 via their effect on the IFN-λ pathway. These results help to clarify the possible role of HSV-1 infection in AD pathogenesis.

%B J Alzheimers Dis %V 60 %P 1055-1063 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984602?dopt=Abstract %R 10.3233/JAD-170520 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Molecular Mechanisms Underlying Neuroprotective Effect of Intranasal Administration of Human Hsp70 in Mouse Model of Alzheimer's Disease. %A Evgen'ev, Michail B %A Krasnov, George S %A Nesterova, Inna V %A Garbuz, David G %A Karpov, Vadim L %A Morozov, Alexey V %A Snezhkina, Anastasiya V %A Samokhin, Alexander N %A Sergeev, Alexander %A Kulikov, Alexei M %A Bobkova, Natalia V %X

Heat shock protein 70, encoded by the HSPA1A gene in humans, is a key component of the machinery that protects neuronal cells from various stress conditions and whose production significantly declines during the course of aging and as a result of several neurodegenerative diseases. Herein, we investigated whether sub-chronic intranasal administration of exogenous Hsp70 (eHsp70) exerts a neuroprotective effect on the temporal cortex and areas of the hippocampus in transgenic 5XFAD mice, a model of Alzheimer's disease. The quantitative analysis of neuronal pathologies in the compared groups, transgenic (Tg) versus non-transgenic (nTg), revealed high level of abnormalities in the brains of transgenic mice. Treatment with human recombinant Hsp70 had profound rejuvenation effect on both neuronal morphology and functional state in the temporal cortex and hippocampal regions in transgenic mice. Hsp70 administration had a smaller, but still significant, effect on the functional state of neurons in non-transgenic mice as well. Using deep sequencing, we identified multiple differentially expressed genes (DEGs) in the hippocampus of transgenic and non-transgenic mice. Furthermore, this analysis demonstrated that eHsp70 administration strongly modulates the spectrum of DEGs in transgenic animals, reverting to a pattern similar to that observed in non-transgenic age-matched mice, which included upregulation of genes responsible for amine transport, transmission of nerve impulses and other pathways that are impaired in 5XFAD mice. Overall, our data indicate that Hsp70 treatment may be an effective therapeutic against old age diseases of the Alzheimer's type.

%B J Alzheimers Dis %V 59 %P 1415-1426 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28759972?dopt=Abstract %R 10.3233/JAD-170398 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Montreal Cognitive Assessment: Normative Data from a Large Swedish Population-Based Cohort. %A Borland, Emma %A Nägga, Katarina %A Nilsson, Peter M %A Minthon, Lennart %A Nilsson, Erik D %A Palmqvist, Sebastian %X

BACKGROUND: The Montreal Cognitive Assessment (MoCA) has a high sensitivity for detecting cognitive dysfunction. Swedish normative data does not exist and international norms are often derived from populations where cognitive impairment has not been screened for and not been thoroughly assessed to exclude subjects with dementia or mild cognitive impairment.

OBJECTIVE: To establish norms for MoCA and develop a regression-based norm calculator based on a large, well-examined cohort.

METHODS: MoCA was administered on 860 randomly selected elderly people from a population-based cohort from the EPIC study. Cognitive dysfunction was screened for and further assessed at a memory clinic. After excluding cognitively impaired participants, normative data was derived from 758 people, aged 65-85.

RESULTS: MoCA cut-offs (-1 to -2 standard deviations) for cognitive impairment ranged from <25 to <21 for the lowest educated and <26 to <24 for the highest educated, depending on age group. Significant predictors for MoCA score were age, sex and level of education.

CONCLUSION: We present detailed normative MoCA data and cut-offs according to the DSM-5 criteria for cognitive impairment based on a large population-based cohort of elderly individuals, screened and thoroughly investigated to rule out cognitive impairment. Level of education, sex, and age should be taken in account when evaluating MoCA score, which is facilitated by our online regression-based calculator that provide percentile and z-score for a subject's MoCA score.

%B J Alzheimers Dis %V 59 %P 893-901 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697562?dopt=Abstract %R 10.3233/JAD-170203 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Mortality Risk after Diagnosis of Early-Onset Alzheimer's Disease versus Late-Onset Alzheimer's Disease: A Propensity Score Matching Analysis. %A Chang, Ki Jung %A Hong, Chang Hyung %A Lee, Kang Soo %A Kang, Dae Ryong %A Lee, Jeong Dong %A Choi, Seong Hye %A Kim, Seong Yoon %A Na, Duk L %A Seo, Sang Won %A Kim, Do-Kwan %A Lee, Yunhwan %A Chung, Young Ki %A Lim, Ki Young %A Noh, Jai Sung %A Park, Jungsik %A Son, Sang Joon %X

BACKGROUND/OBJECTIVE: We aimed to compare the risk of mortality in patients with early-onset Alzheimer's disease (EOAD) versus those with late-onset AD (LOAD) using a large number of study subjects. We applied propensity score matching (PSM) to minimize confounding biases in the comparison between EOAD and LOAD.

METHODS: We obtained data from elderly Korean subjects with AD (n = 3,611) at baseline from the CREDOS cohort study, which was conducted from November 2005 to July 2013. We conducted PSM to reduce the bias due to confounding variables related to survival in patients with AD. The risks of mortality associated with EOAD and LOAD were evaluated by Cox proportional hazard analyses, controlling for relevant covariates.

RESULTS: After propensity score matching, 312 subjects with EOAD and 624 subjects with LOAD were selected for further analysis. The Cox proportional hazard analysis showed that patients with EOAD are at a greater risk for mortality compared to those with LOAD (Hazard Ratio: 2.01, 95% CI: 1.01-4.00, p-value: 0.04) when controlling for the direct effect of aging on mortality. The results did not change after adjusting for age at diagnosis, general cognitive function, nutritional factor related to body mass index, and physical disability using activities of daily living. The results support the assumption that EOAD takes a more malignant course than LOAD.

CONCLUSIONS: Our results provide support for the idea that EOAD takes a clinical course that is distinct from that of LOAD, especially as pertains to the risk of mortality.

%B J Alzheimers Dis %V 56 %P 1341-1348 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157103?dopt=Abstract %R 10.3233/JAD-161181 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Motor Phenotype in Neurodegenerative Disorders: Gait and Balance Platform Study Design Protocol for the Ontario Neurodegenerative Research Initiative (ONDRI). %A Montero-Odasso, Manuel %A Pieruccini-Faria, Frederico %A Bartha, Robert %A Black, Sandra E %A Finger, Elizabeth %A Freedman, Morris %A Greenberg, Barry %A Grimes, David A %A Hegele, Robert A %A Hudson, Christopher %A Kleinstiver, Peter W %A Lang, Anthony E %A Masellis, Mario %A McLaughlin, Paula M %A Munoz, Douglas P %A Strother, Stephen %A Swartz, Richard H %A Symons, Sean %A Tartaglia, Maria Carmela %A Zinman, Lorne %A Strong, Michael J %A McIlroy, William %X

BACKGROUND: The association of cognitive and motor impairments in Alzheimer's disease and other neurodegenerative diseases is thought to be related to damage in the common brain networks shared by cognitive and cortical motor control processes. These common brain networks play a pivotal role in selecting movements and postural synergies that meet an individual's needs. Pathology in this "highest level" of motor control produces abnormalities of gait and posture referred to as highest-level gait disorders. Impairments in cognition and mobility, including falls, are present in almost all neurodegenerative diseases, suggesting common mechanisms that still need to be unraveled.

OBJECTIVE: To identify motor-cognitive profiles across neurodegenerative diseases in a large cohort of patients.

METHODS: Cohort study that includes up to 500 participants, followed every year for three years, across five neurodegenerative disease groups: Alzheimer's disease/mild cognitive impairment, frontotemporal degeneration, vascular cognitive impairment, amyotrophic lateral sclerosis, and Parkinson's disease. Gait and balance will be assessed using accelerometers and electronic walkways, evaluated at different levels of cognitive and sensory complexity, using the dual-task paradigm.

RESULTS: Comparison of cognitive and motor performances across neurodegenerative groups will allow the identification of motor-cognitive phenotypes through the standardized evaluation of gait and balance characteristics.

CONCLUSIONS: As part of the Ontario Neurodegenerative Research Initiative (ONDRI), the gait and balance platform aims to identify motor-cognitive profiles across neurodegenerative diseases. Gait assessment, particularly while dual-tasking, will help dissect the cognitive and motor contribution in mobility and cognitive decline, progression to dementia syndromes, and future adverse outcomes including falls and mortality.

%B J Alzheimers Dis %V 59 %P 707-721 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671116?dopt=Abstract %R 10.3233/JAD-170149 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Motoric Cognitive Risk Syndrome: Association with Incident Dementia and Disability. %A Doi, Takehiko %A Shimada, Hiroyuki %A Makizako, Hyuma %A Tsutsumimoto, Kota %A Verghese, Joe %A Suzuki, Takao %X

BACKGROUND: It is important to examine the etiology of motoric cognitive risk syndrome (MCR) and its association with dementia and disability to obtain biological insights and to develop preventive strategies.

OBJECTIVE: This study aimed to examine the association of MCR with incidence of dementia and disability in a Japanese community-dwelling sample of older adults.

METHODS: Participants were 4,235 older adults (50% women, mean age: 72.0 years). MCR was diagnosed at baseline using established criteria in non-demented seniors with self-reported cognitive complaints and slow gait. Incident cases of dementia were identified from insurance data monthly. Disability was regarded as certification by long-term care insurance.

RESULTS: At baseline, 265 participants (6.3%) met criteria for MCR. During follow-up (mean duration: 29 months), there were 138 incident cases of dementia (3.3%) and 207 incident cases of disability (4.9%). Cox-proportional hazards models, adjusted for demographical data, lifestyle, and medical conditions, showed that presence of MCR at baseline was a major risk factor for developing dementia (HR 2.49, 95% CI 1.52-4.10, p < 0.001). MCR also predicted risk for disability (HR 1.69, 95% CI 1.08-2.02, p < 0.001).

CONCLUSIONS: MCR is helpful in the short-term prediction of risk for dementia and disability in the elderly Japanese population. Identification of seniors with MCR is recommended for early detection and instituting preventive measures for reducing the risk of dementia and disability.

%B J Alzheimers Dis %V 59 %P 77-84 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582865?dopt=Abstract %R 10.3233/JAD-170195 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Mouse Models of Alzheimer's Disease. %A Esquerda-Canals, Gisela %A Montoliu-Gaya, Laia %A Güell-Bosch, Jofre %A Villegas, Sandra %X

Alzheimer's disease (AD) is a neurodegenerative disorder that nowadays affects more than 40 million people worldwide and it is predicted to exponentially increase in the coming decades. Because no curative treatment exists, research on the pathophysiology of the disease, as well as the testing of new drugs, are mandatory. For these purposes, animal models constitute a valuable, although perfectible tool. This review takes a tour through several aspects of mouse models of AD, such as the generation of transgenic models, the relevance of the promoter driving the expression of the transgenes, and the concrete transgenes used to simulate AD pathophysiology. Then, transgenic mouse lines harboring mutated human genes at several loci such as APP, PSEN1, APOEɛ4, and ob (leptin) are reviewed. Therefore, not only the accumulation of the Aβ peptide is emulated but also cholesterol and insulin metabolism. Further novel information about the disease will allow for the development of more accurate animal models, which in turn will undoubtedly be helpful for bringing preclinical research closer to clinical trials in humans.

%B J Alzheimers Dis %V 57 %P 1171-1183 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304309?dopt=Abstract %R 10.3233/JAD-170045 %0 Journal Article %J J Alzheimers Dis %D 2017 %T mTORC2 (Rictor) in Alzheimer's Disease and Reversal of Amyloid-β Expression-Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons. %A Lee, Han-Kyu %A Kwon, Bumsup %A Lemere, Cynthia A %A de la Monte, Suzanne %A Itamura, Kyohei %A Ha, Austin Y %A Querfurth, Henry W %X

Mammalian target of rapamycin complex 1 (mTORC1), a nutrient sensor and central controller of cell growth and proliferation, is altered in various models of Alzheimer's disease (AD). Even less studied or understood in AD is mammalian target of rapamycin complex 2 (mTORC2) that influences cellular metabolism, in part through the regulations of Akt/PKB and SGK. Dysregulation of insulin/PI3K/Akt signaling is another important feature of AD pathogenesis. We found that both total mTORC1 and C2 protein levels and individual C1 and C2 enzymatic activities were decreased in human AD brain samples. In two rodent AD models, mTORC1 and C2 activities were also decreased. In a neuronal culture model of AD characterized by accumulation of cellular amyloid-β (Aβ)42, mTORC1 activity was reduced. Autophagic vesicles and markers were correspondingly increased and new protein synthesis was inhibited, consistent with mTORC1 hypofunction. Interestingly, mTORC2 activity in neural culture seemed resistant to the effects of intracellular amyloid. In various cell lines, Aβ expression provoked insulin resistance, characterized by inhibition of stimulated Akt phosphorylation, and an increase in negative mTORC1 regular, p-AMPK, itself a nutrient sensor. Rapamycin decreased phospho-mTOR and to lesser degree p-Rictor. This further suppression of mTORC1 activity protected cells from Aβ-induced toxicity and insulin resistance. More striking, Rictor over-expression fully reversed the Aβ-effects on primary neuronal cultures. Finally, using in vitro assay, Rictor protein addition completely overcame oligomeric Aβ-induced inhibition of the PDK-Akt activation step. We conclude that striking a new balance by restoring mTORC2 abundance and/or inhibition of mTORC1 has therapeutic potential in AD.

%B J Alzheimers Dis %V 56 %P 1015-1036 %G eng %N 3 %R 10.3233/JAD-161029 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Multi-Cohort Study of ApoE ɛ4 and Amyloid-β Effects on the Hippocampus in Alzheimer's Disease. %A Khan, Wasim %A Giampietro, Vincent %A Banaschewski, Tobias %A Barker, Gareth J %A Bokde, Arun L W %A Büchel, Christian %A Conrod, Patricia %A Flor, Herta %A Frouin, Vincent %A Garavan, Hugh %A Gowland, Penny %A Heinz, Anreas %A Ittermann, Bernd %A Lemaître, Hervé %A Nees, Frauke %A Paus, Tomas %A Pausova, Zdenka %A Rietschel, Marcella %A Smolka, Michael N %A Ströhle, Andreas %A Gallinat, Jeurgen %A Vellas, Bruno %A Soininen, Hilkka %A Kloszewska, Iwona %A Tsolaki, Magda %A Mecocci, Patrizia %A Spenger, Christian %A Villemagne, Victor L %A Masters, Colin L %A Muehlboeck, J-Sebastian %A Bäckman, Lars %A Fratiglioni, Laura %A Kalpouzos, Grégoria %A Wahlund, Lars-Olof %A Schumann, Gunther %A Lovestone, Simon %A Williams, Steven C R %A Westman, Eric %A Simmons, Andrew %X

The apolipoprotein E (APOE) gene has been consistently shown to modulate the risk of Alzheimer's disease (AD). Here, using an AD and normal aging dataset primarily consisting of three AD multi-center studies (n = 1,781), we compared the effect of APOE and amyloid-β (Aβ) on baseline hippocampal volumes in AD patients, mild cognitive impairment (MCI) subjects, and healthy controls. A large sample of healthy adolescents (n = 1,387) was also used to compared hippocampal volumes between APOE groups. Subjects had undergone a magnetic resonance imaging (MRI) scan and APOE genotyping. Hippocampal volumes were processed using FreeSurfer. In the AD and normal aging dataset, hippocampal comparisons were performed in each APOE group and in ɛ4 carriers with positron emission tomography Aβ who were dichotomized (Aβ+/Aβ-) using previous cut-offs. We found a linear reduction in hippocampal volumes with ɛ4 carriers possessing the smallest volumes, ɛ3 carriers possessing intermediate volumes, and ɛ2 carriers possessing the largest volumes. Moreover, AD and MCI ɛ4 carriers possessed the smallest hippocampal volumes and control ɛ2 carriers possessed the largest hippocampal volumes. Subjects with both APOE ɛ4 and Aβ+ had the lowest hippocampal volumes when compared to Aβ- ɛ4 carriers, suggesting a synergistic relationship between APOE ɛ4 and Aβ. However, we found no hippocampal volume differences between APOE groups in healthy 14-year-old adolescents. Our findings suggest that the strongest neuroanatomic effect of APOE ɛ4 on the hippocampus is observed in AD and groups most at risk of developing the disease, whereas hippocampi of old and young healthy individuals remain unaffected.

%B J Alzheimers Dis %V 56 %P 1159-1174 %8 2017 %G eng %N 3 %R 10.3233/JAD-161097 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Multifunctional Biocompatible Drug Candidate is Highly Effective in Delaying Pathological Signs of Alzheimer's Disease in 5XFAD Mice. %A Segal-Gavish, Hadar %A Danino, Ortal %A Barhum, Yael %A Ben-Zur, Tali %A Shai, Ella %A Varon, David %A Offen, Daniel %A Fischer, Bilha %X

BACKGROUND: Metal-ion-chelation was suggested to prevent zinc and copper ions-induced amyloid-β (Aβ) aggregation and oxidative stress, both implicated in the pathophysiology of Alzheimer's disease (AD). In a quest for biocompatible metal-ion chelators potentially useful for AD therapy, we previously tested a series of nucleoside 5'-phosphorothioate derivatives as agents for decomposition of Cu(I)/Cu(II)/Zn(II)-Aβ-aggregates, and as inhibitors of OH radicals formation in Cu(I) or Fe(II) /H2O2 solution. Specifically, in our recent study we have identified 2-SMe-ADP(α-S), designated as SAS, as a most promising neuroprotectant.

OBJECTIVE: To further explore SAS ability to protect the brain from Aβ toxicity both in vitro and in vivo.

METHODS: We evaluated SAS ability to decompose or inhibit the formation of Aβ42-M(II) aggregates, and rescue primary neurons and astrocytes from Aβ42 toxicity. Furthermore, we aimed at exploring the therapeutic effect of SAS on behavioral and cognitive deficits in the 5XFAD mouse model of AD.

RESULTS: We found that SAS can rescue primary culture of neurons and astrocytes from Aβ42 toxicity and to inhibit the formation and dissolve Aβ42-Zn(II)/Cu(II) aggregates. Furthermore, we show that SAS treatment can prevent behavioral disinhibition and ameliorate spatial working memory deficits in 5XFAD mice. Notably, the mice were treated at the age of 2 months, before the onset of AD symptoms, for a duration of 2 months, while the effect was demonstrated at the age of 6 months.

CONCLUSION: Our results indicate that SAS has the potential to delay progression of core pathological characteristics of AD in the 5XFAD mouse model.

%B J Alzheimers Dis %V 58 %P 389-400 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453480?dopt=Abstract %R 10.3233/JAD-161236 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Multifunctional Compound AD-35 Improves Cognitive Impairment and Attenuates the Production of TNF-α and IL-1β in an Aβ25-35-induced Rat Model of Alzheimer's Disease. %A Li, Lin %A Xu, Shaofeng %A Liu, Lifei %A Feng, Rentian %A Gong, Yongxiang %A Zhao, Xuyang %A Li, Jiang %A Cai, Jie %A Feng, Nan %A Wang, Ling %A Wang, Xiaoliang %A Peng, Ying %X

The dyshomeostasis of transition metal ions, accumulation of amyloid-β (Aβ) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer's disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-Aβ species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced Aβ aggregation in vitro and showed disassembly of Aβ aggregates. The effects of AD-35 on cognitive impairments and neuroinflammatory changes caused by intracerebroventricular injection of Aβ25-35 were studied in rats. Compared to sham group, Aβ25-35 injection significantly led to learning and memory deficits, astrocyte activation, and pro-inflammatory cytokines releases (TNF-α and IL-1β). Further studies indicated that the phosphorylation of extracellular signal-regulated kinase was involved in astrocyte activation and pro-inflammatory cytokines production. Oral administration of AD-35 could markedly attenuate Aβ25-35 injection-induced astrocyte activation, pro-inflammatory cytokines TNF-α and IL-1β release, and memory deficits. On the contrary, donepezil only showed inhibition of IL-1β production, but failed to block astrocyte activation and TNF-α production. These results showed that AD-35 would be a novel multi-mechanism drug for the prevention and/or treatment of AD.

%B J Alzheimers Dis %V 56 %P 1403-1417 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157092?dopt=Abstract %R 10.3233/JAD-160587 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Multimerization State of the Amyloid-β42 Amyloid Peptide Governs its Interaction Network with the Extracellular Matrix. %A Salza, Romain %A Lethias, Claire %A Ricard-Blum, Sylvie %X

The goals of this work were i) to identify the interactions of amyloid-β (Aβ)42 under monomeric, oligomeric, and fibrillar forms with the extracellular matrix (ECM) and receptors, ii) to determine the influence of Aβ42 supramolecular organization on these interactions, and iii) to identify the molecular functions, biological processes, and pathways targeted by Aβ42 in the ECM. The ECM and cell surface partners of Aβ42 and its supramolecular forms were identified with protein and glycosaminoglycan (GAG) arrays (81 molecules in triplicate) probed by surface plasmon resonance imaging. The number of partners of Aβ42 increased upon its multimerization, ranging from 4 for the peptide up to 53 for the fibrillar aggregates. The peptide interacted only with ECM proteins but their percentage among Aβ42 partners decreased upon multimerization. Aβ42 and its supramolecular forms recognized different molecular features on their partners, and the partners of Aβ42 fibrillar forms were enriched in laminin IV-A, N-terminal, and EGF-like domains. Aβ42 oligomerization triggered interactions with receptors, whereas Aβ42 fibrillogenesis promoted binding to GAGs, proteoglycans, enzymes, and growth factors and the ability to interact with perineuronal nets. Fibril aggregation bind to further membrane proteins including tumor endothelial marker-8, syndecan-4, and discoidin-domain receptor-2. The partners of the Aβ42 supramolecular forms are enriched in proteins contributing to cell growth and/or maintenance, involved in integrin cell surface interactions and expressed in kidney cancer, preadipocytes, and dentin. In conclusion, the supramolecular assembly of Aβ42 governs its ability to interact in vitro with ECM proteins, remodeling and crosslinking ECM enzymes, proteoglycans, and receptors.

%B J Alzheimers Dis %V 56 %P 991-1005 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106549?dopt=Abstract %R 10.3233/JAD-160751 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Multimodal Cognitive Enhancement Therapy for Patients with Mild Cognitive Impairment and Mild Dementia: A Multi- Center, Randomized, Controlled, Double-Blind, Crossover Trial. %A Han, Ji Won %A Lee, Hyeonggon %A Hong, Jong Woo %A Kim, Kayoung %A Kim, Taehyun %A Byun, Hye Jin %A Ko, Ji Won %A Youn, Jong Chul %A Ryu, Seung-Ho %A Lee, Nam-Jin %A Pae, Chi-Un %A Kim, Ki Woong %X

We developed and evaluated the effect of Multimodal Cognitive Enhancement Therapy (MCET) consisting of cognitive training, cognitive stimulations, reality orientation, physical therapy, reminiscence therapy, and music therapy in combination in older people with mild cognitive impairment (MCI) or mild dementia. This study was a multi-center, double-blind, randomized, placebo-controlled, two-period cross-over study (two 8-week treatment phases separated by a 4-week wash-out period). Sixty-four participants with MCI or dementia whose Clinical Dementia Rating was 0.5 or 1 were randomized to the MCET group or the mock-therapy (placebo) group. Outcomes were measured at baseline, week 9, and week 21. Fifty-five patients completed the study. Mini-Mental State Examination (effect size = 0.47, p = 0.013) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (effect size = 0.35, p = 0.045) scores were significantly improved in the MCET compared with mock-therapy group. Revised Memory and Behavior Problems Checklist frequency (effect size = 0.38, p = 0.046) and self-rated Quality of Life - Alzheimer's Disease (effect size = 0.39, p = 0.047) scores were significantly improved in the MCET compared with mock-therapy. MCET improved cognition, behavior, and quality of life in people with MCI or mild dementia more effectively than conventional cognitive enhancing activities did.

%B J Alzheimers Dis %V 55 %P 787-796 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802233?dopt=Abstract %R 10.3233/JAD-160619 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Multiple Mechanisms Linking Type 2 Diabetes and Alzheimer's Disease: Testosterone as a Modifier. %A Asih, Prita R %A Tegg, Michelle L %A Sohrabi, Hamid %A Carruthers, Malcolm %A Gandy, Samuel E %A Saad, Farid %A Verdile, Giuseppe %A Ittner, Lars M %A Martins, Ralph N %X

Evidence in support of links between type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) has increased considerably in recent years. AD pathological hallmarks include the accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated tau in the brain, which are hypothesized to promote inflammation, oxidative stress, and neuronal loss. T2DM exhibits many AD pathological features, including reduced brain insulin uptake, lipid dysregulation, inflammation, oxidative stress, and depression; T2DM has also been shown to increase AD risk, and with increasing age, the prevalence of both conditions increases. In addition, amylin deposition in the pancreas is more common in AD than in normal aging, and although there is no significant increase in cerebral Aβ deposition in T2DM, the extent of Aβ accumulation in AD correlates with T2DM duration. Given these similarities and correlations, there may be common underlying mechanism(s) that predispose to both T2DM and AD. In other studies, an age-related gradual loss of testosterone and an increase in testosterone resistance has been shown in men; low testosterone levels can also occur in women. In this review, we focus on the evidence for low testosterone levels contributing to an increased risk of T2DM and AD, and the potential of testosterone treatment in reducing this risk in both men and women. However, such testosterone treatment may need to be long-term, and would need regular monitoring to maintain testosterone at physiological levels. It is possible that a combination of testosterone therapy together with a healthy lifestyle approach, including improved diet and exercise, may significantly reduce AD risk.

%B J Alzheimers Dis %V 59 %P 445-466 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28655134?dopt=Abstract %R 10.3233/JAD-161259 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Music Perception in Dementia. %A Golden, Hannah L %A Clark, Camilla N %A Nicholas, Jennifer M %A Cohen, Miriam H %A Slattery, Catherine F %A Paterson, Ross W %A Foulkes, Alexander J M %A Schott, Jonathan M %A Mummery, Catherine J %A Crutch, Sebastian J %A Warren, Jason D %X

Despite much recent interest in music and dementia, music perception has not been widely studied across dementia syndromes using an information processing approach. Here we addressed this issue in a cohort of 30 patients representing major dementia syndromes of typical Alzheimer's disease (AD, n = 16), logopenic aphasia (LPA, an Alzheimer variant syndrome; n = 5), and progressive nonfluent aphasia (PNFA; n = 9) in relation to 19 healthy age-matched individuals. We designed a novel neuropsychological battery to assess perception of musical patterns in the dimensions of pitch and temporal information (requiring detection of notes that deviated from the established pattern based on local or global sequence features) and musical scene analysis (requiring detection of a familiar tune within polyphonic harmony). Performance on these tests was referenced to generic auditory (timbral) deviance detection and recognition of familiar tunes and adjusted for general auditory working memory performance. Relative to healthy controls, patients with AD and LPA had group-level deficits of global pitch (melody contour) processing while patients with PNFA as a group had deficits of local (interval) as well as global pitch processing. There was substantial individual variation within syndromic groups. Taking working memory performance into account, no specific deficits of musical temporal processing, timbre processing, musical scene analysis, or tune recognition were identified. The findings suggest that particular aspects of music perception such as pitch pattern analysis may open a window on the processing of information streams in major dementia syndromes. The potential selectivity of musical deficits for particular dementia syndromes and particular dimensions of processing warrants further systematic investigation.

%B J Alzheimers Dis %V 55 %P 933-949 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802226?dopt=Abstract %R 10.3233/JAD-160359 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Natural Product Curcumin as a Potential Coadjuvant in Alzheimer's Treatment. %A Morales, Inelia %A Cerda-Troncoso, Cristóbal %A Andrade, Víctor %A Maccioni, Ricardo B %X

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive cognitive impairment of patients, affecting around 12% of people older than 65 years old. WHO estimated that over 48.6 million all over the world suffer this disease. On the basis of cumulative results on our research, we have postulated the neuroimmunomodulation hypothesis that appears to provide a reasonable explanation of both the preclinical and clinical observations. In this context, the long-term activation of the innate immune system triggers an anomalous cascade of molecular signals, finally leading to tau oligomerization in the pathway to neuronal degeneration. In the present scenario of the failure of many anti-AD drugs, nutraceutical compounds provide an avenue for AD prevention and possibly as coadjuvants in the treatment of this disease. Recent discoveries point to the relevance of curcumin, a natural anti-inflammatory agent, in controlling oxidative stress and improving cholinergic function in the brain, even though the mechanisms underlying these actions are unknown. We investigated the effects of curcumin in cultures of neuronal cells. For this study, we exposed cells to prooxidant conditions, both in the presence and absence of curcumin. Our data reveal that curcumin exert a strong neuroprotective effect in N2a cells, thus preventing toxicity by oxidative agents H2O2 and Fe +3. This is supported by results that indicate that curcumin control the neurodegenerative effects of both oxidative agents, relieving cells from the loss of neuritogenic processes induced by prooxidants. In addition, curcumin was able to slow down the tau aggregation curve and disassemble tau pathological oligomeric structures. Data suggest that curcumin could be a potential compound for prevention of cognitive disorders associated with AD.

%B J Alzheimers Dis %V 60 %P 451-460 %G eng %N 2 %R 10.3233/JAD-170354 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Network-Based Substrate of Cognitive Reserve in Alzheimer's Disease. %A Serra, Laura %A Mancini, Matteo %A Cercignani, Mara %A Di Domenico, Carlotta %A Spanò, Barbara %A Giulietti, Giovanni %A Koch, Giacomo %A Marra, Camillo %A Bozzali, Marco %X

Cognitive reserve (CR) is known to modulate the clinical features of Alzheimer's disease (AD). This concept may be critical for the development of non-pharmacological interventions able to slow down patients' cognitive decline in the absence of disease-modifying treatments. We aimed at identifying the neurobiological substrates of CR (i.e., neural reserve) over the transition between normal aging and AD, by assessing the underlying brain networks and their topological properties. A cohort of 154 participants (n = 68 with AD, n = 61 with amnestic mild cognitive impairment (aMCI), and 25 healthy subjects) underwent resting-state functional MRI and neuropsychological testing. Within each group, participants were classified as having high or low CR, and functional connectivity measures were compared, within group, between high and low CR individuals. Network-based statistics and topological network properties derived from graph theory were explored. Connectivity differences between high and low CR were evident only for aMCI patients, with participants with high CR showing a significant increase of connectivity in a network involving mainly fronto-parietal nodes. Conversely, they showed significantly decreased connectivity in a network involving fronto-temporo-cerebellar nodes. Consistently, changes to topological measures were observed in either direction, and were associated with measures of global cognitive function. These findings support the hypothesis that CR impacts on neurodegenerative process in the early phase of AD only. In addition, they fit with the existence of a "neural reserve", characterized by specific neural networks and their efficiency. It remains to be demonstrated whether interventions later in life can modulate this "neural reserve".

%B J Alzheimers Dis %V 55 %P 421-430 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662319?dopt=Abstract %R 10.3233/JAD-160735 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neural Basis of Apathy in Patients with Amnestic Mild Cognitive Impairment. %A Kazui, Hiroaki %A Takahashi, Ryuichi %A Yamamoto, Yuki %A Yoshiyama, Kenji %A Kanemoto, Hideki %A Suzuki, Yukiko %A Sato, Shunsuke %A Azuma, Shingo %A Suehiro, Takashi %A Shimosegawa, Eku %A Ishii, Kazunari %A Tanaka, Toshihisa %X

BACKGROUND: Although apathy is associated with damage to the frontal and temporal lobes in Alzheimer's disease (AD), the crucial regions for apathy in patients with amnestic mild cognitive impairment (aMCI) are unknown.

OBJECTIVE: To identify brain regions associated with apathy in aMCI patients.

METHODS: The subjects of this study were 98 aMCI patients who were entered in our dementia registry between March 1, 2009 and April 30, 2015 and who satisfied our criteria for aMCI. The association between the apathy score of the Neuropsychiatric Inventory and regional gray matter volume was analyzed using voxel-based morphometry. The association between apathy score and regional cerebral blood flow (rCBF) measured with single photon emission computed tomography (SPECT) was analyzed using Statistical Parametric Mapping.

RESULTS: The aMCI patients were classified into aMCI with and without "SPECT images suggestive of AD" (aMCI-AD+ and aMCI-AD-, respectively) based on the Z-score summation analysis method. In aMCI-AD+ (n = 31), apathy was significantly and negatively correlated with gray matter volume in the right caudate nucleus and with rCBF in five regions (left posterior-medial frontal lobe, right superior frontal lobe, bilateral culmen-fusiform gyri, and left occipital lobe). In aMCI-AD-(n = 67), apathy was significantly and negatively correlated with gray matter volumes in five regions but it was not correlated with rCBF in any regions.

CONCLUSION: In patients with a high probability of being in the aMCI stage of AD, apathy was associated with atrophy of the right caudate nucleus and hypoperfusion in the frontal, temporal and occipital lobes.

%B J Alzheimers Dis %V 55 %P 1403-1416 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858707?dopt=Abstract %R 10.3233/JAD-160223 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neural Correlates of Self-Reference Effect in Early Alzheimer's Disease. %A Gaubert, Malo %A Villain, Nicolas %A Landeau, Brigitte %A Mézenge, Florence %A Egret, Stéphanie %A Perrotin, Audrey %A Belliard, Serge %A de la Sayette, Vincent %A Eustache, Francis %A Desgranges, Béatrice %A Chételat, Gaël %A Rauchs, Géraldine %X

Information that is processed with reference to the self (i.e., self-referential processing, SRP) is generally associated with better remembering than information processed in a semantic condition. This benefit of self on memory performance is called self-reference effect (SRE). In the present study, we assessed changes in the SRE and SRP-related brain activity in patients diagnosed with mild cognitive impairment or early Alzheimer's disease (MCI/AD). Fifteen patients with confirmed amyloid-β deposits (positive florbetapir-PET scan) and 28 healthy controls (negative florbetapir-PET scan) were included. Participants either had to judge personality trait adjectives with reference to themselves (self condition) or to a celebrity (other condition), or determine whether these adjectives were positive or not (semantic condition). These adjectives were then presented with distractors in a surprise recognition task. Functional MRI data were acquired during both the judgment and recognition tasks. The SRE was observed in controls, but reduced in patients. Both controls and patients activated cortical midline structures when judging items with reference to themselves, but patients exhibited reduced activity in the angular gyrus. In patients, activity at encoding in the angular gyrus positively correlated with subsequent recognition accuracy in the self condition (self accuracy). This region also exhibited significant hypometabolism and Aβ burden, both related to self accuracy. By contrast, there were no differences in brain activity during recognition, either between the self and semantic conditions, or between groups. These results highlight SRE impairment in patients with MCI/AD, despite intact activity in cortical midline structures, and suggest that dysfunction of the angular gyrus is related to this impairment.

%B J Alzheimers Dis %V 56 %P 717-731 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035923?dopt=Abstract %R 10.3233/JAD-160561 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neural Dynamics of Multiple Object Processing in Mild Cognitive Impairment and Alzheimer's Disease: Future Early Diagnostic Biomarkers? %A Bagattini, Chiara %A Mazza, Veronica %A Panizza, Laura %A Ferrari, Clarissa %A Bonomini, Cristina %A Brignani, Debora %X

The aim of this study was to investigate the behavioral and electrophysiological dynamics of multiple object processing (MOP) in mild cognitive impairment (MCI) and Alzheimer's disease (AD), and to test whether its neural signatures may represent reliable diagnostic biomarkers. Behavioral performance and event-related potentials [N2pc and contralateral delay activity (CDA)] were measured in AD, MCI, and healthy controls during a MOP task, which consisted in enumerating a variable number of targets presented among distractors. AD patients showed an overall decline in accuracy for both small and large target quantities, whereas in MCI patients, only enumeration of large quantities was impaired. N2pc, a neural marker of attentive individuation, was spared in both AD and MCI patients. In contrast, CDA, which indexes visual short term memory abilities, was altered in both groups of patients, with a non-linear pattern of amplitude modulation along the continuum of the disease: a reduction in AD and an increase in MCI. These results indicate that AD pathology shows a progressive decline in MOP, which is associated to the decay of visual short-term memory mechanisms. Crucially, CDA may be considered as a useful neural signature both to distinguish between healthy and pathological aging and to characterize the different stages along the AD continuum, possibly becoming a reliable candidate for an early diagnostic biomarker of AD pathology.

%B J Alzheimers Dis %V 59 %P 643-654 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671112?dopt=Abstract %R 10.3233/JAD-161274 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neurocognitive and Behavioral Indexes for Identifying the Amnestic Subtypes of Mild Cognitive Impairment. %A Cid-Fernández, Susana %A Lindín, Mónica %A Díaz, Fernando %X

Early identification of amnestic mild cognitive impairment (aMCI) subtypes is important for early diagnosis and prognosis of Alzheimer's disease. Healthy, single-domain (sdaMCI) and multiple-domain aMCI (mdaMCI) participants performed an auditory-visual distraction-attention task. Event-related brain potentials (ERPs) were recorded while the participants performed the task to evaluate Go/NoGo N2 and P3 ERP components. The results showed the expected behavioral and cognitive decline in mdaMCI participants relative to controls (fewer hits, longer reaction times [RTs], slightly smaller Go-N2 and NoGo-N2 amplitudes), while sdaMCI participants showed some decline (slightly longer RTs, smaller Go- and NoGo-N2 amplitudes) along with some unexpected results (a late positive slow wave, PSW) and good levels of execution. In addition, some of these parameters proved to be useful markers. Thus, the number of hits was the best marker for diagnosing mdaMCI participants (distinguishing them from controls, from sdaMCI participants, and from both groups together), while the PSW amplitude was the best marker for diagnosing sdaMCI participants (distinguishing them from controls, and from control & mdaMCI participants).

%B J Alzheimers Dis %V 60 %P 633-649 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869473?dopt=Abstract %R 10.3233/JAD-170369 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer's Disease. %A Ferguson, Sherry A %A Panos, John J %A Sloper, Daniel %A Varma, Vijayalakshmi %X

BACKGROUND: Alzheimer's disease (AD) presents with an earlier onset age and increased symptom severity in African Americans and Hispanics.

OBJECTIVE: Although the prevalence of plaques and tangles may not exhibit ethnicity-related differences, levels of neurodegenerative proteins have not been described.

METHODS: Here, levels of five proteins (i.e., S100B, sRAGE, GDNF, Aβ40, and Aβ42) and the Aβ42/Aβ40 ratio were measured in postmortem samples of the middle temporal gyrus (BA21) from age-matched African Americans and Caucasians with AD (n = 6/gender/ethnicity).

RESULTS: S100B levels were increased 17% in African Americans (p < 0.003) while sRAGE was mildly decreased (p < 0.09). Aβ42 levels were increased 121% in African Americans (p < 0.02), leading to a 493% increase in the Aβ42/Aβ40 ratio (p < 0.002). Analysis of GDNF levels did not indicate any significant effects. There were no significant effects of gender and no significant ethnicity with gender interactions on any analyte. Effect size calculations indicated "medium" to "very large" effects.

CONCLUSION: S100B is typically elevated in AD cases; however, the increased levels in African Americans here may be indicative of increased severity in specific populations. Increased Aβ42/Aβ40 ratios in the current study are compatible with increased disease severity and might indicate increased AD pathogenesis in African Americans. Overall, these results are compatible with a hypothesis of increased neuroinflammation in African Americans with AD.

%B J Alzheimers Dis %V 59 %P 57-66 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582866?dopt=Abstract %R 10.3233/JAD-170204 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neurofibrillary Tangles of Aβx-40 in Alzheimer's Disease Brains. %A Lacosta, Ana-María %A Insua, Daniel %A Badi, Hassnae %A Pesini, Pedro %A Sarasa, Manuel %X

The two pathognomonic lesions in the brain of AD patients are senile plaques and intraneuronal neurofibrillary tangles (NFT). Previous studies have demonstrated that amyloid-β (Aβ) is a component of both senile plaques and NFTs, and have showed that intracellular accumulation of Aβ is toxic for cells and precedes the appearance of extracellular amyloid deposits. Here we report that there are numerous intraneuronal NFT and extraneuronal NFT immunoreactive for Aβx-40 in which there is no co-localization with tau staining suggesting the existence of two different neurodegenerating populations associated with the intracellular accumulation of either tau protein or Aβx-40 in AD.

%B J Alzheimers Dis %V 58 %P 661-667 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453491?dopt=Abstract %R 10.3233/JAD-170163 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neuroimaging and its Relevance to Understanding Pathways Linking Diabetes and Cognitive Dysfunction. %A Moran, Chris %A Beare, Richard %A Phan, Thanh %A Starkstein, Sergio %A Bruce, David %A Romina, Mizrahi %A Srikanth, Velandai %X

Diabetes mellitus is associated with an elevated risk of cognitive impairment and dementia. Cerebrovascular disease and neurodegeneration are two major pathways that may explain the effect of diabetes on the brain and therefore deserve investigation. Neuroimaging provides an effective way to investigate the contribution of these pathways in vivo, guiding further mechanistic research and providing biomarkers for clinical correlation or interventional studies. In this paper, we present a narrative review of the state of play with neuroimaging evidence in studies of people with diabetes mellitus, how these data are useful in understanding mechanistic links between diabetes and brain impairment, and possible ways that the field may develop in the future.

%B J Alzheimers Dis %V 59 %P 405-419 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527209?dopt=Abstract %R 10.3233/JAD-161166 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neuroimaging Feature Terminology: A Controlled Terminology for the Annotation of Brain Imaging Features. %A Iyappan, Anandhi %A Younesi, Erfan %A Redolfi, Alberto %A Vrooman, Henri %A Khanna, Shashank %A Frisoni, Giovanni B %A Hofmann-Apitius, Martin %X

Ontologies and terminologies are used for interoperability of knowledge and data in a standard manner among interdisciplinary research groups. Existing imaging ontologies capture general aspects of the imaging domain as a whole such as methodological concepts or calibrations of imaging instruments. However, none of the existing ontologies covers the diagnostic features measured by imaging technologies in the context of neurodegenerative diseases. Therefore, the Neuro-Imaging Feature Terminology (NIFT) was developed to organize the knowledge domain of measured brain features in association with neurodegenerative diseases by imaging technologies. The purpose is to identify quantitative imaging biomarkers that can be extracted from multi-modal brain imaging data. This terminology attempts to cover measured features and parameters in brain scans relevant to disease progression. In this paper, we demonstrate the systematic retrieval of measured indices from literature and how the extracted knowledge can be further used for disease modeling that integrates neuroimaging features with molecular processes.

%B J Alzheimers Dis %V 59 %P 1153-1169 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731430?dopt=Abstract %R 10.3233/JAD-161148 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neuronal Expression of Truncated Tau Efficiently Promotes Neurodegeneration in Animal Models: Pitfalls of Toxic Oligomer Analysis. %A Skrabana, Rostislav %A Kovacech, Branislav %A Filipcik, Peter %A Zilka, Norbert %A Jadhav, Santosh %A Smolek, Tomas %A Kontsekova, Eva %A Novak, Michal %X

Animal models of neurodegeneration induced by neuronal expression of truncated tau protein emerge as an important tool for understanding the pathogenesis of human tauopathies and for therapy development. Here we highlight common features of truncated tau models and make a critical assessment of possible pitfalls in their analysis. Particularly, the amount of soluble tau oligomers, which are suspected to be neurotoxic agents participating on the spreading of pathology inside the brain, may be overestimated due to a post-lysis oxidative tau oligomerization. Using a mouse brain lysate spiked with recombinant truncated and full length tau forms, we show that tau oligomers might inadvertently be produced during the isolation procedure. This finding is further corroborated by the analysis of brain lysates originated from a mouse model expressing truncated tau variant. Our results underline the necessity of thiol-protecting conditions during the analysis of tau oligomers involved in the etiopathogenesis of various tauopathies including Alzheimer's disease.

%B J Alzheimers Dis %V 58 %P 1017-1025 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527208?dopt=Abstract %R 10.3233/JAD-161124 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neurons Derived from Induced Pluripotent Stem Cells of Patients with Down Syndrome Reproduce Early Stages of Alzheimer's Disease Type Pathology in vitro. %A Dashinimaev, Erdem B %A Artyuhov, Alexander S %A Bolshakov, Alexey P %A Vorotelyak, Ekaterina A %A Vasiliev, Andrey V %X

People with Down syndrome (DS) are at high risk of developing pathology similar to Alzheimer's disease (AD). Modeling of this pathology in vitro may be useful for studying this phenomenon. In this study, we analyzed three different cultures of neural cells carrying trisomy of chromosome 21, which were generated by directed differentiation from induced pluripotent stem cells (iPS cells). We report here that in vitro generated DS neural cells have abnormal metabolism of amyloid-β (Aβ) manifested by increased secretion and accumulation of Aβ granules of Aβ42 pathological isoform with upregulated expression of the APP gene. Additionally, we found increased expression levels of genes that are considered to be associated with AD (BACE2, RCAN1, ETS2, TMED10), as compared to healthy controls. Thus, the neural cells generated from induced pluripotent stem cells with DS reproduce initial cellular signs of AD-type pathology and can be useful tools for modeling and studying this variant of AD in vitro.

%B J Alzheimers Dis %V 56 %P 835-847 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059787?dopt=Abstract %R 10.3233/JAD-160945 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neuroprotective Effect of TREM-2 in Aging and Alzheimer's Disease Model. %A Raha, Animesh Alexander %A Henderson, James W %A Stott, Simon R W %A Vuono, Romina %A Foscarin, Simona %A Friedland, Robert P %A Zaman, Shahid H %A Raha-Chowdhury, Ruma %X

Neuroinflammation and activation of innate immunity are early events in neurodegenerative diseases including Alzheimer's disease (AD). Recently, a rare mutation in the gene Triggering receptor expressed on myeloid cells 2 (TREM2) has been associated with a substantial increase in the risk of developing late onset AD. To uncover the molecular mechanisms underlying this association, we investigated the RNA and protein expression of TREM2 in APP/PS1 transgenic mice. Our findings suggest that TREM2 not only plays a critical role in inflammation, but is also involved in neuronal cell survival and in neurogenesis. We have shown that TREM2 is a soluble protein transported by macrophages through ventricle walls and choroid plexus, and then enters the brain parenchyma via radial glial cells. TREM2 protein is essential for neuroplasticity and myelination. During the late stages of life, a lack of TREM2 protein may accelerate aging processes and neuronal cell loss and reduce microglial activity, ultimately leading to neuroinflammation. As inflammation plays a major role in neurodegenerative diseases, a lack of TREM2 could be a missing link between immunomodulation and neuroprotection.

%B J Alzheimers Dis %V 55 %P 199-217 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662313?dopt=Abstract %R 10.3233/JAD-160663 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neuropsychiatric Symptoms and Alzheimer's Disease Biomarkers Predict Driving Decline: Brief Report. %A Babulal, Ganesh M %A Stout, Sarah H %A Head, Denise %A Holtzman, David M %A Fagan, Anne M %A Morris, John C %A Roe, Catherine M %X

We examined whether neuropsychiatric symptoms (NPS) interact with cerebrospinal fluid (CSF) biomarkers (amyloid-β42 [Aβ42], tau, phosphorylated tau181 [ptau181], tau/Aβ42, and ptau181/Aβ42) of Alzheimer's disease pathology to predict driving decline among cognitively-normal older adults (N = 116) aged ≥65. Cox proportional hazards models examined time to receiving a rating of marginal or fail on the driving test. Age, education, and gender were adjusted in the models. Participants with more abnormal CSF (Aβ42, tau/Aβ42, ptau181/Aβ42) and NPS were faster to receive a marginal/fail on the road test compared to those without NPS. NPS interact with abnormal CSF biomarkers to impact driving performance among cognitively-normal older adults.

%B J Alzheimers Dis %V 58 %P 675-680 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453487?dopt=Abstract %R 10.3233/JAD-170067 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neuropsychiatric Symptoms and Cognitive Impairment: Understanding the Importance of Co-Morbid Symptoms. %A Mortby, Moyra E %A Burns, Richard %A Eramudugolla, Ranmalee %A Ismail, Zahinoor %A Anstey, Kaarin J %X

BACKGROUND: Neuropsychiatric symptoms (NPS) are common in older adults with cognitive impairment, yet little is known about population-based prevalence and clinical implications of co-morbid symptom presentation across the spectrum from normal cognition to dementia.

OBJECTIVE: To characterize the prevalence of NPS and explore the clinical implications of co-morbid symptom presentation.

METHODS: Cross-sectional study of 1,417 older adults (aged 73-79) with dementia (n = 40); with mild cognitive impairment (MCI; n = 133); who are 'cognitively normal, but-at-risk' (CN-AR; n = 397); and who are cognitively normal (n = 847). NPS were assessed by the Neuropsychiatric Inventory. Cluster analyses were conducted using a latent class analysis (LCA).

RESULTS: NPS are highly prevalent across the cognitive function spectrum (30.8% -80%). NPS were associated with a 3-fold increased risk of dementia, a 2-fold increased risk of MCI, and a 1.5-times increased risk of CN-AR. Each additional co-morbid symptom was associated with an additional 1.5-times increased risk of dementia, but not MCI or CN-AR. LCA revealed four distinctive sub-populations: 1) frontal/low comorbidity; 2) high prevalence/high comorbidity; 3) affective/low comorbidity; and 4) sleep/low comorbidity.

CONCLUSION: Our findings confirm previous reports on the prevalence of NPS in community-based samples and are consistent with the profiles of NPS domain characteristics of MCI and dementia. Number of co-morbid NPS and not symptom clusters are associated with increased risk of dementia. Understanding such patterns will help inform our understanding of mild behavioral disorders and assist with clinical assessment.

%B J Alzheimers Dis %V 59 %P 141-153 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598846?dopt=Abstract %R 10.3233/JAD-170050 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neuropsychological Profile in the C9ORF72 Associated Behavioral Variant Frontotemporal Dementia. %A Suhonen, Noora-Maria %A Haanpää, Ramona M %A Korhonen, Ville %A Jokelainen, Jari %A Pitkäniemi, Anni %A Heikkinen, Anna-Leena %A Krüger, Johanna %A Hartikainen, Päivi %A Helisalmi, Seppo %A Hiltunen, Mikko %A Hänninen, Tuomo %A Remes, Anne M %X

While the C9ORF72 expansion is a major cause of behavioral variant frontotemporal dementia (bvFTD), little is known of the resultant cognitive profile. Our aim was to characterize the neuropsychological profile of the C9ORF72 associated bvFTD. We contrasted structured neuropsychological assessments of the C9ORF72 expansion carrier bvFTD patients (n = 26) with non-carrier bvFTD patients (n = 47) and those with Alzheimer's disease (AD) (n = 47). As compared to the non-carrier bvFTD patients, the C9ORF72 expansion carriers performed at a higher level in an immediate verbal memory test while showing poorer phonemic verbal fluency. Additionally, the expansion carriers committed more errors in the Stroop test and the Alternating S task relative to the non-carriers. Finally, while the AD patients outperformed both bvFTD patient groups in working memory, their performance was more impaired in episodic memory tasks relative to the bvFTD groups. We conclude that bvFTD patients carrying the C9ORF72 expansion may display more pronounced executive deficits together with less severe verbal memory impairment as compared to their non-carrier bvFTD counterparts. Knowledge of the specific neuropsychological features associated with the C9ORF72 related bvFTD may aid in the early diagnosis of the disease as well as in targeting genetic testing.

%B J Alzheimers Dis %V 58 %P 479-489 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453474?dopt=Abstract %R 10.3233/JAD-161142 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neuropsychological Symptoms in Sporadic Creutzfeldt-Jakob Disease Patients in Germany. %A Krasnianski, Anna %A Bohling, Geeske T %A Heinemann, Uta %A Varges, Daniela %A Meissner, Bettina %A Schulz-Schaeffer, Walter J %A Reif, Andreas %A Zerr, Inga %X

BACKGROUND: The polymorphism at codon 129 of the prion protein gene (PRNP) and the PrPSc types 1 and 2 belong to a molecular classification of sporadic Creutzfeldt-Jakob disease (sCJD) that correlates well with the clinical and neuropathological phenotype of sCJD.

OBJECTIVE: The aim of the study was to perform the first detailed evaluation of neuropsychological deficits in a large group of definite sCJD patients with known molecular subtype.

METHODS: We analyzed neuropsychological symptoms in a cohort of 248 sCJD patients with known M129 V polymorphism of PRNP and prion protein type.

RESULTS: Neuropsychological symptoms were very frequent in our patients (96%) and occurred as early as in the first third of the disease course. Besides amnesia and impaired attention (89% each), frontal lobe syndrome (75%), aphasia (63%), and apraxia (57%) were the most common neuropsychological deficits. There was no statistically significant difference with regard to frequency of neuropsychological symptoms between the subtypes. In MV2 and VV2 patients, the onset of neuropsychological symptoms was significantly later than in all other subtypes.

CONCLUSION: We provide the first detailed analysis of neuropsychological symptoms in a large group of sCJD patients with known M129 V genotype and prion protein type. We suggest that the rate of progression of neuropsychological symptoms is subtype-specific. These data may improve the diagnosis in atypical sCJD subtypes.

%B J Alzheimers Dis %V 59 %P 329-337 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598840?dopt=Abstract %R 10.3233/JAD-161129 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neurovascular Specifications in the Alzheimer-Like Brain of Mice Affected by Focal Cerebral Ischemia: Implications for Future Therapies. %A Michalski, Dominik %A Hofmann, Sarah %A Pitsch, Roman %A Grosche, Jens %A Härtig, Wolfgang %X

Alzheimer's disease (AD), the most frequent type of dementia, is a prototypical neurodegenerative disease, but shares with stroke certain common risk factors. Consequently, how vascular pathology may modulate AD pathogenesis has gained scientific attention. Therefore, aside from typical features of AD (e.g., amyloid-β, tau hyperphosphorylation, and cholinergic dysfunction), changes within the 'neurovascular unit' (NVU) are of particular interest. This study focused on cholinergic, choline acetyltransferase (ChAT)-immunopositive, and tyrosine hydroxylase (TH)-containing neurons in association with the vasculature to explore the neurovascular complex of the AD brain affected by stroke. Wild-type and triple-transgenic (3xTg) mice of different ages underwent unilateral permanent focal cerebral ischemia. Histochemical analyses comprised diverse neuronal and vascular NVU components, and markers of AD. Immunofluorescence labeling confirmed the existence of Aβ deposits and phospho-tau together with glial reactions and morphologically altered endothelia, visualized by Solanum tuberosum lectin. Twenty-four hours after ischemia induction, immunoreactivities for ChAT and TH declined in the ischemia-affected striatum and, at least in part, in the ischemic border zone and ipsilateral neocortex. Correlation analyses indicated simultaneous degeneration of neuronal and vascular components. A trend for more severe affection of ChAT was observed in younger as compared with older mice. The present findings suggest complex interactions within the NVU of the AD-like brain affected by ischemia, comprising alterations of the cholinergic system in conjunction with vascular pathology. Hence, it may be worthwhile to explore the impact of a cellular stabilization approach on vascular and glial elements in AD in terms of a potential disease-alleviating strategy.

%B J Alzheimers Dis %V 59 %P 655-674 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671120?dopt=Abstract %R 10.3233/JAD-170185 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neutrophil Gelatinase-Associated Lipocalin and its Receptors in Alzheimer's Disease (AD) Brain Regions: Differential Findings in AD with and without Depression. %A Dekens, Doortje W %A Naudé, Petrus J W %A Engelborghs, Sebastiaan %A Vermeiren, Yannick %A Van Dam, Debby %A Oude Voshaar, Richard C %A Eisel, Ulrich L M %A De Deyn, Peter P %X

Co-existing depression worsens Alzheimer's disease (AD) pathology. Neutrophil gelatinase-associated lipocalin (NGAL) is a newly identified (neuro)inflammatory mediator in the pathophysiologies of both AD and depression. This study aimed to compare NGAL levels in healthy controls, AD without depression (AD-D), and AD with co-existing depression (AD+D) patients. Protein levels of NGAL and its receptors, 24p3R and megalin, were assessed in nine brain regions from healthy controls (n = 19), AD-D (n = 19), and AD+D (n = 21) patients. NGAL levels in AD-D patients were significantly increased in brain regions commonly associated with AD. In the hippocampus, NGAL levels were even further increased in AD+D subjects. Unexpectedly, NGAL levels in the prefrontal cortex of AD+D patients were comparable to those in controls. Megalin levels were increased in BA11 and amygdala of AD+D patients, while no changes in 24p3R were detected. These findings indicate significant differences in neuroimmunological regulation between AD patients with and without co-existing depression. Considering its known effects, elevated NGAL levels might actively promote neuropathological processes in AD with and without depression.

%B J Alzheimers Dis %V 55 %P 763-776 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716662?dopt=Abstract %R 10.3233/JAD-160330 %0 Journal Article %J J Alzheimers Dis %D 2017 %T New Gold in Them Thar Hills: Testing a Novel Supply Route for Plant-Derived Galanthamine. %A Fraser, Mariecia D %A Davies, John R T %A Chang, Xianmin %X

Many secondary plant compounds are synthesized in response to stressed growing conditions. We tested the feasibility of exploiting this feature in a novel strategy for the commercial production of the plant alkaloid galanthamine. Experimental lines of Narcissus pseudonarcissus were established under marginal upland permanent pasture at four different sites. Over 80% of bulbs successfully established at each site. There was no effect of altitude or planting density on galanthamine concentrations within vegetative tissues, which were higher than anticipated. The results confirm that planting N. pseudonarcissus under grass competition in upland areas could offer a novel and sustainable source of plant-derived galanthamine.

%B J Alzheimers Dis %V 55 %P 1321-1325 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27834779?dopt=Abstract %R 10.3233/JAD-160791 %0 Journal Article %J J Alzheimers Dis %D 2017 %T NFATc2 Modulates Microglial Activation in the AβPP/PS1 Mouse Model of Alzheimer's Disease. %A Manocha, Gunjan D %A Ghatak, Atreyi %A Puig, Kendra L %A Kraner, Susan D %A Norris, Christopher M %A Combs, Colin K %X

Alzheimer's disease (AD) brains are characterized by fibrillar amyloid-β (Aβ) peptide containing plaques and associated reactive microglia. The proinflammatory phenotype of the microglia suggests that they may negatively affect disease course and contribute to behavioral decline. This hypothesis predicts that attenuating microglial activation may provide benefit against disease. Prior work from our laboratory and others has characterized a role for the transcription factor, nuclear factor of activated T cells (NFAT), in regulating microglial phenotype in response to different stimuli, including Aβ peptide. We observed that the NFATc2 isoform was the most highly expressed in murine microglia cultures, and inhibition or deletion of NFATc2 was sufficient to attenuate the ability of the microglia to secrete cytokines. In order to determine whether the NFATc2 isoform, in particular, was a valid immunomodulatory target in vivo, we crossed an NFATc2-/- line to a well-known AD mouse model, an AβPP/PS1 mouse line. As expected, the AβPP/PS1 x NFATc2-/- mice had attenuated cytokine levels compared to AβPP/PS1 mice as well as reduced microgliosis and astrogliosis with no effect on plaque load. Although some species differences in relative isoform expression may exist between murine and human microglia, it appears that microglial NFAT activity is a viable target for modulating the proinflammatory changes that occur during AD.

%B J Alzheimers Dis %V 58 %P 775-787 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505967?dopt=Abstract %R 10.3233/JAD-151203 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Nitrosylation of Vesicular Transporters in Brain of Amyloid Precursor Protein/Presenilin 1 Double Transgenic Mice. %A Wang, Ying %A Zhou, Zhu %A Tan, Hua %A Zhu, Shenghua %A Wang, Yiran %A Sun, Yingxia %A Li, Xin-Min %A Wang, Jun-Feng %X

Nitric oxide can attack thiol groups of cysteine residues in proteins and induce protein cysteine S-nitrosylation. Cholinergic and glutamatergic systems are dysregulated in Alzheimer's disease. Vesicular acetylcholine transporter (VAChT) and vesicular glutamate transporter 1 (VGLUT1) are important in packaging acetylcholine and glutamate into vesicles, which is an important step for neurotransmission. Previously we found that VAChT and VGLUT1 can be nitrosylated and that S-nitrosylation of these transporters inhibits vesicular uptake of acetylcholine and glutamate. To understand the role of VAChT and VGLUT1 nitrosylation in the pathophysiological development of Alzheimer's disease, we analyzed nitrosylation of VAChT and VGLUT1 in brain of amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice, an animal model for Alzheimer's disease. Using a Morris water maze test, we found that 9- and 12-month-old APP/PS1 mice showed memory deficit, compared to wild type mice. We further found that total protein nitrosylation was increased in frontal cortex and hippocampus of 9- and 12-month-old APP/PS1 mice. Although nitrosylation of VAChT and VGLUT1 was not changed in hippocampus of 9- and 12-month-old APP/PS1 mice, nitrosylation of VAChT and VGLUT1 was significantly increased in frontal cortex of APP/PS1 mice at these ages. We also found that nitrosylation of VAChT and VGLUT1 was increased in hippocampus (but not frontal cortex) of 3-month-old APP/PS1 mice. These findings suggest that nitrosylation of VAChT and VGLUT1 may be associated with dysfunctional acetylcholinergic and glutamatergic neurotransmission in Alzheimer's disease.

%B J Alzheimers Dis %V 55 %P 1683-1692 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911305?dopt=Abstract %R 10.3233/JAD-160700 %0 Journal Article %J J Alzheimers Dis %D 2017 %T No Genetic Overlap Between Circulating Iron Levels and Alzheimer's Disease. %A Lupton, Michelle K %A Benyamin, Beben %A Proitsi, Petroula %A Nyholt, Dale R %A Ferreira, Manuel A %A Montgomery, Grant W %A Heath, Andrew C %A Madden, Pamela A %A Medland, Sarah E %A Gordon, Scott D %A Lovestone, Simon %A Tsolaki, Magda %A Kloszewska, Iwona %A Soininen, Hilkka %A Mecocci, Patrizia %A Vellas, Bruno %A Powell, John F %A Bush, Ashley I %A Wright, Margaret J %A Martin, Nicholas G %A Whitfield, John B %X

Iron deposition in the brain is a prominent feature of Alzheimer's disease (AD). Recently, peripheral iron measures have also been shown to be associated with AD status. However, it is not known whether these associations are causal: do elevated or depleted iron levels throughout life have an effect on AD risk? We evaluate the effects of peripheral iron on AD risk using a genetic profile score approach by testing whether variants affecting iron, transferrin, or ferritin levels selected from GWAS meta-analysis of approximately 24,000 individuals are also associated with AD risk in an independent case-control cohort (n∼10,000). Conversely, we test whether AD risk variants from a GWAS meta-analysis of approximately 54,000 account for any variance in iron measures (n∼9,000). We do not identify a genetic relationship, suggesting that peripheral iron is not causal in the initiation of AD pathology.

%B J Alzheimers Dis %V 59 %P 85-99 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582860?dopt=Abstract %R 10.3233/JAD-170027 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Non-Phosphorylated Tau as a Potential Biomarker of Alzheimer's Disease: Analytical and Diagnostic Characterization. %A Lewczuk, Piotr %A Lelental, Natalia %A Lachmann, Ingolf %A Holzer, Max %A Flach, Katharina %A Brandner, Sebastian %A Engelborghs, Sebastiaan %A Teunissen, Charlotte E %A Zetterberg, Henrik %A Molinuevo, José Luis %A Mroczko, Barbara %A Blennow, Kaj %A Popp, Julius %A Parnetti, Lucilla %A Chiasserini, Davide %A Perret-Liaudet, Armand %A Spitzer, Philipp %A Maler, Juan Manuel %A Kornhuber, Johannes %X

BACKGROUND: Virtually nothing is known about a potential diagnostic role of non-phospho-epitopes of Tau (Non-P-Tau) in cerebrospinal fluid (CSF).

OBJECTIVE: To establish and analytically and clinically characterize the first assay capable to measure concentrations of Non-P-Tau in human CSF.

METHODS: An antibody (1G2) was developed that selectively binds to the Tau molecule non-phosphorylated at the positions T175 and T181, and was used in establishing a sandwich ELISA capable to measure Non-P-Tau in human CSF, following analytical and clinical validation of the method.

RESULTS: The 1G2 antibody shows decreasing reactivity to tau peptides containing phosphorylation mainly at positions T175 and T181. Detection limit of the assay is 25 pg/ml; the coefficients of variation (CVs) of the optical densities of the repeated standard curves were between 3.6-15.9%. Median intra-assay imprecision of double measurements was 4.8%; inter-assay imprecision was in the range of 11.2% - 15.3%. Non-P-Tau concentrations are stable in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in patients with Alzheimer's disease in stage of mild cognitive impairment or dementia (AD/MCI, n = 58, 109.2±32.0 pg/mL) compared to the non-demented Controls (n = 42, 62.1±9.3 pg/mL, p < 0.001). At the cut-off of 78.3 pg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively.

CONCLUSION: For the first time, an assay is reported to reliably measure concentrations of non-phosphorylated Tau in human CSF.

%B J Alzheimers Dis %V 55 %P 159-170 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662295?dopt=Abstract %R 10.3233/JAD-160448 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Normal Vitamin Levels and Nutritional Indices in Alzheimer's Disease Patients with Mild Cognitive Impairment or Dementia with Normal Body Mass Indexes. %A Ulstein, Ingun %A Bøhmer, Thomas %X

Evidence supports an association between vitamin deficiencies and cognitive decline in Alzheimer's disease (AD). If vitamin deficiencies are causative for AD development, they should be detectable during very early stages of AD. Here we investigated nutritional factors among home-living patients diagnosed with mild cognitive impairment (MCI) or mild dementia due to AD, compared to healthy controls. Our study included 73 patients with AD (25 with MCI, 48 with dementia) and 63 cognitively intact age-matched controls. All participants underwent cognitive testing, somatic examination, and measurements of vitamins A, B1, B6, folate, B12, C, D, and E, and F2-α-isoprostane. Results are given as mean (SD). MMSE scores were 29.1 (1.0) for healthy controls, 27.4 (1.8) for patients with MCI, and 24.3 (3.2) for patients with dementia. Vitamin concentrations for the these groups, respectively, were as follows: B1 (nmol/l), 157 (29), 161 (35), and 161 (32); B6 (nmol/l), 57 (63), 71 (104), and 58 (44); folate (mmol/l), 23 (9), 26 (10), and 23 (11); B12 (pmol/l), 407 (159), 427 (116), and 397 (204); C (μmol/l), 63 (18), 61 (16), and 63 (29); A (μmol/l), 2.3 (0.6), 2.2 (0.5), and 2.3(0.5); E (μmol/l), 36 (6.3), 36 (6.9), and 36 (8.2); 25-OH vitamin D (nmol/l), 65 (18), 61 (19), and 65 (20); and 8-iso-PGFα (pg/ml), 64 (27); 60 (19), and 66 (51). These concentrations did not significantly differ (p≤0.05) between the three groups. Our results do not support the hypothesis that vitamin deficiencies play a causative role in the development of early cognitive impairment.

%B J Alzheimers Dis %V 55 %P 717-725 %8 2016 Oct 5 %G eng %N 2 %R 10.3233/JAD-160393 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Novel Assessment and Profiling of Multidimensional Apathy in Alzheimer's Disease. %A Radakovic, Ratko %A Starr, John M %A Abrahams, Sharon %X

BACKGROUND: Apathy is a complex multidimensional syndrome frequently reported in Alzheimer's disease (AD) and is associated with impaired awareness. Here we present a psychometrically robust method to profile apathy in AD.

OBJECTIVES: To determine the validity and reliability of a multidimensional apathy measure, the Dimensional Apathy Scale (DAS), and explore the apathy subtype profile and its associations in AD.

METHODS: 102 people with AD and 55 healthy controls were recruited. Participants completed the DAS, the Apathy Evaluation Scale (AES), Geriatric Depression Short form (GDS-15), and Lawton Instrumental Activities of Daily Living (LIADL). Psychometric properties of the DAS were determined. AD-Control comparison was performed to explore group differences on the DAS. Latent Class Analysis (LCA) was used to explore the profile of apathy in AD.

RESULTS: The DAS had a good to excellent Cronbach's standardized alpha (self-rated = 0.85, informant/carer-rated = 0.93) and good convergent and divergent validity against standard apathy (AES) and depression (GDS-15) measures. Group comparison showed people with AD were significantly higher for all apathy subtypes than controls (p < 0.001), and lacking in awareness over all apathy subtype deficits. LCA showed three distinct AD subgroups, with 42.2% in the Executive-Initiation apathy, 28.4% in the Global apathy, and 29.4% in the Minimal apathy group.

CONCLUSIONS: The DAS is a psychometrically robust method of assessing multidimensional apathy in AD. The apathy profiles in AD are heterogeneous, with additional specific impairments relating to awareness dependent on apathy subtype.

%B J Alzheimers Dis %V 60 %P 57-67 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28759970?dopt=Abstract %R 10.3233/JAD-170292 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Novel Blood-Based Biomarkers of Cognition, Stress, and Physical or Cognitive Training in Older Adults at Risk of Dementia: Preliminary Evidence for a Role of BDNF, Irisin, and the Kynurenine Pathway. %A Küster, Olivia C %A Laptinskaya, Daria %A Fissler, Patrick %A Schnack, Cathrin %A Zügel, Martina %A Nold, Verena %A Thurm, Franka %A Pleiner, Sina %A Karabatsiakis, Alexander %A von Einem, Björn %A Weydt, Patrick %A Liesener, André %A Borta, Andreas %A Woll, Alexander %A Hengerer, Bastian %A Kolassa, Iris-Tatjana %A von Arnim, Christine A F %X

 Psychosocial stress and physical, cognitive, and social activity predict the risk of cognitive decline and dementia. The aim of this study was to elucidate brain-derived neurotrophic factor (BDNF), irisin, and the kynurenine pathway (KP) as potential underlying biological correlates. We evaluated associations of irisin and the KP with BDNF in serum and with cognition, stress, and activities. Furthermore, changes in serum concentrations of BDNF, irisin, and KP metabolites were investigated after physical or cognitive training. Forty-seven older adults at risk of dementia were assigned to 10 weeks of physical training, cognitive training, or a wait-list control condition. Previous physical, cognitive, and social activities and stressful life events were recorded; global cognition, episodic memory, and executive functions were assessed. Serum levels of L-kynurenine, kynurenic acid, 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN) were determined by validated assays based on liquid chromatography coupled to tandem mass spectrometry. BDNF and irisin serum levels were determined with enzyme-linked immunosorbent assays. BDNF and irisin correlated positively with global cognition and episodic memory, while the neurotoxic metabolite QUIN correlated negatively with executive functions. Stressful life events were associated with reduced BDNF and increased 3-HK. 3-HK decreased after cognitive training, while BDNF tended to increase after physical training. This suggests that psychosocial stress as well as cognitive and physical training may impact BDNF serum levels and the KP. Irisin and QUIN may constitute novel serum biomarkers of cognitive impairment, in addition to BDNF. Larger scale trials are needed to replicate and extend these novel findings.

%B J Alzheimers Dis %V 59 %P 1097-1111 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731451?dopt=Abstract %R 10.3233/JAD-170447 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Novel Loss-of-Function GRN Mutation p.(Tyr229*): Clinical and Neuropathological Features. %A Kuuluvainen, Liina %A Pöyhönen, Minna %A Pasanen, Petra %A Siitonen, Maija %A Rummukainen, Jaana %A Tienari, Pentti J %A Paetau, Anders %A Myllykangas, Liisa %X

Mutations in the progranulin (GRN) gene represent about 5-10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia. Gene expression studies showed decreased GRN gene expression in mutation carriers' blood samples. In conclusion, we describe a novel GRN, p.(Tyr229*) mutation, resulting in haploinsufficiency of GRN and a severe neuropathologic FTLD phenotype.

%B J Alzheimers Dis %V 55 %P 1167-1174 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767988?dopt=Abstract %R 10.3233/JAD-160647 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Novel Method for Direct Assessment of Everyday Competence Among Older Adults. %A Czaja, Sara J %A Loewenstein, David A %A Sabbag, Samir A %A Curiel, Rosie E %A Crocco, Elizabeth %A Harvey, Philip D %X

BACKGROUND: Recent findings indicate that impairments in functional performance do occur among individuals diagnosed with mild cognitive impairment (MCI). Most assessment strategies for everyday competence are associated with challenges with reliability, are typically in paper and pencil format, or require in-person administration by a trained professional.

OBJECTIVE: This paper reports on a novel technology-based assessment battery of everyday competence that includes ecologically valid simulations of daily activities important to independence.

METHODS: The sample included 85 non-cognitively impaired older adults aged 65+ and 62 older adults diagnosed with amnestic MCI (aMCI). Participants completed standard measures of cognitive abilities and the computerized battery of everyday tasks, which included simulations of a doctor's visit; and medication and financial management tasks.

RESULTS: The older adults with aMCI performed significantly poorer on all three tasks in the everyday task battery. Performance on these measures were also moderately correlated with standard measures of cognitive abilities and showed good test-retest reliability.

CONCLUSIONS: The results show that it is feasible to use a technology-based assessment battery of everyday tasks with both non-cognitively impaired older adults and older adults with MCI. The use of this type of battery can overcome many of the logistic constraints associated with current functional assessment protocols.

%B J Alzheimers Dis %V 57 %P 1229-1238 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304300?dopt=Abstract %R 10.3233/JAD-161183 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Novel Phospho-Tau Monoclonal Antibody Generated Using a Liposomal Vaccine, with Enhanced Recognition of a Conformational Tauopathy Epitope. %A Theunis, Clara %A Adolfsson, Oskar %A Crespo-Biel, Natalia %A Piorkowska, Kasia %A Pihlgren, Maria %A Hickman, David T %A Gafner, Valerie %A Borghgraef, Peter %A Devijver, Herman %A Pfeifer, Andrea %A Van Leuven, Fred %A Muhs, Andreas %X

The microtubule-associated protein Tau is an intrinsically unfolded, very soluble neuronal protein. Under still unknown circumstances, Tau protein forms soluble oligomers and insoluble aggregates that are closely linked to the cause and progression of various brain pathologies, including Alzheimer's disease. Previously we reported the development of liposome-based vaccines and their efficacy and safety in preclinical mouse models for tauopathy. Here we report the use of a liposomal vaccine for the generation of a monoclonal antibody with particular characteristics that makes it a valuable tool for fundamental studies as well as a candidate antibody for diagnostic and therapeutic applications. The specificity and affinity of antibody ACI-5400 were characterized by a panel of methods: (i) measuring the selectivity for a specific phospho-Tau epitope known to be associated with tauopathy, (ii) performing a combination of peptide and protein binding assays, (iii) staining of brain sections from mouse preclinical tauopathy models and from human subjects representing six different tauopathies, and (iv) evaluating the selective binding to pathological epitopes on extracts from tauopathy brains in non-denaturing sandwich assays. We conclude that the ACI-5400 antibody binds to protein Tau phosphorylated at S396 and favors a conformation that is typically present in the brain of tauopathy patients, including Alzheimer's disease.

%B J Alzheimers Dis %V 56 %P 585-599 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035925?dopt=Abstract %R 10.3233/JAD-160695 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Novel PSEN1 K311R Mutation Discovered in Chinese Families with Late-Onset Alzheimer's Disease Affects Amyloid-β Production and Tau Phosphorylation. %A Dong, Jing %A Qin, Wei %A Wei, Cuibai %A Tang, Yi %A Wang, Qi %A Jia, Jianping %X

BACKGROUND: Presenilin-1 (PSEN1) is the most frequently mutated gene in familial Alzheimer's disease (AD), whereas only several novel mutations have been reported in China and functional studies were seldom conducted.

OBJECTIVE: We describe a novel PSEN1 K311R mutation in two Chinese families with late-onset AD and its functional impact on amyloid-β protein precursor (AβPP) processing and tau phosphorylation.

METHODS: The mutation was detected by direct sequencing of PSEN1 exon 9. HEK293 cells stably expressing wild-type APP695 (HEK293-APP695wt) were transfected with plasmids containing human wild-type PSEN1, PSEN1 K311R mutation, and PSEN1 E280A mutation to compare the K311R mutation's effects on AβPP processing with other groups. In addition, each group of cells were co-transfected with plasmids harboring PSEN1 and human wild-type MAPT complementary DNA to study the mutation's impacts on tau phosphorylation.

RESULTS: The K311R mutation was detected in probands of two late-onset AD families. Expression of the K311R or E280A mutation increased amyloid-β (Aβ)42 levels but decreased Aβ40 levels, resulting in an overall increase in the Aβ42/Aβ40 ratio compared to those in wild-type PSEN1 transfected cells (p < 0.05). The K311R or E280A mutation also increased the levels of phosphorylated tau compared to wild-type PSEN1 (p < 0.05).

CONCLUSION: The K311R mutation might contribute to AD pathogenesis by overproducing toxic Aβ species and enhancing tau phosphorylation. Further in-depth studies are needed to decipher the pathogenic mechanisms of the K311R mutation in terms of AβPP cleavage, tau phosphorylation, and other presenilin-1 mediated functional pathways.

%B J Alzheimers Dis %V 57 %P 613-623 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269784?dopt=Abstract %R 10.3233/JAD-161188 %0 Journal Article %J J Alzheimers Dis %D 2017 %T N-Terminal Pro-B Type Natriuretic Peptide is Associated with Mild Cognitive Impairment in the General Population. %A Kara, Kaffer %A Mahabadi, Amir Abbas %A Weimar, Christian %A Winkler, Angela %A Neumann, Till %A Kälsch, Hagen %A Dragano, Nico %A Moebus, Susanne %A Erbel, Raimund %A Jöckel, Karl-Heinz %A Jokisch, Martha %X

BACKGROUND: N-terminal pro-B type natriuretic peptide (NT-proBNP) is a marker of cardiac stress and is linked with silent cardiac diseases. While associations of cognitive impairment with manifest cardiovascular diseases are established, data on whether subclinical elevation of NT-proBNP levels below clinically established threshold of heart failure is related with cognitive functioning, especially mild cognitive impairment (MCI), is rare.

OBJECTIVE: Aim of the present study was to investigate the cross-sectional association of NT-proBNP levels and MCI in a population-based study sample without heart failure.

METHODS: We used data from the second examination of the population based Heinz-Nixdorf-Recall-Study. Subjects with overt coronary heart disease and subjects with NT-proBNP levels indicating potential heart failure (NT-proBNP≥300 pg/ml) were excluded from this analysis. Participants performed a validated brief cognitive assessment and were classified either as MCI [subtypes: amnestic-MCI (aMCI), non-amnestic-MCI (naMCI)], or cognitively-normal.

RESULTS: We included 419 participants with MCI (63.1±7.4 y; 47% men; aMCI n = 209; naMCI n = 210) and 1,206 cognitively normal participants (62.42±7.1 y; 48% men). NT-proBNP-levels≥125 pg/ml compared to <125 pg/ml were associated with MCI in fully adjusted models (OR 1.65 (1.23;2.23) in the total sample, 1.73 (1.09;2.74) in men and 1.63(1.10;2.41) in women). For aMCI, the fully adjusted OR was 1.53 (1.04;2.25) and for naMCI, the fully adjusted OR was 1.34 (1.09; 166) in the total sample.

CONCLUSION: Within normal ranges and without manifest heart failure, higher NT-proBNPlevels are associated with MCI and both MCI subtypes independent of traditional cardiovascular risk factors and sociodemographic parameters.

%B J Alzheimers Dis %V 55 %P 359-369 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636851?dopt=Abstract %R 10.3233/JAD-160635 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Occupational Attainment as Risk Factor for Progression from Mild Cognitive Impairment to Alzheimer's Disease: A CREDOS Study. %A Myung, Woojae %A Lee, Chunsoo %A Park, Jin Hong %A Woo, Sook-Young %A Kim, Seonwoo %A Kim, Sangha %A Chung, Jae Won %A Kang, Hyo Shin %A Lim, Shinn-Won %A Choi, Junbae %A Na, Duk L %A Kim, Seong Yoon %A Lee, Jae-Hong %A Han, Seol-Heui %A Choi, Seong Hye %A Kim, Sang Yun %A Carroll, Bernard J %A Kim, Doh Kwan %X

High occupational attainment has been known as a marker of cognitive reserve. Previous studies in the general population have shown that high occupational attainment is associated with reduced risk of Alzheimer's disease (AD). However, few studies have assessed the effect of occupational attainment on the clinical course of mild cognitive impairment (MCI). In this study, we evaluated whether individuals with high occupational attainment show more frequent progression from MCI to AD. Participants (n = 961) with MCI were recruited from a nationwide, hospital-based multi-center cohort, and were followed for up to 60 months (median: 17.64, interquartile range [12.36, 29.28]). We used Cox regression for competing risks to analyze the effect of occupational attainment on development of AD, treating dementia other than AD as a competing risk. Among the 961 individuals with MCI, a total of 280 (29.1%) converted to dementia during the follow-up period. The risk of progression to AD was higher in the individuals with high occupational attainment after controlling for potential confounders (hazard ratio = 1.83, 95% confidence interval = 1.25-2.69, p = 0.002). High occupational attainment in individuals with MCI is an independent risk factor for higher progression rate of MCI to AD. This result suggests that the protective effect of high occupational attainment against cognitive decline disappears in the MCI stage, and that careful assessment of occupational history can yield important clinical information for prognosis in individuals with MCI.

%B J Alzheimers Dis %V 55 %P 283-292 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662289?dopt=Abstract %R 10.3233/JAD-160257 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Odor Identification Screening Improves Diagnostic Classification in Incipient Alzheimer's Disease. %A Quarmley, Megan %A Moberg, Paul J %A Mechanic-Hamilton, Dawn %A Kabadi, Sushila %A Arnold, Steven E %A Wolk, David A %A Roalf, David R %X

BACKGROUND: Measurements of olfaction may serve as useful biomarkers of incipient dementia. Here we examine the improvement in diagnostic accuracy of Alzheimer's disease (AD) and mild cognitive impairment (MCI) when assessing both cognitive functioning and odor identification.

OBJECTIVE: To determine the utility of odor identification as a supplementary screening test in incipient AD.

METHODS: Sniffin' Sticks Odor Identification Test (SS-OIT) and the Montreal Cognitive Assessment (MoCA) were administered in 262 AD, 174 MCI [150 amnestic (aMCI), and 24 non-amnestic (naMCI)], and 292 healthy older adults (HOA).

RESULTS: Odor identification scores were higher in HOA relative to MCI or AD groups, and MCI outperformed AD. Odor identification scores were higher in aMCI single domain than aMCI multiple domain. Complementing MoCA scores with the SS-OIT significantly improved diagnostic accuracy of individuals with AD and MCI, including within MCI subgroups.

DISCUSSION: Odor identification is a useful supplementary screening tool that provides additional information relevant for clinical categorization of AD and MCI, including those who are at highest risk to convert to AD.

%B J Alzheimers Dis %V 55 %P 1497-1507 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27886011?dopt=Abstract %R 10.3233/JAD-160842 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Of Mice and Men: Comparative Analysis of Neuro-Inflammatory Mechanisms in Human and Mouse Using Cause-and-Effect Models. %A Kodamullil, Alpha Tom %A Iyappan, Anandhi %A Karki, Reagon %A Madan, Sumit %A Younesi, Erfan %A Hofmann-Apitius, Martin %X

Perturbance in inflammatory pathways have been identified as one of the major factors which leads to neurodegenerative diseases (NDD). Owing to the limited access of human brain tissues and the immense complexity of the brain, animal models, specifically mouse models, play a key role in advancing the NDD field. However, many of these mouse models fail to reproduce the clinical manifestations and end points of the disease. NDD drugs, which passed the efficacy test in mice, were repeatedly not successful in clinical trials. There are numerous studies which are supporting and opposing the applicability of mouse models in neuroinflammation and NDD. In this paper, we assessed to what extend a mouse can mimic the cellular and molecular interactions in humans at a mechanism level. Based on our mechanistic modeling approach, we investigate the failure of a neuroinflammation targeted drug in the late phases of clinical trials based on the comparative analyses between the two species.

%B J Alzheimers Dis %V 59 %P 1045-1055 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731442?dopt=Abstract %R 10.3233/JAD-170255 %0 Journal Article %J J Alzheimers Dis %D 2017 %T One-Year Evolution of Behavioral and Psychological Symptoms of Dementia in Patients Initially Hospitalized in Cognitive Behavioral Units: The EVITAL Prospective Cohort. %A Rouch, Isabelle %A Pongan, Elodie %A Trombert, Béatrice %A Fabre, Florence %A Auguste, Nicolas %A Sellier, Claire %A Freulon, Magalie %A Jacqueline, Sophie %A Federico, Denis %A Mouchoux, Christelle %A Martin-Gaujard, Géraldine %A Krolak-Salmon, Pierre %A Laurent, Bernard %A Dorey, Jean-Michel %X

BACKGROUND: The 2008-2012 French Alzheimer's Plan has provided hospital Cognitive and Behavioral Units (CBU) to improve the management of patients with productive behavioral and psychological symptoms of dementia (BPSD). Little is known concerning the behavioral outcome of these patients after discharge.

OBJECTIVE: The present study investigated the long-term evolution of BPSD over one year after CBU discharge.

METHODS: The EVITAL cohort included 221 participants admitted to the CBUs of 3 French hospitals. BPSD were collected using the Neuropsychiatric Inventory (NPI) at admission and 3, 6, and 12 months after hospitalization. The global NPI score evolution was assessed using a linear mixed-effect model. A four-factor model of the NPI including behavioral dyscontrol, psychosis, mood, and agitation subscores was also analyzed.

RESULTS: Our analysis focused on 148 patients followed up during 12 months and evaluated at each visit. The global NPI score was 48.5 (SD 21.7) at baseline, 28.8 (SD 18.7) at 3-month, 23.2 (SD 16.4) at 6-month and 20.9 (SD 15.9) at 12-month follow-up. The score significantly decreased from baseline to follow-up (F = 109.3 p < 0.0001). Moreover, the decrease was observed for each NPI subscores. The Clinical Dementia Rating (CDR) scale score was significantly linked to the baseline NPI score (t = 2.76, p = 0.009). Conversely, the NPI decline was observed whatever the CDR level.

CONCLUSION: The present study showed a decrease in the global NPI score and all its subscores during the year following the CBU hospitalization, regardless of the initial CDR score.

%B J Alzheimers Dis %V 57 %P 147-155 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222514?dopt=Abstract %R 10.3233/JAD-161023 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Only White Matter Hyperintensities Predicts Post-Stroke Cognitive Performances Among Cerebral Small Vessel Disease Markers: Results from the TABASCO Study. %A Molad, Jeremy %A Kliper, Efrat %A Korczyn, Amos D %A Ben Assayag, Einor %A Ben Bashat, Dafna %A Shenhar-Tsarfaty, Shani %A Aizenstein, Orna %A Shopin, Ludmila %A Bornstein, Natan M %A Auriel, Eitan %X

BACKGROUND: White matter hyperintensities (WMH) were shown to predict cognitive decline following stroke or transient ischemic attack (TIA). However, WMH are only one among other radiological markers of cerebral small vessel disease (SVD).

OBJECTIVE: The aim of this study was to determine whether adding other SVD markers to WMH improves prediction of post-stroke cognitive performances.

METHODS: Consecutive first-ever stroke or TIA patients (n = 266) from the Tel Aviv Acute Brain Stroke Cohort (TABASCO) study were enrolled. MRI scans were performed within seven days of stroke onset. We evaluated the relationship between cognitive performances one year following stroke, and previously suggested total SVD burden score including WMH, lacunes, cerebral microbleeds (CMB), and perivascular spaces (PVS).

RESULTS: Significant negative associations were found between WMH and cognition (p < 0.05). Adding other SVD markers (lacunes, CMB, PVS) to WMH did not improve predication of post-stroke cognitive performances. Negative correlations between SVD burden score and cognitive scores were observed for global cognitive, memory, and visual spatial scores (all p < 0.05). However, following an adjustment for confounders, no associations remained significant.

CONCLUSION: WMH score was associated with poor post-stroke cognitive performance. Adding other SVD markers or SVD burden score, however, did not improve prediction.

%B J Alzheimers Dis %V 56 %P 1293-1299 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157096?dopt=Abstract %R 10.3233/JAD-160939 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Optical Coherence Tomography Reveals Retinal Neuroaxonal Thinning in Frontotemporal Dementia as in Alzheimer's Disease. %A Ferrari, Laura %A Huang, Su-Chun %A Magnani, Giuseppe %A Ambrosi, Alessandro %A Comi, Giancarlo %A Leocani, Letizia %X

BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are leading causes of cognitive decline. Optical coherence tomography (OCT) allows the measurement of thickness of retinal neuroaxonal layers. While in AD and mild cognitive impairment (MCI), retinal nerve fiber layer (RNFL) thinning is frequently reported, less information is available on ganglion cell layer-inner plexiform layer (GCL-IPL). Data on FTD are lacking.

OBJECTIVE: To obtain cross-sectional information on RNFL and GCL-IPL thickness among MCI, AD, FTD, and healthy controls (HC), and their correlations with dementia severity.

METHODS: Peripapillary OCT scans were obtained in 27 MCI, 39 AD, 17 FTD, 49 HC using high-definition Heidelberg Spectral-domain OCT, with RNFL and GCL-IPL thickness measurement. Statistical analysis tested group effects and correlation with gender, disease duration and severity (Mini-Mental State Examination, MMSE).

RESULTS: RNFL showed a significant group effect [F(4,132) = 3.786, p = 0.006], being reduced versus controls in MCI (p = 0.033), moderate AD (p = 0.025), and FTD (p < 0.001), and versus mild AD in FTD (p = 0.042). GCL-IPL showed a significant group effect as well [F(4,121) = 5.104, p < 0.001], with reduction in moderate AD versus HC (p < 0.001), MCI (p = 0.037), and mild AD (p = 0.009); in FTD versus HC (p = 0.002) and mild AD (p = 0.038). In AD, GCL-IPL correlated with MMSE (r = 0.487, p = 0.003), without significant effects of age, gender, or disease duration.

CONCLUSION: Retinal neuroaxonal thinning occurs in MCI/AD consistently with previous reports, as well as in FTD. Correlation with disease severity in AD suggests that retinal and brain neurodegeneration may occur in parallel to some extent, and prompts larger studies aimed at providing surrogate endpoints for clinical trials in AD.

%B J Alzheimers Dis %V 56 %P 1101-1107 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106555?dopt=Abstract %R 10.3233/JAD-160886 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Orexin Impairs the Phagocytosis and Degradation of Amyloid-β Fibrils by Microglial Cells. %A An, Hoyoung %A Cho, Mi-Hyang %A Kim, Dong-Hou %A Chung, Seockhoon %A Yoon, Seung-Yong %X

BACKGROUND: Intracranial accumulation of amyloid-β (Aβ) is a characteristic finding of Alzheimer's disease (AD). It is thought to be the result of Aβ overproduction by neurons and impaired clearance by several systems, including degradation by microglia. Sleep disturbance is now considered a risk factor for AD, but studies focusing on how sleep modulates microglial handling of Aβ have been scarce.

OBJECTIVE: To determine whether phagocytosis and degradation of extracellular Aβ fibrils by BV2 microglial cells were impaired by treatment with orexin-A/B, a major modulator of the sleep-wake cycle, which may mimic sleep deprivation conditions.

METHODS: BV2 cells were treated with orexin and Aβ for various durations and phagocytic and autophagic processes for degradation of extracellular Aβ were examined.

RESULTS: After treatment with orexin, the formation of actin filaments around Aβ fibrils, which is needed for phagocytosis, was impaired, and phagocytosis regulating molecules such as PI3K, Akt, and p38-MAPK were downregulated in BV2 cells. Orexin also suppressed autophagic flux, through disruption of the autophagosome-lysosome fusion process, resulting in impaired Aβ degradation in BV2 cells.

CONCLUSIONS: Our results demonstrate that orexin can hinder clearance of Aβ through the suppression of phagocytosis and autophagic flux in microglia. This is a novel mechanism linking AD and sleep, and suggests that attenuated microglial function, due to sleep deprivation, may increase Aβ accumulation in the brain.

%B J Alzheimers Dis %V 58 %P 253-261 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387679?dopt=Abstract %R 10.3233/JAD-170108 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Overexpression of Kinesin Superfamily Motor Proteins in Alzheimer's Disease. %A Hares, Kelly %A Miners, James Scott %A Cook, Amelia Jane %A Rice, Claire %A Scolding, Neil %A Love, Seth %A Wilkins, Alastair %X

Defects in motor protein-mediated neuronal transport mechanisms have been implicated in a number of neurodegenerative disorders but remain relatively little studied in Alzheimer's disease (AD). Our aim in the present study was to assess the expression of the anterograde kinesin superfamily motor proteins KIF5A, KIF1B, and KIF21B, and to examine their relationship to levels of hyperphosphorylated tau, amyloid-β protein precursor (AβPP), and amyloid-β (Aβ) in human brain tissue. We used a combination of qPCR, immunoblotting, and ELISA to perform these analyses in midfrontal cortex from 49 AD and 46 control brains. Expression of KIF5A, KIF1B, and KIF21B at gene and protein level was significantly increased in AD. KIF5A protein expression correlated inversely with the levels of AβPP and soluble Aβ in AD brains. Upregulation of KIFs may be an adaptive response to impaired axonal transport in AD.

%B J Alzheimers Dis %V 60 %P 1511-1524 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29060936?dopt=Abstract %R 10.3233/JAD-170094 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Overexpression of Ubiquilin-1 Alleviates Alzheimer's Disease-Caused Cognitive and Motor Deficits and Reduces Amyloid-β Accumulation in Mice. %A Adegoke, Oludotun O %A Qiao, Fangfang %A Liu, Yanying %A Longley, Kirsty %A Feng, Shelley %A Wang, Hongmin %X

Ubiquilin-1 (Ubqln1) is a ubiquitin-like protein that has been implicated in Alzheimer's disease (AD). However, whether Ubqln1 modulates learning and memory and alters AD-like behavior and/or pathology has not been determined in animal models. To understand the function of Ubqln1 in vivo, we previously generated Ubqln1 transgenic (TG) mice that overexpress mouse Ubqln1. With the model, we here characterized the TG mouse cognitive behaviors and found that Ubqln1 TG mice showed better spatial learning and memory capabilities than their wild-type littermates in both radial arm water maze and Y-maze tests. Additionally, we crossed the Ubqln1 TG mice with the AβPPswe/PSEN1dE9 double transgenic AD mouse to generate the AD/Ubqln1 triple TG (AD/TG) mice. Our results suggest that at 12 months of age following the onset of AD, AD/TG mice showed better spatial learning and memory than AD mice. AD/TG mice also exhibited better motor function than AD mice at the same age. Furthermore, compared to AD mice, AD/TG mice showed significant reduction in amyloid-β 40 (Aβ40) and Aβ42 levels in the cerebral cortex and in the hippocampus at the post-onset stage. The number of Aβ plaques was significantly decreased in the cerebral cortex of AD/TG mice at this post-onset stage. Moreover, mature AβPP level in AD/TG hippocampus was lower than that in AD hippocampus. These data not only provide a direct link between overexpression of Ubqln1 and altered learning and memory, but also raise the possibility that Ubqln1 is a potential therapeutic target for treating AD and possibly other neurodegenerative disorders.

%B J Alzheimers Dis %V 59 %P 575-590 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598849?dopt=Abstract %R 10.3233/JAD-170173 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Oxidative Stress, Synaptic Dysfunction, and Alzheimer's Disease. %A Tönnies, Eric %A Trushina, Eugenia %X

Alzheimer's disease (AD) is a devastating neurodegenerative disorder without a cure. Most AD cases are sporadic where age represents the greatest risk factor. Lack of understanding of the disease mechanism hinders the development of efficacious therapeutic approaches. The loss of synapses in the affected brain regions correlates best with cognitive impairment in AD patients and has been considered as the early mechanism that precedes neuronal loss. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive oxygen species (ROS) associated with age- and disease-dependent loss of mitochondrial function, altered metal homeostasis, and reduced antioxidant defense directly affect synaptic activity and neurotransmission in neurons leading to cognitive dysfunction. In addition, molecular targets affected by ROS include nuclear and mitochondrial DNA, lipids, proteins, calcium homeostasis, mitochondrial dynamics and function, cellular architecture, receptor trafficking and endocytosis, and energy homeostasis. Abnormal cellular metabolism in turn could affect the production and accumulation of amyloid-β (Aβ) and hyperphosphorylated Tau protein, which independently could exacerbate mitochondrial dysfunction and ROS production, thereby contributing to a vicious cycle. While mounting evidence implicates ROS in the AD etiology, clinical trials with antioxidant therapies have not produced consistent results. In this review, we will discuss the role of oxidative stress in synaptic dysfunction in AD, innovative therapeutic strategies evolved based on a better understanding of the complexity of molecular mechanisms of AD, and the dual role ROS play in health and disease.

%B J Alzheimers Dis %V 57 %P 1105-1121 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059794?dopt=Abstract %R 10.3233/JAD-161088 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Oxygen and Glucose Deprivation Alter Synaptic Distribution of Tau Protein: The Role of Phosphorylation. %A Mavroeidi, Panagiota %A Mavrofrydi, Olga %A Pappa, Elpiniki %A Panopoulou, Myrto %A Papazafiri, Panagiota %A Haralambous, Sylva %A Efthimiopoulos, Spiros %X

Alterations in tau synaptic distribution are considered to underlie synaptic dysfunction observed in Alzheimer's disease (AD). In the present study, brain blood hypoperfusion was simulated in mouse brain slices, and tau levels and phosphorylation were investigated in total extracts, as well as in postsynaptic density fractions (PSDs) and non-PSDs obtained through differential extraction and centrifugation. Oxygen deprivation (OD) resulted in tau dephosphorylation at several AD-related residues and activation of GSK3β and phosphatase PP2A. On the contrary, glucose deprivation (GD) did not affect total levels of cellular tau or its phosphorylation despite inactivation of GSK3β. However, tau distribution in PSD and non-PSD fractions and the pattern of tau phosphorylation in these compartments is highly complex. In PSDs, tau was increased under GD conditions and decreased under OD conditions. GD resulted in tau dephosphorylation at Ser199, Ser262, and Ser396 while OD resulted in tau hyperphosphorylation at Ser199 and Ser404. In the non-PSD fraction, GD or OD resulted in lower levels of tau, but the phosphorylation status of tau was differentially affected. In GD conditions, tau was found dephosphorylated at Ser199, Thr205, and Ser404 and hyperphosphorylated at Ser262. However, in OD conditions tau was found hyperphosphorylated at Thr205, SerSer356, Ser396, and Ser404. Combined OD and GD resulted in degradation of cellular tau and dephosphorylation of PSD tau at Ser396 and Ser404. These results indicate that oxygen deprivation causes dephosphorylation of tau, while GD and OD differentially affect distribution of total tau and tau phosphorylation variants in neuronal compartments by activating different mechanisms.

%B J Alzheimers Dis %V 60 %P 593-604 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869464?dopt=Abstract %R 10.3233/JAD-170157 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Pain Assessment in Dementia: Evaluation of a Point-of-Care Technological Solution. %A Atee, Mustafa %A Hoti, Kreshnik %A Parsons, Richard %A Hughes, Jeffery D %X

Pain is common among people with moderate to severe dementia, but inability of patients to self-report means it often goes undetected and untreated. We developed the electronic Pain Assessment Tool (ePAT) to address this issue. A point-of-care App, it utilizes facial recognition technology to detect facial micro-expressions indicative of pain. ePAT also records the presence of pain-related behaviors under five additional domains (Voice, Movement, Behavior, Activity, and Body). In this observational study, we assessed the psychometric properties of ePAT compared to the Abbey Pain Scale (APS). Forty aged care residents (70% females) over the age of 60 years, with moderate to severe dementia and a history of pain-related condition(s) were recruited into the study. Three hundred and fifty-three paired pain assessments (either at rest or post-movement) were recorded and analyzed. The ePAT demonstrated excellent concurrent validity (r = 0.882, 95% CI: 0.857-0.903) and good discriminant validity. Inter-rater reliability score was good overall (weighted κ= 0.74, 95% CI: 0.68-0.80) while internal consistency was excellent. ePAT has psychometric properties which make it suitable for use in non-communicative patients with dementia. ePAT also has the advantage of automated facial expression assessment which provides objective and reproducible evidence of the presence of pain.

%B J Alzheimers Dis %V 60 %P 137-150 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28800333?dopt=Abstract %R 10.3233/JAD-170375 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Palmitate Increases β-site AβPP-Cleavage Enzyme 1 Activity and Amyloid-β Genesis by Evoking Endoplasmic Reticulum Stress and Subsequent C/EBP Homologous Protein Activation. %A Marwarha, Gurdeep %A Rostad, Stephen %A Lilek, Jaclyn %A Kleinjan, Mason %A Schommer, Jared %A Ghribi, Othman %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Aspartic Acid Endopeptidases %K Cell Line, Tumor %K Dose-Response Relationship, Drug %K Endoplasmic Reticulum Stress %K Gene Expression Regulation %K Hippocampus %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Neuroblastoma %K Palmitates %K RNA, Messenger %K Signal Transduction %K Transcription Factor CHOP %K Transcription Factors %K Transfection %X

Epidemiological studies implicate diets rich in saturated free fatty acids (sFFA) as a potential risk factor for developing Alzheimer's disease (AD). In particular, high plasma levels of the sFFA palmitic acid (palmitate) were shown to inversely correlate with cognitive function. However, the cellular mechanisms by which sFFA may increase the risk for AD are not well known. Endoplasmic reticulum (ER) stress has emerged as one of the signaling pathways initiating and fostering the neurodegenerative changes in AD by increasing the aspartyl protease β-site AβPP cleaving enzyme 1 (BACE1) and amyloid-β (Aβ) genesis. In this study, we determined the extent to which palmitate increases BACE1 and Aβ levels in vitro and in vivo as well as the potential role of ER stress as cellular mechanism underlying palmitate effects. We demonstrate, in palmitate-treated SH-SY5Y neuroblastoma cells and in the hippocampi of palmitate-enriched diet-fed mice, that palmitate evokes the activation of the C/EBP Homologous Protein (CHOP), a transcription factor that is specifically responsive to ER stress. Induction of CHOP expression is associated with increased BACE1 mRNA, protein and activity levels, and subsequent enhanced amyloidogenic processing of amyloid-β protein precursor (AβPP) that culminates in a substantial increase in Aβ genesis. We further show that CHOP is an indispensable molecular mediator of palmitate-induced upregulation in BACE1 activity and Aβ genesis. Indeed, we show that Chop-/- mice and CHOP knocked-down SH-SY5Y neuroblastoma cells do not exhibit the same commensurate degree of palmitate-induced increase in BACE1 expression levels and Aβ genesis.

%B J Alzheimers Dis %V 57 %P 907-925 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304295?dopt=Abstract %R 10.3233/JAD-161130 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Passive Assessment of Routine Driving with Unobtrusive Sensors: A New Approach for Identifying and Monitoring Functional Level in Normal Aging and Mild Cognitive Impairment. %A Seelye, Adriana %A Mattek, Nora %A Sharma, Nicole %A Witter, Phelps %A Brenner, Ariella %A Wild, Katherine %A Dodge, Hiroko %A Kaye, Jeffrey %X

BACKGROUND: Driving is a key functional activity for many older adults, and changes in routine driving may be associated with emerging cognitive decline due to early neurodegenerative disease. Current methods for assessing driving such as self-report are inadequate for identifying and monitoring subtle changes in driving patterns that may be the earliest signals of functional change in developing mild cognitive impairment (MCI).

OBJECTIVE: This proof of concept study aimed to establish the feasibility of continuous driving monitoring in a sample of cognitively normal and MCI older adults for an average of 206 days using an unobtrusive driving sensor and demonstrate that derived sensor-based driving metrics could effectively discriminate between MCI and cognitively intact groups.

METHODS: Novel objective driving measures derived from 6 months of routine driving monitoring were examined in older adults with intact cognition (n = 21) and MCI (n = 7) who were enrolled in the Oregon Center for Aging and Technology (ORCATECH) longitudinal assessment program.

RESULTS: Unobtrusive continuous monitoring of older adults' routine driving using a driving sensor was feasible and well accepted. MCI participants drove fewer miles and spent less time on the highway per day than cognitively intact participants. MCI drivers showed less day-to-day fluctuations in their driving habits than cognitively intact drivers.

CONCLUSION: Sensor-based driving measures are objective, unobtrusive, and can be assessed every time a person drives his or her vehicle to identify clinically meaningful changes in daily driving. This novel methodology has the potential to be useful for the early detection and monitoring of changes in daily functioning within individuals.

%B J Alzheimers Dis %V 59 %P 1427-1437 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731434?dopt=Abstract %R 10.3233/JAD-170116 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer's Disease. %A Darst, Burcu F %A Koscik, Rebecca L %A Racine, Annie M %A Oh, Jennifer M %A Krause, Rachel A %A Carlsson, Cynthia M %A Zetterberg, Henrik %A Blennow, Kaj %A Christian, Bradley T %A Bendlin, Barbara B %A Okonkwo, Ozioma C %A Hogan, Kirk J %A Hermann, Bruce P %A Sager, Mark A %A Asthana, Sanjay %A Johnson, Sterling C %A Engelman, Corinne D %X

Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer's disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer's Project's meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-β (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging in 168 individuals, and cerebrospinal fluid Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.

%B J Alzheimers Dis %V 55 %P 473-484 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662287?dopt=Abstract %R 10.3233/JAD-160195 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Pazopanib Reduces Phosphorylated Tau Levels and Alters Astrocytes in a Mouse Model of Tauopathy. %A Javidnia, Monica %A Hebron, Michaeline L %A Xin, Yue %A Kinney, Nikolas G %A Moussa, Charbel E-H %X

Hyperphosphorylation and aggregation of tau protein is a critical factor in many neurodegenerative diseases. These diseases are increasing in prevalence, and there are currently no cures. Previous work from our group and others has shown that tyrosine kinase inhibitors (TKIs) can stimulate autophagy, decrease pathological proteins, and improve symptoms in models of neurodegeneration. Here we examined the role of pazopanib in mouse models that express either human mutant P301L tau (TauP301L) or triple mutant amyloid precursor protein (3x-AβPP). The TauP301L mouse expresses P301L tau under the control of a prion promoter in both neurons and astrocytes, reminiscent of some human tauopathies. Pazopanib crosses the blood-brain barrier with no detectable peripheral off-side effects, and decreases p-tau in TauP301L mice. Pazopanib reaches a brain concentration sufficient for inhibition of several tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs). Further, pazopanib does not affect microglia but reduces astrocyte levels toward nontransgenic controls in TauP301L mice. Pazopanib does not alter amyloid beta levels or astrocytes in 3x-AβPP mice but modulates a number of inflammatory markers (IP-10, MIP-1α, MIP-1β, and RANTES). These data suggest that pazopanib may be involved in p-tau clearance and modulation of astrocytic activity in models of tauopathies.

%B J Alzheimers Dis %V 60 %P 461-481 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869476?dopt=Abstract %R 10.3233/JAD-170429 %0 Journal Article %J J Alzheimers Dis %D 2017 %T PCSK9 Promotes oxLDL-Induced PC12 Cell Apoptosis Through the Bcl-2/Bax-Caspase 9/3 Signaling Pathway. %A Liu, Lu-Shan %A Bai, Xue-Qin %A Gao, Ya %A Wu, Qi %A Ren, Zhong %A Li, Qing %A Pan, Li-Hong %A He, Ni-Ya %A Peng, Juan %A Tang, Zhi-Han %K Amyloid beta-Peptides %K Analysis of Variance %K Animals %K Apoptosis %K bcl-2-Associated X Protein %K Caspases %K Culture Media, Serum-Free %K Dose-Response Relationship, Drug %K Flow Cytometry %K Lipid Metabolism %K Lipoproteins, LDL %K PC12 Cells %K Peptide Fragments %K Proprotein Convertase 9 %K Proto-Oncogene Proteins c-bcl-2 %K Rats %K RNA, Messenger %K RNA, Small Interfering %K Signal Transduction %K Transfection %X

BACKGROUND: Hyperlipidemia is a risk factor for neurodegenerative diseases. Proprotein convertase subtilisin / Kexin type 9 (PCSK9) degrades hepatic low-density lipoprotein receptor (LDLR) to regulate lipid metabolism. It is unclear if PCSK9 plays a role in neurodegenerative diseases.

OBJECTIVE: This study was designed to determine whether PCSK9 is crucial between hyperlipidemia and Alzheimer's disease. The interrelationship between PCSK9 and neuronal apoptosis was explored in PC12 cells in response to treatment with oxidized low-density lipoprotein (oxLDL).

METHODS: Cultured PC12 cells were serum-starved and incubated with different concentrations of oxLDL for 24 h. Intracytoplasmic lipid droplets were observed by oil red O staining. Morphological assessment of apoptotic cells was performed using Hoechst 33258 staining and flow cytometry analysis. The expression of mRNA and protein was detected by reverse-transcription polymerase chain reaction (RT-PCR) and western blot analyses, respectively. Transfection of small interfering RNA (siRNA) into PC12 cells was conducted using HiperFect Transfection Reagent. Concentrations of Aβ40 and Aβ42 were detected by enzyme-linked immunosorbent assay (ELISA) kit.

RESULTS: Intracellular lipid content, the number of apoptotic cells, and PCSK9 expression were increased in PC12 cells after oxLDL treatment. Transfection with PCSK9 siRNA reduced the oxLDL-induced apoptosis of PC12 cells. We further confirmed the involvement of Bcl-2/Bax-Caspase (9, 3) signaling pathway in the regulation of PC12 cells apoptosis.β-Secretase 1, another target gene of PCSK9, was downregulated in PC12 cells in response to oxLDL treatment. Aβ40 and Aβ42 contents were also decreased.

CONCLUSION: PCSK9 promotes oxLDL-induced PC12 cell apoptosis through the Bcl-2/Bax-Caspase 9/3 signaling pathway.

%B J Alzheimers Dis %V 57 %P 723-734 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304296?dopt=Abstract %R 10.3233/JAD-161136 %0 Journal Article %J J Alzheimers Dis %D 2017 %T PE859, A Novel Curcumin Derivative, Inhibits Amyloid-β and Tau Aggregation, and Ameliorates Cognitive Dysfunction in Senescence-Accelerated Mouse Prone 8. %A Okuda, Michiaki %A Fujita, Yuki %A Hijikuro, Ichiro %A Wada, Mei %A Uemura, Takuya %A Kobayashi, Yukako %A Waku, Tomonori %A Tanaka, Naoki %A Nishimoto, Takaaki %A Izumi, Yasuhiko %A Kume, Toshiaki %A Akaike, Akinori %A Takahashi, Takashi %A Sugimoto, Hachiro %X

Aggregation of amyloid-β (Aβ) and tau plays a crucial role in the onset and progression of Alzheimer's disease (AD). Therefore, the inhibition of Aβ and tau aggregation may represent a potential therapeutic target for AD. Herein, we designed and synthesized both Aβ and tau dual aggregation inhibitors based on the structure of curcumin and developed the novel curcumin derivative PE859. In this study, we investigated the inhibitory activity of PE859 on Aβ aggregationin vitro and the therapeutic effects of PE859 on cognitive dysfunction via dual inhibition of Aβ and tau aggregation in vivo. PE859 inhibited Aβ aggregation in vitro and protected cultured cells from Aβ-induced cytotoxicity. Furthermore, PE859 ameliorated cognitive dysfunction and reduced the amount of aggregated Aβ and tau in brains of senescence-accelerated mouse prone 8 (SAMP8). These results warrant consideration of PE859 as a candidate drug for AD.

%B J Alzheimers Dis %V 59 %P 313-328 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598836?dopt=Abstract %R 10.3233/JAD-161017 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Pen-2 and Presenilin are Sufficient to Catalyze Notch Processing. %A Hu, Chen %A Xu, Junjie %A Zeng, Linlin %A Li, Ting %A Cui, Mei-Zhen %A Xu, Xuemin %X

Presenilin-1 (PS1) or presenilin-2 (PS2), nicastrin (NCT), anterior pharynx-defective 1 (Aph-1), and presenilin enhancer-2 (Pen-2) have been considered the minimal essential subunits required to form an active γ-secretase complex. Besides PS, which has been widely believed to function as the catalytic subunit of the complex, the functional roles of the other subunits in the γ-secretase complex remain debatable. In the current study, we set out to determine the role of Pen-2 in γ-secretase activity. To this end, using knockout cells in combination with siRNA and immunoprecipitation approaches, our results revealed that Pen-2 together with presenilin are sufficient to form a functionally active enzyme to process Notch. Specifically, our data demonstrated that Pen-2 plays a crucial role in substrate binding, a mechanism by which Pen-2 contributes directly to the catalytic mechanism of γ-secretase activity. Our data also suggested that there may be different requirements for components to process AβPP and Notch. This information would be important for therapeutic strategy aimed at inhibition or modulation of γ-secretase activity.

%B J Alzheimers Dis %V 56 %P 1263-1269 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28234257?dopt=Abstract %R 10.3233/JAD-161094 %0 Journal Article %J J Alzheimers Dis %D 2017 %T People with Dementia Can Learn Compensatory Movement Maneuvers for the Sit-to-Stand Task: A Randomized Controlled Trial. %A Werner, Christian %A Wiloth, Stefanie %A Lemke, Nele Christin %A Kronbach, Florian %A Jansen, Carl-Philipp %A Oster, Peter %A Bauer, Jürgen M %A Hauer, Klaus %X

BACKGROUND: A complex motor skill highly relevant to mobility in everyday life (e.g., sit-to-stand [STS] transfer) has not yet been addressed in studies on motor learning in people with dementia (PwD).

OBJECTIVE: To determine whether a dementia-specific motor learning exercise program enables PwD to learn compensatory STS maneuvers commonly taught in geriatric rehabilitation therapy to enhance patients' STS ability.

METHODS: Ninety-seven patients with mild-to-moderate dementia (Mini-Mental State Examination: 21.9±2.9 points) participated in a double-blinded, randomized, placebo-controlled trial with 10-week intervention and 3-month follow-up period. The intervention group (IG, n = 51) underwent a motor learning exercise program on compensatory STS maneuvers specifically designed for PwD. The control group (CG, n = 46) performed a low-intensity motor placebo activity. Primary outcomes were scores of the Assessment of Compensatory Sit-to-stand Maneuvers in People with Dementia (ACSID), which covers the number of recalled and initiated, and of effectively performed compensatory STS maneuvers. Secondary outcomes included temporal and kinematic STS characteristics measured by a body-fixed motion sensor (BFS, DynaPort® Hybrid).

RESULTS: The IG significantly improved in all ACSID scores compared to the CG (p < 0.001). Secondary analysis confirmed learning effects for all BFS-based outcomes (p < 0.001-0.006). Learning gains were sustained during follow-up for most outcomes.

CONCLUSION: People with mild-to-moderate dementia can learn and retain compensatory STS maneuvers in response to a dementia-specific motor learning exercise program. This is the first study that demonstrated preserved motor learning abilities in PwD by using a motor skill highly relevant to everyday life.

%B J Alzheimers Dis %V 60 %P 107-120 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28759967?dopt=Abstract %R 10.3233/JAD-170258 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Perception and Reality of Cognitive Function: Information Processing Speed, Perceived Memory Function, and Perceived Task Difficulty in Older Adults. %A Torrens-Burton, Anna %A Basoudan, Nasreen %A Bayer, Antony J %A Tales, Andrea %X

This study examines the relationships between two measures of information processing speed associated with executive function (Trail Making Test and a computer-based visual search test), the perceived difficulty of the tasks, and perceived memory function (measured by the Memory Functioning Questionnaire) in older adults (aged 50+ y) with normal general health, cognition (Montreal Cognitive Assessment score of 26+), and mood. The participants were recruited from the community rather than through clinical services, and none had ever sought or received help from a health professional for a memory complaint or mental health problem. For both the trail making and the visual search tests, mean information processing speed was not correlated significantly with perceived memory function. Some individuals did, however, reveal substantially slower information processing speeds (outliers) that may have clinical significance and indicate those who may benefit most from further assessment and follow up. For the trail making, but not the visual search task, higher levels of subjective memory dysfunction were associated with a greater perception of task difficulty. The relationship between actual information processing speed and perceived task difficulty also varied with respect to the task used. These findings highlight the importance of taking into account the type of task and metacognition factors when examining the integrity of information processing speed in older adults, particularly as this measure is now specifically cited as a key cognitive subdomain within the diagnostic framework for neurocognitive disorders.

%B J Alzheimers Dis %V 60 %P 1601-1609 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984584?dopt=Abstract %R 10.3233/JAD-170599 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Peripheral versus Central Index of Metabolic Dysfunction and Associations with Clinical and Pathological Outcomes in Alzheimer's Disease. %A McLimans, Kelsey E %A Webb, Joseph L %A Anantharam, Vellareddy %A Kanthasamy, Anumantha %A Willette, Auriel A %X

BACKGROUND/OBJECTIVE: Insulin-like growth factor binding protein 2 (IGFBP-2) regulates blood glucose levels, facilitates hippocampal synaptic plasticity and may have a predictive value for Alzheimer's disease (AD) diagnosis.

METHODS: IGFBP-2 levels were studied in plasma in 566 subjects and in cerebrospinal fluid (CSF) in 245 subjects across the AD spectrum from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Variants in the IGFBP-2 gene were examined. Linear mixed modeling in SPSS tested main effects of IGFBP-2 and interactions with APOE4 on neurocognitive indices and biomarkers. Voxel-wise regression was used to gauge IGFBP-2 and regional grey matter and glucose metabolism associations.

RESULTS: Each point increase in IGFBP-2 corresponded to a three times greater likelihood of having mild cognitive impairment (MCI) or AD. IGFBP-2 showed beneficial associations with respect to cognitive scores in individuals with two APOE4 alleles. Higher IGFBP-2 predicted higher insulin resistance, but not CSF amyloid or tau. Voxel-wise analyses showed that plasma IGFBP-2 predicted lower grey matter volume and FDG metabolism in a large area spanning the frontal, temporal, and occipital lobes. CSF IGFBP-2 levels showed similar voxel-wise analysis results, but were uniquely associated with CSF amyloid and tau. Analysis of single nucleotide polymorphisms (SNPs) in IGFBP-2 showed that subjects carrying risk alleles versus common alleles had increased risk of AD and lower memory scores. Voxel-wise analyses of these SNPs also implicated the hippocampus and prefrontal cortex.

CONCLUSIONS: IGFBP-2 is associated with AD risk and outcomes; plasma IGFBP-2 provides stronger predictive power for brain outcomes, while CSF IGFBP-2 provides improved predictive accuracy for AD CSF biomarkers.

%B J Alzheimers Dis %V 60 %P 1313-1324 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28968233?dopt=Abstract %R 10.3233/JAD-170263 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Persistence with Antihypertensive Drugs in Patients with Hypertension and Dementia in Germany. %A Jacob, Louis %A Adam-Schnepf, Leonie %A Kostev, Karel %X

BACKGROUND: Hypertension, a chronic disease resulting from aging and its related physiopathological dysregulations, is often associated with dementia.

OBJECTIVE: The goal was to analyze the persistence with antihypertensive drugs in patients affected by both hypertension and dementia in Germany.

METHODS: This study included hypertension patients who were initially treated with antihypertensive drugs in 1,262 general practices in Germany between January 2013 and December 2015 (index date). Patients with hypertension and comorbid dementia were matched (1 : 1) to patients without dementia by age, gender, type of residence (nursing home versus home-care setting), physician, and initial antihypertensive therapy, using a propensity score method. The primary outcome was the rate of patients without treatment discontinuation with antihypertensive drugs in cases and controls in the 12 months following the index date. Cox regressions were used to determine the impact of dementia on persistence with antihypertensive treatment.

RESULTS: This study included 2,191 patients with hypertension and comorbid dementia and 2,191 patients with hypertension but without dementia. The mean age was 79.3 years (SD = 10.3 years) in both groups. Twelve months after initiation of antihypertensive therapy, 73.5% of cases and 69.5% of controls were persistent (p < 0.001). Dementia was associated with a significant decrease in the risk of non-persistence with antihypertensive drugs in the entire population (HR = 0.86, 95% CI: 0.79-0.93). This finding was corroborated in five different subgroups (age ≤60 years, age 61-70 years, men, women, and patients living in home-care settings).

CONCLUSIONS: Dementia was found to be a protective factor for persistence with antihypertensive drugs in Germany.

%B J Alzheimers Dis %V 60 %P 505-510 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869477?dopt=Abstract %R 10.3233/JAD-170452 %0 Journal Article %J J Alzheimers Dis %D 2017 %T PET Imaging of Tau Pathology and Relationship to Amyloid, Longitudinal MRI, and Cognitive Change in Down Syndrome: Results from the Down Syndrome Biomarker Initiative (DSBI). %A Rafii, Michael S %A Lukic, Ana S %A Andrews, Randolph D %A Brewer, James %A Rissman, Robert A %A Strother, Stephen C %A Wernick, Miles N %A Pennington, Craig %A Mobley, William C %A Ness, Seth %A Matthews, Dawn C %X

BACKGROUND: Adults with Down syndrome (DS) represent an enriched population for the development of Alzheimer's disease (AD), which could aid the study of therapeutic interventions, and in turn, could benefit from discoveries made in other AD populations.

OBJECTIVES: 1) Understand the relationship between tau pathology and age, amyloid deposition, neurodegeneration (MRI and FDG PET), and cognitive and functional performance; 2) detect and differentiate AD-specific changes from DS-specific brain changes in longitudinal MRI.

METHODS: Twelve non-demented adults, ages 30 to 60, with DS were enrolled in the Down Syndrome Biomarker Initiative (DSBI), a 3-year, observational, cohort study to demonstrate the feasibility of conducting AD intervention/prevention trials in adults with DS. We collected imaging data with 18F-AV-1451 tau PET, AV-45 amyloid PET, FDG PET, and volumetric MRI, as well as cognitive and functional measures and additional laboratory measures.

RESULTS: All amyloid negative subjects imaged were tau-negative. Among the amyloid positive subjects, three had tau in regions associated with Braak stage VI, two at stage V, and one at stage II. Amyloid and tau burden correlated with age. The MRI analysis produced two distinct volumetric patterns. The first differentiated DS from normal (NL) and AD, did not correlate with age or amyloid, and was longitudinally stable. The second pattern reflected AD-like atrophy and differentiated NL from AD. Tau PET and MRI atrophy correlated with several cognitive and functional measures.

CONCLUSIONS: Tau accumulation is associated with amyloid positivity and age, as well as with progressive neurodegeneration measurable using FDG and MRI. Tau correlates with cognitive decline, as do AD-specific hypometabolism and atrophy.

%B J Alzheimers Dis %V 60 %P 439-450 %8 2017 %G eng %N 2 %R 10.3233/JAD-170390 %0 Journal Article %J J Alzheimers Dis %D 2017 %T PET Tau and Amyloid-β Burden in Mild Alzheimer's Disease: Divergent Relationship with Age, Cognition, and Cerebrospinal Fluid Biomarkers. %A Koychev, Ivan %A Gunn, Roger N %A Firouzian, Azadeh %A Lawson, Jennifer %A Zamboni, Giovanna %A Ridha, Basil %A Sahakian, Barbara J %A Rowe, James B %A Thomas, Alan %A Rochester, Lynn %A Ffytche, Dominic %A Howard, Robert %A Zetterberg, Henrik %A MacKay, Clare %A Lovestone, Simon %X

BACKGROUND: Combining PET amyloid-β (Aβ) and tau imaging may be critical for tracking disease progression in Alzheimer's disease (AD).

OBJECTIVE: We sought to characterize the relationship between Aβ and tau ligands as well as with other measures of pathology.

METHODS: We conducted a multi-center observational study in early AD (MMSE >20) participants aged 50 to 85 y. The schedule included cognitive assessments (ADAS-Cog) and CSF measurement of Aβ and tau at baseline and 6 months; PET-CT imaging with Aβ ([18F]AV45) and tau ([18F]AV1451) ligands at baseline.

RESULTS: 22 participants took part in the study with 20 completing its 6-month duration and 12 having both tau and amyloid PET. The PET biomarker analysis revealed a strong negative correlation between age and tau in multiple regions. Entorhinal cortex tau and age interacted significantly in terms of cognitive change over 6 months which may have been to older participants deteriorating faster despite lower levels of cortical tau. Cortical Aβ associated with entorhinal cortex tau while CSF tau/Aβ ratio correlated strongly with cortical tau but not Aβ.

CONCLUSION: The negative relationship between age and cortical tau whereby younger patients with mild AD had relatively greater tau burden is potentially important. It suggests that younger-age onset AD may be primarily driven by tau pathology while AD developing later may depend on a multitude of pathological mechanisms. These data also suggest that PET-tau performs better than PET-amyloid in predicting the best validated AD diagnostic marker- the CSF total tau/Aβ ratio.

%B J Alzheimers Dis %V 60 %P 283-293 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28800330?dopt=Abstract %R 10.3233/JAD-170129 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Phenotype-Dependent Interactions between N-acetyl-L-Aspartate and Acetyl-CoA in Septal SN56 Cholinergic Cells Exposed to an Excess of Zinc. %A Zyśk, Marlena %A Bielarczyk, Hanna %A Gul-Hinc, Sylwia %A Dyś, Aleksandra %A Gapys, Beata %A Ronowska, Anna %A Sakowicz-Burkiewicz, Monika %A Szutowicz, Andrzej %X

Pyruvate dehydrogenase reaction utilizing glucose-derived pyruvate is an almost exclusive source of acetyl-CoA in different cell mitochondrial compartments of the brain. In neuronal mitochondria, the largest fraction of acetyl-CoA is utilized for energy production and the much smaller one for N-acetyl-L-aspartate (NAA) synthesis. Cholinergic neurons, unlike others, require additional amounts of acetyl-CoA for acetylcholine synthesis. Therefore, several neurotoxic signals, which inhibit pyruvate dehydrogenase, generate deeper shortages of acetyl-CoA and greater mortality of cholinergic neurons than noncholinergic ones. NAA is considered to be a marker of neuronal energy status in neuropathic brains. However, there is no data on putative differential fractional distribution of the acetyl-CoA pool between energy producing and NAA or acetylcholine synthesizing pathways in noncholinergic and cholinergic neurons, respectively. Therefore, the aim of this study was to investigate whether zinc-excess, a common excitotoxic signal, may evoke differential effects on the NAA metabolism in neuronal cells with low and high expression of the cholinergic phenotype. Differentiated SN56 neuronal cells, displaying a high activity of choline acetyltransferase and rates of acetylcholine synthesis, contained lower levels of acetyl-CoA and NAA, being more susceptible to ZnCl2 exposition that the nondifferentiated SN56 or differentiated dopaminergic SHSY5Y neuronal and astroglial C6 cells. Differentiated SN56 accumulated greater amounts of Zn2 + from extracellular space than the other ones, and displayed a stronger suppression of pyruvate dehydrogenase complex activity and acetyl-CoA, NAA, ATP, acetylcholine levels, and loss of viability. These data indicate that the acetyl-CoA synthesizing system in neurons constitutes functional unity with energy generating and NAA or acetylcholine pathways of its utilization, which are uniformly affected by neurotoxic conditions.

%B J Alzheimers Dis %V 56 %P 1145-1158 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106547?dopt=Abstract %R 10.3233/JAD-160693 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Phospho-Tau Accumulation and Structural Alterations of the Golgi Apparatus of Cortical Pyramidal Neurons in the P301S Tauopathy Mouse Model. %A Antón-Fernández, Alejandro %A Merchán-Rubira, Jesús %A Avila, Jesús %A Hernández, Félix %A DeFelipe, Javier %A Muñoz, Alberto %X

The Golgi apparatus (GA) is a highly dynamic organelle involved in the processing and sorting of cellular proteins. In Alzheimer's disease (AD), it has been shown to decrease in size and become fragmented in neocortical and hippocampal neuronal subpopulations. This fragmentation and decrease in size of the GA in AD has been related to the accumulation of hyperphosphorylated tau. However, the involvement of other pathological factors associated with the course of the disease, such as the extracellular accumulation of amyloid-β (Aβ) aggregates, cannot be ruled out, since both pathologies are present in AD patients. Here we use the P301S tauopathy mouse model to examine possible alterations of the GA in neurons that overexpress human tau (P301S mutated gene) in neocortical and hippocampal neurons, using double immunofluorescence techniques and confocal microscopy. Quantitative analysis revealed that neurofibrillary tangle (NFT)-bearing neurons had important morphological alterations and reductions in the surface area and volume of the GA compared with NFT-free neurons. Since in this mouse model there are no Aβ aggregates typical of AD, the present findings support the idea that the progressive accumulation of phospho-tau is associated with structural alterations of the GA, and that these changes may occur in the absence of Aβ pathology.

%B J Alzheimers Dis %V 60 %P 651-661 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922155?dopt=Abstract %R 10.3233/JAD-170332 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Physical Activity in Midlife is not Associated with Cognitive Health in Later Life Among Cognitively Normal Older Adults. %A Gross, Alden L %A Lu, Haidong %A Meoni, Lucy %A Gallo, Joseph J %A Schrack, Jennifer A %A Sharrett, A Richey %X

BACKGROUND: Links between physical activity and dementia are based primarily on cross-sectional data or studies with unsatisfactory follow-up.

OBJECTIVE: We leveraged three decades of follow-up from an established cohort to determine whether physical activity in midlife is associated with late-life cognition and dementia.

METHODS: The Johns Hopkins Precursors study (n = 646) enrolled participants from 1948-1964 and administered questions about physical activity, from which we calculated metabolic equivalents (MET h/day), and exercise from 1978-present. Cognitive tests were administered in 2008. Dementia was adjudicated through 2011. To characterize associations with midlife physical activity, we used linear regression for cognitive tests and Cox proportional hazards models for dementia onset. Models adjusted for age, sex, smoking, diabetes, and hypertension.

RESULTS: No physical activity measure from 1978 was associated with late-life cognition or onset of dementia. Both MET h/day (β= 0.007, 95% CI: 0.002, 0.013) and regular exercise (β= 0.357, 95% CI: 0.202, 0.513) in 2006, however, were associated with better cognition in 2008.

CONCLUSION: Findings from this 30-year cohort study that physical activity measured recently, but not in mid-life, is associated with late-life cognition fits with null findings from randomized trials and other observational studies with extensive follow-up. Cross-sectional findings may be misleading due to reverse causation.

%B J Alzheimers Dis %V 59 %P 1349-1358 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28759969?dopt=Abstract %R 10.3233/JAD-170290 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Physical Exercise Moderates the Relationship of Apolipoprotein E (APOE) Genotype and Dementia Risk: A Population-Based Study. %A Fenesi, Barbara %A Fang, Hanna %A Kovacevic, Ana %A Oremus, Mark %A Raina, Parminder %A Heisz, Jennifer J %X

Genetics and lifestyle independently determine dementia risk, but the interaction is unclear. We assessed the interactive relationship of apolipoprotein E (APOE) genotype and physical exercise on dementia risk over a 5-year period in 1,646 older adults from the Canadian Study of Health and Aging who were dementia-free at baseline. Physical exercise moderated the relationship between genotype and dementia (p < 0.01). Specifically, for APOE ɛ4 non-carriers, the odds of developing dementia were higher in non-exercisers than exercisers (OR = 1.98, 95% CI = 1.44, 2.71, p < 0.001), whereas, for APOE ɛ4 carriers, the odds of developing dementia were not significantly different between non-exercisers and exercisers (OR = 0.71, 95% CI = 0.46, 1.31, p = 0.34). Given that most individuals are not at genetic risk, physical exercise may be an effective strategy for preventing dementia.

%B J Alzheimers Dis %V 56 %P 297-303 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911292?dopt=Abstract %R 10.3233/JAD-160424 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Physical Exercise with Music Maintains Activities of Daily Living in Patients with Dementia: Mihama-Kiho Project Part 21. %A Satoh, Masayuki %A Ogawa, Jun-Ichi %A Tokita, Tomoko %A Nakaguchi, Noriko %A Nakao, Koji %A Kida, Hirotaka %A Tomimoto, Hidekazu %X

BACKGROUND: Recent studies suggest that combined non-pharmacological interventions are more beneficial than single interventions for primary and secondary prevention of dementia. We previously reported enhanced effects of physical exercise with music (ExM) on cognitive function in normal elderly people compared to exercise alone.

OBJECTIVE: To identify if ExM improves cognitive function and activities of daily livings (ADLs) in dementia patients over cognitive stimulation (CS).

METHODS: We enrolled 85 patients with mild to moderate dementia. Forty-three subjects performed ExM developed by the Yamaha Music Foundation, and 42 subjects performed cognitive stimulation using portable game consoles and drills involving easy calculations, mazes, and mistake-searching in pictures. Interventions were performed once a week for 40 minutes. Before and after the six-month intervention, patients were assessed using neuropsychological batteries, and ADLs were assessed by patients' caregivers using the functional independence measure (FIM). Voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) was used to assess medial temporal lobe atrophy.

RESULTS: Twenty-three subjects dropped out during the intervention. Thirty-one patients from each group were analyzed. Post-intervention, both groups showed significantly improved visuospatial function. Significant benefits were observed in psychomotor speed or memory in the ExM or CS groups, respectively. FIM scores, reflecting ADLs, and VSRAD scores were significantly preserved in the ExM group, but significantly worsened in the CS group.

CONCLUSIONS: ExM produced greater positive effects on cognitive function and ADLs in patients with mild to moderate dementia than CS, excluding memory. Optimal interventions for dementia will likely be achieved by combining ExMand CS.

%B J Alzheimers Dis %V 57 %P 85-96 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222531?dopt=Abstract %R 10.3233/JAD-161217 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Pitfall of Behavioral Variant Frontotemporal Dementia Mimics Despite Multidisciplinary Application of the FTDC Criteria. %A Krudop, Welmoed A %A Dols, Annemieke %A Kerssens, Cora J %A Eikelenboom, Piet %A Prins, Niels D %A Möller, Christiane %A Schouws, Sigfried %A Rhebergen, Didi %A van Exel, Eric %A van der Flier, Wiesje M %A Sikkes, Sietske %A Scheltens, Philip %A Stek, Max L %A Pijnenburg, Yolande A L %X

BACKGROUND: The behavioral variant of frontotemporal dementia (bvFTD) has a broad differential diagnosis including other neurological and psychiatric disorders. Psychiatric misdiagnoses occur in up to 50% of bvFTD patients. Numbers on misdiagnosis of bvFTD in psychiatric disorders are lacking.

OBJECTIVE: The aim of our study was to investigate the frequency and characteristics of bvFTD misdiagnoses in psychiatric disorders and other neurologic disorders.

METHODS: Thirty-five patients with a (possible or probable) bvFTD diagnosis made by specialized memory clinic neurologists were included. Change in diagnosis after consulting a psychiatrist at baseline was recorded as well as change in diagnosis after two years of multidisciplinary neuropsychiatric follow-up. Differences in cognitive and behavioral profiles were investigated per diagnostic group after follow-up (bvFTD, psychiatry, other neurologic disorders). Clinical profiles are described in detail.

RESULTS: In 17 patients (48.5%), the bvFTD baseline diagnosis changed: Two at baseline after psychiatric consultation, and 15 after two years of multidisciplinary follow-up. Eleven (64.5%) of these 17 patients (31.5% of total) were reclassified with a psychiatric diagnosis. We found no differences for cognitive baseline profiles between patients with bvFTD versus psychiatric diagnoses.

CONCLUSION: In almost half of cases, the initial bvFTD diagnosis was changed after follow-up, most often into a psychiatric disorder. A multidisciplinary neuropsychiatric approach in the diagnostic process of bvFTD results in the identification of treatable disorders. Our findings illustrate a limited specificity of the [18F]FDG-PET-scan and the bvFTD criteria in a neuropsychiatric cohort, especially combined with certain clinical symptoms, like disinhibition, apathy, or loss of empathy.

%B J Alzheimers Dis %V 60 %P 959-975 %8 2017 %G eng %N 3 %R 10.3233/JAD-170608 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Plasma Amyloid-β and Alzheimer's Disease-Related Changes in Late-Life Depression. %A Yamazaki, Chiemi %A Tamaoki, Toshio %A Nunomura, Akihiko %A Tamai, Kenichi %A Yasuda, Kazuyuki %A Motohashi, Nobutaka %X

To elucidate an involvement of amyloid dysmetabolism in the pathophysiology of depression, we investigated associations of plasma amyloid-β (Aβ) levels with Alzheimer's disease-related changes in neuroimaging and cognitive dysfunction in patients with late-life depression. Higher plasma Aβ40, but not Aβ42 nor Aβ40/Aβ42 ratio, was associated with higher degree of parahippocampal atrophy and lower verbal fluency performance. Indeed, high plasma Aβ40 predicted poor cognitive prognosis of depressed patients with mild cognitive impairment. As an anti-depressive treatment, electroconvulsive therapy (ECT) resulted in a marginally significant reduction of plasma Aβ40 compared to pharmacotherapy alone, suggesting protective effects of ECT against amyloid dysmetabolism.

%B J Alzheimers Dis %V 58 %P 349-354 %G eng %N 2 %R 10.3233/JAD-170111 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Plasma Amyloid-β Levels, Cerebral Small Vessel Disease, and Cognition: The Rotterdam Study. %A Hilal, Saima %A Akoudad, Saloua %A van Duijn, Cornelia M %A Niessen, Wiro J %A Verbeek, Marcel M %A Vanderstichele, Hugo %A Stoops, Erik %A Ikram, M Arfan %A Vernooij, Meike W %X

BACKGROUND: Plasma amyloid-β (Aβ) levels are increasingly studied as a potential, accessible marker of cognitive impairment and dementia. The most common plasma Aβ isoforms, i.e., Aβ1-40 and Aβ1-42 have been linked with risk of Alzheimer's disease. However, it remains under-explored whether plasma Aβ levels including novel Aβ1-38 relate to vascular brain disease and cognition in a preclinical-phase of dementiaObjective:To examine the association of plasma Aβ levels (i.e., Aβ1-38, Aβ1-40, and Aβ1-42) with markers of cerebral small vessel disease (SVD) and cognition in a large population-based setting.

METHODS: We analyzed plasma Aβ1 levels in 1201 subjects from two independent cohorts of the Rotterdam Study. Markers of SVD [lacunes, white matter hyperintensity (WMH) volume] were assessed on brain MRI (1.5T). Cognition was assessed by a detailed neuropsychological battery. In each cohort, the association of Aβ levels with SVD and cognition was performed using regression models. Estimates were then pooled across cohorts using inverse variance meta-analysis with fixed effects.

RESULTS: Higher levels of plasma Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-40/ Aβ1-42 ratio were associated with increasing lacunar and microbleeds counts. Moreover, higher levels of Aβ1-40 and Aβ1-40/ Aβ1-42 were significantly associated with larger WMH volumes. With regard to cognition, a higher level of Aβ1-38 Aβ1-40 and Aβ1-40/ Aβ1-42 was related to worse performance on cognitive test specifically in memory domain.

CONCLUSION: Higher plasma levels of Aβ levels are associated with subclinical markers of vascular disease and poorer memory. Plasma Aβ levels thus mark the presence of vascular brain pathology.

%B J Alzheimers Dis %V 60 %P 977-987 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984600?dopt=Abstract %R 10.3233/JAD-170458 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Plasma Amyloid-β Peptides in Type 2 Diabetes: A Matched Case-Control Study. %A Peters, Kirsten E %A Davis, Wendy A %A Taddei, Kevin %A Martins, Ralph N %A Masters, Colin L %A Davis, Timothy M E %A Bruce, David G %X

BACKGROUND: Plasma amyloid-β (Aβ) levels have rarely been investigated in type 2 diabetes despite its known associations with Alzheimer's disease.

OBJECTIVE: To compare blood plasma Aβ concentrations (Aβ40 and Aβ42) in cognitively normal individuals with and without type 2 diabetes.

METHODS: Plasma Aβ40 and Aβ42 were measured in 194 participants with diabetes recruited from the community-based Fremantle Diabetes Study Phase II cohort (mean age 71 years, 59% males) and 194 age-, sex-, and APOEɛ4 allele-matched, control subjects without diabetes from the Australian Imaging, Biomarkers and Lifestyle Study using a multiplex microsphere-based immunoassay.

RESULTS: Plasma Aβ40 and Aβ42 were normally distributed in the controls but were bimodal in the participants with diabetes. Median Aβ40 and Aβ42 concentrations were significantly lower in those with type 2 diabetes (Aβ40 median [inter-quartile range]: 125.0 [52.6-148.3] versus 149.3 [134.0-165.6] pg/mL; Aβ42: 26.9 [14.5-38.3] versus 33.6 [28.0-38.9] pg/mL, both p < 0.001) while the ratio Aβ42:Aβ40 was significantly higher (0.26 [0.23-0.32] versus 0.22 [0.19-0.25], p < 0.001). After adjustment, participants with diabetes and plasma Aβ40 levels in the low peak of the bimodal distribution were significantly more likely to have normal to high estimated glomerular filtration rates (odds ratio (95% CI): 2.40 (1.20-4.80), p = 0.013) although the group with diabetes had lower renal function overall.

CONCLUSION: Type 2 diabetes is associated with altered plasma concentrations of Aβ peptides and is an important source of variation that needs to be taken into account when considering plasma Aβ peptides as biomarkers for Alzheimer's disease.

%B J Alzheimers Dis %V 56 %P 1127-1133 %G eng %N 3 %R 10.3233/JAD-161050 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Plasma Proteomic Profiles of Cerebrospinal Fluid-Defined Alzheimer's Disease Pathology in Older Adults. %A Dayon, Loïc %A Wojcik, Jérôme %A Núñez Galindo, Antonio %A Corthésy, John %A Cominetti, Ornella %A Oikonomidi, Aikaterini %A Henry, Hugues %A Migliavacca, Eugenia %A Bowman, Gene L %A Popp, Julius %X

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers of the beta-amyloid and microtubule associated protein tau metabolism have proven the capacity to improve classification of subjects developing Alzheimer's disease (AD). The blood plasma proteome was characterized to further elaborate upon the mechanisms involved and identify proteins that may improve classification of older adults developing an AD dementia.

OBJECTIVE: Identify and describe plasma protein expressions that best classify subjects with CSF-defined presence of AD pathology and cerebral amyloidosis.

METHODS: We performed a cross-sectional analysis of samples collected from community-dwelling elderly with (n = 72) or without (n = 48) cognitive impairment. CSF Aβ1-42, tau, and phosphorylated tau (P-tau181) were measured using ELISA, and mass spectrometry quantified the plasma proteomes. Presence of AD pathology was defined as CSF P-tau181/Aβ1-42 > 0.0779, and presence of amyloidosis was defined as CSF Aβ1-42 < 724 pg/mL.

RESULTS: Two hundred and forty-eight plasma proteins were quantified. Plasma proteins did not improve classification of the AD CSF biomarker profile in the whole sample. When the analysis was separately performed in the cognitively impaired individuals, the diagnosis accuracy of AD CSF profile was 88.9% with 19 plasma proteins included. Within the full cohort, there were 16 plasma proteins that improved diagnostic accuracy of cerebral amyloidosis to 92.4%.

CONCLUSION: Plasma proteins improved classification accuracy of AD pathology in cognitively-impaired older adults and appeared representative of amyloid pathology. If confirmed, those candidates could serve as valuable blood biomarkers of the preclinical stages of AD or risk of developing AD.

%B J Alzheimers Dis %V 60 %P 1641-1652 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125490?dopt=Abstract %R 10.3233/JAD-170426 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Plasma Tau Association with Brain Atrophy in Mild Cognitive Impairment and Alzheimer's Disease. %A Deters, Kacie D %A Risacher, Shannon L %A Kim, Sungeun %A Nho, Kwangsik %A West, John D %A Blennow, Kaj %A Zetterberg, Henrik %A Shaw, Leslie M %A Trojanowski, John Q %A Weiner, Michael W %A Saykin, Andrew J %X

BACKGROUND: Peripheral (plasma) and central (cerebrospinal fluid, CSF) measures of tau are higher in Alzheimer's disease (AD) relative to prodromal stages and controls. While elevated CSF tau concentrations have been shown to be associated with lower grey matter density (GMD) in AD-specific regions, this correlation has yet to be examined for plasma in a large study.

OBJECTIVE: Determine the neuroanatomical correlates of plasma tau using voxel-based analysis.

METHODS: Cross-sectional data for 508 ADNI participants were collected for clinical, plasma total-tau (t-tau), CSF amyloid (Aβ42) and tau, and MRI variables. The relationship between plasma tau and GMD and between CSF t-tau and GMD were assessed on a voxel-by-voxel basis using regression models. Age, sex, APOEɛ4 status, diagnosis, and total intracranial volume were used as covariates where appropriate. Participants were defined as amyloid positive (Aβ+) if CSF Aβ42 was <192 pg/mL.

RESULTS: Plasma tau was negatively correlated with GMD in the medial temporal lobe (MTL), precuneus, thalamus, and striatum. The associations with thalamus and striatum were independent of diagnosis. A negative correlation also existed between plasma tau and GMD in Aβ+ participants in the MTL, precuneus, and frontal lobe. When compared to CSF t-tau, plasma tau showed a notably different associated brain atrophy pattern, with only small overlapping regions in the fusiform gyrus.

CONCLUSION: Plasma tau may serve as a non-specific marker for neurodegeneration but is still relevant to AD considering low GMD was associated with plasma tau in Aβ+ participants and not Aβ-participants.

%B J Alzheimers Dis %V 58 %P 1245-1254 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550246?dopt=Abstract %R 10.3233/JAD-161114 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Pleiotropic Effect of Human ApoE4 on Cerebral Ceramide and Saturated Fatty Acid Levels. %A den Hoedt, Sandra %A Janssen, Carola I F %A Astarita, Giuseppe %A Piomelli, Daniele %A Leijten, Frank P J %A Crivelli, Simone M %A Verhoeven, Adrie J M %A De Vries, Helga E %A Walter, Jochen %A Martinez-Martinez, Pilar %A Sijbrands, Eric J G %A Kiliaan, Amanda J %A Mulder, Monique T %X

BACKGROUND: Apolipoprotein E (ApoE) is known for its role in lipid trafficking and the ɛ4 allele is a risk factor for late onset Alzheimer's disease (AD). Recently, aberrant ceramide and fatty acid (FA) levels have been implicated in AD.

OBJECTIVE: To determine the specific effects of human ApoE4 (hE4) on cerebral ceramide and FA content during chow or a high fat/high cholesterol (HFHC) diet.

METHODS: Cerebral ceramide and FA profiles were determined by LC-MSMS in 15-month-old female wild-type (WT), ApoE-knockout (E0), and hE4-knockin mice fed chow or a HFHC diet for 3 months. mRNA levels of genes involved in ceramide and FA metabolism were determined by qPCR.

RESULTS: Similar to E0, hE4 mice displayed lower cerebral total ceramide, Cer16 : 0, and Cer24 : 1 levels than WT mice on both diets. Akin to WT mice, hE4 mice had lower total and saturated FA levels on chow than E0 mice. The HFHC diet significantly increased total and saturated FA levels in hE4 mice. Chow-fed hE4 mice showed lower mRNA levels of ceramide synthase (CerS) 6, acid sphingomyelinase, and of most ceramide and FA transporters than WT and E0 mice. The HFHC diet downregulated the expression of CerSs in hE4 and WT mice, and of ceramide and FA transporters in WT mice, but not in E0 mice.

CONCLUSION: hE4 reduced cerebral ceramide levels to levels observed in E0 mice independent of diet. The HFHC diet increased cerebral FA levels in hE4 mice. This was associated with alterations in the expression of ceramide and FA transporters specifically in hE4 mice.

%B J Alzheimers Dis %V 60 %P 769-781 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035926?dopt=Abstract %R 10.3233/JAD-160739 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Polymorphonuclear Neutrophil Functions are Differentially Altered in Amnestic Mild Cognitive Impairment and Mild Alzheimer's Disease Patients. %A Le Page, Aurélie %A Lamoureux, Julie %A Bourgade, Karine %A Frost, Eric H %A Pawelec, Graham %A Witkowski, Jacek M %A Larbi, Anis %A Dupuis, Gilles %A Fülöp, Tamás %X

The mechanisms of neurodegeneration in Alzheimer's disease (AD) remain under investigation. Alterations in the blood-brain barrier facilitate exchange of inflammatory mediators and immune cells between the brain and the periphery in AD. Here, we report analysis of phenotype and functions of polymorphonuclear neutrophils (PMN) in peripheral blood from patients with amnestic mild cognitive impairment (aMCI, n = 13), patients with mild AD (mAD, n = 15), and healthy elderly controls (n = 13). Results showed an increased expression of CD177 in mAD but not in healthy or aMCI patients. IL-8 stimulated increased expression of the CD11b integrin in PMN of healthy subjects in vitro but PMN of aMCI and mAD patients failed to respond. CD14 and CD16 expression was lower in PMN of mAD but not in aMCI individuals relative to controls. Only PMN of aMCI subjects expressed lower levels of CD88. Phagocytosis toward opsonized E. coli was differentially impaired in PMN of aMCI and mAD subjects whereas the capacity to ingest Dextran particles was absent only in mAD subjects. Killing activity was severely impaired in aMCI and mAD subjects whereas free radical production was only impaired in mAD patients. Inflammatory cytokine (TNFα, IL-6, IL-1β, IL-12p70) and chemokine (MIP-1α, MIP-1β, IL-8) production in response to LPS stimulation was very low in aMCI and nearly absent in mAD subjects. TLR2 expression was low only in aMCI. Our data showed a differentially altered capacity of PMN of aMCI and mAD subjects to respond to pathological aggression that may impact impaired responses associated with AD development.

%B J Alzheimers Dis %V 60 %P 23-42 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28777750?dopt=Abstract %R 10.3233/JAD-170124 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Positive and Negative Experiences of Social Support and Risk of Dementia in Later Life: An Investigation Using the English Longitudinal Study of Ageing. %A Khondoker, Mizanur %A Rafnsson, Snorri Bjorn %A Morris, Stephen %A Orrell, Martin %A Steptoe, Andrew %X

BACKGROUND: Having a network of close relationships may reduce the risk of developing dementia. However, social exchange theory suggests that social interaction entails both rewards and costs. The effects of quality of close social relationships in later life on the risk of developing dementia are not well understood.

OBJECTIVE: To investigate the effects of positive and negative experiences of social support within key relationships (spouse or partner, children, other immediate family, and friends) on the risk of developing dementia in later life.

METHODS: We analyzed 10-year follow up data (2003/4 to 2012/13) in a cohort of 10,055 dementia free (at baseline) core participants aged 50 years and over from the English Longitudinal Study of Ageing (ELSA). Incidence of dementia was identified from participant or informant reported physician diagnosed dementia or overall score of informant-completed IQCODE questionnaire. Effects of positive and negative experiences of social support measured at baseline on risk of developing dementia were investigated using proportional hazards regression accommodating interval censoring of time-to-dementia.

RESULTS: There were 340 (3.4%) incident dementia cases during the follow-up. Positive social support from children significantly reduced the risk of dementia (hazard ratio, HR = 0.83, p = 0.042, 95% CI: 0.69 to 0.99). Negative support from other immediate family (HR = 1.26, p = 0.011, CI: 1.05 to 1.50); combined negative scores from spouse and children (HR = 1.23, p = 0.046, CI: 1.004 to 1.51); spouse, children, and other family (HR = 1.27, p = 0.021, CI = 1.04 to 1.56); other family & friends (HR = 1.25, p = 0.033, CI: 1.02 to 1.55); and the overall negative scores (HR = 1.31, p = 0.019, CI: 1.05 to 1.64) all were significantly associated with increased risk of dementia.

CONCLUSION: Positive social support from children is associated with reduced risk of developing dementia whereas experiences of negative social support from children and other immediate family increase the risk. Further research is needed to better understand the causal mechanisms that drive these associations.

%B J Alzheimers Dis %V 58 %P 99-108 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387667?dopt=Abstract %R 10.3233/JAD-161160 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Potentially Inappropriate Medication, Anticholinergic Burden, and Mortality in People Attending Memory Clinics. %A Cross, Amanda J %A George, Johnson %A Woodward, Michael C %A Ames, David %A Brodaty, Henry %A Wolfe, Rory %A Connors, Michael H %A Elliott, Rohan A %X

BACKGROUND: There is limited evidence regarding the association between potentially inappropriate medications (PIM) and mortality in older people with cognitive impairment.

OBJECTIVE: To examine whether use of medications considered to be potentially inappropriate in older people with cognitive impairment (PIMcog) and anticholinergic cognitive burden (ACB) were associated with mortality in people who attended memory clinics.

METHODS: Cross-sectional and longitudinal analyses of data from the Prospective Research In MEmory clinics (PRIME) study. Participants were community-dwelling people who attended nine memory clinics and had a diagnosis of mild cognitive impairment or dementia. PIMcog was defined as any medication considered potentially inappropriate for a person with cognitive impairment according to Beers or STOPP criteria. Anticholinergic burden was calculated using the ACB scale. Time-dependent Cox-proportional hazards regression was used to analyze associations between PIMcog use/ACB score and all-cause mortality over a three-year follow-up period. The regression model included the baseline variables: age, gender, education, cognitive diagnoses, total number of medications, disease-burden, cognition, physical function, and neuropsychiatric symptoms.

RESULTS: Of 964 participants, 360 (37.3%) used one or more PIMcog at some time during the study; most commonly anticholinergics and sedatives. 624 (64.7%) participants used a medication with potential or definite anticholinergic properties (ACB>0) at some point during the study. Both PIMcog use (adjusted hazard ratio: 1.42 95% CI: 1.12-1.80) and ACB score (adjusted hazard ratio: 1.18 95% CI: 1.06-1.32) were associated with mortality.

CONCLUSION: Use of PIMcogs and medications with anticholinergic properties was common among memory clinic patients and both were associated with mortality.

%B J Alzheimers Dis %V 60 %P 349-358 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869467?dopt=Abstract %R 10.3233/JAD-170265 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Potentially Inappropriate Medication in Community-Dwelling Primary Care Patients who were Screened Positive for Dementia. %A Wucherer, Diana %A Eichler, Tilly %A Hertel, Johannes %A Kilimann, Ingo %A Richter, Steffen %A Michalowsky, Bernhard %A Thyrian, Jochen René %A Teipel, Stefan %A Hoffmann, Wolfgang %X

BACKGROUND: Potentially inappropriate medication (PIM) in older people is a risk factor for adverse drug effects. This risk is even higher in older people with dementia (PWD).

OBJECTIVE: Our study aimed to determine (1) the prevalence of PIM among primary care patients who were screened positive for dementia and (2) the sociodemographic and clinical variables associated with the use of PIM.

METHODS: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is a general practitioner-based, cluster-randomized, controlled intervention study to implement and evaluate an innovative concept of collaborative dementia care management in Germany. The comprehensive baseline assessment includes a home medication review. The present analyses are based on the data from 448 study participants (age 70+, DemTect <9). PIMs were identified using the list of Potentially Inappropriate Medications in the Elderly (Priscus).

RESULTS: (1) A total of 99 study participants (22%) received at least one PIM. The highest prevalence was found for antidepressants, benzodiazepines, and analgetics. The most frequently prescribed PIMs were amitriptyline, etoricoxib, and doxazosin. (2) Use of a PIM was significantly associated with a diagnosis of a mental or behavioral disorder.

CONCLUSIONS: The prescription rate of PIMs for community-dwelling PWD was comparable with the rates found for the general population of older people in Germany (20-29%). Antidepressants with anticholinergic properties and long-acting benzodiazepines were the most prescribed PIMs, despite having an unfavorable benefit-risk ratio. This high prevalence of PIM prescriptions in a vulnerable population of PWD indicates that standard care for dementia should include careful medication review and management.

%B J Alzheimers Dis %V 55 %P 691-701 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716668?dopt=Abstract %R 10.3233/JAD-160581 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Preclinical Amyloid-β and Axonal Degeneration Pathology in Delirium. %A Idland, Ane-Victoria %A Wyller, Torgeir Bruun %A Støen, Randi %A Eri, Lars Magne %A Frihagen, Frede %A Ræder, Johan %A Chaudhry, Farrukh Abbas %A Hansson, Oskar %A Zetterberg, Henrik %A Blennow, Kaj %A Bogdanovic, Nenad %A Brækhus, Anne %A Watne, Leiv Otto %X

BACKGROUND: The clinical relevance of brain β-amyloidosis in older adults without dementia is not established. As delirium and dementia are strongly related, studies on patients with delirium may give pathophysiological clues.

OBJECTIVE: To determine whether the Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau) are associated with delirium in hip fracture patients with and without dementia.

METHODS: CSF was collected in conjunction to spinal anesthesia in 129 patients. Delirium was assessed using the Confusion Assessment Method once daily in all patients, both pre- and postoperatively. The diagnosis of dementia at admission was based upon clinical consensus. CSF levels of Aβ42, T-tau, and P-tau were analyzed.

RESULTS: In patients without dementia, we found lower CSF Aβ42 levels (median, 310 ng/L versus 489 ng/L, p = 0.006), higher T-tau levels (median, 505 ng/L versus 351 ng/L, p = 0.02), but no change in P-tau in patients who developed delirium (n = 16) compared to those who remained lucid (n = 49). Delirious patients also had lower ratios of Aβ42 to T-tau (p < 0.001) and P-tau (p = 0.001) relative to those without delirium. CSF Aβ42 and T-tau remained significantly associated with delirium status in adjusted analyses. In patients with dementia, CSF biomarker levels did not differ between those with (n = 54) and without delirium (n = 10).

CONCLUSION: The reduction in CSF Aβ42, indicating β-amyloidosis, and increase in T-tau, indicating neurodegeneration, in hip fracture patients without dementia developing delirium indicates that preclinical AD brain pathology is clinically relevant and possibly plays a role in delirium pathophysiology.

%B J Alzheimers Dis %V 55 %P 371-379 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662296?dopt=Abstract %R 10.3233/JAD-160461 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Precuneus Failures in Subjects of the PSEN1 E280A Family at Risk of Developing Alzheimer's Disease Detected Using Quantitative Electroencephalography. %A Ochoa, John Fredy %A Alonso, Joan Francesc %A Duque, Jon Edinson %A Tobón, Carlos Andrés %A Baena, Ana %A Lopera, Francisco %A Mañanas, Miguel Angel %A Hernández, Alher Mauricio %X

BACKGROUND: Presenilin-1 (PSEN1) mutations are the most common cause of familial early onset Alzheimer's disease (AD). The PSEN1 E280A (E280A) mutation has an autosomal dominant inheritance and is involved in the production of amyloid-β. The largest family group of carriers with E280A mutation is found in Antioquia, Colombia. The study of mutation carriers provides a unique opportunity to identify brain changes in stages previous to AD. Electroencephalography (EEG) is a low cost and minimally invasiveness technique that enables the following of brain changes in AD.

OBJECTIVE: To examine how previous reported differences in EEG for Theta and Alpha-2 rhythms in E280A subjects are related to specific regions in cortex and could be tracked across different ages.

METHODS: EEG signals were acquired during resting state from non-carriers and carriers, asymptomatic and symptomatic subjects from E280A kindred from Antioquia, Colombia. Independent component analysis (ICA) and inverse solution methods were used to locate brain regions related to differences in Theta and Alpha-2 bands.

RESULTS: ICA identified two components, mainly related to the Precuneus, where the differences in Theta and Alpha-2 exist simultaneously at asymptomatic and symptomatic stages. When the ratio between Theta and Alpha-2 is used, significant correlations exist with age and a composite cognitive scale.

CONCLUSION: Theta and Alpha-2 rhythms are altered in E280A subjects. The alterations are possible to track at Precuneus regions using EEG, ICA, and inverse solution methods.

%B J Alzheimers Dis %V 58 %P 1229-1244 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550254?dopt=Abstract %R 10.3233/JAD-161291 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Predicting Development of Amyotrophic Lateral Sclerosis in Frontotemporal Dementia. %A Van Langenhove, Tim %A Piguet, Olivier %A Burrell, James R %A Leyton, Cristian %A Foxe, David %A Abela, Melissa %A Bartley, Lauren %A Kim, Woojin S %A Jary, Eve %A Huang, Yue %A Dobson-Stone, Carol %A Kwok, John B %A Halliday, Glenda M %A Hodges, John R %X

BACKGROUND: A proportion of patients with frontotemporal dementia (FTD) also develop amyotrophic lateral sclerosis (ALS).

OBJECTIVE: We aimed to establish the risk of developing ALS in patients presenting with FTD and to identify the relevant clinical variables associated with progression from FTD to FTD-ALS.

METHODS: Of 218 consecutive patients with FTD, 10.1% had a dual FTD-ALS diagnosis at presentation. The remaining 152 FTD patients with follow-up of at least 12 months were included in the present study. We calculated the rate of progression to FTD-ALS and compared the baseline characteristics of FTD patients who developed ALS to those who did not develop ALS.

RESULTS: Five percent of FTD patients developed ALS. The incidence rate of ALS was 6.7/100 patient-years in patients with FTD symptoms since 1 year, which declined with duration of FTD symptoms. No FTD patients developed ALS after 5 years. Five out of 8 FTD patients who developed ALS had presented with a mixed behavioral variant FTD and progressive non-fluent aphasia (bvFTD+PNFA) phenotype, 2 with bvFTD, and 1 with PNFA. Progression to FTD-ALS was significantly more frequent in patients with bvFTD+PNFA compared to those without this phenotype (p < 0.0001, OR 38.3, 95% CI: 7.3 to 199.2), and in FTD patients who carried the C9orf72 repeat expansion compared to those without the repeat expansion (p = 0.02, OR 8.0, 95% CI: 1.7 to 38.6).

CONCLUSIONS: FTD patients with a mixed bvFTD+PNFA phenotype and with a C9orf72 repeat expansion should be closely monitored for the possible development of ALS. The risk of developing ALS in FTD appears to decline with the duration of FTD symptoms.

%B J Alzheimers Dis %V 58 %P 163-170 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387671?dopt=Abstract %R 10.3233/JAD-161272 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prediction Model of Conversion to Dementia Risk in Subjects with Amnestic Mild Cognitive Impairment: A Longitudinal, Multi-Center Clinic-Based Study. %A Jang, Hyemin %A Ye, Byoung Seok %A Woo, Sookyoung %A Kim, Sun Woo %A Chin, Juhee %A Choi, Seong Hye %A Jeong, Jee Hyang %A Yoon, Soo Jin %A Yoon, Bora %A Park, Kyung Won %A Hong, Yun Jeong %A Kim, Hee Jin %A Lockhart, Samuel N %A Na, Duk L %A Seo, Sang Won %X

BACKGROUND: Patients with amnestic mild cognitive impairment (aMCI) have an increased risk of dementia. However, conversion rate varies. Therefore, predicting the dementia conversion in these patients is important.

OBJECTIVE: We aimed to develop a nomogram to predict dementia conversion in aMCI subjects using neuropsychological profiles.

METHODS: A total of 338 aMCI patients from two hospital-based cohorts were used in analysis. All patients were classified into 1) verbal, visual, or both, 2) early or late, and 3) single or multiple-domain aMCI according to the modality, severity of memory dysfunction, and multiplicity of involved cognitive domains, respectively. Patients were followed up, and conversion to dementia within 3 years was defined as the primary outcome. Our patients were divided into a training data set and a validation data set. The associations of potential covariates with outcome were tested, and nomogram was constructed by logistic regression model. We also developed another model with APOE data, which included 242 patients.

RESULTS: In logistic regression models, both modalities compared with visual only (OR 4.44, 95% CI 1.83-10.75, p = 0.001), late compared to early (OR 2.59, 95% CI 1.17-5.72, p = 0.019), and multiple compared to single domain (OR 3.51, 95% CI 1.62-7.60, p = 0.002) aMCI were significantly associated with dementia conversion within 3 years. A nomogram incorporating these clinical variables was constructed on the training data set and validated on the validation data set. Both nomograms with and without APOE data showed good prediction performance (c-statistics ≥ 0.75).

CONCLUSIONS: This study showed that several neuropsychological profiles of aMCI are significantly associated with imminent dementia conversion, and a nomogram incorporating these clinical subtypes is simple and useful to help to predict disease progression.

%B J Alzheimers Dis %V 60 %P 1579-1587 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28968237?dopt=Abstract %R 10.3233/JAD-170507 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prediction of Conversion to Alzheimer's Disease with Longitudinal Measures and Time-To-Event Data. %A Li, Kan %A Chan, Wenyaw %A Doody, Rachelle S %A Quinn, Joseph %A Luo, Sheng %X

BACKGROUND: Identifying predictors of conversion to Alzheimer's disease (AD) is critically important for AD prevention and targeted treatment.

OBJECTIVE: To compare various clinical and biomarker trajectories for tracking progression and predicting conversion from amnestic mild cognitive impairment to probable AD.

METHODS: Participants were from the ADNI-1 study. We assessed the ability of 33 longitudinal biomarkers to predict time to AD conversion, accounting for demographic and genetic factors. We used joint modelling of longitudinal and survival data to examine the association between changes of measures and disease progression. We also employed time-dependent receiver operating characteristic method to assess the discriminating capability of the measures.

RESULTS: 23 of 33 longitudinal clinical and imaging measures are significant predictors of AD conversion beyond demographic and genetic factors. The strong phenotypic and biological predictors are in the cognitive domain (ADAS-Cog; RAVLT), functional domain (FAQ), and neuroimaging domain (middle temporal gyrus and hippocampal volume). The strongest predictor is ADAS-Cog 13 with an increase of one SD in ADAS-Cog 13 increased the risk of AD conversion by 2.92 times.

CONCLUSION: Prediction of AD conversion can be improved by incorporating longitudinal change information, in addition to baseline characteristics. Cognitive measures are consistently significant and generally stronger predictors than imaging measures.

%B J Alzheimers Dis %V 58 %P 361-371 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28436391?dopt=Abstract %R 10.3233/JAD-161201 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prediction of Incipient Alzheimer's Disease Dementia in Patients with Mild Cognitive Impairment. %A Ardekani, Babak A %A Bermudez, Elaine %A Mubeen, Asim M %A Bachman, Alvin H %X

BACKGROUND: Mild cognitive impairment (MCI) is a transitional stage from normal aging to Alzheimer's disease (AD) dementia. It is extremely important to develop criteria that can be used to separate the MCI subjects at imminent risk of conversion to Alzheimer-type dementia from those who would remain stable. We have developed an automatic algorithm for computing a novel measure of hippocampal volumetric integrity (HVI) from structural MRI scans that may be useful for this purpose.

OBJECTIVE: To determine the utility of HVI in classification between stable and progressive MCI patients using the Random Forest classification algorithm.

METHODS: We used a 16-dimensional feature space including bilateral HVI obtained from baseline and one-year follow-up structural MRI, cognitive tests, and genetic and demographic information to train a Random Forest classifier in a sample of 164 MCI subjects categorized into two groups [progressive (n = 86) or stable (n = 78)] based on future conversion (or lack thereof) of their diagnosis to probable AD.

RESULTS: The overall accuracy of classification was estimated to be 82.3% (86.0% sensitivity, 78.2% specificity). The accuracy in women (89.1%) was considerably higher than that in men (78.9%). The prediction accuracy achieved in women is the highest reported in any previous application of machine learning to AD diagnosis in MCI.

CONCLUSION: The method presented in this paper can be used to separate stable MCI patients from those who are at early stages of AD dementia with high accuracy. There may be stronger indicators of imminent AD dementia in women with MCI as compared to men.

%B J Alzheimers Dis %V 55 %P 269-281 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662309?dopt=Abstract %R 10.3233/JAD-160594 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Predictors of Discharge Destinations and Three-Month Evolution of Patients Initially Hospitalized in a Cognitive Behavioral Unit. %A Pongan, Elodie %A Dorey, Jean-Michel %A Krolak-Salmon, Pierre %A Federico, Denis %A Sellier, Claire %A Auguste, Nicolas %A Fabre, Florence %A Laurent, Bernard %A Trombert-Paviot, Béatrice %A Rouch, Isabelle %X

BACKGROUND: Previous studies showed that a third of patients living at home entered an institution after hospitalization in Cognitive and Behavioral Units (CBUs).

OBJECTIVE: The main objective of this study was to identify predictors of discharge destination for these patients. The secondary objective was to estimate whether institutionalization can have an impact on a patient's long-term prognosis.

METHODS: The study population was selected from the EVITAL study and included 140 participants living at home before hospitalization in CBUs. Factors favoring nursing-home admission were investigated and the impact of discharge destinations (i.e., home or nursing home) on patients' prognosis was examined.

RESULTS: Institutionalized patients were more likely to be women (F = 4.7; p = 0.03), with a higher dementia severity (F = 9.82; p = 0.007), often living alone (F = 19.69; p = 0.001), with a caregiver other than spouse (F = 8.93; p = 0.003), and with a higher patient quality of life (QoL) according to the caregiver (F = 11.73; p = 0.001). When using multivariate logistic linear regressions, we showed a relationship between marital status (OR = 0.19, 95% CI: 0.08-0.43, p < 0.001), dementia severity (OR = 0.15, 95% CI: 0.03-0.79, p = 0.03), QoL (OR = 0.88, 95% CI: 0.79-0.98, p = 0.017), and institutionalization. At three months, a higher overall rate of rehospitalization (F = 12.21; p < 0.001) and rehospitalization for behavioral and psychological symptoms of dementia (F = 6.76; p = 0.006) were observed for patients staying at home after CBU discharge.

CONCLUSION: Our study allows for a better understanding of the institutionalization risk factors of the patients hospitalized in CBUs. Identification of these factors could help clinicians to better support patients and to help the transition to be smoother. Moreover, our results suggest that prognosis of institutionalized patients is not unfavorable when compared with patients staying at home.

%B J Alzheimers Dis %V 60 %P 1259-1266 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28968235?dopt=Abstract %R 10.3233/JAD-170419 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Preliminary Study on the Feasibility of Using a Virtual Reality Cognitive Training Application for Remote Detection of Mild Cognitive Impairment. %A Zygouris, Stelios %A Ntovas, Konstantinos %A Giakoumis, Dimitrios %A Votis, Konstantinos %A Doumpoulakis, Stefanos %A Segkouli, Sofia %A Karagiannidis, Charalampos %A Tzovaras, Dimitrios %A Tsolaki, Magda %X

BACKGROUND: It has been demonstrated that virtual reality (VR) applications can be used for the detection of mild cognitive impairment (MCI).

OBJECTIVE: The aim of this study is to provide a preliminary investigation on whether a VR cognitive training application can be used to detect MCI in persons using the application at home without the help of an examiner.

METHODS: Two groups, one of healthy older adults (n = 6) and one of MCI patients (n = 6) were recruited from Thessaloniki day centers for cognitive disorders and provided with a tablet PC with custom software enabling the self-administration of the Virtual Super Market (VSM) cognitive training exercise. The average performance (from 20 administrations of the exercise) of the two groups was compared and was also correlated with performance in established neuropsychological tests.

RESULTS: Average performance in terms of duration to complete the given exercise differed significantly between healthy(μ  = 247.41 s/ sd = 89.006) and MCI (μ= 454.52 s/ sd = 177.604) groups, yielding a correct classification rate of 91.8% with a sensitivity and specificity of 94% and 89% respectively for MCI detection. Average performance also correlated significantly with performance in Functional Cognitive Assessment Scale (FUCAS), Test of Everyday Attention (TEA), and Rey Osterrieth Complex Figure test (ROCFT).

DISCUSSION: The VR application exhibited very high accuracy in detecting MCI while all participants were able to operate the tablet and application on their own. Diagnostic accuracy was improved compared to a previous study using data from only one administration of the exercise. The results of the present study suggest that remote MCI detection through VR applications can be feasible.

%B J Alzheimers Dis %V 56 %P 619-627 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035922?dopt=Abstract %R 10.3233/JAD-160518 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prevalence and Correlates of Behavioral Disorders in Old Age Subjects with Cognitive Impairment: Results from the ReGAl Project. %A Boccardi, Virginia %A Conestabile Della Staffa, Manuela %A Baroni, Marta %A Ercolani, Sara %A Croce, Michele Francesco %A Ruggiero, Carmelinda %A Mecocci, Patrizia %X

BACKGROUND: Presence of behavioral and psychological symptoms of dementia (BPSD) is very common in subjects with cognitive impairment, representing an important determinant of disease progression, institutionalization, and worse prognosis. Knowledge of the prevalence and correlates of BPSD in community-living old subjects with cognitive impairment is limited so far, but it is essential for establishing specifically tailored care and cure in such a vulnerable population.

OBJECTIVE: With this study, we aimed at investigating, in a large sample of old age subjects with cognitive impairment, BPSD prevalence and correlates including the main demographic, clinical, and socio-environmental characteristics.

METHODS: Data were gathered from the ReGAl project (Rete Geriatrica Alzheimer; Geriatric Network on Alzheimer's disease), a large longitudinal Italian multicentric clinical-based study, promoted by the Italian Society of Gerontology and Geriatrics (SIGG).

RESULTS: We evaluated data from 4,157 old-age subjects affected by mild cognitive impairment (MCI) (541; 13%) or dementia (3616; 87%). 85.2% of all the population presented with at least one BPSD. Using a factor analysis, we identified four factors of BPSD: psychotic, affective, maniac, and impulse control behaviors. Logistic regression analyses revealed that among the main demographic, clinical, and socio-environmental aspects considered, only comorbidity was associated with all factors, independently of multiple covariates.

CONCLUSION: Identification of BPSD is crucial in everyday clinical practice and necessary to develop specific interventions and to define appropriate outcomes in their management. BPSD occur in a complex psychopathological context, influenced by several demographic and environmental factors that must be taken into account for a correct diagnosis and treatment.

%B J Alzheimers Dis %V 60 %P 1275-1283 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036823?dopt=Abstract %R 10.3233/JAD-170494 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prevalence of Use of Cardiovascular Drugs in Dementia Patients Treated in General Practices in Germany. %A Jacob, Louis %A Bohlken, Jens %A Kostev, Karel %X

BACKGROUND: Dementia is a chronic disease associated with numerous cardiovascular disorders.

OBJECTIVE: To analyze the prevalence of cardiovascular drug use in dementia patients treated in general practices in Germany.

METHODS: The present study included patients who were diagnosed with dementia (Alzheimer's disease, vascular dementia, or unspecified dementia) in 2015. The main outcome measure was the proportion of patients using cardiovascular drugs. Demographical and clinical variables included age, sex, dementia type, and cardiovascular co-diagnoses. A multivariate logistic regression model was used to analyze the association between cardiovascular drug use and these variables.

RESULTS: We identified 7,987 and 1,268 dementia patients with and without prescriptions for cardiovascular drugs, respectively. The share of individuals who received cardiovascular treatments was 86.3%. Diuretics (20.9%), beta blocking agents (20.0%), and ACE inhibitors (17.4%) were the three most commonly prescribed types of medications. Patients between the ages of 71-80 (OR = 1.59), 81-90 (OR = 1.61), and over 90 years (OR = 1.48) were more likely to receive cardiovascular drugs than patients under the age of 70 years. Moreover, compared to those with unspecified dementia, individuals with Alzheimer's disease had a lower chance while those with vascular dementia had a higher chance of being prescribed these drugs (ORs equal to 0.81 and 1.22, respectively). Finally, we found a positive association between the use of cardiovascular drugs and all co-diagnoses (ORs ranging from 1.23 to 7.12).

CONCLUSION: The prevalence of cardiovascular drug use in dementia patients was around 86%. This use was significantly associated with such factors as age, type of dementia, and co-diagnoses.

%B J Alzheimers Dis %V 56 %P 1519-1524 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222532?dopt=Abstract %R 10.3233/JAD-161234 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prevalence, Risk Factors, and Complaints Screening Tool Exploration of Subjective Cognitive Decline in a Large Cohort of the Chinese Population. %A Hao, Lixiao %A Wang, Xiaoni %A Zhang, Ling %A Xing, Yue %A Guo, Qihao %A Hu, Xiaochen %A Mu, Bin %A Chen, Yili %A Chen, Guanqun %A Cao, Jing %A Zhi, Xiaodong %A Liu, Jiaojiao %A Li, Xuanyu %A Yang, Liu %A Li, Jiachen %A Du, Wenying %A Sun, Yu %A Wang, Ting %A Liu, Zhen %A Liu, Zheng %A Zhao, Xuexue %A Li, Hongyan %A Yu, Yang %A Wang, Xue %A Jia, Jianguo %A Han, Ying %X

BACKGROUND: Substantial studies have reported the prevalence and the affecting factors of subjective cognitive decline (SCD). The complaints screening scale has also been used for probing. However, little is known in China.

OBJECTIVE: To investigate the prevalence and risk factors of SCD, and explore an SCD complaints screening scale in China.

METHODS: Stratified cluster random sampling was conducted. 2,689 residents aged 60-80 years completed questionnaire 1. 814 residents were included for clinical and neuropsychological evaluations. Two standards were used to make the diagnosis of mild cognitive impairment (MCI) and SCD, and a preliminary screening rate comparison was carried out. Finally, we assessed the risk factors of SCD and the correlation between the SCD-questionnaire 9 (SCD-Q9) and the Auditory Verbal Learning Test-Long Delay Free Recall (AVLT-LR).

RESULTS: 1) Standard 1 (ADNI2): the prevalence of SCD was 18.8% (95% CI = 14.7-22.9%) and zero conformed to six criteria (SCD plus). 2) Standard 2 (Jak/Bondi): the prevalence of SCD was 14.4% (95% CI = 10.7-18.1%). 3) Standard 1 had a relatively higher "false" positive rate, whereas Standard 2 had higher "false" negative rate. 4) Age, low education, fewer close friends, and daily drinking were independent risk factors for SCD progressing to MCI. 5) Total points of SCD-Q9 were negatively correlated to the value of AVLT-LR.

CONCLUSIONS: The prevalence of SCD is high in the ShunYi District in Beijing, China. Age, low education, less social support, and daily drinking are independent risk factors. The brief SCD-Q9 can be used as a reference.

%B J Alzheimers Dis %V 60 %P 371-388 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869471?dopt=Abstract %R 10.3233/JAD-170347 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prevention of Amyloid-β and Tau Pathologies, Associated Neurodegeneration, and Cognitive Deficit by Early Treatment with a Neurotrophic Compound. %A Baazaoui, Narjes %A Iqbal, Khalid %X

To date, neither any effective treatment nor prevention of Alzheimer's disease (AD), a major dementia causing disorder, are available. Herein, we investigated the secondary prevention of neurodegeneration, amyloid-β (Aβ) and tau pathologies with a neurotrophic compound P021 in 3xTg-AD mice. Previous work found that P021 can rescue at mild to moderate stages Aβ and tau pathologies in 3xTg-AD mice. To determine its potential clinical application, we sought to test the preventive effect of P021 on Aβ and tau pathologies by starting the treatment during the period of synaptic compensation several months before the appearance of any overt pathology in 3xTg-AD mice. We started a continuous treatment with P021 in 3-month-old female animals and followed its effect at 9-, 15- and 18-months post-treatment. Neurodegeneration at the above time points was studied using Fluorojade C staining, and tau and Aβ pathologies both immunohistochemically and by Western blots. Cognitive performance was studied by assessing episodic memory with Novel Object Recognition task at 16-17-months post-treatment. We found that P021 treatment initiated during the synaptic compensation period can prevent neurodegeneration, Aβ and tau pathologies, rescue episodic memory impairment, and markedly reduce mortality rate. These findings for the first time show effective prevention of AD changes with a neurotrophic compound that targets neurogenesis and synaptic plasticity, suggesting that improving the health of the neuronal network can prevent AD.

%B J Alzheimers Dis %V 58 %P 215-230 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387677?dopt=Abstract %R 10.3233/JAD-170075 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prion Protein Interactome: Identifying Novel Targets in Slowly and Rapidly Progressive Forms of Alzheimer's Disease. %A Zafar, Saima %A Shafiq, Mohsin %A Younas, Neelam %A Schmitz, Matthias %A Ferrer, Isidre %A Zerr, Inga %X

Rapidly progressive Alzheimer's disease (rpAD) is a variant of AD distinguished by a rapid decline in cognition and short disease duration from onset to death. While attempts to identify rpAD based on biomarker profile classifications have been initiated, the mechanisms which contribute to the rapid decline and prion mimicking heterogeneity in clinical signs are still largely unknown. In this study, we characterized prion protein (PrP) expression, localization, and interactome in rpAD, slow progressive AD, and in non-dementia controls. PrP along with its interacting proteins were affinity purified with magnetic Dynabeads Protein-G, and were identified using Q-TOF-ESI/MS analysis. Our data demonstrated a significant 1.2-fold decrease in di-glycosylated PrP isoforms specifically in rpAD patients. Fifteen proteins appeared to interact with PrP and only two proteins3/4histone H2B-type1-B and zinc alpha-2 protein3/4were specifically bound with PrP isoform isolated from rpAD cases. Our data suggest distinct PrP involvement in association with the altered PrP interacting protein in rpAD, though the pathophysiological significance of these interactions remains to be established.

%B J Alzheimers Dis %V 59 %P 265-275 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671123?dopt=Abstract %R 10.3233/JAD-170237 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Proactive Self in Space: How Egocentric and Allocentric Spatial Impairments Contribute to Anosognosia in Alzheimer's Disease. %A Serino, Silvia %A Riva, Giuseppe %X

In addition to impairments in episodic and spatial memory, anosognosia (i.e., loss of awareness of the deficient aspect of own cognitive functioning) may be considered an important cognitive marker of Alzheimer's disease (AD). However, although a growing body of interesting models have been proposed to explain this early symptom, what is still missing is a unifying framework of all the characteristic signs occurring in patients with AD that may guide the search for its causal neuropathological process and, ultimately, the etiological process. This contribution will first show how anosognosia may be related to the above-mentioned episodic and spatial memory impairment through a unifying framework of all these characteristic signs, i.e., the continuous interaction between different spatial representations. Second, we hypothesize that a break in the interaction between different spatial representations, as we suggest occurs in AD, may contribute significantly both to the early impairments in spatial and episodic memory, and to a deficient self-awareness since it may interfere with the capacity of the brain to detect predictive errors.

%B J Alzheimers Dis %V 55 %P 881-892 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767990?dopt=Abstract %R 10.3233/JAD-160676 %0 Journal Article %J J Alzheimers Dis %D 2017 %T proBDNF Accelerates Brain Amyloid-β Deposition and Learning and Memory Impairment in APPswePS1dE9 Transgenic Mice. %A Chen, Jia %A Zhang, Tao %A Jiao, Shusheng %A Zhou, Xinfu %A Zhong, Jinhua %A Wang, Yanjiang %A Liu, Juan %A Deng, Juan %A Wang, Shuiping %A Xu, Zhiqiang %X

BACKGROUND: Alzheimer's disease (AD) is pathologically known for the amyloid-β (Aβ) deposition, neurofibrillary tangles, and neuronal loss in the brain. The precursor of brain-derived neurotrophic factor (proBDNF) before proteolysis has opposing functions to its mature form in neuronal survival and neurite growth. However, the role of proBDNF in the pathogenesis of AD remains unclear.

OBJECTIVE: To investigate the effects of proBDNF on neurons in vitro, and on learning and memory impairment and brain Aβ production in a transgenic AD mouse model (APPswePS1dE9).

METHODS: We here examined the effects of proBDNF on the viability (MTT assay) and neurite growth (morphologic measurement) of the primary neurons in vitro. After the intracerebroventricular injection of adeno-associated virus-proBDNF (AAV-proBDNF), we then investigated the learning and memory impairment (Morris water maze) and Aβ deposition in the brains of the AD mice.

RESULTS: The results showed that proBDNF could inhibit neuronal viability and neurite growth in vitro, enhance Aβ levels, and accelerate its deposition in the brain, which was consistent with the learning and memory impairment of AD mice, likely dependent on the membrane receptor of p75NTR.

CONCLUSIONS: Our findings suggest that proBDNF may exert a crucially negative effect during AD pathogenesis andprogression.

%B J Alzheimers Dis %V 59 %P 941-949 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697556?dopt=Abstract %R 10.3233/JAD-161191 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prodromal Dementia with Lewy Bodies and Prodromal Alzheimer's Disease: A Comparison of the Cognitive and Clinical Profiles. %A Sadiq, Dilman %A Whitfield, Tim %A Lee, Lean %A Stevens, Tim %A Costafreda, Sergi %A Walker, Zuzana %X

BACKGROUND: Dementia must be diagnosed accurately and early in the disease course to allow pathology-specific treatments to be effective. Dementia with Lewy bodies (DLB) is often misdiagnosed as Alzheimer's disease (AD), especially at the prodromal stage.

OBJECTIVE: To compare the clinical and neuropsychological profiles of Mild Cognitive Impairment (MCI) patients who, at follow-up, progressed to AD (retrospectively AD-MCI) or DLB (retrospectively DLB-MCI) or remained MCI.

METHODS: This longitudinal study used an unselected sample from a memory clinic database. A total of 1,848 new patients were seen at the memory clinic between 1994-2015. Of these, 560 patients (30%) had an initial diagnosis of MCI and were considered for the study. Inclusion criteria were patients who had a diagnosis of MCI at initial assessment and a minimum of 12 months' follow-up.

RESULTS: Of the 429 MCI patients with follow-up data, 164 (38%) remained MCI, 107 (25%) progressed to AD, and 21 (5%) progressed to DLB. The remainder progressed to alternative diagnoses. At baseline, DLB-MCI patients performed significantly worse on visuospatial function and letter fluency tests than both AD-MCI and stable-MCI groups, and better on episodic memory tests than the AD-MCI group. At baseline, DLB-MCI patients had a significantly higher mean UPDRS score and were more likely to have REM sleep behavior disorder and fluctuating cognition.

CONCLUSION: DLB-MCI patients have a specific cognitive and neuropsychiatric profile which should alert clinicians to the possibility of prodromal DLB. This is relevant when considered in the context of early disease-specific therapy.

%B J Alzheimers Dis %V 58 %P 463-470 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453473?dopt=Abstract %R 10.3233/JAD-161089 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Progression of Alzheimer's Disease: Are Fast Decliners Really Fast? A Four-Year Follow-Up. %A Barocco, Federica %A Spallazzi, Marco %A Concari, Letizia %A Gardini, Simona %A Pelosi, Annalisa %A Caffarra, Paolo %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Cognition Disorders %K Disease Progression %K Female %K Humans %K Longitudinal Studies %K Male %K Psychiatric Status Rating Scales %K ROC Curve %K Time Factors %X

BACKGROUND: The rate of cognitive and functional decline in Alzheimer's disease (AD) changes across individuals.

OBJECTIVES: Our purpose was to assess whether the concept of "fast decline" really fits its definition and whether cognitive and functional variables at onset can predict the progression of AD.

METHODS: 324 AD patients were included. We retrospectively examined their Mini-Mental State Examination (MMSE) total score and sub-items, Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL) at baseline and every six months for a 4-year follow-up. Patients were divided into "fast decliners" (n = 62), defined by a loss ≥5 points on the MMSE score within the first year from the baseline; "intermediate decliners" (n = 37), by a loss ≥5 points after the first year and before the 18th month; or "slow decliners" (n = 225), composed of the remaining patients.

RESULTS: At baseline, the groups did not differ on demographic, clinical, and cognitive variables. The decline at the end of the 4-year follow-up period seems to be similar among the different decline clusters. Predictors of disease progression have not been identified; only the MMSE total score at 12 months <14/30 was indicative of a poor prognosis.

CONCLUSIONS: Even with the limitation due to the small sample size, the lack of differences in the disease progression in time in the different clusters suggest the inconsistency of the so-called "fast decliners". This study was unable to show any significant difference among clusters of AD progression within a 4-year time interval. Further studies should better clarify whether a more consistent distinction exists between slow and fast decliners.

%B J Alzheimers Dis %V 57 %P 775-786 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304306?dopt=Abstract %R 10.3233/JAD-161264 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Prospective Study on the Association between Uric Acid and Cognitive Function among Middle-Aged and Older Chinese. %A Wang, Tong %A Wu, Yili %A Sun, Yongye %A Zhai, Long %A Zhang, Dongfeng %X

BACKGROUND: Uric acid (UA) is a powerful antioxidant that may have neuroprotective properties, yet it is also a risk factor of vascular disease that predisposes individuals to cognitive impairment. Results from longitudinal studies on UA and cognitive decline remain controversial.

OBJECTIVE: We examined the associations of baseline plasma UA level with follow-up cognitive function as well as cognitive decline over time among a large sample of middle-aged and older Chinese.

METHODS: Data from China Health and Retirement Longitudinal Study (CHARLS) were used. Cognitive function, including episodic memory, mental intactness, and global cognition, were tested twice with 2-year interval. Plasma UA was measured at baseline. Basic demographics, life habits, and health status were considered as potential confounders. Multiple linear regression models and mixed-effects regression models were fitted.

RESULTS: A total of 12,798 individuals aged above 45 years were eligible with the follow-up time ranging from 1.33 to 2.42 years. Both global cognitive function and mental intactness declined, while episodic memory remained stable over time. In multiple linear regression models, compared with the lowest baseline UA level, 3rd baseline UA quartile was associated with better follow-up global cognitive function (b = 0.425, p = 0.041) and episodic memory (b = 0.413, p = 0.004), and highest baseline UA quartile was associated with better follow-up mental intactness (b = 0.253, p = 0.041) in males; highest baseline UA level was associated with better follow-up cognition for each measure (b = 0.281∼0.768, p≤0.046) in females. Mixed-effects regression models suggested no significant baseline UA-by-time interactions on any cognitive measure.

CONCLUSION: Higher baseline UA level was associated with better cognition in later life but not with rates of cognitive decline among middle-aged and older Chinese.

%B J Alzheimers Dis %V 58 %P 79-86 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387669?dopt=Abstract %R 10.3233/JAD-161243 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Protein Expression of BACE1 is Downregulated by Donepezil in Alzheimer's Disease Platelets. %A Sarno, Tamires Alves %A Talib, Leda Leme %A Joaquim, Helena Passarelli Giroud %A Bram, Jessyka Maria de França %A Gattaz, Wagner Farid %A Forlenza, Orestes Vicente %X

BACKGROUND: Abnormal amyloid-β protein precursor (AβPP) metabolism is a key feature of Alzheimer's disease (AD). Platelets contain most of the enzymatic machinery required for AβPP processing, and correlates of intracerebral abnormalities have been demonstrated in platelets of patients with AD. Thus, AβPP-related molecules in platelets may be regarded as peripheral markers of AD.

OBJECTIVE: We sought to determine the protein expression of the AβPP secretases (ADAM10, BACE1, and PSEN1) and AβPP ratio in platelets of patients with mild or moderate AD compared to healthy controls. We further determined whether the protein expression of these markers might be modified by chronic treatment with donepezil.

METHODS: Platelet samples were obtained from patients and controls at baseline and after 3 and 6 months of continuous treatment with therapeutic doses of donepezil. The protein expression of platelet markers was determined by western blotting.

RESULTS: AD patients had a significant decrease in AβPP ratio, ADAM10, and PSEN1 compared to controls at baseline, but these differences were not modified by the treatment. Nonetheless, a significant reduction in the protein expression of BACE1 was observed in patients treated with donepezil for 6 months.

CONCLUSION: Our results corroborate previous findings from our group and others of decreased AβPP ratio and protein expression of ADAM10 in AD. We further show that PSEN1 is decreased in AD platelets, and that the protein expression of BACE1 is downregulated by chronic treatment with donepezil. This effect may be interpreted as evidence of disease modification.

%B J Alzheimers Dis %V 55 %P 1445-1451 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858713?dopt=Abstract %R 10.3233/JAD-160813 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Protein Phosphorylation is a Key Mechanism in Alzheimer's Disease. %A Oliveira, Joana %A Costa, Márcio %A de Almeida, Maria Soares Cachide %A da Cruz E Silva, Odete A B %A Henriques, Ana Gabriela %X

Altered protein phosphorylation states of several proteins are closely associated with Alzheimer's disease (AD). Among these are the amyloid-β protein precursor (AβPP) and the tau protein. In fact, altered protein phosphorylation states already provide strong biomarkers for AD diagnosis, as is the case with hyperphosphorylated tau. It follows that modulating signaling cascades provides an attractive avenue for exploring novel therapeutic strategies. This review focuses on some of the major protein kinases and protein phosphatases relevant to AD. Of particular relevance, posttranslational modifications dynamically regulate protein activity, subcellular localization, and stability. Protein phosphorylation states can mediate complex formation as well as regulate protein function, and this is important for cellular physiology but can likewise contribute to the development of neuropathological conditions. Furthermore, applying a system approach provides a more comprehensive understanding of the signaling events associated with AD and highlights possible convergence points that may contribute to the different AD pathological hallmarks.

%B J Alzheimers Dis %V 58 %P 953-978 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527217?dopt=Abstract %R 10.3233/JAD-170176 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Proteomics Analysis of Blood Serums from Alzheimer's Disease Patients Using iTRAQ Labeling Technology. %A Shen, Liming %A Liao, Liping %A Chen, Cheng %A Guo, Yi %A Song, Dalin %A Wang, Yong %A Chen, Youjiao %A Zhang, Kaoyuan %A Ying, Ming %A Li, Shuiming %A Liu, Qiong %A Ni, Jiazuan %X

Alzheimer' disease (AD) is the most common form of dementia affecting up to 6% of the population over the age of 65. In order to discover differentially expressed proteins that might serve as potential biomarkers, the serums from AD patients and healthy controls were compared and analyzed using the proteomics approach of isobaric tagging for relative and absolute quantitation (iTRAQ). For the first time, AD biomarkers in serums are investigated in the Han Chinese population using iTRAQ labeled proteomics strategy. Twenty-two differentially expressed proteins were identified and out of which nine proteins were further validated with more sample test. Another three proteins that have been reported in the literature to be potentially associated with AD were also investigated for alteration in expression level. Functions of those proteins were mainly related to the following processes: amyloid-β (Aβ) metabolism, cholesterol transport, complement and coagulation cascades, immune response, inflammation, hemostasis, hyaluronan metabolism, and oxidative stress. These results support current views on the molecular mechanism of AD. For the first time, differential expression of zinc-alpha-2-glycoprotein (AZGP1), fibulin-1 (FBLN1), platelet basic protein (PPBP), thrombospondin-1 (THBS1), S100 calcium-binding protein A8 (S100A8), and S100 calcium-binding protein A9 (S100A9) were detected in the serums of AD patients compared with healthy controls. These proteins might play a role in AD pathophysiology and serve as potential biomarkers for AD diagnosis. Specifically, our results strengthened the crucial role of Aβ metabolism and blood coagulation in AD pathogenesis and proteins related to these two processes may be used as peripheral blood biomarkers for AD.

%B J Alzheimers Dis %V 56 %P 361-378 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911324?dopt=Abstract %R 10.3233/JAD-160913 %0 Journal Article %J J Alzheimers Dis %D 2017 %T PSD-93 Attenuates Amyloid-β-Mediated Cognitive Dysfunction by Promoting the Catabolism of Amyloid-β. %A Yu, Linjie %A Liu, Yi %A Yang, Hui %A Zhu, Xiaolei %A Cao, Xiang %A Gao, Jun %A Zhao, Hui %A Xu, Yun %X

Amyloid-β (Aβ) is a key neuropathological hallmark of Alzheimer's disease (AD). Postsynaptic density protein 93 (PSD-93) is a key scaffolding protein enriched at postsynaptic sites. The aim of the present study was to examine whether PSD-93 overexpression could alleviate Aβ-induced cognitive dysfunction in APPswe/PS1dE9 (APP/PS1) mice by reducing Aβ levels in the brain. The level of PSD-93 was significantly decreased in the hippocampus of 6-month-old APP/PS1 mice compared with that in wild-type mice. Following lentivirus-mediated PSD-93 overexpression, cognitive function, synaptic function, and amyloid burden were investigated. The open field test, Morris water maze test, and fear condition test revealed that PSD-93 overexpression ameliorated spatial memory deficits in APP/PS1 mice. The facilitation of long-term potentiation induction was observed in APP/PS1 mice after PSD-93 overexpression. The expression of somatostatin receptor 4 (SSTR4) and neprilysin was increased, while the amyloid plaque load and Aβ levels were decreased in the brains of APP/PS1 mice. Moreover, PSD-93 interacted with SSTR4 and affected the level of SSTR4 on cell membrane, which was associated with the ubiquitination. Together, these findings suggest that PSD-93 attenuates spatial memory deficits and decreases amyloid levels in APP/PS1 mice, which might be associated with Aβ catabolism, and overexpression of PSD-93 might be a potential therapy for AD.

%B J Alzheimers Dis %V 59 %P 913-927 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697571?dopt=Abstract %R 10.3233/JAD-170320 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Psychosocial Risk and Protective Factors and Incident Mild Cognitive Impairment and Dementia in Community Dwelling Elderly: Findings from the Singapore Longitudinal Ageing Study. %A Rawtaer, Iris %A Gao, Qi %A Nyunt, Ma Shwe Zin %A Feng, Lei %A Chong, Mei Sian %A Lim, Wee Shiong %A Lee, Tih-Shih %A Yap, Philip %A Yap, Keng Bee %A Ng, Tze Pin %X

BACKGROUND: Indicators of social isolation or support such as living alone, loneliness, being married, and life satisfaction are possible psychosocial risk and protective factors for dementia.

OBJECTIVE: We investigate the associations of these overlapping psychosocial factors with incident MCI-dementia (neurocognitive disorder) in a population cohort.

METHODS: Using data from 1601 participants of the Singapore Longitudinal Ageing Study (SLAS) who were free of MCI or dementia at baseline and followed up to 8 years, we estimated hazards ratio (HR) of association of living alone, loneliness, being married, and high life satisfaction with incident MCI-dementia.

RESULTS: In univariate analyses, individual HRs of association with incident MCI-dementia for living alone was 1.86 [1.18 - 2.95], (p = 0.008), loneliness was 1.26 [0.86 - 1.84], (p = 0.23), being married was 0.54 [0.39 - 0.75] (p < 0.0001), and being very satisfied with life was 0.59 [0.38-0.91]), (p = 0.017). Adjusted mutually for other psychosocial variables, and for age, sex, education, ethnicity, smoking, alcohol, dyslipidemia, hypertension, diabetes, central obesity, history of stroke or heart disease, APOE-ɛ4, depression, physical, social, and productive activities, only being married (0.68 [0.47-0.99], p = 0.044), and being very satisfied with life (0.61 [0.39 - 0.96], p = 0.034) remained significant variables associated with lower risks of developing MCI-dementia.

CONCLUSION: Individuals who were married and those who were very satisfied with life are protected against the risk of developing MCI and dementia. Controlling for the adverse effects of being without spousal support and low life satisfaction, living alone or a feeling of loneliness were not associated with increased risk of MCI-dementia.

%B J Alzheimers Dis %V 57 %P 603-611 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269770?dopt=Abstract %R 10.3233/JAD-160862 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Psychotic Symptoms Associated with Poor Renal Function in Mild Cognitive Impairment and Dementias. %A Kunschmann, Ralf %A Busse, Stefan %A Frodl, Thomas %A Busse, Mandy %X

Patients suffering from cognitive decline such as mild cognitive impairment or neurodegenerative disorders including Alzheimer's dementia, vascular dementia, frontotemporal dementia, and Lewy body dementia are often accompanied by symptoms like psychosis, depression, agitation, and apathy. Aging increases not only the prevalence of dementia but also the development of kidney disorders, which had emerged as possible risk factor of cognitive impairment and dementia. However, a contribution of renal dysfunction to psychosis associated with cognitive decline remains to be investigated. We addressed the question whether patients diagnosed with mild cognitive impairment or dementia and co-symptoms show alterations in serum parameters. Analyzing 309 patients in total, we detected a positive correlation between the occurrence of psychotic symptoms and increased retention parameters in serum, including creatinine and urea levels and the estimated glomerular filtration rates. This was in particular detected in female patients. In male patients, psychotic symptoms were associated with an increased number of leukocytes in blood. We propose that clinicians should be aware of psychotic symptoms in patients with reduced cognitive functions that could be associated with changes in the retention parameters.

%B J Alzheimers Dis %V 58 %P 243-252 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387674?dopt=Abstract %R 10.3233/JAD-161306 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Psychotropic Polypharmacy in Patients with Dementia: Prevalence and Predictors. %A Nørgaard, Ane %A Jensen-Dahm, Christina %A Gasse, Christiane %A Hansen, Elsebet Steno %A Waldemar, Gunhild %X

BACKGROUND: Antipsychotics and other psychotropics are frequently used to treat neuropsychiatric symptoms in patients with dementia, even though the evidence for effect is limited. Concerns have been raised about the safety of antipsychotics, but concomitant use of multiple psychotropic drug classes (psychotropic polypharmacy) may also pose a risk for patients.

OBJECTIVE: To investigate the prevalence and predictors associated with use of psychotropic polypharmacy in patients with dementia.

METHODS: A population-based study using nationwide registers. Patients with dementia were identified among all Danish residents ≥65 years on January 1, 2012. Data on prescriptions and comorbidity was included in the analysis. Overlapping prescriptions for different psychotropic drug classes were used to determine psychotropic polypharmacy. A multivariable logistic regression analysis was conducted to evaluate factors independently associated with the prescription of other psychotropic drug classes among patients already using antipsychotics.

RESULTS: Among all patients registered with dementia (34,553), 25.3% (8,728) used ≥2 psychotropic drugs. Among patients treated with antipsychotics 75.8% (5,403) used at least one other psychotropic drug during the antipsychotic treatment period. Nursing home residency, number of non-psychotropic medications used in 2011, and prior psychiatric diagnosis were associated with psychotropic polypharmacy among antipsychotic drug users. The most frequent combination of psychotropic drugs was antipsychotics and antidepressants.

CONCLUSION: Concomitant use of psychotropic drugs was frequent in dementia patients. Patients living in nursing homes had the highest risk of receiving a combination of antipsychotics and other psychotropic drugs. Concomitant use of psychotropics may cause adverse events, and potential consequences for patients' safety call for further investigation.

%B J Alzheimers Dis %V 56 %P 707-716 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035931?dopt=Abstract %R 10.3233/JAD-160828 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Pupillary Responses as a Biomarker of Early Risk for Alzheimer's Disease. %A Granholm, Eric L %A Panizzon, Matthew S %A Elman, Jeremy A %A Jak, Amy J %A Hauger, Richard L %A Bondi, Mark W %A Lyons, Michael J %A Franz, Carol E %A Kremen, William S %X

Task-evoked pupillary responses may be a psychophysiological biomarker of early risk for mild cognitive impairment (MCI) and Alzheimer's disease (AD). Pupil dilation during cognitive tasks reflects cognitive effort until compensatory capacity is surpassed and performance declines are manifest, and reflects activation in the locus coeruleus, where degenerative changes have been found in the earliest stages of AD. We recorded pupillary responses during digit span recall in 918 participants ages 56-66. Despite normal performance, amnestic single-domain MCI (S-MCI) participants showed greater pupil dilation than non-amnestic S-MCI and cognitively normal (CN) participants at lower cognitive loads. Multi-domain MCI (M-MCI) participants failed to modulate effort across cognitive loads and showed poorer performance. Pupillary responses differentiated MCI and CN groups. Amnestic S-MCI participants required compensatory effort to maintain performance, consistent with increased risk for decline. Greater effort in CN individuals might indicate risk for MCI. Results are consistent with dysfunction in locus coeruleus-linked brain systems. This brief task shows promise as a biomarker for early MCI and AD risk prediction.

%B J Alzheimers Dis %V 56 %P 1419-1428 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157098?dopt=Abstract %R 10.3233/JAD-161078 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Quantification of Butyrylcholinesterase Activity as a Sensitive and Specific Biomarker of Alzheimer's Disease. %A Macdonald, Ian R %A Maxwell, Selena P %A Reid, George A %A Cash, Meghan K %A DeBay, Drew R %A Darvesh, Sultan %X

Amyloid-β (Aβ) plaques are a neuropathological hallmark of Alzheimer's disease (AD); however, a significant number of cognitively normal older adults can also have Aβ plaques. Thus, distinguishing AD from cognitively normal individuals with Aβ plaques (NwAβ) based on Aβ plaque detection is challenging. It has been observed that butyrylcholinesterase (BChE) accumulates in plaques preferentially in AD. Thus, detecting BChE-associated plaques has the potential as an improved AD biomarker. We present Aβ, thioflavin-S, and BChE quantification of 26 postmortem brain tissues; AD (n = 8), NwAβ (n = 6), cognitively normal without plaques (n = 8), and other common dementias including corticobasal degeneration, frontotemporal dementia with tau, dementia with Lewy bodies, and vascular dementia. Pathology burden in the orbitofrontal cortex, entorhinal cortex, amygdala, and hippocampal formation was determined and compared. The predictive value of Aβ and BChE quantification was determined, via receiver-operating characteristic plots, to evaluate their AD diagnostic performance using sensitivity, specificity, and area under curve (AUC) metrics. In general, Aβ and BChE-associated pathology were greater in AD, particularly in the orbitofrontal cortex. In this region, the largest increase (9.3-fold) was in BChE-associated pathology, observed between NwAβ and AD, due to the virtual absence of BChE-associated plaques in NwAβ brains. Furthermore, BChE did not associate with pathology of the other dementias. In this sample, BChE-associated pathology provided better diagnostic performance (AUC = 1.0, sensitivity/specificity = 100% /100%) when compared to Aβ (AUC = 0.98, 100% /85.7%). These findings highlight the predictive value of BChE as a biomarker for AD that could facilitate timely disease diagnosis and management.

%B J Alzheimers Dis %V 58 %P 491-505 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453492?dopt=Abstract %R 10.3233/JAD-170164 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Quantitative 3D Telomeric Imaging of Buccal Cells Reveals Alzheimer's Disease-Specific Signatures. %A Garcia, Angeles %A Mathur, Shubha %A Kalaw, Maria Carmela %A McAvoy, Elizabeth %A Anderson, James %A Luedke, Angela %A Itorralba, Justine %A Mai, Sabine %X

This study validates and expands on our previous work that assessed three-dimensional (3D) nuclear telomere profiling in buccal cells of Alzheimer's disease (AD) patients and non-AD controls (Mathur et al., J Alzheimers Dis 39, 35-48, 2014). While the previous study used age- and gender-matched caregiver controls, the current study consented a new cohort of 44 age- and gender-matched healthy non-caregiver controls and 44 AD study participants. 3D telomeric profiles of buccal cells of AD patients and their non-AD controls were examined with participant information blinded to the analysis. In agreement with our previous study, we demonstrate that 3D telomeric profiles allow for the distinction between AD and non-AD individuals. This validation cohort provides an indication that the total number of 3D telomeric signals and their telomere lengths may be a suitable biomarker to differentiate between AD and non-AD and between mild, moderate, and severe AD. Further studies with larger sample sizes are required to move this technology further toward the clinic.

%B J Alzheimers Dis %V 58 %P 139-145 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387668?dopt=Abstract %R 10.3233/JAD-161169 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice. %A Liu, Peng %A Reichl, John H %A Rao, Eshaan R %A McNellis, Brittany M %A Huang, Eric S %A Hemmy, Laura S %A Forster, Colleen L %A Kuskowski, Michael A %A Borchelt, David R %A Vassar, Robert %A Ashe, Karen H %A Zahs, Kathleen R %X

There exist several dozen lines of transgenic mice that express human amyloid-β protein precursor (AβPP) with Alzheimer's disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the types and amounts of Aβ that they generate and in their spatiotemporal patterns of expression of Aβ assemblies, providing a toolkit to study Aβ amyloidosis and the influence of Aβ aggregation on brain function. More complete quantitative descriptions of the types of Aβ assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aβ toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ∼4.5 times that of 21-month-old Tg2576 mice and ∼15 times that of 21-24-month-old rTg9191 mice. Plaque-size distributions changed across the lifespan in a line- and region-dependent manner. We also compared the dense-core plaque burdens in the mice to those measured in a set of pathologically-confirmed AD cases from the Nun Study. Cortical plaque burdens in Tg2576, APPSwePS1ΔE9, and 5XFAD mice eventually far exceeded those measured in the human cohort.

%B J Alzheimers Dis %V 56 %P 743-761 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059792?dopt=Abstract %R 10.3233/JAD-161027 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Quantitative Erythrocyte Omega-3 EPA Plus DHA Levels are Related to Higher Regional Cerebral Blood Flow on Brain SPECT. %A Amen, Daniel G %A Harris, William S %A Kidd, Parris M %A Meysami, Somayeh %A Raji, Cyrus A %X

BACKGROUND: The interrelationships between omega-3 fatty acids status, brain perfusion, and cognition are not well understood.

OBJECTIVE: To evaluate if SPECT brain imaging of cerebral perfusion and cognition varies as a function of omega-3 fatty acid levels.

METHODS: A random sample of 166 study participants was drawn from a psychiatric referral clinical for which erythrocyte quantification of omega-3 eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) (the Omega-3 Index) was available. Quantitative brain SPECT was done on 128 regions based on a standard anatomical Atlas Persons with erythrocyte EPA+DHA concentrations were dichotomized based on membership in top 50th percentile versus bottom 50th percentile categories. Two-sample t-tests were done to identify statistically significant differences in perfusion between the percentile groups. Partial correlations were modeled between EPA+DHA concentration and SPECT regions. Neurocognitive status was assessed using computerized testing (WebNeuro) and was separately correlated to cerebral perfusion on brain SPECT imaging and omega-3 EPA+DHA levels.

RESULTS: Partial correlation analyses showed statistically significant relationships between higher omega-3 levels and cerebral perfusion were in the right parahippocampal gyrus (r = 0.20, p = 0.03), right precuneus (r = 0.20, p = 0.03), and vermis subregion 6 (p = 0.21, p = 0.03). Omega-3 Index levels separately correlated to the feeling subsection of the WebNeuro (r = 0.25, p = 0.01).

CONCLUSION: Quantitative omega-3 EPA+DHA erythrocyte concentrations are independently correlated with brain perfusion on SPECT imaging and neurocognitive tests. These results have implications for the role of omega-3 fatty acids toward contributing to cognitive reserve.

%B J Alzheimers Dis %V 58 %P 1189-1199 %G eng %N 4 %R 10.3233/JAD-170281 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Quantitative Magnetic Resonance Abnormalities in Creutzfeldt-Jakob Disease and Fatal Insomnia. %A Grau-Rivera, Oriol %A Calvo, Anna %A Bargalló, Nuria %A Monté, Gemma C %A Nos, Carlos %A Lladó, Albert %A Molinuevo, José Luis %A Gelpi, Ellen %A Sánchez-Valle, Raquel %X

BACKGROUND: Quantitative neuroimaging might unveil abnormalities in prion diseases that are not perceivable at visual inspection. On the other hand, scarce studies have quantified volumetric changes in prion diseases.

OBJECTIVES: We aim to characterize volumetric and diffusion tensor imaging (DTI) changes in patients with prion diseases who presented with either Creutzfeldt-Jakob disease (CJD) or fatal insomnia (FI) phenotype.

METHODS: Twenty patients with prion diseases- 15 with CJD and 5 with fatal insomnia (FI)- and 40 healthy controls were examined with a 3-Tesla magnetic resonance imaging scanner. Images were segmented and normalized with SPM12. DTI maps were obtained with FMRIB Software Library. Whole-brain voxel-wise and region-of-interest analyses of volumetric and DTI changes were performed with SPM12. White matter (WM) changes were also analyzed with tract-based spatial statistics. Semiquantitive assessment of neuropathological parameters was compared with DTI metrics in thalamus from 11 patients.

RESULTS: Patients with CJD and FI presented significant atrophy in thalamus and cerebellum. In CJD, mean diffusivity (MD) was decreased in striatum and increased in subcortical WM, while both increased and decreased values were observed across different thalamic nuclei. In FI, MD was increased in thalamus and cerebellum. Spongiform change and PrPSc deposition were more intense in thalamus in CJD than in FI, although no significant correlations arose with MD values in the nuclei studied.

CONCLUSION: Volumetric and DTI abnormalities suggest a central common role of the thalamus in prion diseases. We report, for the first time, quantitative MRI changes in FI, and provide further evidence of WM involvement in prion diseases.

%B J Alzheimers Dis %V 55 %P 431-443 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662320?dopt=Abstract %R 10.3233/JAD-160750 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Radiological-Pathological Correlation in Alzheimer's Disease: Systematic Review of Antemortem Magnetic Resonance Imaging Findings. %A Dallaire-Théroux, Caroline %A Callahan, Brandy L %A Potvin, Olivier %A Saikali, Stéphan %A Duchesne, Simon %X

BACKGROUND: The standard method of ascertaining Alzheimer's disease (AD) remains postmortem assessment of amyloid plaques and neurofibrillary degeneration. Vascular pathology, Lewy bodies, TDP-43, and hippocampal sclerosis are frequent comorbidities. There is therefore a need for biomarkers that can assess these etiologies and provide a diagnosis in vivo.

OBJECTIVE: We conducted a systematic review of published radiological-pathological correlation studies to determine the relationship between antemortem magnetic resonance imaging (MRI) and neuropathological findings in AD.

METHODS: We explored PubMed in June-July 2015 using "Alzheimer's disease" and combinations of radiological and pathological terms. After exclusion following screening and full-text assessment of the 552 extracted manuscripts, three others were added from their reference list. In the end, we report results based on 27 articles.

RESULTS: Independently of normal age-related brain atrophy, AD pathology is associated with whole-brain and hippocampal atrophy and ventricular expansion as observed on T1-weighted images. Moreover, cerebral amyloid angiopathy and cortical microinfarcts are also related to brain volume loss in AD. Hippocampal sclerosis and TDP-43 are associated with hippocampal and medial temporal lobe atrophy, respectively. Brain volume loss correlates more strongly with tangles than with any other pathological finding. White matter hyperintensities observed on proton density, T2-weighted and FLAIR images are strongly related to vascular pathologies, but are also associated with other histological changes such as gliosis or demyelination.

CONCLUSION: Cerebral atrophy and white matter changes in the living brain reflect underlying neuropathology and may be detectable using antemortem MRI. In vivo MRI may therefore be an avenue for AD pathological staging.

%B J Alzheimers Dis %V 57 %P 575-601 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28282807?dopt=Abstract %R 10.3233/JAD-161028 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Radiopharmaceuticals for Assessment of Altered Metabolism and Biometal Fluxes in Brain Aging and Alzheimer's Disease with Positron Emission Tomography. %A Xie, Fang %A Peng, Fangyu %X

Aging is a risk factor for Alzheimer's disease (AD). There are changes of brain metabolism and biometal fluxes due to brain aging, which may play a role in pathogenesis of AD. Positron emission tomography (PET) is a versatile tool for tracking alteration of metabolism and biometal fluxes due to brain aging and AD. Age-dependent changes in cerebral glucose metabolism can be tracked with PET using 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG), a radiolabeled glucose analogue, as a radiotracer. Based on different patterns of altered cerebral glucose metabolism, 18F-FDG PET was clinically used for differential diagnosis of AD and Frontotemporal dementia (FTD). There are continued efforts to develop additional radiopharmaceuticals or radiotracers for assessment of age-dependent changes of various metabolic pathways and biometal fluxes due to brain aging and AD with PET. Elucidation of age-dependent changes of brain metabolism and altered biometal fluxes is not only significant for a better mechanistic understanding of brain aging and the pathophysiology of AD, but also significant for identification of new targets for the prevention, early diagnosis, and treatment of AD.

%B J Alzheimers Dis %V 59 %P 527-536 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671127?dopt=Abstract %R 10.3233/JAD-170280 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Raman Spectrometric Detection Methods for Early and Non-Invasive Diagnosis of Alzheimer's Disease. %A Huang, Chia-Chi %A Isidoro, Ciro %X

The continuous increasing rate of patients suffering of Alzheimer's disease (AD) worldwide requires the adoption of novel techniques for non-invasive early diagnosis and monitoring of the disease. Here we review the various Raman spectroscopic techniques, including Fourier Transform-Raman spectroscopy, surface-enhanced Raman scattering spectroscopy, coherent anti-Stokes Raman scattering spectroscopy, and confocal Raman microspectroscopy, that could be used for the diagnosis of AD. These techniques have shown the potential to detect AD biomarkers, such as the amyloid-β peptide and the tau protein, or the neurotransmitters involved in the disease (e.g., Glutamate and γ-Aminobutyric acid), or the typical structural alterations in specific brain areas. The possibility to detect the specific biomarkers in liquid biopsies and to obtain high resolution 3D microscope images of the affected area make the Raman spectroscopy a valuable ally in the early diagnosis and monitoring of AD.

%B J Alzheimers Dis %V 57 %P 1145-1156 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304304?dopt=Abstract %R 10.3233/JAD-161238 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral ELND005 (scyllo-Inositol) in Young Adults with Down Syndrome without Dementia. %A Rafii, Michael S %A Skotko, Brian G %A McDonough, Mary Ellen %A Pulsifer, Margaret %A Evans, Casey %A Doran, Eric %A Muranevici, Gabriela %A Kesslak, Patrick %A Abushakra, Susan %A Lott, Ira T %X

BACKGROUND: ELND005 (scyllo-Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer's disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia.

OBJECTIVE: To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia.

METHODS: This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase II study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who met study eligibility criteria were randomly assigned in a 2 : 1:1 ratio to receive ELND005 at either 250 mg twice daily (BID) or 250 mg once daily (QD) or matching placebo for 4 weeks.

RESULTS: There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing.

CONCLUSION: Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy.

%B J Alzheimers Dis %V 58 %P 401-411 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453471?dopt=Abstract %R 10.3233/JAD-160965 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Rapidly Progressive Frontotemporal Dementia Associated with MAPT Mutation G389R. %A Sun, Lin %A Chen, Kathryn %A Li, Xia %A Xiao, Shifu %X

Frontotemporal dementia includes a large spectrum of neurodegenerative disorders. Here, we report the case of a young patient with MAPT mutation G389R, who was 27 years old when he progressively developed severe behavioral disturbances. Initially, he presented with slowly progressive personality change. After 1 year, he exhibited moderate dementia with extrapyramidal and pyramidal symptoms. MRI showed frontotemporal atrophy. He rapidly progressed to severe dementia 3 years after onset. Genetic testing revealed a heterozygous guanine to cytosine mutation at the first base of codon 389 (c.1165G>A) of MAPT, the tau gene, resulting in a glycine to arginine substitution in the patient and two unaffected relatives. We predicted the model of mutant tau protein through I-TASSER software, and speculated the structural change of tau protein caused by mutant site. We also detected the MAPT gene transcript and methylation of samples from peripheral blood leucocytes in an attempt to explain the possible mechanisms of incomplete penetrance, although there were not positive findings. This case is remarkable because of the early onset and rapid progression of the disease.

%B J Alzheimers Dis %V 55 %P 777-785 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802239?dopt=Abstract %R 10.3233/JAD-160802 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity. %A Louwersheimer, Eva %A Cohn-Hokke, Petra E %A Pijnenburg, Yolande A L %A Weiss, Marjan M %A Sistermans, Erik A %A Rozemuller, Annemieke J %A Hulsman, Marc %A van Swieten, John C %A van Duijn, Cock M %A Barkhof, Frederik %A Koene, Teddy %A Scheltens, Philip %A van der Flier, Wiesje M %A Holstege, Henne %X

BACKGROUND: The major genetic risk factor for late onset Alzheimer's disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants.

OBJECTIVE: To identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD.

METHODS: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members.

RESULTS: All affected family members were homozygous for the APOE-ɛ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ɛ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AβPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AβPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities.

CONCLUSION: We hypothesize that next to APOE-ɛ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aβ processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.

%B J Alzheimers Dis %V 56 %P 63-74 %G eng %N 1 %R 10.3233/JAD-160091 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Recent Increases in Hippocampal Tau Pathology in the Aging Japanese Population: The Hisayama Study. %A Hamasaki, Hideomi %A Honda, Hiroyuki %A Okamoto, Tsuyoshi %A Koyama, Sachiko %A Suzuki, Satoshi O %A Ohara, Tomoyuki %A Ninomiya, Toshiharu %A Kiyohara, Yutaka %A Iwaki, Toru %X

BACKGROUND: The Hisayama study is a prospective cohort study of lifestyle-related diseases that commenced in 1961. Through it, a significant increasing trend in the prevalence of Alzheimer's disease has been observed over the past 18 years.

OBJECTIVES: We sought to investigate the increases in brain pathology related to Alzheimer's disease using automated MATLAB morphometric analyses for quantifying tau pathology.

METHODS: We examined a series of autopsied cases from Hisayama residents obtained between 1998 and 2003 (group A: 203 cases), and between 2009 and 2014 (group B: 232 cases). We developed custom software in MATLAB to analyze abnormal tau deposits quantitatively. Specimens were immunostained with both anti-amyloid-β-protein and anti-phosphorylated tau antibodies.

RESULTS: Both the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria for senile plaques and Braak stage for NFT were higher in group B. Morphometric analyses of the hippocampi also revealed a trend toward increased tau pathology in both men and women over 80 years of age in group B. The increases were also significant when the subjects were examined independently according to high or low CERAD scores and in all levels of AD neuropathologic change according to the National Institute on Aging-Alzheimer's Association guidelines (2012).

CONCLUSION: We revealed a recent trend of increased tauopathy in the older people, which is partly independent of amyloid-β pathology.

%B J Alzheimers Dis %V 55 %P 613-624 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716666?dopt=Abstract %R 10.3233/JAD-160521 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Recent Progress in Alzheimer's Disease Research, Part 1: Pathology. %A Hane, Francis T %A Lee, Brenda Y %A Leonenko, Zoya %X

The field of Alzheimer's disease (AD) research has grown exponentially over the past few decades, especially since the isolation and identification of amyloid-β from postmortem examination of the brains of AD patients. Recently, the Journal of Alzheimer's Disease (JAD) put forth approximately 300 research reports which were deemed to be the most influential research reports in the field of AD since 2010. JAD readers were asked to vote on these most influential reports. In this 3-part review, we review the results of the 300 most influential AD research reports to provide JAD readers with a readily accessible, yet comprehensive review of the state of contemporary research. Notably, this multi-part review identifies the "hottest" fields of AD research providing guidance for both senior investigators as well as investigators new to the field on what is the most pressing fields within AD research. Part 1 of this review covers pathogenesis, both on a molecular and macro scale. Part 2 review genetics and epidemiology, and part 3 covers diagnosis and treatment. This part of the review, pathology, reviews amyloid-β, tau, prions, brain structure, and functional changes with AD and the neuroimmune response of AD.

%B J Alzheimers Dis %V 57 %P 1-28 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222507?dopt=Abstract %R 10.3233/JAD-160882 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Recent Progress in Alzheimer's Disease Research, Part 2: Genetics and Epidemiology. %A Robinson, Morgan %A Lee, Brenda Y %A Hane, Francis T %X

This is the second part of a three-part review series reviewing the most important advances in Alzheimer's disease (AD) research since 2010. This review covers the latest research on genetics and epidemiology. Epidemiological and genetic studies are revealing important insights into the etiology of, and factors that contribute to AD, as well as areas of priority for research into mechanisms and interventions. The widespread adoption of genome wide association studies has provided compelling evidence of the genetic complexity of AD with genes associated with such diverse physiological function as immunity and lipid metabolism being implicated in AD pathogenesis.

%B J Alzheimers Dis %V 57 %P 317-330 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28211812?dopt=Abstract %R 10.3233/JAD-161149 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Recent Progress in Alzheimer's Disease Research, Part 3: Diagnosis and Treatment. %A Hane, Francis T %A Robinson, Morgan %A Lee, Brenda Y %A Bai, Owen %A Leonenko, Zoya %A Albert, Mitchell S %K Alzheimer Disease %K Biomarkers %K Biomedical Research %K Humans %K Neuroimaging %X

The field of Alzheimer's disease (AD) research has grown exponentially over the past few decades, especially since the isolation and identification of amyloid-β from postmortem examination of the brains of AD patients. Recently, the Journal of Alzheimer's Disease (JAD) put forth approximately 300 research reports which were deemed to be the most influential research reports in the field of AD since 2010. JAD readers were asked to vote on these most influential reports. In this 3-part review, we review the results of the 300 most influential AD research reports to provide JAD readers with a readily accessible, yet comprehensive review of the state of contemporary research. Notably, this multi-part review identifies the "hottest" fields of AD research providing guidance for both senior investigators as well as investigators new to the field on what is the most pressing fields within AD research. Part 1 of this review covers pathogenesis, both on a molecular and macro scale. Part 2 review genetics and epidemiology, and part 3 covers diagnosis and treatment. This part of the review, diagnosis and treatment, reviews the latest diagnostic criteria, biomarkers, imaging, and treatments in AD.

%B J Alzheimers Dis %V 57 %P 645-665 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269772?dopt=Abstract %R 10.3233/JAD-160907 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Recovery from Proactive Semantic Interference and MRI Volume: A Replication and Extension Study. %A Loewenstein, David A %A Curiel, Rosie E %A DeKosky, Steven %A Rosselli, Monica %A Bauer, Russell %A Grieg-Custo, Maria %A Penate, Ailyn %A Li, Chunfei %A Lizagarra, Gabriel %A Golde, Todd %A Adjouadi, Malek %A Duara, Ranjan %X

BACKGROUND: The rise in incidence of Alzheimer's disease (AD) has led to efforts to advance early detection of the disease during its preclinical stages. To achieve this, the field needs to develop more sensitive cognitive tests that relate to biological markers of disease pathology. Failure to recover from proactive interference (frPSI) is one such cognitive marker that is associated with volumetric reductions in the hippocampus, precuneus, and other AD-prone regions, and to amyloid load in the brain.

OBJECTIVE: The current study attempted to replicate and extend our previous findings that frPSI is a sensitive marker of early AD, and related to a unique pattern of volumetric loss in AD prone areas.

METHODS: Three different memory measures were examined relative to volumetric loss and cortical thickness among 45 participants with amnestic mild cognitive impairment.

RESULTS: frPSI was uniquely associated with reduced volumes in the hippocampus (r = 0.50) precuneus (r = 0.41), and other AD prone regions, replicating previous findings. Strong associations between frPSI and lower entorhinal cortex volumes and cortical thickness (r≥0.60) and precuneus (r = 0.50) were also observed.

CONCLUSION: Unique and strong associations between volumetric reductions and frPSI as observed by Loewenstein and colleagues were replicated. Together with cortical thickness findings, these results indicate that frPSI is worthy of further study as a sensitive and early cognitive marker of AD.

%B J Alzheimers Dis %V 59 %P 131-139 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598850?dopt=Abstract %R 10.3233/JAD-170276 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Recovery from Proactive Semantic Interference in Mild Cognitive Impairment and Normal Aging: Relationship to Atrophy in Brain Regions Vulnerable to Alzheimer's Disease. %A Loewenstein, David A %A Curiel, Rosie E %A Wright, Clinton %A Sun, Xiaoyan %A Alperin, Noam %A Crocco, Elzabeth %A Czaja, Sara J %A Raffo, Arlene %A Penate, Ailyn %A Melo, Jose %A Capp, Kimberly %A Gamez, Monica %A Duara, Ranjan %X

BACKGROUND: There is growing evidence that proactive semantic interference (PSI) and failure to recover from PSI may represent early features of Alzheimer's disease (AD).

OBJECTIVE: This study investigated the association between PSI, recovery from PSI, and reduced MRI volumes in AD signature regions among cognitively impaired and unimpaired older adults.

METHODS: Performance on the LASSI-L (a novel test of PSI and recovery from PSI) and regional brain volumetric measures were compared between 38 cognitively normal (CN) elders and 29 older participants with amnestic mild cognitive impairment (MCI). The relationship between MRI measures and performance on the LASSI-L as well as traditional memory and non-memory cognitive measures was also evaluated in both diagnostic groups.

RESULTS: Relative to traditional neuropsychological measures, MCI patients' failure to recover from PSI was associated with reduced volumes in the hippocampus (rs = 0.48), precuneus (rs = 0.50); rostral middle frontal lobules (rs = 0.54); inferior temporal lobules (rs = 0.49), superior parietal lobules (rs = 0.47), temporal pole (rs = 0.44), and increased dilatation of the inferior lateral ventricle (rs = -0.49). For CN elders, only increased inferior lateral ventricular size was associated with vulnerability to PSI (rs = -0.49), the failure to recover from PSI (rs = -0.57), and delayed recall on the Hopkins Verbal Learning Test-Revised (rs = -0.48).

DISCUSSION: LASSI-L indices eliciting failure to recover from PSI were more highly associated with more MRI regional biomarkers of AD than other traditional cognitive measures. These results as well as recent amyloid imaging studies with otherwise cognitively normal subjects, suggest that recovery from PSI may be a sensitive marker of preclinical AD and deserves further investigation.

%B J Alzheimers Dis %V 56 %P 1119-1126 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106554?dopt=Abstract %R 10.3233/JAD-160881 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Reduced Cardiovascular Functions in Patients with Alzheimer's Disease. %A Jin, Wang-Sheng %A Bu, Xian-Le %A Wang, Ye-Ran %A Li, Ling %A Li, Wei-Wei %A Liu, Yu-Hui %A Zhu, Chi %A Yao, Xiu-Qing %A Chen, Yang %A Gao, Chang-Yue %A Zhang, Tao %A Gao, Chang-Yue %A Zhou, Hua-Dong %A Zeng, Fan %A Wang, Yan-Jiang %X

Previous studies have suggested that cardiovascular functions might play a critical role in Alzheimer's disease (AD) pathogenesis. However, the relationship among heart function, blood flow of cerebral vessels, and AD remains unclear. In the present study, AD patients (n = 34) and age- and gender-matched cognitively normal controls (n = 34) were recruited. Comorbidity information was collected. The ejection fraction was measured using echocardiography, and the mean velocity, pulsatility index (PI), and resistance index (RI) of the basilar artery (BA), left terminal internal carotid artery (LTICA), and right terminal internal carotid artery (RTICA) were measured using transcranial Doppler. The lacunae, white matter changes, and plaque in the aortic arch and carotid arteries were collected from brain magnetic resonance imaging and computed tomography angiography images. Compared with normal controls, AD patients had lower ejection fractions and cerebral blood flow velocities and a higher RI and PI in the BA, LTICA, and RTICA, as well as more plaques in the aortic and carotid arteries. In the multivariate logistic regression analysis, the ejection fraction and the mean velocity of the BA and LTICA were independently associated with AD after adjusting for age, gender, education, vascular risk factors, arterial plaques, and brain ischemic lesions detected in the brain images. These findings suggest that heart function and vascular condition may play important roles in AD pathogenesis. Improving cardiovascular functions could be a promising approach for the prevention and treatment of AD.

%B J Alzheimers Dis %V 58 %P 919-925 %G eng %N 3 %R 10.3233/JAD-170088 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Reduced Cerebral Blood Flow in Mild Cognitive Impairment Assessed Using Phase-Contrast MRI. %A de Eulate, Reyes García %A Goñi, Irene %A Galiano, Alvaro %A Vidorreta, Marta %A Recio, Miriam %A Riverol, Mario %A Zubieta, José L %A Fernández-Seara, María A %X

There is increasing evidence of a vascular contribution to Alzheimer's disease (AD). In some cases, prior work suggests that chronic brain hypoperfusion could play a prime pathogenic role contributing to the accumulation of amyloid-β,while other studies favor the hypothesis that vascular dysfunction and amyloid pathology are independent, although synergistic, mechanisms contributing to cognitive impairment. Vascular dysfunction can be evaluated by assessing cerebral blood flow impairment. Phase contrast velocity mapping by MRI offers a non-invasive means of quantifying the total inflow of blood to the brain. This quantitative parameter could be a sensitive indicator of vascular disease at early stages of AD. In this work, phase contrast MRI was used to evaluate cerebral hemodynamics in patients with subjective memory complaints, amnestic mild cognitive impairment, and mild to moderate AD, and compare them with control subjects. Results showed that blood flow and velocity were decreased in the patients with cognitive dysfunction and the decrease correlated with the degree of cognitive impairment as assessed by means of neuropsychological tests. Total cerebral blood flow measurements were clearly reduced in AD patients, but more importantly appeared to be sensitive enough to distinguish between healthy subjects and those with mild cognitive impairment. A quantitative measurement of total brain blood flow could potentially predict vascular dysfunction and compromised brain perfusion in early stages of AD.

%B J Alzheimers Dis %V 58 %P 585-595 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453476?dopt=Abstract %R 10.3233/JAD-161222 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Reduced Cerebrospinal Fluid Concentration of Apolipoprotein A-I in Patients with Alzheimer's Disease. %A Johansson, Per %A Almqvist, Erik G %A Bjerke, Maria %A Wallin, Anders %A Johansson, Jan-Ove %A Andreasson, Ulf %A Blennow, Kaj %A Zetterberg, Henrik %A Svensson, Johan %X

BACKGROUND: Apolipoprotein E (ApoE) has been extensively studied in Alzheimer's disease (AD), but little is known of apolipoprotein A-I (ApoA-I) in cerebrospinal fluid (CSF).

OBJECTIVE: Plasma lipids as well as ApoA-I and ApoE in plasma and CSF were determined and related to Mini-Mental State Examination (MMSE) score, APOE genotype, and CSF AD biomarkers.

METHODS: Consecutive patients with AD (n = 29), stable mild cognitive impairment (n = 13), other dementias (n = 14), and healthy controls (n = 18) were included at a single center.

RESULTS: AD patients had higher plasma triglycerides and lower CSF ApoA-I concentration than controls (both p < 0.05). CSF ApoE concentration was reduced in other dementias (p < 0.01). In AD as well as other dementias, the ratios between CSF and plasma concentrations of both ApoA-I and ApoE were lower than those in the controls. ApoA-I and ApoE in plasma and CSF were not influenced by APOEɛ4 allele distribution. In the total study population (n = 74), CSF ApoA-I correlated positively with MMSE score (r = 0.26, p < 0.05) and negatively with CSF P-tau (r = -0.25, p < 0.05). CSF ApoE correlated positively with CSF concentrations of T-tau and P-tau in the total study population and in AD patients.

CONCLUSION: CSF ApoA-I was reduced in AD patients and associated with measures of cognitive function and AD disease status. The mechanisms underlying the decreased CSF:plasma ratios of ApoA-I and ApoE in AD and other dementias need to be explored in further studies.

%B J Alzheimers Dis %V 59 %P 1017-1026 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697566?dopt=Abstract %R 10.3233/JAD-170226 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Reduction of RPT6/S8 (a Proteasome Component) and Proteasome Activity in the Cortex is associated with Cognitive Impairment in Lewy Body Dementia. %A Alghamdi, Amani %A Vallortigara, Julie %A Howlett, David R %A Broadstock, Martin %A Hortobágyi, Tibor %A Ballard, Clive %A Thomas, Alan J %A O'Brien, John T %A Aarsland, Dag %A Attems, Johannes %A Francis, Paul T %A Whitfield, David R %X

Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (chymotrypsin- and PGPH-) activities have also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus' cortex were selected as regions of interest from Parkinson's disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer's disease (AD, n = 16), and control (n = 24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p < 0.001; Bonferroni post hoc test) in prefrontal cortex and parietal cortex compared with controls. Strong associations were observed between RPT6 levels in prefrontal, parietal cortex, and anterior cingulate gyrus and cognitive impairment (p = 0.001, p = 0.001, and p = 0.008, respectively). These findings highlight the involvement of the UPS in Lewy body dementia and indicate that targeting the UPS may have the potential to slow down or reduce the progression of cognitive impairment in DLB and PDD.

%B J Alzheimers Dis %V 57 %P 373-386 %G eng %N 2 %R 10.3233/JAD-160946 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Relation of Odor Identification with Alzheimer's Disease Markers in Cerebrospinal Fluid and Cognition. %A Reijs, Babette L R %A Ramakers, Inez H G B %A Elias-Sonnenschein, Lyzel %A Teunissen, Charlotte E %A Koel-Simmelink, Marleen %A Tsolaki, Magda %A Wahlund, Lars-Olof %A Waldemar, Gunhild %A Hausner, Lucrezia %A Johannsen, Peter %A Vanderstichele, Hugo %A Verhey, Frans %A Devanand, D P %A Visser, Pieter Jelle %X

BACKGROUND: Impaired olfactory function is an early characteristic of Alzheimer's disease (AD), but it remains unclear if odor identification also relates to early markers of AD in cerebrospinal fluid (CSF).

OBJECTIVE: To investigate the association between odor identification and amyloid-β 1-42 (Aβ42) and total tau (t-tau) concentrations in CSF. In addition, to examine the relation between odor identification and cognitive function at baseline and at follow-up, and whether these associations are moderated by CSF Aβ42 and t-tau and apolipoprotein E (APOE) genotype.

METHODS: We included 160 individuals (40 with normal cognition, 45 with mild cognitive impairment (MCI), 42 with AD-type dementia, and 26 individuals with non-AD dementia) from the EDAR study. Individuals were recruited from six memory clinics across Europe. Odor identification was tested with the brief University of Pennsylvania Smell Identification Test. CSF Aβ42 and t-tau were assessed with INNO-BIA AlzBio3 Luminex assay. Neuropsychological assessment included tests for verbal memory, verbal fluency, attention, executive function, and visuoconstruction. Follow-up was performed within 3 years after baseline.

RESULTS: Lower odor identification scores correlated with increased CSF t-tau concentrations and with lower scores on all cognitive measures at baseline independent of diagnostic group. Lower odor identification scores predicted decline on the MMSE in the total group, and decline on wordlist learning and delayed recall in APOE ɛ4 carriers and in individuals with abnormal Aβ42.

CONCLUSION: Odor identification impairment may be an indicator of neuronal injury rather than amyloid pathology.

%B J Alzheimers Dis %V 60 %P 1025-1034 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984603?dopt=Abstract %R 10.3233/JAD-170564 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Relationship between Markers of Inflammation and Degeneration in the Central Nervous System and the Blood-Brain Barrier Impairment in Alzheimer's Disease. %A Muszyński, Paweł %A Kulczyńska-Przybik, Agnieszka %A Borawska, Renata %A Litman-Zawadzka, Ala %A Słowik, Agnieszka %A Klimkowicz-Mrowiec, Aleksandra %A Pera, Joanna %A Dziedzic, Tomasz %A Mroczko, Barbara %X

BACKGROUND: It is known that YKL-40- a marker of glial inflammation, and VILIP-1- a marker of neuronal injury, reflect functional and structural changes in AD brains, although there is limited data concerning their potential influence on blood-brain barrier (BBB) homeostasis.

OBJECTIVE: Therefore, the aim of our study was to investigate the relationship between markers of inflammation and degeneration in the central nervous system (CNS) of patients with AD and mild cognitive impairment (MCI) as well as immunological response in CNS and BBB function.

METHODS: Cerebrospinal fluid (CSF) concentrations of proteins tested were determined in 45 AD patients, 18 MCI subjects, and 23 non-demented controls using ELISA method.

RESULTS: CSF concentrations of YKL-40 were significantly higher in MCI and AD patients, whereas CSF levels of VILIP-1 were statistically higher in the AD group as compared to the subjects without cognitive deficits. Elevated concentrations of YKL-40 correlated significantly with increased albumin quotient and decreased Aβ42/40 ratio in AD patients and with IgG quotient in the total study group. We did not find a relationship between VILIP-1 and immunological parameters reflecting BBB dysfunction and humoral immune response.

CONCLUSION: Our findings indicate that YKL-40 may contribute to decreased stability and increased permeability of BBB in AD patients. It is assumed that YKL-40 is implicated in the development of brain barriers, although its precise mechanism of action in the BBB disruption remains unrevealed. Further studies on larger groups of patients are required to confirm our hypothesis.

%B J Alzheimers Dis %V 59 %P 903-912 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697565?dopt=Abstract %R 10.3233/JAD-170220 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Relationship of Bilingualism Compared to Monolingualism to the Risk of Cognitive Decline or Dementia: A Systematic Review and Meta-Analysis. %A Mukadam, Naaheed %A Sommerlad, Andrew %A Livingston, Gill %X

BACKGROUND: Bilingualism may contribute to cognitive reserve, protect against cognitive decline, and delay the onset of dementia.

OBJECTIVE: We systematically reviewed evidence about the effect of bilingualism on subsequent cognitive decline or dementia.

METHODS: We searched electronic databases and references for longitudinal studies comparing cognitive decline in people who were bilingual with those who were monolingual and evaluated study quality. We conducted meta-analyses using random effects models to calculate pooled odds ratio of incident dementia.

RESULTS: We included 13/1,156 eligible articles. Meta-analysis of prospective studies of the effects of bilingualism on future dementia gave a combined Odds Ratio of dementia of 0.96 (95% CI 0.74-1.23) in bilingual participants (n = 5,527) compared to monolinguals. Most retrospective studies found that bilingual people were reported to develop symptoms of cognitive decline at a later age than monolingual participants.

CONCLUSION: We did not find that bilingualism protects from cognitive decline or dementia from prospective studies. Retrospective studies are more prone to confounding by education, or cultural differences in presentation to dementia services and are therefore not suited to establishing causative links between risk factors and outcomes.

%B J Alzheimers Dis %V 58 %P 45-54 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387680?dopt=Abstract %R 10.3233/JAD-170131 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Relationship of Brain Amyloid Load and APOE Status to Regional Cortical Thinning and Cognition in the ADNI Cohort. %A Li, Chunfei %A Loewenstein, David A %A Duara, Ranjan %A Cabrerizo, Mercedes %A Barker, Warren %A Adjouadi, Malek %X

BACKGROUND: Both amyloid (Aβ) load and APOE4 allele are associated with neurodegenerative changes in Alzheimer's disease (AD) prone regions and with risk for cognitive impairment.

OBJECTIVE: To evaluate the unique and independent contribution of APOE4 allele status (E4+∖E4-), Aβ status (Amy+∖Amy-), and combined APOE4 and Aβ status on regional cortical thickness (CoTh) and cognition among participants diagnosed as cognitively normal (CN, n = 251), early mild cognitive impairment (EMCI, n = 207), late mild cognitive impairment (LMCI, n = 196), and mild AD (n = 162) from the ADNI.

METHODS: A series of two-way ANCOVAs with post-hoc Tukey HSD tests, controlling independently for Aβ and APOE4 status and age were examined.

RESULTS: Among LMCI and AD participants, cortical thinning was widespread in association with Amy+ status, whereas in association with E4+ status only in the inferior temporal and medial orbito-frontal regions. Among CN and EMCI participants, E4+ status, but not Amy+ status, was independently associated with increased CoTh, especially in limbic regions [e.g., in the entorhinal cortex, CoTh was 0.123 mm greater (p = 0.002) among E4+ than E4-participants]. Among CN and EMCI, both E4+ and Amy+ status were independently associated with cognitive impairment, which was greatest among those with combined E4 + and Amy+ status.

CONCLUSION: Decreased CoTh is independently associated with Amy+ status in many brain regions, but with E4+ status in very restricted number of brain regions. Among CN and EMCI participants, E4 + status is associated with increased CoTh, in medial and inferior temporal regions, although cognitive impairment at this state is independently associated with Amy+ and E4 + status. These findings imply a unique pathophysiological mechanism for E4 + status in AD and its progression.

%B J Alzheimers Dis %V 59 %P 1269-1282 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731444?dopt=Abstract %R 10.3233/JAD-170286 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Relationships Between Components of Metabolic Syndrome and Mild Cognitive Impairment Subtypes: A Cross-Sectional Study of Japanese Older Adults. %A Bae, Seongryu %A Shimada, Hiroyuki %A Lee, Sangyoon %A Makizako, Hyuma %A Lee, Sungchul %A Harada, Kazuhiro %A Doi, Takehiko %A Tsutsumimoto, Kota %A Hotta, Ryo %A Nakakubo, Sho %A Park, Hyuntae %A Suzuki, Takao %X

BACKGROUND: The associations between components of metabolic syndrome (MetS) and mild cognitive impairment (MCI) subtypes remain unclear.

OBJECTIVE: The study aim was to identify the prevalence of MetS for MCI subtypes and to investigate sex differences in the association between MetS and MCI subtypes in older Japanese adults.

METHODS: The study analyzed data from 3,312 men and women aged 70 years or more. MetS was diagnosed according to International Diabetes Federation criteria. Participants completed cognitive tests and were categorized into normal cognition, amnestic MCI (aMCI), and non-amnestic MCI (naMCI). The associations between MetS and its components and MCI subtypes were analyzed using multiple logistic regression.

RESULTS: MetS prevalence was greater in participants with naMCI (men: p = 0.030; women: p = 0.040). Participants with naMCI showed higher odds ratios (OR) of MetS (men: 2.45, 95% confidence intervals (CI): 1.13-5.32; women: OR: 1.94, 95% CI: 1.12-3.39) compared with participants with normal cognition. MetS was not associated with aMCI. Analysis of MetS components showed that raised glucose (OR: 1.62, 95% CI: 1.19-2.22) and reduced high-density lipoprotein cholesterol (OR: 1.97, 95% CI: 1.25-3.12) were associated with naMCI in men. In women, raised blood pressure (OR: 1.42, 95% CI: 1.03-1.94) and raised glucose (OR: 1.32, 95% CI: 1.02-1.71) were associated with naMCI.

CONCLUSION: MetS was associated only with naMCI regardless of sex, which suggests etiologic differences in MCI subtypes. We also found sex differences in the relationship between naMCI risk and MetS and its components.

%B J Alzheimers Dis %V 60 %P 913-921 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922149?dopt=Abstract %R 10.3233/JAD-161230 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Relationships of Dietary Patterns, Foods, and Micro- and Macronutrients with Alzheimer's Disease and Late-Life Cognitive Disorders: A Systematic Review. %A Solfrizzi, Vincenzo %A Custodero, Carlo %A Lozupone, Madia %A Imbimbo, Bruno P %A Valiani, Vincenzo %A Agosti, Pasquale %A Schilardi, Andrea %A D'Introno, Alessia %A La Montagna, Maddalena %A Calvani, Mariapaola %A Guerra, Vito %A Sardone, Rodolfo %A Abbrescia, Daniela I %A Bellomo, Antonello %A Greco, Antonio %A Daniele, Antonio %A Seripa, Davide %A Logroscino, Giancarlo %A Sabbá, Carlo %A Panza, Francesco %X

In the last decade, the association between diet and cognitive function or dementia has been largely investigated. In the present article, we systematically reviewed observational studies published in the last three years (2014-2016) on the relationship among dietary factors and late-life cognitive disorders at different levels of investigation (i.e., dietary patterns, foods and food-groups, and dietary micro- and macronutrients), and possible underlying mechanisms of the proposed associations. From the reviewed evidence, the National Institute on Aging-Alzheimer's Association guidelines for Alzheimer's disease (AD) and cognitive decline due to AD pathology introduced some evidence suggesting a direct relation between diet and changes in the brain structure and activity. There was also accumulating evidence that combinations of foods and nutrients into certain patterns may act synergistically to provide stronger health effects than those conferred by their individual dietary components. In particular, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline. Moreover, also other emerging healthy dietary patterns such as the Dietary Approach to Stop Hypertension (DASH) and the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diets were associated with slower rates of cognitive decline and significant reduction of AD rate. Furthermore, some foods or food groups traditionally considered harmful such as eggs and red meat have been partially rehabilitated, while there is still a negative correlation of cognitive functions with saturated fatty acids and a protective effect against cognitive decline of elevated fish consumption, high intake of monounsaturated fatty acids and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA.

%B J Alzheimers Dis %V 59 %P 815-849 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697569?dopt=Abstract %R 10.3233/JAD-170248 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Relative Incidence of Seizures and Myoclonus in Alzheimer's Disease, Dementia with Lewy Bodies, and Frontotemporal Dementia. %A Beagle, Alexander J %A Darwish, Sonja M %A Ranasinghe, Kamalini G %A La, Alice L %A Karageorgiou, Elissaios %A Vossel, Keith A %X

BACKGROUND: Patients with Alzheimer's disease (AD) are more prone to seizures and myoclonus, but relative risk of these symptoms among other dementia types is unknown.

OBJECTIVE: To determine incidence of seizures and myoclonus in the three most common neurodegenerative dementias: AD, dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD).

METHODS: Our institution's medical records were reviewed for new-onset unprovoked seizures and myoclonus in patients meeting criteria for AD (n = 1,320), DLB (n = 178), and FTD (n = 348). Cumulative probabilities of developing seizures and myoclonus were compared between diagnostic groups, whereas age-stratified incidence rates were determined relative to control populations.

RESULTS: The cumulative probability of developing seizures after disease onset was 11.5% overall, highest in AD (13.4%) and DLB (14.7%) and lowest in FTD (3.0%). The cumulative probability of developing myoclonus was 42.1% overall, highest in DLB (58.1%). The seizure incidence rates, relative to control populations, were nearly 10-fold in AD and DLB, and 6-fold in FTD. Relative seizure rates increased with earlier age-at-onset in AD (age <50, 127-fold; 50-69, 21-fold; 70+, 2-fold) and FTD (age <50, 53-fold; 50-69, 9-fold), and relative myoclonus rates increased with earlier age-at-onset in all groups. Seizures began an average of 3.9 years after the onset of cognitive or motor decline, and myoclonus began 5.4 years after onset.

CONCLUSIONS: Seizures and myoclonus occur with greater incidence in patients with AD, DLB, and FTD than in the general population, but rates vary with diagnosis, suggesting varied pathomechanisms of network hyperexcitability. Patients often experience these symptoms early in disease, suggesting hyperexcitability could be an important target for interventions.

%B J Alzheimers Dis %V 60 %P 211-223 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826176?dopt=Abstract %R 10.3233/JAD-170031 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Remyelination: A Potential Therapeutic Strategy for Alzheimer's Disease? %A Sun, Junjun %A Zhou, Hong %A Bai, Feng %A Zhang, Zhijun %A Ren, Qingguo %X

Myelin is a lipid-rich multilamellar membrane that wraps around long segments of neuronal axons and it increases the conduction of action potentials, transports the necessary trophic support to the neuronal axons, and reduces the energy consumed by the neuronal axons. Together with axons, myelin is a prerequisite for the higher functions of the central nervous system and complex forms of network integration. Myelin impairments have been suggested to lead to neuronal dysfunction and cognitive decline. Accumulating evidence, including brain imaging and postmortem and genetic association studies, has implicated myelin impairments in Alzheimer's disease (AD). Increasing data link myelin impairments with amyloid-β (Aβ) plaques and tau hyperphosphorylation, which are both present in patients with AD. Moreover, aging and apolipoprotein E (ApoE) may be involved in the myelin impairments observed in patients with AD. Decreased neuronal activity, increased Aβ levels, and inflammation further damage myelin in patients with AD. Furthermore, treatments that promote myelination contribute to the recovery of neuronal function and improve cognition. Therefore, strategies targeting myelin impairment may provide therapeutic opportunities for patients with AD.

%B J Alzheimers Dis %V 58 %P 597-612 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453483?dopt=Abstract %R 10.3233/JAD-170036 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Retrograde Amnesia for Episodic and Semantic Memories in Amnestic Mild Cognitive Impairment. %A De Simone, Maria Stefania %A Fadda, Lucia %A Perri, Roberta %A De Tollis, Massimo %A Aloisi, Marta %A Caltagirone, Carlo %A Carlesimo, Giovanni Augusto %X

Retrograde amnesia (RA), which includes loss of memory for past personal events (autobiographical RA) and for acquired knowledge (semantic RA), has been largely documented in patients with amnestic mild cognitive impairment (aMCI). However, previous studies have produced controversial results particularly concerning the temporal extent of memory impairment. Here we investigated whether, with the onset of hippocampal pathology, age of memory acquisition and retrieval frequency play different roles in modulating the progressive loss of semantic and episodic contents of retrograde memory respectively. For this purpose, aMCI patients and healthy controls were tested for the ability to recall semantic and autobiographical information related to famous public events as a function of both age of acquisition and retrieval frequency. In aMCI patients, we found that the impairment in recollecting past personal incidents was modulated by the combined action of memory age and retrieval frequency, because older and more frequently retrieved episodes are less susceptible to loss than more recent and less frequently retrieved ones. On the other side, we found that the loss of semantic information depended only on memory age, because the remoteness of the trace allows for better preservation of the memory. Our results provide evidence that the loss of the two components of retrograde memory is regulated by different mechanisms. This supports the view that diverse neural mechanisms are involved in episodic and semantic memory trace storage and retrieval, as postulated by the Multiple Trace Theory.

%B J Alzheimers Dis %V 59 %P 241-250 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598852?dopt=Abstract %R 10.3233/JAD-170317 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Rhamnolipids, Microbial Virulence Factors, in Alzheimer's Disease. %A Andreadou, Eleni %A Pantazaki, Anastasia A %A Daniilidou, Makrina %A Tsolaki, Magda %X

Alzheimer's disease (AD) has been attributed to chronic bacterial infections. The recognition of human microbiota as a substantial contributor to health and disease is relatively recent and growing. During evolution, mammals live in a symbiotic state with myriads of microorganisms that survive at a diversity of tissue micro-surroundings. Microbes produce a plethora of secretory products [amyloids, lipopolysaccharides, virulence factors rhamnolipids (RLs), toxins, and a great number of neuroactive compounds]. The contribution of infectious microbial components to the pathophysiology of the human central nervous system including AD is considered potentially substantial, but the involvement of the RLs has never been reported. Here, RLs were isolated from serum and identified through various conventional methods including the colorimetric orcinol method, thin-layer chromatography, attenuated total reflection Fourier transform infrared (ATR-FTIR), and dot blot using antibodies against RLs. Dot blot demonstrated elevated RL levels in sera of AD patients compared to controls (p = 0.014). Moreover, ELISA showed similarly elevated RL levels in cerebrospinal fluid of both AD (0.188 versus 0.080) (p = 0.04) and mild cognitive impairment (0.188 versus 0.129) (p = 0.088) patients compared to healthy, and are well-correlated with the AD stages severity assessed using the Mini-Mental State Examination. These results provide conclusive evidence for the newly-reported implication of RLs in AD, adding it to the list of bacterial components, opening new avenues for AD investigation. Moreover, they strengthen and vindicate the divergence of research toward the exploration of bacterial involvement in AD generation and progression.

%B J Alzheimers Dis %V 59 %P 209-222 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598837?dopt=Abstract %R 10.3233/JAD-161020 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Risk Factors and Pathological Substrates Associated with Agitation/Aggression in Alzheimer's Disease: A Preliminary Study using NACC Data. %A Sennik, Simrin %A Schweizer, Tom A %A Fischer, Corinne E %A Munoz, David G %X

BACKGROUND: Neuropsychiatric symptoms are common manifestations of Alzheimer's disease (AD). A number of studies have targeted psychosis, i.e., hallucinations and delusions in AD, but few have assessed agitation/aggression in AD.

OBJECTIVE: To investigate the risk factors and pathological substrates associated with presence [A(+)] and absence [A(-)] of agitation/aggression (A) in autopsy-confirmed AD.

METHODS: Data was collected from the UDS data as of 2015 on the NACC database. Patients were stratified as intermediate (IAD) or high (HAD) pathological load of AD. Clinical diagnoses were not considered; additional pathological diagnoses were treated as variables. Analysis of data did not include a control group or corrections for multiple comparisons.

RESULTS: 1,716 patients met the eligibility criteria; 31.2% of the IAD and 47.8% of the HAD patients were A(+), indicating an association with severity of pathology (p = 0.001). Risk factors for A(+) included: age at initial visit, age at death, years of education, smoking (in females), recent cardiac events (in males), and clinical history of traumatic brain injury (TBI) (in males). A history of hypertension was not related to A(+). In terms of comorbidity, clinical diagnosis of Lewy body dementia syndrome was associated with A(+) but the association was not confirmed when pathological diagnosis based on demonstration of Lewy bodies was used as the criterion. The additional presence of phosphorylated TDP-43, but not tau pathologies, was associated with A(+)HAD. Vascular lesions, including lacunes, large arterial infarcts, and severity of atherosclerosis were negatively associated with A(+). Associated symptoms included delusions, hallucinations, and depression, but not irritability, aberrant motor behavior, sleep and night time behavioral changes, or changes in appetite and eating habits.

CONCLUSIONS: Smoking, TBI, and phosphorylated TDP-43 are associated with A(+)AD in specific groups, respectively. A(+) is directly associated with AD pathology load and inversely with vascular lesions.

%B J Alzheimers Dis %V 55 %P 1519-1528 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911311?dopt=Abstract %R 10.3233/JAD-160780 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Risk Factors for Mild Cognitive Impairment in German Primary Care Practices. %A Jacob, Louis %A Bohlken, Jens %A Kostev, Karel %X

BACKGROUND: Mild cognitive impairment (MCI) is a common mental disorder affecting around 16% of elderly people without dementia. MCI is considered an intermediate state between normal cognition and dementia.

OBJECTIVE: To analyze risk factors for the development of MCI in German primary care practices.

METHODS: In total, 3,604 MCI patients and 3,604 controls without MCI were included between January 2010 and December 2015. Several disorders potentially associated with MCI were determined. Multivariate logistic regression models were fitted with MCI as a dependent variable and other disorders as potential predictors.

RESULTS: The mean age was 75.2 years and 45.3% of patients were men. MCI development was found to be associated with 12 disorders: intracranial injury, anxiety disorder, depression, mental and behavioral disorders due to alcohol use, stroke, hyperlipidemia, obesity, hypertension, Parkinson's disease, sleep disorder, coronary heart disease, and diabetes with odds ratios ranging from 1.13 (diabetes) to 2.27 (intracranial injury).

CONCLUSION: Intracranial injury, anxiety, and depression showed the strongest association with MCI. Further analyses are needed to gain a better understanding of the MCI risk factors.

%B J Alzheimers Dis %V 56 %P 379-384 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911316?dopt=Abstract %R 10.3233/JAD-160875 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Risk Factors, Neuroanatomical Correlates, and Outcome of Neuropsychiatric Symptoms in Alzheimer's Disease. %A Poulin, Stéphane P %A Bergeron, David %A Dickerson, Bradford C %X

BACKGROUND: An integrative model of neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) is lacking.

OBJECTIVE: In this study, we investigated the risk factors, anatomy, biology, and outcomes of NPS in AD.

METHODS: 181 subjects were included from the Alzheimer's Disease Neuroimaging Study (ADNI). NPS were assessed with the Neuropsychiatric Inventory Questionnaire at baseline and 6 months. NPI >3 was used as a threshold for NPS positivity. Three NPS courses were characterized: 1) minimal/absent (negative at 0 and 6 months, n = 77); 2) fluctuating (positive only at one time point, n = 53); 3) persistent (positive at both time points, n = 51). We examined the association between NPS course and family history of dementia, personal history of psychiatric disorders, cerebrospinal fluid biomarkers, atrophy patterns, as well as longitudinal cognitive and functional measures at 12 and 24 months (MMSE, CDR-SOB, FAQ).

RESULTS: AD subjects with absent, fluctuating, or persistent NPS had similar CSF amyloid-β and tau levels. AD subjects with minimal/absent NPS had less personal history of psychiatric disorders (35%) than those with fluctuating (57%; p = 0.015) or persistent NPS (47%, not significant). At 24 months, AD subjects with persistent NPS had worse cognitive (MMSE; p = 0.05) and functional (CDR-SOB; p = 0.016) outcomes. Dorsolateral prefrontal atrophy was seen in persistent NPS, but not in fluctuating NPS.

CONCLUSIONS: Our results suggest that individuals with personal history of psychiatric disorders might be more vulnerable to develop NPS throughout the course of AD. The worst cognitive and functional outcomes associated with NPS in AD underscores the importance of monitoring NPS early in the disease course.

%B J Alzheimers Dis %V 60 %P 483-493 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869463?dopt=Abstract %R 10.3233/JAD-160767 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Risk of Mortality Associated with Antipsychotic Monotherapy and Polypharmacy Among Community-Dwelling Persons with Alzheimer's Disease. %A Koponen, Marjaana %A Taipale, Heidi %A Lavikainen, Piia %A Tanskanen, Antti %A Tiihonen, Jari %A Tolppanen, Anna-Maija %A Ahonen, Riitta %A Hartikainen, Sirpa %X

We aimed to analyze the risk of non-cancer mortality according to duration of antipsychotic use and to compare the risk associated with polypharmacy and monotherapy among community-dwellers with Alzheimer's disease (AD). The risk of mortality between most frequently used antipsychotic drugs was compared. Data from a nationwide register-based MEDALZ study that included all 70,718 community-dwellers newly diagnosed with AD during 2005-2011 in Finland was utilized. Death, excluding cancer as direct cause of death, was extracted from Causes of Death Register. Incident antipsychotic use was compared with time without antipsychotics with Cox proportional hazard models. Antipsychotic use was associated with an increased risk of mortality (adjusted hazard ratio [aHR] 1.61; 95% Confidence Interval [CI] 1.53-1.70). The absolute difference in mortality rate was 4.58 (95% CI 4.53-4.63) deaths per 100 person-years. The risk of mortality was increased from the first days of use and attenuated gradually but remained increased even after two years of use (aHR 1.30; 95% CI 1.16-1.46). Compared with nonuse, antipsychotic polypharmacy (aHR 2.88; 95% CI 2.38-3.49) was associated with an increased risk of mortality than monotherapy (aHR 1.57; 95% CI 1.49-1.66). Haloperidol was associated with higher risk of mortality (aHR 1.52; 95% CI 1.14-2.02) and quetiapine with lower risk (aHR 0.84; 95% CI 0.75-0.94) compared with risperidone. In conclusion, the findings support current treatment guidelines on having a high threshold for antipsychotic initiation among persons with AD. Antipsychotic polypharmacy and long-term use should be avoided and drug choice should be weighed against risk/benefit evidence.

%B J Alzheimers Dis %V 56 %P 107-118 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27935554?dopt=Abstract %R 10.3233/JAD-160671 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Road Less Traveled: Alternative Pathways for Action-Verb Processing in Parkinson's Disease. %A Abrevaya, Sofía %A Sedeño, Lucas %A Fitipaldi, Sol %A Pineda, David %A Lopera, Francisco %A Buritica, Omar %A Villegas, Andrés %A Bustamante, Catalina %A Gomez, Diana %A Trujillo, Natalia %A Pautassi, Ricardo %A Ibáñez, Agustín %A García, Adolfo M %X

Action verbs are critically embodied in motor brain networks. In Parkinson's disease (PD), damage to the latter compromises access to such words. However, patients are not fully incapable of processing them, as their performance is far from floor level. Here we tested the hypothesis that action-verb processing in PD may rely on alternative disembodied semantic circuits. Seventeen PD patients and 15 healthy controls listened to action verbs and nouns during functional MRI scanning. Using cluster-mass analysis with a permutation test, we assessed task-related functional connectivity considering seeds differentially engaged by action and non-action words (namely, putamen and M1 versus posterior superior temporal lobe, respectively). The putamen seed showed reduced connectivity within the basal ganglia in patients for both lexical categories. However, only action verbs recruited different cortical networks in each group. Specifically, the M1 seed exhibited more anterior connectivity for controls and more posterior connectivity for patients, with no differences in the temporal seed. Moreover, the patients' level of basal ganglia atrophy positively correlated with their reliance on M1-posterior connectivity during action-verb processing. PD patients seem to have processed action verbs via non-motor cortical networks subserving amodal semantics. Such circuits may afford alternative pathways to process words when default embodied mechanisms are disturbed. Moreover, the greater the level of basal ganglia atrophy, the greater the patients' reliance on this alternative route. Our findings offer new insights into differential neurofunctional mechanisms recruited to process action semantics in PD.

%B J Alzheimers Dis %V 55 %P 1429-1435 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27834777?dopt=Abstract %R 10.3233/JAD-160737 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Role of ADAM10 in Alzheimer's Disease. %A Yuan, Xiang-Zhen %A Sun, Sen %A Tan, Chen-Chen %A Yu, Jin-Tai %A Tan, Lan %X

As a member of the A Disintegrin And Metalloproteinase (ADAM) family, ADAM10 has been identified as the constitutive α-secretase in the process of amyloid-β protein precursor (AβPP) cleavage and plays a critical role in reducing the generation of the amyloid-β (Aβ) peptides. Recent studies have demonstrated its beneficial role in alleviating the pathologic impairment in Alzheimer's disease (AD) both in vitro and in vivo. However, the role of ADAM10 in AD and the underlying molecular mechanisms are still not well established. Increasing evidence indicates that ADAM10 not only reduces the generation of Aβ but may also affect the pathology of AD through potential mechanisms including reducing tau pathology, maintaining normal synaptic functions, and promoting hippocampal neurogenesis and the homeostasis of neuronal networks. Mechanistically, ADAM10 regulates these functions by interacting with postsynaptic substrates in brain, especially synaptic cell receptors and adhesion molecules. Furthermore, ADAM10 protein in platelets seems to be a promising biomarker for AD diagnosis. This review will summarize the role of ADAM10 in AD and highlight its functions besides its role as the α-secretase in AβPP cleavage. Meanwhile, we will discuss the therapeutic potential of ADAM10 in treating AD.

%B J Alzheimers Dis %V 58 %P 303-322 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28409746?dopt=Abstract %R 10.3233/JAD-170061 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Role of Cerebrovascular Disease on Cognitive and Functional Status and Psychosis in Severe Alzheimer's Disease. %A Kim, Julia %A Schweizer, Tom A %A Fischer, Corinne E %A Munoz, David G %X

BACKGROUND: The pathophysiology behind psychosis in patients with Alzheimer's disease (AD) remains unknown. Vascular risk factors have been recognized as an important modifier of the clinical presentation of AD.

OBJECTIVE: The purpose of our study is to investigate the mechanism through which vascular risk factors mediate psychosis and whether or not it involves cerebrovascular lesions.

METHODS: Data was provided by the National Alzheimer's Coordinating Centre. The Uniform Data Set was used to collect information on subject-reported history of vascular risk factors, clinician-reported state of cognitive performance, and presence of psychosis based on the Neuropsychiatric Inventory Questionnaire (NPI-Q). The Neuropathology Data Set was used to evaluate the presence of vascular lesions and the severity of AD pathology. Subjects with high probability of AD based on the NIA/AA Reagan criteria were included in the analysis.

RESULTS: We identified 1,459 patients with high probability of AD and corresponding NPI-Q scores. We confirmed the association between hypertension and diabetes on psychosis, specifically in delusions and the co-occurrence of delusions and hallucinations. Furthermore, the presence of white matter rarefaction based on pathological evaluation was associated with hallucinations. A history of vascular risk factors was positively associated with vascular lesions. However, vascular lesions in the presence of vascular risk factors did not increase the likelihood of psychosis. Furthermore, vascular lesions were not associated with greater cognitive or functional impairments in this group with severe AD pathology.

CONCLUSION: Vascular risk factors and vascular lesions are independently associated with psychosis in patients with severe AD. However, vascular lesions are not the mechanism through which vascular risk factors mediate psychosis.

%B J Alzheimers Dis %V 55 %P 381-389 %G eng %N 1 %R 10.3233/JAD-160506 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Role of Glutamate and NMDA Receptors in Alzheimer's Disease. %A Wang, Rui %A Reddy, P Hemachandra %X

Excitatory glutamatergic neurotransmission via N-methyl-d-aspartate receptor (NMDAR) is critical for synaptic plasticity and survival of neurons. However, excessive NMDAR activity causes excitotoxicity and promotes cell death, underlying a potential mechanism of neurodegeneration occurred in Alzheimer's disease (AD). Studies indicate that the distinct outcomes of NMDAR-mediated responses are induced by regionalized receptor activities, followed by different downstream signaling pathways. The activation of synaptic NMDARs initiates plasticity and stimulates cell survival. In contrast, the activation of extrasynaptic NMDARs promotes cell death and thus contributes to the etiology of AD, which can be blocked by an AD drug, memantine, an NMDAR antagonist that selectively blocks the function of extrasynaptic NMDARs.

%B J Alzheimers Dis %V 57 %P 1041-1048 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662322?dopt=Abstract %R 10.3233/JAD-160763 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Role of Niemann-Pick Type C Disease Mutations in Dementia. %A Cupidi, Chiara %A Frangipane, Francesca %A Gallo, Maura %A Clodomiro, Alessandra %A Colao, Rosanna %A Bernardi, Livia %A Anfossi, Maria %A Conidi, Maria Elena %A Vasso, Franca %A Curcio, Sabrina Anna Maria %A Mirabelli, Maria %A Smirne, Nicoletta %A Torchia, Giusi %A Muraca, Maria Gabriella %A Puccio, Gianfranco %A Di Lorenzo, Raffaele %A Zampieri, Stefania %A Romanello, Milena %A Dardis, Andrea %A Maletta, Raffaele Giovanni %A Bruni, Amalia Cecilia %X

BACKGROUND: Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance.

OBJECTIVE: To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus.

METHODS: We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients.

RESULTS: Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222 S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2.

CONCLUSIONS: Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.

%B J Alzheimers Dis %V 55 %P 1249-1259 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27792009?dopt=Abstract %R 10.3233/JAD-160214 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Role of Single-Subject Brain Metabolic Patterns in the Early Differential Diagnosis of Primary Progressive Aphasias and in Prediction of Progression to Dementia. %A Cerami, Chiara %A Dodich, Alessandra %A Greco, Lucia %A Iannaccone, Sandro %A Magnani, Giuseppe %A Marcone, Alessandra %A Pelagallo, Elisabetta %A Santangelo, Roberto %A Cappa, Stefano F %A Perani, Daniela %X

BACKGROUND AND OBJECTIVE: Primary progressive aphasia (PPA) is a clinical syndrome due to different neurodegenerative conditions in which an accurate early diagnosis needs to be supported by a reliable diagnostic tool at the individual level. In this study, we investigated in PPA the FDG-PET brain metabolic patterns at the single-subject level, in order to assess the case-to-case variability and its relationship with clinical-neuropsychological findings.

MATERIAL AND METHODS: 55 patients (i.e., 11 semantic variant/sv-PPA, 19 non fluent variant/nfv-PPA, 17 logopenic variant/lv-PPA, 3 slowly progressive anarthria/SPA, and 5 mixed PPA/m-PPA) were included. Clinical-neuropsychological information and FDG-PET data were acquired at baseline. A follow-up of 27.4±12.55 months evaluated the clinical progression. Brain metabolism was analyzed using an optimized and validated voxel-based SPM method at the single-subject level.

RESULTS: FDG-PET voxel-wise metabolic assessment revealed specific metabolic signatures characterizing each PPA variant at the individual level, reflecting the underlying neurodegeneration in language networks. Notably, additional dysfunctional patterns predicted clinical progression to specific dementia conditions. In the case of nfv-PPA, a metabolic pattern characterized by involvement of parietal, subcortical and brainstem structures predicted progression to a corticobasal degeneration syndrome or to progressive supranuclear palsy. lv-PPA and sv-PPA cases who progressed to Alzheimer's disease and frontotemporal dementia at the follow-up presented with extended bilateral patterns at baseline.

DISCUSSION: Our results indicate that FDG-PET voxel-wise imaging is a valid biomarker for the early differential diagnosis of PPAs and for the prediction of progression to specific dementia condition. This study supports the use of FDG-PET imaging quantitative assessment in clinical settings for a better characterization of PPA individuals and prognostic definition of possible endo-phenotypes.

%B J Alzheimers Dis %V 55 %P 183-197 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662315?dopt=Abstract %R 10.3233/JAD-160682 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Role of Suppressor of Cytokine Signaling 3 (SOCS3) in Altering Activated Microglia Phenotype in APPswe/PS1dE9 Mice. %A Iwahara, Naotoshi %A Hisahara, Shin %A Kawamata, Jun %A Matsumura, Akihiro %A Yokokawa, Kazuki %A Saito, Taro %A Fujikura, Mai %A Manabe, Tatsuo %A Suzuki, Hiromi %A Matsushita, Takashi %A Suzuki, Syuuichirou %A Shimohama, Shun %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Brain %K Cells, Cultured %K Disease Models, Animal %K Female %K Humans %K Interleukin-6 %K Lipopolysaccharides %K Male %K Mice, Inbred C57BL %K Mice, Transgenic %K Microglia %K Neurons %K Presenilin-1 %K Suppressor of Cytokine Signaling 3 Protein %K Tumor Necrosis Factor-alpha %X

In response to changes of the central nervous system environment, microglia are capable of acquiring diverse phenotypes for cytotoxic or immune regulation and resolution of injury. Alzheimer's disease (AD) pathology also induces several microglial activations, resulting in production of pro-inflammatory cytokines and reactive oxygen species or clearance of amyloid-β (Aβ) through phagocytosis. We previously demonstrated that microglial activation and increase in oxidative stress started from the middle age in APPswe/PS1dE9 mice, and hypothesized that M1 activation occurs in middle-aged AD mice by Aβ stimulation. In the present study, we analyzed in vivo expressions of pro-inflammatory cytokines (M1 microglial markers), M2 microglial markers, and suppressor of cytokine signaling (SOCS) family, and examined the microglial phenotypic profile in APPswe/PS1dE9 mice. Then we compared the in vitro gene expression patterns of Aβ- and lipopolysaccharide (LPS)-stimulated primary-cultured microglia. Microglia in APPswe/PS1dE9 mice exhibited an M1-like phenotype, expressing tumor necrosis factor α (TNFα) but not interleukin 6 (IL6). Aβ-stimulated primary-cultured microglia also expressed TNFα but not IL6, whereas LPS-stimulated primary-cultured microglia expressed both pro-inflammatory cytokines. Furthermore, both microglia in APPswe/PS1dE9 mice and Aβ-stimulated primary-cultured microglia expressed SOCS3. Reduction of SOCS3 expression in Aβ-challenged primary-cultured microglia resulted in upregulation of IL6 expression. Our findings indicate that SOCS3 suppresses complete polarization to M1 phenotype through blocking IL6 production, and Aβ-challenged primary-cultured microglia replicate the in vivo gene expression pattern of microglia in APPswe/PS1dE9 mice. Aβ may induce the M1-like phenotype through blocking of IL6 by SOCS3.

%B J Alzheimers Dis %V 55 %P 1235-1247 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27814300?dopt=Abstract %R 10.3233/JAD-160887 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Rosetta Stone for Amyloid Fibrils: The Key Role of Ring-Like Oligomers in Amyloidogenesis. %A Galzitskaya, Oxana V %A Selivanova, Olga M %X

Deeper understanding of processes of protein misfolding, aggregation, formation of oligomers, protofibrils, and fibrils is crucial for the development of future medicine in treatment of amyloid-related diseases. While numerous reports illuminate the field, the above processes are extremely complex, as they depend on many varying parameters, such as the peptide concentration, temperature, pH, presence of metal ions, lipids, and organic solvents. Different mechanisms of amyloid fibril formation have been proposed, but the process of the oligomer-to-fibril transition is the least agreed upon. Our studies of a number of amyloidogenic proteins and peptides (insulin, Aβ peptides, the Bgl2 protein from the yeast cell wall), as well as their amyloidogenic fragments, have allowed us to propose a model of the fibril structure generation. We have found that the main building block of fibrils of any morphology is a ring-like oligomer. The varying models of interaction of ring oligomers with each other revealed in our studies make it possible to explain their polymorphism. Crucially, the amino acid sequence determines the oligomer structure for the given protein/peptide.

%B J Alzheimers Dis %V 59 %P 785-795 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671122?dopt=Abstract %R 10.3233/JAD-170230 %0 Journal Article %J J Alzheimers Dis %D 2017 %T S-Adenosylmethionine Attenuates Oxidative Stress and Neuroinflammation Induced by Amyloid-β Through Modulation of Glutathione Metabolism. %A Li, Qian %A Cui, Jing %A Fang, Chen %A Liu, Min %A Min, Guowen %A Li, Liang %X

Oxidative stress and neuroinflammation are mainly involved in the pathogenic mechanisms of Alzheimer's disease (AD). Amyloid-β (Aβ), the main component of senile plaques, is a kind of strong inducer of oxidative stress. Glutathione is an endogenous antioxidant protecting cells from oxidative injury. S-adenosylmethionine (SAM) produced in the methionine cycle is the primary methyl donor and the precursor of glutathione. In this study, the Aβ intrahippocampal injection rat model and cultured SH-SY5Y cells were used to explore the neuroprotective effect of SAM. We found that SAM could protect cells against Aβ-induced cellular injury by inhibition of oxidative stress and neuroinflammation. SAM administration could increase the endogenous antioxidant glutathione and potentiate the antioxidant enzymes activities. SAM might act as an antioxidant and be a potential candidate therapy for AD patients.

%B J Alzheimers Dis %V 58 %P 549-558 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453493?dopt=Abstract %R 10.3233/JAD-170177 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Is Salivary Chromogranin A a Valid Psychological Stress Biomarker During Sensory Stimulation in People with Advanced Dementia? %A Valdiglesias, Vanessa %A Maseda, Ana %A Lorenzo-López, Laura %A Pásaro, Eduardo %A Millán-Calenti, José C %A Laffon, Blanca %X

Salivary chromogranin A (sCgA) is gaining attention as a biomarker of psychological stress. The objective of this work was to determine whether individualized music intervention and multisensory stimulation environment (MSSE) in a Snoezelen room produce changes in sCgA in severely demented older patients, and to assess the possible existence of differences in sCgA levels between the two types of interventions. Older adults with severe dementia (n = 22) were randomly assigned to two intervention groups. They participated in MSSE or individualized music interventions in 30-min weekly sessions for 16 weeks. Levels of sCgA were evaluated before and after a session, or 30-min interval, at four different time points: before starting the trial, in the middle and end of the intervention period, and two months later. Comparison of sCgA values obtained after each session with those obtained before (or at the same hour in before trial and follow-up samplings) showed no significant differences either in the individualized music or in the MSSE group at any sampling time. Comparison between the two types of interventions, both before and after each session, in the four sampling times, did not produce any significant difference either. Furthermore, no significant correlation was obtained between agitation, anxiety, cognitive function, and dementia severity with sCgA levels. In conclusion, despite beneficial effects of both individualized music and MSSE interventions being previously reported on neuropsychiatric outcomes for older patients with dementia, sCgA seems to not be a good indicator of these benefits.

%B J Alzheimers Dis %V 55 %P 1509-1517 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27886013?dopt=Abstract %R 10.3233/JAD-160893 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sample Size Estimation for Alzheimer's Disease Trials from Japanese ADNI Serial Magnetic Resonance Imaging. %A Fujishima, Motonobu %A Kawaguchi, Atsushi %A Maikusa, Norihide %A Kuwano, Ryozo %A Iwatsubo, Takeshi %A Matsuda, Hiroshi %X

BACKGROUND: Little is known about the sample sizes required for clinical trials of Alzheimer's disease (AD)-modifying treatments using atrophy measures from serial brain magnetic resonance imaging (MRI) in the Japanese population.

OBJECTIVE: The primary objective of the present study was to estimate how large a sample size would be needed for future clinical trials for AD-modifying treatments in Japan using atrophy measures of the brain as a surrogate biomarker.

METHODS: Sample sizes were estimated from the rates of change of the whole brain and hippocampus by the k-means normalized boundary shift integral (KN-BSI) and cognitive measures using the data of 537 Japanese Alzheimer's Neuroimaging Initiative (J-ADNI) participants with a linear mixed-effects model. We also examined the potential use of ApoE status as a trial enrichment strategy.

RESULTS: The hippocampal atrophy rate required smaller sample sizes than cognitive measures of AD and mild cognitive impairment (MCI). Inclusion of ApoE status reduced sample sizes for AD and MCI patients in the atrophy measures.

CONCLUSION: These results show the potential use of longitudinal hippocampal atrophy measurement using automated image analysis as a progression biomarker and ApoE status as a trial enrichment strategy in a clinical trial of AD-modifying treatment in Japanese people.

%B J Alzheimers Dis %V 56 %P 75-88 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911297?dopt=Abstract %R 10.3233/JAD-160621 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Screening for Alzheimer's Disease: Cognitive Impairment in Self-Referred and Memory Clinic-Referred Patients. %A Kirsebom, Bjørn-Eivind %A Espenes, Ragna %A Waterloo, Knut %A Hessen, Erik %A Johnsen, Stein Harald %A Bråthen, Geir %A Aarsland, Dag %A Fladby, Tormod %X

BACKGROUND: Cognitive assessment is essential in tracking disease progression in AD. Presently, cohorts including preclinical at-risk participants are recruited by different means, which may bias cognitive and clinical features. We compared recruitment strategies to levels of cognitive functioning.

OBJECTIVE: We investigate recruitment source biases in self-referred and memory clinic-referred patient cohorts to reveal potential differences in cognitive performance and demographics among at-risk participants.

METHODS: We included 431 participants 40-80 years old. Participants were classified as controls (n = 132) or symptom group (n = 299). The symptom group comprised of subjective cognitive decline (SCD, n = 163) and mild cognitive impairment (MCI, n = 136). We compared cognitive performance and demographics in memory clinic-referrals (n = 86) to self-referred participants responding to advertisements and news bulletins (n = 179). Participants recruited by other means were excluded from analysis (n = 34).

RESULTS: At symptom group level, we found significant reductions in cognitive performance in memory clinic-referrals compared to self-referrals. However, here reductions were only found within the MCI group. We found no differences in cognitive performance due to recruitment within the SCD group. The MCI group was significantly impaired compared to controls on all measures. Significant reductions in learning, and executive functions were also found for the SCD group.

CONCLUSION: Regardless of recruitment method, both the SCD and MCI groups showed reductions in cognitive performance compared to controls. We found differences in cognitive impairment for memory clinic-referrals compared to self-referrals only within the MCI group, SCD-cases being equally affected irrespective of referral type.

%B J Alzheimers Dis %V 60 %P 1621-1631 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984581?dopt=Abstract %R 10.3233/JAD-170385 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Screening for Mild Cognitive Impairment and Dementia with Automated, Anonymous Online and Telephone Cognitive Self-Tests. %A Van Mierlo, Lisa D %A Wouters, Hans %A Sikkes, Sietske A M %A van der Flier, Wiesje M %A Prins, Niels D %A Bremer, Jonne A E %A Koene, Teddy %A Van Hout, Hein P J %X

BACKGROUND: Many older people worry about cognitive decline. Early cognitive screening in an anonymous and easily accessible manner may reassure older people who are unnecessarily worried about normal cognitive aging while it may also expedite help seeking in case of suspicious cognitive decline.

OBJECTIVE: To develop and validate online and telephone-based automated self-tests of cognitive function.

METHODS: We examined the feasibility and validity of the self-tests in a prospective study of 117 participants of whom 34 had subjective cognitive decline (SCD), 30 had mild cognitive impairment (MCI), and 53 had dementia. The ability of these self-tests to accurately distinguish MCI and dementia from SCD was examined with ROC curves. Convergent validity was examined by calculating rank correlations between the self-tests and neuropsychological tests.

RESULTS: Both the online and telephone cognitive self-tests were feasible, because the majority of participants (86% and 80%, respectively) were able to complete them. The online self-test had adequate diagnostic accuracy in the screening for MCI and dementia versus SCD with an Area under the Curve (AUC) of 0.86 (95% CI: 0.78-0.93). The AUC of the MMSE was 0.82 (95% CI: 0.74-0.89). By contrast, the telephone self-test had lower diagnostic accuracy (AUC = 0.75, 95% CI: 0.64-0.86). Both self-tests had good convergent validity as demonstrated by moderate to strong rank correlations with neuropsychological tests.

CONCLUSION: We demonstrated good diagnostic accuracy and convergent validity for the online self-test of cognitive function. It is therefore a promising tool in the screening for MCI and dementia.

%B J Alzheimers Dis %V 56 %P 249-259 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911296?dopt=Abstract %R 10.3233/JAD-160566 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Secular Trends in the Incidence of Dementia in a Multi-Ethnic Community. %A Noble, James M %A Schupf, Nicole %A Manly, Jennifer J %A Andrews, Howard %A Tang, Ming-Xin %A Mayeux, Richard %X

BACKGROUND: Determination of secular trends in cognitive aging is important for prioritization of resources, services, and research in aging populations. Prior studies have identified declining dementia incidence associated with changes in cardiovascular risk factors and increased educational attainment. However, few studies have examined these factors in multi-ethnic cohorts.

OBJECTIVE: To identify secular trends in the incidence rate of dementia in an elderly population.

METHODS: Participants in this study were drawn from the Washington Heights-Inwood Columbia Aging Project, a multi-ethnic cohort study of northern Manhattan residents aged 65 years and older. Cox proportional hazards models were used to examine differences in the incidence of dementia in cohorts recruited in 1992 and 1999, with age at dementia or age at last follow-up visit as the "time-to-event" variable.

RESULTS: Overall, there was a 41% reduction in the hazard ratio for dementia among participants in the 1999 cohort compared with those in the 1992 cohort, adjusting for age, sex, race, and baseline memory complaints (HR = 0.59). The reduction in incidence was greatest among non-Hispanic Whites and African-Americans and lowest among Hispanic participants (HRs = 0.60, 0.52 and 0.64, respectively), and was associated with increases in level of educational attainment, especially among African-Americans. Reduction in incidence of dementia was also greater among persons 75 years or older than among younger participants (HR = 0.52 versus HR = 0.69).

CONCLUSIONS: Our results support previous findings that secular trends in dementia incidence are changing, including in aging minority populations.

%B J Alzheimers Dis %V 60 %P 1065-1075 %8 2017 Oct 03 %G eng %N 3 %R 10.3233/JAD-170300 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Selenium Levels in Serum, Red Blood Cells, and Cerebrospinal Fluid of Alzheimer's Disease Patients: A Report from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL). %A Cardoso, Bárbara R %A Hare, Dominic J %A Bush, Ashley I %A Li, Qiao-Xin %A Fowler, Christopher J %A Masters, Colin L %A Martins, Ralph N %A Ganio, Katherine %A Lothian, Amber %A Mukherjee, Soumya %A Kapp, Eugene A %A Roberts, Blaine R %X

Selenium (Se) protects cells against oxidative stress damage through a range of bioactive selenoproteins. Increased oxidative stress is a prominent feature of Alzheimer's disease (AD), and previous studies have shown that Se deficiency is associated with age-related cognitive decline. In this study, we assessed Se status in different biofluids from a subgroup of participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. As Se in humans can either be an active component of selenoproteins or inactive via non-specific incorporation into other proteins, we used both size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and tandem mass spectrometry to characterize selenoproteins in serum. We observed no differences in total Se concentration in serum or cerebrospinal fluid of AD subjects compared to mildly cognitively impairment patients and healthy controls. However, Se levels in erythrocytes were decreased in AD compared to controls. SEC-ICP-MS analysis revealed a dominant Se-containing fraction. This fraction was subjected to standard protein purification and a bottom-up proteomics approach to confirm that the abundant Se in the fraction was due, in part, to selenoprotein P. The lack of change in the Se level is at odds with our previous observations in a Brazilian population deficient in Se, and we attribute this to the Australian cohort being Se-replete.

%B J Alzheimers Dis %V 57 %P 183-193 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222503?dopt=Abstract %R 10.3233/JAD-160622 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Selenomethionine Attenuates the Amyloid-β Level by Both Inhibiting Amyloid-β Production and Modulating Autophagy in Neuron-2a/AβPPswe Cells. %A Zhang, Zhong-Hao %A Wu, Qiu-Yan %A Chen, Chen %A Zheng, Rui %A Chen, Yao %A Liu, Qiong %A Ni, Jia-Zuan %A Song, Guo-Li %X

Alzheimer's disease (AD) is a complex and progressive neurological disorder, and amyloid-β (Aβ) has been recognized as the major cause of AD. Inhibiting Aβ production and/or enhancing the clearance of Aβ to reduce its levels are still the effective therapeutic strategies pursued in anti-AD research. In previous studies, we have reported that selenomethionine (Se-Met), a major form of selenium in animals and humans with significant antioxidant capacity, can reduce both amyloid-β (Aβ) deposition and tau hyperphosphorylation in a triple transgenic mouse model of AD. In this study, a Se-Met treatment significantly decreased the Aβ levels in Neuron-2a/AβPPswe (N2asw) cells, and the anti-amyloid effect of Se-Met was attributed to its ability to inhibit Aβ generation by suppressing the activity of BACE1. Furthermore, both the LC3-II/LC3-I ratio and the number of LC3-positive puncta were significantly decreased in Se-Met-treated cells, suggesting that Se-Met also promoted Aβ clearance by modulating the autophagy pathway. Subsequently, Se-Met inhibited the initiation of autophagy through the AKT-mTOR-p70S6K signaling pathway and enhanced autophagic turnover by promoting autophagosome-lysosome fusion and autophagic clearance. Our results further highlight the potential therapeutic effects of Se-Met on AD.

%B J Alzheimers Dis %V 59 %P 591-602 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671121?dopt=Abstract %R 10.3233/JAD-170216 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Selenoprotein S Reduces Endoplasmic Reticulum Stress-Induced Phosphorylation of Tau: Potential Role in Selenate Mitigation of Tau Pathology. %A Rueli, Rachel H L H %A Torres, Daniel J %A Dewing, Andrea S T %A Kiyohara, Arlene C %A Barayuga, Stephanie M %A Bellinger, Miyoko T %A Uyehara-Lock, Jane H %A White, Lon R %A Moreira, Paula I %A Berry, Marla J %A Perry, George %A Bellinger, Frederick P %X

Previous studies demonstrated that selenium in the form of sodium selenate reduces neurofibrillary tangle formation in Alzheimer's disease models. Hyperphosphorylation of tau, which leads to formation of neurofibrillary tangles in Alzheimer's disease, is increased by endoplasmic reticulum (ER) stress. Selenoprotein S (SelS) is part of an ER membrane complex that removes misfolded proteins from the ER as a means to reduce ER stress. Selenate, as with other forms of selenium, will increase selenoprotein expression. We therefore proposed that increased SelS expression by selenate would contribute to the beneficial actions of selenate in Alzheimer's disease. SelS expression increased with ER stress and decreased under conditions of elevated glucose concentrations in the SH-SY5Y neuronal cell line. Reducing expression of SelS with siRNA promoted cell death in response to ER stress. Selenate increased SelS expression, which significantly correlated with decreased tau phosphorylation. Restricting SelS expression during ER stress conditions increased tau phosphorylation, and also promoted aggregation of phosphorylated tau in neurites and soma. In human postmortem brain, SelS expression coincided with neurofibrillary tangles, but not with amyloid-β plaques. These results indicate that selenate can alter phosphorylation of tau by increasing expression of SelS in Alzheimer's disease and potentially other neurodegenerative disorders.

%B J Alzheimers Dis %V 55 %P 749-762 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802219?dopt=Abstract %R 10.3233/JAD-151208 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Self-Consciousness Deficits in Alzheimer's Disease and Frontotemporal Dementia. %A Arroyo-Anlló, Eva Ma %A Bouston, Adèle Turpin %A Fargeau, Marie-Noëlle %A Orgaz Baz, Begõna %A Gil, Roger %X

Self-consciousness (SC) is multifaceted and considered to be the consciousness of one's own mental states. The main aim of this paper is to compare SC in patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Three groups (control and patient groups) of 23 subjects each were assessed using an SC questionnaire. Both types of dementia clearly induce an alteration of SC. The bvFTD group showed a greater impairment in SC than the AD and control groups. The SC score was strongly associated with frontal functions. The most significantly impaired SC aspects in the bvFTD group were Anosognosia, Introspection, and Moral Judgments. For the AD group, the significantly impaired aspects of SC were Anosognosia and Prospective Memory. The differences in SC between the AD and bvFTD groups were essentially centered on the Anosognosia, Moral Judgments, and Introspection aspects, which were highly impaired in the bvFTD patients. This suggests that SC is related to orbito-frontal functioning and thus, to the default mode network.

%B J Alzheimers Dis %V 55 %P 1437-1443 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858712?dopt=Abstract %R 10.3233/JAD-160770 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sembragiline in Moderate Alzheimer's Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD). %A Nave, Stephane %A Doody, Rachelle S %A Boada, Merce %A Grimmer, Timo %A Savola, Juha-Matti %A Delmar, Paul %A Pauly-Evers, Meike %A Nikolcheva, Tania %A Czech, Christian %A Borroni, Edilio %A Ricci, Benedicte %A Dukart, Juergen %A Mannino, Marie %A Carey, Tracie %A Moran, Emma %A Gilaberte, Inma %A Muelhardt, Nicoletta Milani %A Gerlach, Irene %A Santarelli, Luca %A Ostrowitzki, Susanne %A Fontoura, Paulo %X

BACKGROUND: Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer's disease (AD).

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD.

METHODS: In this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13-20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks.

RESULTS: No differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was - 0.15 (p = 0.865) and 0.90 (p = 0.312) for 1 and 5 mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1 mg and 5 mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p = 0.051) and 1.89 (p = 0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: - 2.80 (p = 0.014; 1 mg) and - 2.64 (p = 0.019; 5 mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median).

CONCLUSIONS: This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline.

%B J Alzheimers Dis %V 58 %P 1217-1228 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550255?dopt=Abstract %R 10.3233/JAD-161309 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sensing of Alzheimer's Disease and Multiple Sclerosis Using Nano-Bio Interfaces. %A Hajipour, Mohammad Javad %A Ghasemi, Forough %A Aghaverdi, Haniyeh %A Raoufi, Mohammad %A Linne, Uwe %A Atyabi, Fatemeh %A Nabipour, Iraj %A Azhdarzadeh, Morteza %A Derakhshankhah, Hossein %A Lotfabadi, Alireza %A Bargahi, Afshar %A Alekhamis, Zahra %A Aghaie, Afsaneh %A Hashemi, Ehsan %A Tafakhori, Abbas %A Aghamollaii, Vajiheh %A Mashhadi, Marzie Maserat %A Sheibani, Sara %A Vali, Hojatollah %A Mahmoudi, Morteza %X

It is well understood that patients with different diseases may have a variety of specific proteins (e.g., type, amount, and configuration) in their plasmas. When nanoparticles (NPs) are exposed to these plasmas, the resulting coronas may incorporate some of the disease-specific proteins. Using gold (Au) NPs with different surface properties and corona composition, we have developed a colorimetric sensor array for the discrimination and detection of two neurodegenerative diseases, Alzheimer's disease (AD) and multiple sclerosis (MS). Applying a variety of techniques, including UV-visible spectra, array response analyses and liquid chromatography-tandem mass spectrometry, we found the corona-NP complexes, obtained from different human serums, had distinct protein composition, including some specific proteins that are known as AD and MS biomarkers. The array responses, analyzed by chemometrics and statistical methods, demonstrate promising capabilities of the sensor to unambiguously identify and discriminate AD and MS. The developed sensor array might enable a simple, inexpensive and rapid detection/discrimination of neurodegenerative diseases.

%B J Alzheimers Dis %V 59 %P 1187-1202 %G eng %N 4 %R 10.3233/JAD-160206 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Serum SHBG Levels are not Associated with Longitudinal Cognitive Decline in Mild Cognitive Impairment. %A Lin, Katherine Amy %A Rundel, Colin %A Doraiswamy, P Murali %X

BACKGROUND: Prior studies have noted gender differences in cognition, imaging, and pathological markers in mild cognitive impairment (MCI) subjects. Sex hormone-binding globulin (SHBG), a major controlling factor in the proportion of bioavailable versus bound testosterone and estrogen, has been proposed to contribute to links between hormones and dementia, but has not yet been investigated fully in a prospective biomarker trial.

OBJECTIVE: This study examined whether, among subjects with MCI, SHBG levels predict future rate of cognitive decline.

METHODS: We examine the effect of gender on cognitive decline and factors modulating potential gender differences in 378 MCI subjects (134 females, 244 males) in the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1), followed for up to 8 years (mean ± SE, 4.0 ± 0.1 years). Cognition was assessed using the ADAS-cog-11. Multivariate models examined the effect of gender covarying for age, ApoE4, baseline cognition, years of education, and SHBG levels.

RESULTS: MCI women declined significantly faster than men in cognition over the follow up period. Baseline SHBG levels differed significantly between men and women (p < 0.0001), and by age in men, but not by ApoE4 status. In the multivariate models, SHBG levels were not a significant predictor of cognitive decline in men or women but ApoE4 status, baseline cognition, years of education, and female gender were.

CONCLUSION: SHBG levels did not influence the rate of cognitive decline in MCI. Further studies to confirm these findings and uncover other potential mechanisms of gender differences in the risk for AD may be warranted.

%B J Alzheimers Dis %V 55 %P 1123-1130 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767986?dopt=Abstract %R 10.3233/JAD-160513 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Severity of Depression Impacts Imminent Conversion from Mild Cognitive Impairment to Alzheimer's Disease. %A Defrancesco, Michaela %A Marksteiner, Josef %A Kemmler, Georg %A Fleischhacker, Walter Wolfgang %A Blasko, Imrich %A Deisenhammer, Eberhard A %X

BACKGROUND: Mild cognitive impairment (MCI) has been suggested to represent a prodromal stage of dementia and to confer a high risk for conversion to dementia Alzheimer's type (DAT).

OBJECTIVES: In this study, we examined the predictive value of depressive symptoms and neuropsychological variables on conversion of MCI to DAT.

METHODS: Neuropsychological and clinical follow-up data of 260 MCI patients seen at the Psychiatric Memory Clinic of the Medical University of Innsbruck between 2005 and 2015 were analyzed retrospectively. Depression was assessed using the Geriatric Depression Scale (GDS). Potential predictors of conversion from MCI to DAT were analyzed by logistic regression analyses and additional survival-analytic methods.

RESULTS: Of the 260 patients (mean age 71.5±7.7 years), 83 (32%) converted to DAT within a mean follow-up time of 3.2±2.2 years and estimated one-year conversion rate of 10.1%. The univariate analysis showed with few exceptions (gender, use of antidepressants, low GDS score) group differences at baseline in patients converted to DAT compared to stable MCI patients. Logistic regression analysis as well as survival analysis revealed moderate to severe depression together with higher age and specific cognitive deficits as predictors of conversion from MCI to DAT.

CONCLUSION: Our results support the predictive value of different neuropsychological measures on the progression of DAT. In addition, we found a strong negative influence of depression on conversion to DAT in MCI patients. These results emphasize the importance of assessing depressive symptoms in the early stages of DAT when evaluating the conversion from MCI to DAT.

%B J Alzheimers Dis %V 59 %P 1439-1448 %G eng %N 4 %R 10.3233/JAD-161135 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sex Difference in Aerobic Exercise Efficacy to Improve Cognition in Older Adults with Vascular Cognitive Impairment: Secondary Analysis of a Randomized Controlled Trial. %A Barha, Cindy K %A Hsiung, Ging-Yuek R %A Best, John R %A Davis, Jennifer C %A Eng, Janice J %A Jacova, Claudia %A Lee, Philip E %A Munkacsy, Michelle %A Cheung, Winnie %A Liu-Ambrose, Teresa %X

Aerobic training (AT) is a promising, non-pharmacological intervention to mitigate the deleterious effects of aging and disease on brain health. However, a large amount of variation exists in its efficacy. This is a secondary analysis of a randomized controlled trial of AT in 71 older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Specifically, we investigated: 1) whether sex moderates the relationship between AT and executive functions, and 2) the role of brain derived neurotrophic factor (BDNF) and gains in functional fitness capacity. Older adults were randomly assigned to either 6-month, thrice-weekly AT or to usual care plus education (CON). At baseline, trial completion, and 6-month follow-up, executive functions were assessed with the Trail Making Test (A & B), verbal digits forward and backward test, and the Stroop Test. Functional fitness capacity was assessed with the 6-Minute Walk Test. Compared with CON, AT significantly improved Trail Making Test performance in females but not males, an effect that was retained at follow-up. AT significantly increased BDNF levels in females but decreased levels in males. On the other hand, AT led to significant gains in functional fitness capacity in males only. This study provides evidence that sex differences exist in AT efficacy on brain health as well as in the biological mechanisms subserving AT.

%B J Alzheimers Dis %V 60 %P 1397-1410 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036816?dopt=Abstract %R 10.3233/JAD-170221 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sex Differences in the Psychophysical Response to Contact Heat in Moderate Cognitive Impairment Alzheimer's Disease: A Cross-Sectional Brief Report. %A Cowan, Ronald L %A Beach, Paul A %A Atalla, Sebastian W %A Dietrich, Mary S %A Bruehl, Stephen P %A Deng, Jie %A Wang, Jinjiao %A Newhouse, Paul A %A Gore, John C %A Monroe, Todd B %X

BACKGROUND: People with Alzheimer's disease (AD) report pain less frequently and receive less pain medication than people without AD. Recent studies have begun to elucidate how pain may be altered in those with AD. However, potential sex differences in pain responsiveness have never been explored in these patients. It is unclear whether sex differences found in prior studies of healthy young and older individuals extend to people with AD.

OBJECTIVE: The purpose of this study was to examine sex differences in the psychophysical response to experimental thermal pain in people with AD.

METHODS: Cross-sectional analysis of 14 male and 14 female age-matched (≥65 years of age, median = 74) and AD severity-matched (Mini-Mental State Exam score <24, median = 16) communicative people who completed thermal psychophysics.

RESULTS: There was a statistically significant main effect of sex for both temperature and unpleasantness ratings that persisted after controlling for average and current pain (mixed-effects general liner model: temperature: p = 0.004, unpleasantness: p < 0.001). Females reported sensing mild pain and moderate pain percepts at markedly lower temperatures than did males (mild: Cohen's d = 0.72, p = 0.051, moderate: Cohen's d = 0.80, p = 0.036). By contrast, males rated mild and moderate thermal pain stimuli as more unpleasant than did females (mild: Cohen's d = 0.80, p = 0.072, moderate: Cohen's d = 1.32, p = 0.006). There were no statistically significant correlations of temperature with perceived unpleasantness for mild or moderate pain (rs = 0.29 and rs = 0.20 respectively, p > 0.05).

CONCLUSIONS: Results suggest experimental pain-related sex differences persist in older adults with AD in a different manner than those previously demonstrated in cognitively intact older adults. These findings could potentially aid in developing targeted pain management approaches in this vulnerable population. Further studies are warranted to replicate the findings from this pilot work.

%B J Alzheimers Dis %V 60 %P 1633-1640 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28968238?dopt=Abstract %R 10.3233/JAD-170532 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sex Impact on Tau-Aggregation and Postsynaptic Protein Levels in the P301L Mouse Model of Tauopathy. %A Buccarello, Lucia %A Grignaschi, Giuliano %A Castaldo, Anna Maria %A Di Giancamillo, Alessia %A Domeneghini, Cinzia %A Melcangi, Roberto Cosimo %A Borsello, Tiziana %X

P301L transgenic (tg) mice well mimic features of human tauopathies and provide a good model for investigating the role of tau in neurodegenerative events. We here analyzed the possible interactions among phosphorylation of tau (p-tau), spine injury, neuronal death, and sex in the P301L mouse model of tauopathy. When compared to control mice (ctr), P301L transgenic mice (tg) presented a lower body weight, reduced survival rate, hyperphosphorylated tau, spine injury, and neuronal loss in both cerebral cortex and hippocampus at 15 months of age. Importantly, we found that pathological features were more pronounced in female than male tg mice. Recent reports underline that tau may be localized within both pre- and post-synaptic compartments, suggesting that it may possibly induce or contribute to synaptic dysfunction. Therefore, we focused our attention on tau localization at dendritic spines. We detected high levels of both tau and p-tau in dendritic spine of P301L transgenic mice. In addition, p-tau correlated with a significant reduction of post-synaptic markers, such as GluN2A, GluN2B, GluA1, GluA2, Drebrin, and PSD-95, in P301L mice. The p-tau levels are higher in female than in male mice, and the increased p-tau was consistent with a proportional decrease in the post-synaptic marker levels analyzed. The P301L-tg females showed a more severe synaptopathy compared to males. Future investigations on the postsynaptic role of p-tau will be necessary to understand its toxic effects and provide insights into new therapeutic targets for maintaining spine integrity, highlighting the importance of tau toxicity as well as the impact of sex on tau-pathology.

%B J Alzheimers Dis %V 56 %P 1279-1292 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157099?dopt=Abstract %R 10.3233/JAD-161087 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sex-Dependent Associations of Serum Uric Acid with Brain Function During Aging. %A Kueider, Alexandra M %A An, Yang %A Tanaka, Toshiko %A Kitner-Triolo, Melissa H %A Studenski, Stephanie %A Ferrucci, Luigi %A Thambisetty, Madhav %X

Serum uric acid (SUA) is an abundant natural antioxidant capable of reducing cellular oxidation, a major cause of neurodegenerative disease. In line with this, SUA levels are lower in Alzheimer's disease; however, the association between SUA and cognition remains unclear. Results from studies examining the effects of SUA on cognition may be difficult to interpret in the context of normal versus pathological aging. This study examined sex-specific associations of baseline SUA with cognition during aging. Data from dementia-free participants initially aged 26-99 (N = 1,451) recruited for the Baltimore Longitudinal Study of Aging (BLSA), were used in the current analyses. SUA was assessed using blood samples collected during research visits. Cognition was measured using five composite scores (verbal memory, attention, executive function, language, and visuospatial ability). At the first study visit, compared with women, men were older, more likely to be White, had more years of education, higher baseline SUA levels, and higher cardiovascular risk scores. Higher baseline SUA was associated with attenuated declines in attention (β= 0.006; p = 0.03) and visuospatial abilities (β= 0.007; p = 0.01) in men. There was a trend to suggest higher baseline SUA in men was associated with attenuated declines in language, but this finding did not reach statistical significance (p = 0.09). There were no significant findings with SUA and cognition in women. In this sample of cognitively healthy, community-dwelling adults, we found that higher SUA levels at baseline were associated with attenuated declines in attention and visuospatial abilities in men. SUA was not associated with cognition or change in cognition over time in women.

%B J Alzheimers Dis %V 60 %P 699-706 %8 2017 %G eng %N 2 %R 10.3233/JAD-170287 %0 Journal Article %J J Alzheimers Dis %D 2017 %T SH2B1 is Involved in the Accumulation of Amyloid-β42 in Alzheimer's Disease. %A Shen, Yijun %A Xia, Yiling %A Meng, Shiquan %A Lim, Nastasia K H %A Wang, Wenan %A Huang, Fude %X

Alzheimer's disease (AD) is characterized by deficits in learning and memory abilities, as well as pathological changes of amyloid-β (Aβ) plaque and neurofibrillary tangle formation in the brain. Insulin has been identified as a modulator of the neuronal pathways involved in learning and memory, and is also implicated as a modulator of Aβ and tau metabolism. Disrupted insulin signaling pathways are evident in AD patients and it is understood that type 2 diabetes can increase the risk of developing AD, suggesting a possible link between metabolic disorders and neurodegeneration. SH2B1 is a key protein in the insulin signaling pathway involved in regulating the activity of the insulin receptor. To further identify the role of the insulin signaling pathway in the pathology of AD, SH2B (dSH2B homologue in flies) in neurons was partially knocked out or overexpressed in an AD Drosophila model expressing Aβ42. Partial knockout of neuronal SH2B in the Aβ42-expressing Drosophila had a detrimental effect on mobility and neurotransmission, and increased levels and intraneuronal accumulation of Aβ42, as assessed by ELISA and immunostaining. Alternatively, partial overexpression of neuronal SH2B in the Aβ42-expressing Drosophila improved lifespan, mobility, and neurotransmission, as well as decreased levels and intraneuronal accumulation of Aβ42. Thus, SH2B1 may be an upstream modulator of Aβ metabolism, acting to inhibit Aβ accumulation, and has a role in the pathogenesis of AD. SH2B1 may therefore have potential as a therapeutic target for this common form of dementia.

%B J Alzheimers Dis %V 55 %P 835-847 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802221?dopt=Abstract %R 10.3233/JAD-160233 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Shape-Attributes of Brain Structures as Biomarkers for Alzheimer's Disease. %A Glozman, Tanya %A Solomon, Justin %A Pestilli, Franco %A Guibas, Leonidas %X

We describe a fully automatic framework for classification of two types of dementia based on the differences in the shape of brain structures. We consider Alzheimer's disease (AD), mild cognitive impairment of individuals who converted to AD within 18 months (MCIc), and normal controls (NC). Our approach uses statistical learning and a feature space consisting of projection-based shape descriptors, allowing for canonical representation of brain regions. Our framework automatically identifies the structures most affected by the disease. We evaluate our results by comparing to other methods using a standardized data set of 375 adults available from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Our framework is sensitive to identifying the onset of Alzheimer's disease, achieving up to 88.13% accuracy in classifying MCIc versus NC, outperforming previous methods.

%B J Alzheimers Dis %V 56 %P 287-295 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911322?dopt=Abstract %R 10.3233/JAD-160900 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Shear-Induced Amyloid Formation in the Brain: II. An Experimental System for Monitoring Amyloid Shear Processes and Investigating Potential Spinal Tap Problems. %A Trumbore, Conrad N %X

Liquid sheared amyloid-β (Aβ) initiates amyloid cascade reactions, producing unstable, potentially toxic oligomers. There is a need for new analytical tools with which to study these oligomers. A very small bore capillary flow system is proposed as a tool for studying the effects of liquid shear in amyloid research. This simple system consists of injecting a short cylindrical liquid sample plug containing dissolved amyloid into a liquid mobile phase flowing through an empty, very small internal diameter capillary tube. For liquid samples containing a single protein sample, under conditions in which there is laminar flow and limited sample protein molecular diffusion, chromatograms monitoring the optical protein absorbance of capillary effluent contain either one or two peaks, depending on the mobile phase flow rate. By controlling the sample diffusion times through changes in flow rate and/or capillary diameter, this tool can be used to generate aliquot samples with precise, reproducible amounts of shear for exploring the effects of variable shear on amyloid systems. The tool can be used for producing in-capillary stopped flow spectra of shear-stressed Aβ monomers as well as for kinetic studies of Aβ dimer- and oligomer-forming reactions between shear stressed Aβ monomers. Many other experiments are suggested using this experimental tool for studying the effects of shear on different Aβ and other amyloid systems, including testing for potentially serious amyloid sampling errors in spinal tap quantitative analysis. The technique has potential as both a laboratory research and a clinical tool.

%B J Alzheimers Dis %V 59 %P 543-557 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671126?dopt=Abstract %R 10.3233/JAD-170259 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Short-Term Response is not Predictive of Long-Term Response to Acetylcholinesterase Inhibitors in Old Age Subjects with Alzheimer's Disease: A "Real World" Study. %A Boccardi, Virginia %A Baroni, Marta %A Smirne, Nicoletta %A Clodomiro, Alessandra %A Ercolani, Sara %A Longo, Annalisa %A Ruggiero, Carmelinda %A Bruni, Amalia C %A Mecocci, Patrizia %X

BACKGROUND: Most of clinical guidelines recommend discontinuing treatment with cholinesterase inhibitors (ChEIs) in patients with Alzheimer's disease (AD) who do not show an initial response to therapy as evaluated with the Mini-Mental State Examination (MMSE) scale. However, understanding the relationship between the initial response to ChEI treatment and the subsequent course of the disease is extremely important in clinical practice, but evidence is limited, particularly in the old-old population.

OBJECTIVE: We aimed at investigating the relationship between short-term and long-term response to ChEI therapy in old age subjects with AD in a "real life" setting.

METHODS: This is a retrospective longitudinal study of 628 old age subjects (≥65 years old) with AD and treated with ChEIs over three year follow-up. The sample was divided into "young-old" (≤75 years) and "old-old" (≥76 years) according to age, and as "responder" and "non-responder" according to the initial (i.e., after three months) response to treatment. Cognitive and functional evaluation was performed by means of MMSE and ADL/IADL, respectively.

RESULTS: In the long run, subjects considered as non-responders showed a lower rate of cognitive decline as compared with responders, with a mean annual decline at MMSE of 1.0 point versus 1.6 points (p < 0.0001), respectively. Old-old non-responders had a slower rate of cognitive (p < 0.0001) and functional decline (p < 0.0001) as compared with responders after three years of observation.

CONCLUSION: Discontinuing ChEI treatment solely for the absence of an initial response is not appropriate, especially in old-old subjects.

%B J Alzheimers Dis %V 56 %P 239-248 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911323?dopt=Abstract %R 10.3233/JAD-160904 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer's Disease. %A Sheng, Min %A Lu, Hanzhang %A Liu, Peiying %A Li, Yang %A Ravi, Harshan %A Peng, Shin-Lei %A Diaz-Arrastia, Ramon %A Devous, Michael D %A Womack, Kyle B %X

BACKGROUND: Alzheimer's disease (AD) is the leading cause of degenerative dementia in the aging population. Patients with AD have alterations in cerebral hemodynamic function including reduced cerebral blood flow (CBF) and cerebral metabolic rate. Therefore, improved cerebrovascular function may be an attractive goal for pharmaceutical intervention in AD.

OBJECTIVE: We wished to observe the acute effects of sildenafil on cerebrovascular function and brain metabolism in patients with AD.

METHODS: We used several novel non-invasive MRI techniques to investigate the alterations of CBF, cerebral metabolic rate of oxygen (CMRO2), and cerebrovascular reactivity (CVR) after a single dose of sildenafil administration in order to assess its physiological effects in patients with AD. CBF, CMRO2, and CVR measurements using MRI were performed before and one hour after the oral administration of 50 mg sildenafil. Baseline Montreal Cognitive Assessment score was also obtained.

RESULTS: Complete CBF and CMRO2 data were obtained in twelve patients. Complete CVR data were obtained in eight patients. Global CBF and CMRO2 significantly increased (p = 0.03, p = 0.05, respectively) following sildenafil administration. Voxel-wise analyses of CBF maps showed that increased CBF was most pronounced in the bilateral medial temporal lobes. CVR significantly decreased after administration of sildenafil.

CONCLUSION: Our data suggest that a single dose of sildenafil improves cerebral hemodynamic function and increases cerebral oxygen metabolism in patients with AD.

%B J Alzheimers Dis %V 60 %P 1351-1364 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036811?dopt=Abstract %R 10.3233/JAD-161006 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Silicic Acid and Beer Consumption Reverses the Metal Imbalance and the Prooxidant Status Induced by Aluminum Nitrate in Mouse Brain. %A González-Muñoz, María José %A Garcimartán, Alba %A Meseguer, Isabel %A Mateos-Vega, Carmen José %A Orellana, José María %A Peña-Fernández, Antonio %A Benedí, Juana %A Sánchez-Muniz, Francisco J %X

BACKGROUND: Emerging evidence suggests that by affecting mineral balance, aluminum (Al) may enhance some events associated with neurodegenerative diseases.

AIM: To examine the effect of Al(NO3)3 exposure on brain Al, cooper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), silicon (Si), and zinc (Zn) levels, and the metal-change implication in brain oxidant and inflammatory status.

METHODS: Four groups of six-week-old male NMRI mice were treated for three months: i) controls, administrated with deionized water; ii) Al, which received Al(NO3)3; iii) Al+silicic acid, which were given Al(NO3)3 plus silicic acid; and iv) Al+beer, which received Al(NO3)3 plus beer.

RESULTS: Brain Al and TBARS levels and TNFα and GPx expressions increased, while Cu, Mn, and Zn levels, and catalase and CuZn-SOD expression decreased (at least, p < 0.05) in Al versus control animals. Al, Si, and TBARS levels and TNFα expression decreased (p < 0.05) in Al+silicic acid and Al+beer specimens while Cu, Mn, and Zn levels and antioxidant expression increased versus the Al group. Brain Al levels correlated negatively with those of Cu, Fe, Mn, and Zn, and catalase, CuZn-SOD, and GPx enzyme expressions but positively with Si and TBARS levels and TNFα expression. Two components of the principal component analysis (PCA) explained 71.2% of total data variance (p < 0.001). PCA connected the pro-oxidant markers with brain Al content, while brain Zn and Cu levels were closer to antioxidant enzyme expression.

CONCLUSION: Administration of Al(NO3)3 induced metal imbalance, inflammation, and antioxidant status impairment in the brain. Those effects were blocked to a significant extent by silicic acid and beer administration.

%B J Alzheimers Dis %V 56 %P 917-927 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059788?dopt=Abstract %R 10.3233/JAD-160972 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Situation Model for Situation-Aware Assistance of Dementia Patients in Outdoor Mobility. %A Yordanova, Kristina %A Koldrack, Philipp %A Heine, Christina %A Henkel, Ron %A Martin, Mike %A Teipel, Stefan %A Kirste, Thomas %X

BACKGROUND: Dementia impairs spatial orientation and route planning, thus often affecting the patient's ability to move outdoors and maintain social activities. Situation-aware deliberative assistive technology devices (ATD) can substitute impaired cognitive function in order to maintain one's level of social activity. To build such a system, one needs domain knowledge about the patient's situation and needs. We call this collection of knowledge situation model.

OBJECTIVE: To construct a situation model for the outdoor mobility of people with dementia (PwD). The model serves two purposes: 1) as a knowledge base from which to build an ATD describing the mobility of PwD; and 2) as a codebook for the annotation of the recorded behavior.

METHODS: We perform systematic knowledge elicitation to obtain the relevant knowledge. The OBO Edit tool is used for implementing and validating the situation model. The model is evaluated by using it as a codebook for annotating the behavior of PwD during a mobility study and interrater agreement is computed. In addition, clinical experts perform manual evaluation and curation of the model.

RESULTS: The situation model consists of 101 concepts with 11 relation types between them. The results from the annotation showed substantial overlapping between two annotators (Cohen's kappa of 0.61).

CONCLUSION: The situation model is a first attempt to systematically collect and organize information related to the outdoor mobility of PwD for the purposes of situation-aware assistance. The model is the base for building an ATD able to provide situation-aware assistance and to potentially improve the quality of life of PwD.

%B J Alzheimers Dis %V 60 %P 1461-1476 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29060937?dopt=Abstract %R 10.3233/JAD-170105 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Skin Autofluorescence Examination as a Diagnostic Tool for Mild Cognitive Impairment in Healthy People. %A Igase, Michiya %A Ohara, Maya %A Igase, Keiji %A Kato, Takeaki %A Okada, Yoko %A Ochi, Masayuki %A Tabara, Yasuharu %A Kohara, Katsuhiko %A Ohyagi, Yasumasa %X

BACKGROUND: Accumulation of advanced glycation endproducts (AGEs) is thought to be involved in the pathogenesis of dementia, especially Alzheimer's disease. Tissue AGE accumulation can be estimated using the relative simple noninvasive measurement of skin autofluorescence (SAF), a method based on the fluorescent properties of some AGEs. However, possible involvement of tissue AGE accumulation in mild cognitive impairment (MCI) has not been fully investigated.

OBJECTIVE: We investigated whether tissue AGE accumulation estimated by SAF is associated with mild cognitive impairment.

METHODS: We analyzed 226 community-dwelling subjects. In addition to several atherosclerosis-related clinical parameters, MCI screening test, assessment of brain atrophy, and SAF were performed on people aged > 40 years. MCI was assessed using the Japanese version of the MCI screening method. Atrophy of the brain was assessed by examining the temporal horn area (THA) by brain MRI.

RESULTS: SAF was significantly higher in participants with MCI than in those with normal cognitive function (2.56±0.55 versus 2.10±0.41; p < 0.001). Logistic regression analyses with adjustment for confounding factors including age and THA showed that high SAF > 2.27 was significantly related to the presence of MCI (odds, 6.402; 95% CI, 1.590-25.773, p = 0.009).

CONCLUSION: We found an association between SAF and MCI, which was independent of brain atrophy, in healthy subjects.

%B J Alzheimers Dis %V 55 %P 1481-1487 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858716?dopt=Abstract %R 10.3233/JAD-160917 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sleep Apnea, Cognitive Profile, and Vascular Changes: An Intriguing Relationship. %A Buratti, Laura %A Viticchi, Giovanna %A Baldinelli, Sara %A Falsetti, Lorenzo %A Luzzi, Simona %A Pulcini, Alessandra %A Petrelli, Cristina %A Provinciali, Leandro %A Silvestrini, Mauro %X

BACKGROUND: Sleep breathing disorders can affect cognitive performances through complex brain anatomical and functional changes.

OBJECTIVE: Our aim was to evaluate the correlations between cognitive performances and obstructive sleep apnea syndrome (OSAS), as well as the possible influence of vascular factors.

METHODS: Thirty-four non-demented OSAS patients and 34 controls were submitted to a neuropsychological evaluation and to a vascular screening including the study of cerebrovascular reactivity by means of the breath-holding index (BHI) calculation. After 6 months, polisomnographic, neuropsychologic, and hemodynamics assessment was repeated in patients.

RESULTS: At baseline, some cognitive performances involved in executive and memory functions were significantly lower in patients with respect to controls. Significantly lower values in mean BHI were also detected in patients with respect to controls (p < 0.0001). At the 6-month evaluation, 18 patients had a reduction in OSAS severity (group 1) and 16 remained stable (group 2). Group 1 patients had a significant improvement in left and mean BHI (p < 0.001) and in short-term (p = 0.02) and long-term Rey Auditory Verbal Learning Test (p < 0.001). No change in cerebrovascular reactivity and cognitive profile was detected in group 2 patients.

CONCLUSIONS: Patients with OSAS may experience a reduced cognitive efficiency. Improvement of OSAS was associated to favorable hemodynamic changes and increased level of performances in verbal memory tasks so suggesting an involvement of vascular underlying mechanisms in sustaining cognitive dysfunctions in OSAS. Our preliminary data suggest the need for further studies to deepen the knowledge about the relationships between OSAS, cerebral hemodynamic compromise, and cognitive impairment risk.

%B J Alzheimers Dis %V 60 %P 1195-1203 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984599?dopt=Abstract %R 10.3233/JAD-170445 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sleep Deprivation Induced Plasma Amyloid-β Transport Disturbance in Healthy Young Adults. %A Wei, Meng %A Zhao, Beiyu %A Huo, Kang %A Deng, Yongning %A Shang, Suhang %A Liu, Jie %A Li, Yanbo %A Ma, Louyan %A Jiang, Yu %A Dang, Liangjun %A Chen, Chen %A Wei, Shan %A Zhang, Juanli %A Yang, Hailei %A Gao, Fan %A Qu, Qiumin %K Adult %K Amyloid beta-Peptides %K Female %K Humans %K Low Density Lipoprotein Receptor-Related Protein-1 %K Male %K Malondialdehyde %K Peptide Fragments %K Receptor for Advanced Glycation End Products %K Sleep Deprivation %K Superoxide Dismutase %K Time Factors %K Young Adult %X

BACKGROUND: Sleep is an important physiological process and beneficial in the removal of brain metabolites and functional recovery. Prior studies have shown that sleep disorders are significant risk factors for Alzheimer's disease (AD).

OBJECTIVE: The present study was designed to characterize the effect of short-term total sleep deprivation (TSD) on plasma amyloid-β (Aβ) concentrations.

METHODS: A clinical trial was conducted between March 1, 2016, and April 1, 2016. Twenty volunteers (age 27.3±3.4 years) with normal cognitive function and sleeping habits were recruited from the local population. Participants underwent 24 h of TSD. Periprocedural blood samples were collected to compare the changes of plasma Aβ42, Aβ40, low-density lipoprotein receptor-related protein (sLRP-1), soluble receptors for advanced glycation end products (sRAGE), and serum superoxide dismutase (SOD) and malonaldehyde (MDA).

RESULTS: TSD increased morning plasma Aβ40 levels by 32.6% (p < 0.001) and decreased the Aβ42/Aβ40 ratio by 19.3% (p < 0.001). A positive relationship was found between TSD duration and plasma Aβ40 level (r = 0.51, p < 0.001) and Aβ40/Aβ42 ratio (r = 0.25, p = 0.003). Plasma concentrations of sLRP1 (p = 0.018) and sRAGE (p = 0.001) decreased significantly after TSD. Aβ40 and Aβ42 plasma concentrations correlated with plasma levels of sLRP1 and sRAGE. Serum SOD decreased after TSD (p = 0.005), whereas serum MDA was increased (p = 0.001).

CONCLUSION: Sleep deprivation can lead to an elevation of plasma Aβ40 and decrease of the Aβ42/Aβ40 ratio. The underlying mechanisms may be related to increased oxidative stress and impaired peripheral Aβ clearance as pathomechanisms of AD.

%B J Alzheimers Dis %V 57 %P 899-906 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304302?dopt=Abstract %R 10.3233/JAD-161213 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Is Sleep Disruption a Risk Factor for Alzheimer's Disease? %A Macedo, Arthur Cassa %A Balouch, Sara %A Tabet, Naji %X

Sleep disturbances are routinely encountered in Alzheimer's disease (AD) and affect about 25-40% of patients in the mild-to-moderate stages of the disease. In many, sleep pathology may represent a symptom of the underlying neurodegeneration. However, a history of sleep disruption occurring years prior to onset of cognitive symptoms could represent a potential risk factor for AD. The aim of the present narrative review was to evaluate current evidence linking sleep disturbances with AD development and to understand the mechanisms that may contribute to this. Although the mechanisms by which poor sleep may contribute to AD genesis is not fully understood, emerging evidence linking disturbances in the sleep wake cycle with Aβ deposition is shedding light on the relationship between sleep pathology and the subsequent development of AD. Aβ burden appears to be enhanced by sleep-wake cycle disruptions and is suspected as being an important mechanism by which sleep disruptions contribute in AD development. Other mechanisms triggered by sleep disruption may also be involved in AD development, such as brain hypoxia, oxidative stress, circadian activity rhythms disturbances, overexpression of orexins, and blood-brain barrier impairment. Further understanding of the link between sleep disturbances and future development of AD is still needed before sleep disturbances are clearly marked as a preventable risk factor for AD. In these circumstances, early lifestyle interventions to help increase the quantity and quality of sleep may have a favorable outcome on decreasing the incidence of AD and this needs to be investigated further.

%B J Alzheimers Dis %V 58 %P 993-1002 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550253?dopt=Abstract %R 10.3233/JAD-161287 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sleep EEG Detects Epileptiform Activity in Alzheimer's Disease with High Sensitivity. %A Horváth, András %A Szűcs, Anna %A Barcs, Gábor %A Kamondi, Anita %X

BACKGROUND: The reported prevalence of epilepsy in Alzheimer's disease (AD) is variable, probably due to the different methodological approaches.

OBJECTIVE: We aimed to define the optimal electroencephalogram (EEG) settings for reliable detection of epileptiform discharges in AD patients.

METHODS: We analyzed 24-h EEGs of 5 patients living with AD and epilepsy. The sensitivity of various length EEGs in detecting epileptiform discharges in different periods of the day, the diurnal distribution of the discharges, and their relation to sleep-stages were calculated.

RESULTS: Significant high correlation was identified between the sensitivity of EEG and the length of recordings (r = 0.972, p = 0.005). The sensitivity of a 30-min EEG-epoch recorded between 8:00 and 16:00 was 0.0375 compared to 0.7 between 0:00 and 8:00 (p = 0.005). The average sensitivity of an 8-h EEG-epoch was≥0.8. 82% of epileptiform discharges occurred during sleep, mainly related to non-REM sleep (p < 0.001).

CONCLUSION: 8-h awake-, or 1-h sleep-EEG provide sufficient sensitivity in detecting epileptiform activity in AD. This needs to be considered in studies on AD-related epilepsy. Recognizing epilepsy in AD patients is essential because it might compromise cognitive functions and accelerate the progression of the disease.

%B J Alzheimers Dis %V 56 %P 1175-1183 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28128769?dopt=Abstract %R 10.3233/JAD-160994 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sleep-Wake Profile in Dementia with Lewy Bodies, Alzheimer's Disease, and Normal Aging. %A Cagnin, Annachiara %A Fragiacomo, Federica %A Camporese, Giulia %A Turco, Matteo %A Bussè, Cinzia %A Ermani, Mario %A Montagnese, Sara %X

BACKGROUND: Alterations of the sleep-wake cycle are common features of neurodegenerative dementia.

OBJECTIVES: To study differences in sleep-wake profiles in dementia with Lewy bodies (DLB), Alzheimer's disease (AD), and healthy controls.

METHODS: 30 DLB and 32 AD patients, and 33 healthy elderly participants were studied. Patients were evaluated for global cognitive impairment, extrapyramidal signs, fluctuations of attention, and behavioral disorders. A comprehensive sleep-wake profile was obtained including a set of questionnaires [Pittsburgh Sleep Quality Index (PSQI), REM Sleep Behavior Disorder Single-Question screen (RBD1Q), Epworth Sleepiness Scale (ESS)] and 12-day sleep diaries.

RESULTS: Patients were matched for age, gender, and disease severity. DLB patients showed more severe daytime somnolence/dysfunction due to somnolence, and a higher proportion of RBD-like symptoms (70%) compared to AD and controls (p < 0.001), regardless of the presence of psychoactive drug treatment. As for sleep timing, DLB patients had a greater number of daytime naps and longer night sleep, with the latter being associated with use of clonazepam. The severity of fluctuations was associated with the presence of RBD (Clinician Assessment of Fluctuation score = RBD+: 5.2±3.7; RBD-: 2.1±3.2, p = 0.04). AD patients reported the best sleep-wake profile, while healthy controls declared the poorest sleep quality, although sleep timing and the quality of wakefulness were comparable between AD and controls.

DISCUSSION: RBD and daytime fluctuations of attention may coexist in DLB and even reciprocally potentiate each other. Self-reports of sleep quality may lead to an underestimation of sleep disturbances in AD, possibly influenced by anosognosia, compared to normal elderly individuals who complain mainly of insomnia.

%B J Alzheimers Dis %V 55 %P 1529-1536 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27886007?dopt=Abstract %R 10.3233/JAD-160385 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Smoking, APOE Genotype, and Cognitive Decline: The Rotterdam Study. %A Wingbermühle, Robin %A Wen, Ke-Xin %A Wolters, Frank J %A Ikram, M Arfan %A Bos, Daniel %X

The association of smoking with preclinical cognitive decline remains unclear and may be modified by the APOEɛ4 genotype. In 5,705 participants (mean age: 63.9±9.1 years; 57.4% women) from the population-based Rotterdam Study, we investigated the relationship between smoking and cognitive decline over a 5.5-year period and examined potential effect modification by APOEɛ4 genotype. We found that current smoking was related to decline in global cognition [difference compared to never smoking: -0.06 (95% C.I.-0.10;-0.01)], as well as decline on specific cognitive tests including the Letter Digit Substitution Task, the 15-Word Learning Test, and the Purdue Pegboard. We found no evidence for effect modification by APOEɛ4 genotype on this relation.

%B J Alzheimers Dis %V 57 %P 1191-1195 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304310?dopt=Abstract %R 10.3233/JAD-170063 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Social Cognition in the Frontal Variant of Alzheimer's Disease: A Case Study. %A Duclos, Harmony %A de la Sayette, Vincent %A Bonnet, Anne-Laure %A Viard, Armelle %A Eustache, Francis %A Desgranges, Béatrice %A Laisney, Mickaël %X

Although frontal presentations of Alzheimer's disease (fv-AD) have already been described in the literature, we still know little about patients' social cognitive abilities, especially their theory of mind (ToM). We report the case of FT, a 61-year-old woman who was diagnosed with fv-AD. Two assessments of social cognition, using a false-belief task, the Reading the Mind in the Eyes test, and a task probing knowledge of social norms, were performed one year apart. FT exhibited cognitive ToM and social knowledge deficits from the onset. Affective ToM was initially preserved, but deteriorated as the disease progressed.

%B J Alzheimers Dis %V 55 %P 459-463 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662316?dopt=Abstract %R 10.3233/JAD-160690 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Social Representation of Dementia: An Analysis of 5,792 Consecutive Cases Evaluated in a Memory Clinic. %A Cañabate, Pilar %A Martínez, Gabriel %A Rosende-Roca, Maitee %A Moreno, Mariola %A Preckler, Silvia %A Valero, Sergi %A Sotolongo, Oscar %A Hernandez, Isabel %A Alegret, Montserrat %A Ortega, Gemma %A Espinosa, Ana %A Mauleón, Ana %A Vargas, Liliana %A Rodríguez, Octavio %A Abdelnour, Carla %A Sánchez, Domingo %A Martín, Elvira %A Ruiz, Agustin %A Tárraga, Lluís %A Boada, Merce %X

BACKGROUND: Different interpretations of cognitive impairment and dementia due to differences in health structures, such as cultural differences could affect the diagnosis and treatment of the condition. it is reasonable to expect that the social and family impact of the disease and coping strategies will differ among societies.

OBJECTIVE: The general aim of this study is to understand the social representations of dementia, its associated practices, and the effects they imply.

METHODS: People diagnosed with clinical dementia and their families were assessed from 2005 to 2015 in the memory clinic of the Fundació ACE, Institut Català de Neurociències Aplicades in Barcelona, Spain.

RESULTS: 9,898 people were examined and 5,792 were diagnosed with dementia. For those with a caregiver (71%), the decision-making fell on the person with dementia in 16.2% of the cases; and for those without a caregiver, in 26.4% of the cases the family did not perceive the deficits as a disease, which led to multiple risk situations (74.6%).

CONCLUSIONS: The recognition of dementia as part of aging is common among families. Consequently, risk situations may arise and diagnosis and access to treatment may be delayed. The incorporation of a social appraisal to the diagnostic process is a necessity to evaluate these situations.

%B J Alzheimers Dis %V 58 %P 1099-1108 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527206?dopt=Abstract %R 10.3233/JAD-161119 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload. %A Cascella, Roberta %A Evangelisti, Elisa %A Bigi, Alessandra %A Becatti, Matteo %A Fiorillo, Claudia %A Stefani, Massimo %A Chiti, Fabrizio %A Cecchi, Cristina %X

An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer's disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained from AD brains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid-β peptide (Aβ42), with intracellular flux of Ca2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells. Specific membrane proteins appear to be involved in the early and transient influx of Ca2+ ions induced by Aβ42 oligomers with high solvent-exposed hydrophobicity (A+), but not in the sustained late influx of the same oligomers and in that induced by Aβ42 oligomers with low solvent-exposed hydrophobicity (A-) in GM1-enriched cells. In addition, A+ oligomers accumulate in proximity of membrane NMDA and AMPA receptors, inducing the early and transient Ca2+ influx, although FRET shows that the interaction is not direct. These results suggest that age-dependent clustering of GM1 within neuronal membranes could induce neurodegeneration in elderly people as a consequence of an increased ability of the lipid bilayers to recruit membrane-permeabilizing oligomers. We also show that both lipid and protein components of the plasma membrane can contribute to neuronal dysfunction, thus expanding the molecular targets for therapeutic intervention in AD.

%B J Alzheimers Dis %V 60 %P 923-938 %G eng %N 3 %R 10.3233/JAD-170340 %0 Journal Article %J J Alzheimers Dis %D 2017 %T SORL1 Variants Show Different Association with Early-Onset and Late-Onset Alzheimer's Disease Risk. %A Liu, Guiyou %A Sun, Jing-Yi %A Xu, Meiling %A Yang, Xiao-Yi %A Sun, Bao-Liang %X

A recent study sequenced the full coding region of SORL1 in 1,255 early-onset Alzheimer's disease (EOAD) cases and 1,938 control individuals, and investigated the contribution of genetic variability in SORL1 to EOAD risk in a European cohort. This study identified six common variants and five low frequency variants in the SORL1 coding sequence. However, none of these 11 variants was significantly associated with EOAD risk after adjusting for multiple testing. We consider whether these 11 SORL1 variants identified in European EOAD contribute to late-onset Alzheimer's disease (LOAD) risk in individuals of European ancestry. Here, we investigated these 11 SORL1 variants identified in European EOAD and LOAD risk in individuals of European ancestry using a large-scale LOAD GWAS. Our results indicate that three genetic variants rs2070045, rs2276412, and rs17125548 as well as their tagged genetic variants contribute to LOAD risk in European population. We further investigate whether these variants could affect SORL1 expression using multiple expression quantitative trait loci (eQTLs) datasets. Our findings suggest that three genetic variants rs2070045, rs1699102, and rs3824968 could significantly regulate SORL1 expression in human brain tissues. We believe that our findings further provide important supplementary information about the involvement of the SORL1 variants in LOAD risk.

%B J Alzheimers Dis %V 58 %P 1121-1128 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527213?dopt=Abstract %R 10.3233/JAD-170005 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Spatial Patterns of Longitudinal Gray Matter Change as Predictors of Concurrent Cognitive Decline in Amyloid Positive Healthy Subjects. %A Araque Caballero, Miguel Ángel %A Klöppel, Stefan %A Dichgans, Martin %A Ewers, Michael %X

A substantial proportion of cognitively healthy elders (HC) show abnormally high amyloid-β (Aβ) deposition, a major pathology of Alzheimer's disease (AD). These subjects are at increased risk of Alzheimer's disease (AD) dementia, and biomarkers are needed to predict their cognitive deterioration. Here we used relevance vector regression (RVR), a pattern-recognition method, to predict concurrent cognitive decline on the basis of longitudinal gray matter (GM) changes, within two a priori, meta-analytically defined functional networks subserving episodic memory and executive function. Ninety-six HC subjects were assessed annually for three years with structural MRI and cognitive tests within the Alzheimer's Disease Neuroimaging Initiative. Presence of abnormal biomarker values of Aβ (Aβ+) were determined with cerebrospinal fluid and amyloid-PET (HC-Aβ+, n=30; with n=66 for normal HC-Aβ-). Using leave-one-out cross-validation, we found that in HC-Aβ+ patterns of GM changes within both networks predicted decline in episodic memory (r=0.61, p<0.001; r=0.40, p=0.03), but not executive function. In HC-Aβ-, GM changes within the executive function network predicted decline in executive function (r=0.44, p<0.001). Previously established region-of-interest (ROI)-based predictors such as changes in hippocampal volume, within an AD-signature multi-ROI, or total GM volume were not predictive of cognitive decline in any group or cognitive domain. RVR analyses unrestricted to the a priori networks yielded compatible results with the restricted case. In conclusion, RVR-derived patterns of subtle cortical GM changes are biomarker candidates of concurrent cognitive decline in aging and subjects at risk for AD.

%B J Alzheimers Dis %V 55 %P 343-358 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662291?dopt=Abstract %R 10.3233/JAD-160327 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Specific Verbal Memory Measures May Distinguish Alzheimer's Disease from Dementia with Lewy Bodies. %A Bussè, Cinzia %A Anselmi, Pasquale %A Pompanin, Sara %A Zorzi, Giovanni %A Fragiacomo, Federica %A Camporese, Giulia %A Di Bernardo, Gian Antonio %A Semenza, Carlo %A Caffarra, Paolo %A Cagnin, Annachiara %X

BACKGROUND: Standard measures of commonly used memory tests may not be appropriate to distinguish different neurodegenerative diseases affecting memory.

OBJECTIVE: To study whether specific measures of verbal memory obtained with the Rey Auditory Verbal Learning test (RAVLT) could help distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD).

METHODS: Twenty-nine DLB and 32 AD patients participated in the study and were followed longitudinally for 3 years until the diagnosis was confirmed according to standard clinical criteria. Twenty-eight healthy elderly subjects served as controls. The following verbal memory measures were evaluated: verbal learning (VL), verbal forgetting (VF), percentage of verbal forgetting (VF%), and serial position effects of the immediate recall performance.

RESULTS: DLB and AD groups have comparable performances at the RAVLT immediate and delayed recall tasks. However, VL was higher in DLB than AD while VF% was greater in AD. With a VF% cut-off ≥75%, AD and DLB patients were differently distributed, with 58% of AD versus 21% of DLB above this cut-off. The recency effect was significant higher in AD than DLB.

DISCUSSION: DLB patients had a better performance in VL than AD, but worse VF and recency effect. These specific measures of verbal memory could be used as cognitive markers in the differential diagnosis between these two conditions.

%B J Alzheimers Dis %V 59 %P 1009-1015 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697561?dopt=Abstract %R 10.3233/JAD-170154 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sphingolipid-Enriched Extracellular Vesicles and Alzheimer's Disease: A Decade of Research. %A Dinkins, Michael B %A Wang, Guanghu %A Bieberich, Erhard %X

Extracellular vesicles (EVs), particularly exosomes, have emerged in the last 10 years as a new player in the progression of Alzheimer's disease (AD) with high potential for being useful as a diagnostic and treatment tool. Exosomes and other EVs are enriched with the sphingolipid ceramide as well as other more complex glycosphingolipids such as gangliosides. At least a subpopulation of exosomes requires neutral sphingomyelinase activity for their biogenesis and secretion. As ceramide is often elevated in AD, exosome secretion may be affected as well. Here, we review the available data showing that exosomes regulate the aggregation and clearance of amyloid-beta (Aβ) and discuss the differences in data from laboratories regarding Aβ binding, induction of aggregation, and glial clearance. We also summarize available data on the role of exosomes in extracellular tau propagation, AD-related exosomal mRNA/miRNA cargo, and the use of exosomes as biomarker and gene therapy vehicles for diagnosis and potential treatment.

%B J Alzheimers Dis %V 60 %P 757-768 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662306?dopt=Abstract %R 10.3233/JAD-160567 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sporadic Cases with Novel Mutations and Pedigree in Hereditary Leukoencephalopathy with Axonal Spheroids. %A Wu, Liyong %A Liu, Jia %A Sha, Longze %A Wang, Xianling %A Li, Jieying %A Dong, Jing %A Jia, Jianping %X

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant hereditary disease, featured by cerebral white matter degeneration with demyelination and axonal spheroids. We collected three gene-confirmed HDLS cases in our neurodegenerative clinic. Two HDLS cases were sporadic with novel mutations, while another case had a family history with previously described mutations. All three cases suffered memory problems with white matter lesions and pyramid signs. No obvious clinical differences were observed between sporadic and familial HDLS cases. Distinct features, such as subcortical calcification in brain computed tomography and asymmetric abnormal MRI signal along the pyramid tracts throughout brainstem and spinal cord (cervical, thoracic, and lumbar segments), were observed in one sporadic case with novel mutation. Therefore, the interactions of genotype-phenotype still need to be further investigated.

%B J Alzheimers Dis %V 56 %P 893-898 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059798?dopt=Abstract %R 10.3233/JAD-161193 %0 Journal Article %J J Alzheimers Dis %D 2017 %T State of Play in Alzheimer's Disease Genetics. %A Zhu, Jin-Bao %A Tan, Chen-Chen %A Tan, Lan %A Yu, Jin-Tai %X

Alzheimer's disease (AD), the main form of dementia in the elderly, is the most common progressive neurodegenerative disease characterized by rapidly progressive cognitive dysfunction and behavior impairment. AD exhibits a considerable heritability and great advances have been made in approaches to searching the genetic etiology of AD. In AD genetic studies, methods have developed from classic linkage-based and candidate-gene-based association studies to genome-wide association studies (GWAS) and next generation sequencing (NGS). The identification of new susceptibility genes has provided deeper insights to understand the mechanisms underlying AD. In addition to searching novel genes associated with AD in large samples, the NGS technologies can also be used to shed light on the 'black matter' discovery even in smaller samples. The shift in AD genetics between traditional studies and individual sequencing will allow biomaterials of each patient as the central unit of genetic studies. This review will cover genetic findings in AD and consequences of AD genetic findings. Firstly, we will discuss the discovery of mutations in APP, PSEN1, PSEN2, APOE, and ADAM10. Then we will summarize and evaluate the information obtained from GWAS of AD. Finally, we will outline the efforts to identify rare variants associated with AD using NGS.

%B J Alzheimers Dis %V 58 %P 631-659 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505974?dopt=Abstract %R 10.3233/JAD-170062 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Stress-Induced Synaptic Dysfunction and Neurotransmitter Release in Alzheimer's Disease: Can Neurotransmitters and Neuromodulators be Potential Therapeutic Targets? %A Jha, Saurabh Kumar %A Jha, Niraj Kumar %A Kumar, Dhiraj %A Sharma, Renu %A Shrivastava, Abhishek %A Ambasta, Rashmi K %A Kumar, Pravir %X

The communication between neurons at synaptic junctions is an intriguing process that monitors the transmission of various electro-chemical signals in the central nervous system. Albeit any aberration in the mechanisms associated with transmission of these signals leads to loss of synaptic contacts in both the neocortex and hippocampus thereby causing insidious cognitive decline and memory dysfunction. Compelling evidence suggests that soluble amyloid-β (Aβ) and hyperphosphorylated tau serve as toxins in the dysfunction of synaptic plasticity and aberrant neurotransmitter (NT) release at synapses consequently causing a cognitive decline in Alzheimer's disease (AD). Further, an imbalance between excitatory and inhibitory neurotransmission systems induced by impaired redox signaling and altered mitochondrial integrity is also amenable for such abnormalities. Defective NT release at the synaptic junction causes several detrimental effects associated with altered activity of synaptic proteins, transcription factors, Ca2+ homeostasis, and other molecules critical for neuronal plasticity. These detrimental effects further disrupt the normal homeostasis of neuronal cells and thereby causing synaptic loss. Moreover, the precise mechanistic role played by impaired NTs and neuromodulators (NMs) and altered redox signaling in synaptic dysfunction remains mysterious, and their possible interlink still needs to be investigated. Therefore, this review elucidates the intricate role played by both defective NTs/NMs and altered redox signaling in synaptopathy. Further, the involvement of numerous pharmacological approaches to compensate neurotransmission imbalance has also been discussed, which may be considered as a potential therapeutic approach in synaptopathy associated with AD.

%B J Alzheimers Dis %V 57 %P 1017-1039 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662312?dopt=Abstract %R 10.3233/JAD-160623 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Subclinical Doses of ATP-Sensitive Potassium Channel Modulators Prevent Alterations in Memory and Synaptic Plasticity Induced by Amyloid-β. %A Salgado-Puga, Karla %A Rodríguez-Colorado, Javier %A Prado-Alcalá, Roberto A %A Peña-Ortega, Fernando %X

In addition to coupling cell metabolism and excitability, ATP-sensitive potassium channels (KATP) are involved in neural function and plasticity. Moreover, alterations in KATP activity and expression have been observed in Alzheimer's disease (AD) and during amyloid-β (Aβ)-induced pathology. Thus, we tested whether KATP modulators can influence Aβ-induced deleterious effects on memory, hippocampal network function, and plasticity. We found that treating animals with subclinical doses (those that did not change glycemia) of a KATP blocker (Tolbutamide) or a KATP opener (Diazoxide) differentially restrained Aβ-induced memory deficit, hippocampal network activity inhibition, and long-term synaptic plasticity unbalance (i.e., inhibition of LTP and promotion of LTD). We found that the protective effect of Tolbutamide against Aβ-induced memory deficit was strong and correlated with the reestablishment of synaptic plasticity balance, whereas Diazoxide treatment produced a mild protection against Aβ-induced memory deficit, which was not related to a complete reestablishment of synaptic plasticity balance. Interestingly, treatment with both KATP modulators renders the hippocampus resistant to Aβ-induced inhibition of hippocampal network activity. These findings indicate that KATP are involved in Aβ-induced pathology and they heighten the potential role of KATP modulation as a plausible therapeutic strategy against AD.

%B J Alzheimers Dis %V 57 %P 205-226 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222502?dopt=Abstract %R 10.3233/JAD-160543 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Subjective Cognitive Complaints in Cognitively Healthy Older Adults and Their Relationship to Cognitive Performance and Depressive Symptoms. %A Marková, Hana %A Andel, Ross %A Stepankova, Hana %A Kopecek, Miloslav %A Nikolai, Tomas %A Hort, Jakub %A Thomas-Antérion, Catherine %A Vyhnálek, Martin %X

BACKGROUND: Subjective cognitive complaints (SCCs) may be an early marker of prodromal Alzheimer's disease.

OBJECTIVES: Using a 10-item yes/no SCCs questionnaire (Le Questionnaire de Plainte Cognitive [QPC]), we evaluated the prevalence and distribution of SCCs in cognitively healthy Czech older adults and examined total score and specific QPC items in relation to depressive symptomology and cognitive performance.

METHODS: A sample of 340 cognitively healthy older community-dwelling volunteers aged 60 or older from the third wave of the longitudinal project National Normative Study of Cognitive Determinants of Healthy Aging, who underwent a comprehensive neuropsychological assessment and completed the QPC and the 15-item Geriatric Depression Scale (GDS-15). Regression analysis was controlled for age when GDS-15 was the outcome and for age and GDS-15 with cognitive domains as the outcome.

RESULTS: 71% reported 1 + SCCs, with prevalence of individual complaints ranging from 4% to 40%. The number of SCCs was associated with GDS-15 (p < 0.001). Personality change (p < 0.001) and Limitation in daily activities (p = 0.002) were significantly associated with higher GDS-15 score and Spatial orientation difficulties (p = 0.019) and Impression of worse memory in comparison to peers (p = 0.012) were significantly associated with lower memory performance.

CONCLUSIONS: We identified some cognitive complaints that were very common in our sample. Overall, a higher number of SCCs in well cognitively functioning individuals was most closely related to depressive symptomatology, while some specific complaints reflected lower memory performance and should be considered when screening for people at risk of cognitive decline.

%B J Alzheimers Dis %V 59 %P 871-881 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697555?dopt=Abstract %R 10.3233/JAD-160970 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Subjective Memory Impairment and Gait Variability in Cognitively Healthy Individuals: Results from a Cross-Sectional Pilot Study. %A Beauchet, Olivier %A Launay, Cyrille P %A Chabot, Julia %A Levinoff, Elise J %A Allali, Gilles %X

BACKGROUND: Increased stride time variability has been associated with memory impairment in mild cognitive impairment. Subjective memory impairment (SMI) is considered the earliest clinical stage of Alzheimer's disease (AD). The association between increased stride time variability and SMI has not been reported.

OBJECTIVE: This study aims to examine the association of stride time variability while performing single and dual tasking with SMI in cognitively healthy individuals (CHI).

METHODS: A total of 126 CHI (15 without SMI, 69 with SMI expressed by participants, 10 with SMI expressed by participant's relative, and 32 with SMI expressed by both participants and their relatives) were included in this cross-sectional study. The coefficient of variation (CoV) of stride time and walking speed were recorded under usual condition and while counting backwards. Age, gender, body mass index, number of drugs taken daily, use of psychoactive drugs, fear of falling, history of previous falls, and walking speed were used as covariates.

RESULTS: The multiple linear regression models showed that greater CoV of stride time while counting backwards, but not while single tasking, was associated with a participant's relative SMI (p = 0.038).

CONCLUSION: This study found a specific association between SMI expressed by a participant's relative and a greater CoV of stride time (i.e., worse performance) while dual tasking, suggesting that the association between gait variability and memory may be present in the earliest stages of memory impairment. Thus, gait variability under dual-task in individuals with SMI expressed by their relatives can be a potential biomarker of AD.

%B J Alzheimers Dis %V 55 %P 965-971 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802231?dopt=Abstract %R 10.3233/JAD-160604 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Successful Object Encoding Induces Increased Directed Connectivity in Presymptomatic Early-Onset Alzheimer's Disease. %A Ochoa, John Fredy %A Alonso, Joan Francesc %A Duque, Jon Edinson %A Tobón, Carlos Andrés %A Mañanas, Miguel Angel %A Lopera, Francisco %A Hernández, Alher Mauricio %X

BACKGROUND: Recent studies report increases in neural activity in brain regions critical to episodic memory at preclinical stages of Alzheimer's disease (AD). Although electroencephalography (EEG) is widely used in AD studies, given its non-invasiveness and low cost, there is a need to translate the findings in other neuroimaging methods to EEG.

OBJECTIVE: To examine how the previous findings using functional magnetic resonance imaging (fMRI) at preclinical stage in presenilin-1 E280A mutation carriers could be assessed and extended, using EEG and a connectivity approach.

METHODS: EEG signals were acquired during resting and encoding in 30 normal cognitive young subjects, from an autosomal dominant early-onset AD kindred from Antioquia, Colombia. Regions of the brain previously reported as hyperactive were used for connectivity analysis.

RESULTS: Mutation carriers exhibited increasing connectivity at analyzed regions. Among them, the right precuneus exhibited the highest changes in connectivity.

CONCLUSION: Increased connectivity in hyperactive cerebral regions is seen in individuals, genetically-determined to develop AD, at preclinical stage. The use of a connectivity approach and a widely available neuroimaging technique opens the possibility to increase the use of EEG in early detection of preclinical AD.

%B J Alzheimers Dis %V 55 %P 1195-1205 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27792014?dopt=Abstract %R 10.3233/JAD-160803 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Synaptic Compensation as a Probable Cause of Prolonged Mild Cognitive Impairment in Alzheimer's Disease: Implications from a Transgenic Mouse Model of the Disease. %A Baazaoui, Narjes %A Flory, Michael %A Iqbal, Khalid %X

Alzheimer's disease (AD) is a slow, progressive neurodegenerative disease in which cognitive decline takes place over a period of several years with a very variable period of mild cognitive impairment (MCI) and, in some cases, relatively long period before progression to dementia. The cognitive deficit during MCI is probably due to neuronal loss, an intermediate level of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) and synaptosis, which is interrupted with a transient compensatory increase. We found impairment in reference memory accompanied by a decrease in the expression of synaptophysin, β-III tubulin, and MAP2 and a trend for GluR1, at 12 weeks of age in 3xTg-AD mice (hAPPSwe, P301L tau, PS1 [M146V] knock-in), a widely used transgenic model of AD. Past 12 weeks, the cross-sectional analysis of different age groups showed a compensatory increase in synaptic markers relative to that in wild type animals in a topographic and time-dependent manner. When studied across time we found that in 3xTg-AD mice, the compensatory phenomenon occurred in parallel in different regions of the brain. However, this attempt of the brain to repair itself was able to only partially rescue cognitive impairment. These findings for the first time raise the intriguing possibility that AD causing mutated transgenes may initially cause an increase in synaptic and dendritic markers as a compensatory mechanism for synaptic deficit, and this phenomenon, though transient, could be the biological basis of the period of MCI seen in AD.

%B J Alzheimers Dis %V 56 %P 1385-1401 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222506?dopt=Abstract %R 10.3233/JAD-160845 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Synaptic Membrane Synthesis in Rats Depends on Dietary Sufficiency of Vitamin C, Vitamin E, and Selenium: Relevance for Alzheimer's Disease. %A Cansev, Mehmet %A Turkyilmaz, Mesut %A Sijben, John W C %A Sevinc, Cansu %A Broersen, Laus M %A van Wijk, Nick %X

Chronic consumption of a diet enriched with nutritional precursors of phospholipids, including uridine and the polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), was shown previously to enhance levels of brain phospholipids and synaptic proteins in rodents. Vitamin C, vitamin E, and selenium may directly affect the breakdown or synthesis of membrane phospholipids. The present study investigated the necessity of antioxidants for the effectiveness of supplementation with uridine plus DHA and EPA (as fish oil) in rats. Rats were randomized to four treatment groups and received, for 6 weeks, one of four experimental diets, i.e., a diet low in antioxidants, a diet high in antioxidants, a diet low in antioxidants supplemented with DHA+EPA+uridine, or a diet high in antioxidants supplemented with DHA+EPA+uridine. On completion of dietary treatment, rats were sacrificed, and brain levels of phospholipids, synaptic proteins, and two enzymes involved in phospholipid synthesis (choline-phosphate cytidylyltransferase, PCYT1A, and choline/ethanolamine phosphotransferase, CEPT1) were analyzed. Levels of phospholipids, the pre- and post-synaptic proteins Synapsin-1 and PSD95, and the enzymes PCYT1A and CEPT1 were significantly enhanced by combined supplementation of DHA+EPA+uridine and antioxidants and not enhanced by supplementation of DHA+EPA+uridine with insufficient antioxidant levels. Our data suggest that dietary vitamin C, vitamin E, and selenium are essential for the phospholipid precursors' effects on increasing levels of membrane phospholipids and synaptic proteins, the indirect indicators of synaptogenesis. Their concomitant supply may be relevant in Alzheimer's disease patients, because the disease is characterized by synapse loss and lower plasma and brain levels of phospholipid precursors and antioxidants.

%B J Alzheimers Dis %V 59 %P 301-311 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598848?dopt=Abstract %R 10.3233/JAD-170081 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Synthesis, Radiosynthesis, and Preliminary in vitro and in vivo Evaluation of the Fluorinated Ceramide Trafficking Inhibitor (HPA-12) for Brain Applications. %A Crivelli, Simone M %A Paulus, Andreas %A Markus, Jozef %A Bauwens, Matthias %A Berkes, Dusan %A De Vries, Helga E %A Mulder, Monique T %A Walter, Jochen %A Mottaghy, Felix M %A Losen, Mario %A Martinez-Martinez, Pilar %X

Ceramide levels are increased in blood and brain tissue of Alzheimer's disease (AD) patients. Since the ceramide transporter protein (CERT) is the only known protein able to mediate non-vesicular transfer of ceramide between organelle membranes, the modulation of CERT function may impact on ceramide accumulation. The competitive CERT inhibitor N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide (HPA-12) interferes with ceramide trafficking. To understand the role of ceramide/CERT in AD, HPA-12 can be a useful tool to modulate ceramide trafficking. Here we first report the synthesis and in vitro properties of HPA-12 radiolabeled with fluorine-18 and present preliminary in vitro and in vivo positron emission tomography (PET) imaging and biodistribution data. In vitro results demonstrated that the fluorination did not alter the biological properties of HPA-12 since the [fluorine-19]HPA-12, interferes with 5-DMB-ceramide trafficking in HeLa cells. Radiolabeled HPA-12, [fluorine-18]HPA-12, was obtained with a radiochemical yield of 90% and a specific activity of 73 MBq/μmol. PET imaging on wild-type mice showed hepatobiliary clearance and a brain uptake on the order of 0.3 standard uptake value (SUV) one hour post injection. Furthermore, the biodistribution data showed that after removal of the blood by intracardial perfusion, radioactivity was still measurable in the brain demonstrating that the [fluorine-18]HPA-12 crosses the blood brain barrier and is retained in the brain.

%B J Alzheimers Dis %V 60 %P 783-794 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922150?dopt=Abstract %R 10.3233/JAD-161231 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Systematic Review of Longitudinal Studies Which Measure Alzheimer's Disease Biomarkers. %A Lawrence, Emma %A Vegvari, Carolin %A Ower, Alison %A Hadjichrysanthou, Christoforos %A De Wolf, Frank %A Anderson, Roy M %X

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease, with no effective treatment or cure. A gold standard therapy would be treatment to slow or halt disease progression; however, knowledge of causation in the early stages of AD is very limited. In order to determine effective endpoints for possible therapies, a number of quantitative surrogate markers of disease progression have been suggested, including biochemical and imaging biomarkers. The dynamics of these various surrogate markers over time, particularly in relation to disease development, are, however, not well characterized. We reviewed the literature for studies that measured cerebrospinal fluid or plasma amyloid-β and tau, or took magnetic resonance image or fluorodeoxyglucose/Pittsburgh compound B-positron electron tomography scans, in longitudinal cohort studies. We summarized the properties of the major cohort studies in various countries, commonly used diagnosis methods and study designs. We have concluded that additional studies with repeat measures over time in a representative population cohort are needed to address the gap in knowledge of AD progression. Based on our analysis, we suggest directions in which research could move in order to advance our understanding of this complex disease, including repeat biomarker measurements, standardization and increased sample sizes.

%B J Alzheimers Dis %V 59 %P 1359-1379 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28759968?dopt=Abstract %R 10.3233/JAD-170261 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tai Chi Chuan and Baduanjin Increase Grey Matter Volume in Older Adults: A Brain Imaging Study. %A Tao, Jing %A Liu, Jiao %A Liu, Weilin %A Huang, Jia %A Xue, Xiehua %A Chen, Xiangli %A Wu, Jinsong %A Zheng, Guohua %A Chen, Bai %A Li, Ming %A Sun, Sharon %A Jorgenson, Kristen %A Lang, Courtney %A Hu, Kun %A Chen, Shanjia %A Chen, Lidian %A Kong, Jian %X

The aim of this study is to investigate and compare how 12-weeks of Tai Chi Chuan and Baduanjin exercise can modulate brain structure and memory function in older adults. Magnetic resonance imaging and memory function measurements (Wechsler Memory Scale-Chinese revised, WMS-CR) were applied at both the beginning and end of the study. Results showed that both Tai Chi Chuan and Baduanjin could significantly increase grey matter volume (GMV) in the insula, medial temporal lobe, and putamen after 12-weeks of exercise. No significant differences were observed in GMV between the Tai Chi Chuan and Baduanjin groups. We also found that compared to healthy controls, Tai Chi Chuan and Baduanjin significantly improved visual reproduction subscores on the WMS-CR. Baduanjin also improved mental control, recognition, touch, and comprehension memory subscores of the WMS-CR compared to the control group. Memory quotient and visual reproduction subscores were both associated with GMV increases in the putamen and hippocampus. Our results demonstrate the potential of Tai Chi Chuan and Baduanjin exercise for the prevention of memory deficits in older adults.

%B J Alzheimers Dis %V 60 %P 389-400 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869478?dopt=Abstract %R 10.3233/JAD-170477 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tailored and Adaptive Computerized Cognitive Training in Older Adults at Risk for Dementia: A Randomized Controlled Trial. %A Bahar-Fuchs, Alex %A Webb, Shannon %A Bartsch, Lauren %A Clare, Linda %A Rebok, George %A Cherbuin, Nicolas %A Anstey, Kaarin J %X

BACKGROUND: Computerized Cognitive Training (CCT) has been shown to improve cognitive function in older adults with mild cognitive impairment (MCI) or mood-related neuropsychiatric symptoms (MrNPS), but many questions remain unresolved.

OBJECTIVE: To evaluate the extent to which CCT benefits older adults with both MCI and MrNPS, and its effects on meta-cognitive and non-cognitive outcomes, as well as establish whether adapting difficulty levels and tailoring to individuals' profile is superior to generic training.

METHODS: Older adults with MCI (n = 9), MrNPS (n = 11), or both (MCI+, n = 25) were randomized into a home-based individually-tailored and adaptive CCT (n = 21) or an active control condition (AC; n = 23) in a double-blind design. Interventions lasted 8-12 weeks and outcomes were assessed after the intervention, and at a 3-month follow-up.

RESULTS: Participants in both conditions reported greater satisfaction with their everyday memory following intervention and at follow-up. However, participants in the CCT condition showed greater improvement on composite measures of memory, learning, and global cognition at follow-up. Participants with MrNPS in the CCT condition were also found to have improved mood at 3-month follow-up and reported using fewer memory strategies at the post-intervention and follow-up assessments. There was no evidence that participants with MCI+ were disadvantaged relative to the other diagnostic conditions. Finally, informant-rated caregiver burden declined at follow-up assessment in the CCT condition relative to the AC condition.

CONCLUSIONS: Home-based CCT with adaptive difficulty and personal tailoring appears superior to more generic CCT in relation to both cognitive and non-cognitive outcomes. Mechanisms of treatment effect and future directions are discussed.

%B J Alzheimers Dis %V 60 %P 889-911 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922158?dopt=Abstract %R 10.3233/JAD-170404 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Targeted Metabolomic Analysis of Soluble Lysates from Platelets of Patients with Mild Cognitive Impairment and Alzheimer's Disease Compared to Healthy Controls: Is PC aeC40:4 a Promising Diagnostic Tool? %A Oberacher, Herbert %A Arnhard, Kathrin %A Linhart, Caroline %A Diwo, Angela %A Marksteiner, Josef %A Humpel, Christian %X

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system. The use of biological fluids in AD diagnosis remains limited to the analysis of specific protein biomarkers in cerebrospinal fluid. However, metabolomic analysis has recently revealed several metabolites in plasma, especially phosphatidylcholines (PC), as putative biomarkers specific for AD. Following on previous reports of platelet abnormalities in AD, we hypothesized that platelets metabolites released in plasma may offer new biomarkers in AD. The aim of the present study was to apply targeted metabolomics to compare metabolites in soluble lysates of platelets from healthy controls (CO), patients with mild cognitive impairment (MCI), and patients with AD in a cohort of 90 subjects. We could target 163 metabolites and quantitative data were obtained for 91 metabolites. Among these, the lipid PC aeC40:4 significantly differentiated AD from CO (p = 0.0009), while four other lipids (PC aaC32:0, PC ae C32:2, PC aeC34:1, and SM(OH)C14:1) differentiated patients with MCI from CO. The combination of three phosphatidylcholines (PC aeC32:2, PC aeC34:1, PCaaC36:5), two lyso-phosphatidylcholines (lysoPC aC18:1, lysoPC aC16:0), and one sphingomyelin (SM(OH) C14:1) constructed a valuable prediction model using the C4.5 decision tree. The diagnosis accuracy for AD versus CO and MCI was 85%. In a blinded follow up conversion study (10 patients with a second blood collection after 9 months), we could verify the clinical diagnosis in 19 out of 20 cases. We propose that soluble platelet PCaeC40:4 is a promising marker to diagnose AD with a cut-off of <0.30μM and that platelets undergo metabolic processes during AD progression.

%B J Alzheimers Dis %V 57 %P 493-504 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269764?dopt=Abstract %R 10.3233/JAD-160172 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases. %A Nilson, Ashley N %A English, Kelsey C %A Gerson, Julia E %A Whittle, T Barton %A Crain, C Nicolas %A Xue, Judy %A Sengupta, Urmi %A Castillo-Carranza, Diana L %A Zhang, Wenbo %A Gupta, Praveena %A Kayed, Rakez %X

It is well-established that inflammation plays an important role in Alzheimer's disease (AD) and frontotemporal lobar dementia (FTLD). Inflammation and synapse loss occur in disease prior to the formation of larger aggregates, but the contribution of tau to inflammation has not yet been thoroughly investigated. Tau pathologically aggregates to form large fibrillar structures known as tangles. However, evidence suggests that smaller soluble aggregates, called oligomers, are the most toxic species and form prior to tangles. Furthermore, tau oligomers can spread to neighboring cells and between anatomically connected brain regions. In addition, recent evidence suggests that inspecting the retina may be a window to brain pathology. We hypothesized that there is a relationship between tau oligomers and inflammation, which are hallmarks of early disease. We conducted immunofluorescence and biochemical analyses on tauopathy mice, FTLD, and AD subjects. We showed that oligomers co-localize with astrocytes, microglia, and HMGB1, a pro-inflammatory cytokine. Additionally, we show that tau oligomers are present in the retina and are associated with inflammatory cells suggesting that the retina may be a valid non-invasive biomarker for brain pathology. These results suggest that there may be a toxic relationship between tau oligomers and inflammation. Therefore, the ability of tau oligomers to spread may initiate a feed-forward cycle in which tau oligomers induce inflammation, leading to neuronal damage, and thus more inflammation. Further mechanistic studies are warranted in order to understand this relationship, which may have critical implications for improving the treatment of tauopathies.

%B J Alzheimers Dis %V 55 %P 1083-1099 %G ENG %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716675?dopt=Abstract %R 10.3233/JAD-160912 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tau Oligomers in Sera of Patients with Alzheimer's Disease and Aged Controls. %A Kolarova, Michala %A Sengupta, Urmi %A Bartos, Ales %A Ricny, Jan %A Kayed, Rakez %X

Although tau protein was long regarded as an intracellular protein with several functions inside the cell, new evidence has shown tau secretion into the extracellular space. The active secretion of tau could be a physiological response of neurons to increased intracellular amounts of tau during the progression of tau pathology. We looked for potential differences in the serum levels of toxic tau oligomers in regards to cognitive impairment of subjects. We detected tau oligomers in the serum of Alzheimer's disease (AD) patients, but they were also present to some extent in the serum of healthy older subjects where the levels positively correlated with aging (Spearman r = 0.26, p = 0.016). On the contrary, we found lower levels of tau oligomers in the serum of mild cognitive impairment (MCI) (p = 0.033) and MCI-AD (p = 0.006) patients. These results could suggest that clearance of extracellular tau proteins takes place, in part, in the periphery. In the case of MCI patients, the lower levels of tau oligomers could be the result of impaired clearance of tau protein from interstitium to blood and consequent accumulation of tau aggregates in the brain.

%B J Alzheimers Dis %V 58 %P 471-478 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453485?dopt=Abstract %R 10.3233/JAD-170048 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tau Pathology Promotes the Reorganization of the Extracellular Matrix and Inhibits the Formation of Perineuronal Nets by Regulating the Expression and the Distribution of Hyaluronic Acid Synthases. %A Li, Yin %A Li, Ze-Xu %A Jin, Tan %A Wang, Zhan-You %A Zhao, Pu %X

Hyaluronic acid (HA) is the backbone of the extracellular matrix (ECM) and provides biochemical and physical support to aggrecan-based perineuronal nets (PNNs), which are associated with the selective vulnerability of neurons in Alzheimer's disease (AD). Here, we showed that HA synthases (HASs), including Has1, Has2, and Has3, were widely expressed in murine central nervous system. All types of HASs were localized to cell bodies of neurons; only Has1 existed in the membranes of neural axons. By using TauP301S transgenic (Tg) mouse model, we found that the axonal-localization of Has1 was abolished in TauP301S overexpressed mouse brain, and the redistribution of Has1 was also observed in human AD brains, suggesting that the localization of Has1 is dependent on intact microtubules which are regulated partially by the phosphorylation and dephosphorylation cycles of tau proteins. Furthermore, Has1 was reduced and Has3 was increased in TauP301S Tg mouse brain, resulting in the upregulation of shorter-chain HA in the ECM. These findings suggest that by abolishing the axonal-localization of Has1 and promoting the expression of Has3 and the synthesis of shorter-chain HA, the tau pathology breaks the balance of ECM components, promotes the reorganization of the ECM, and inhibits the formation of PNNs in the hippocampus, and then regulates neuronal plasticity during the progression of AD.

%B J Alzheimers Dis %V 57 %P 395-409 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28234253?dopt=Abstract %R 10.3233/JAD-160804 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tau Platelets Correlate with Regional Brain Atrophy in Patients with Alzheimer's Disease. %A Slachevsky, Andrea %A Guzmán-Martínez, Leonardo %A Delgado, Carolina %A Reyes, Pablo %A Farías, Gonzalo A %A Muñoz-Neira, Carlos %A Bravo, Eduardo %A Farías, Mauricio %A Flores, Patricia %A Garrido, Cristian %A Becker, James T %A Lopez, Oscar L %A Maccioni, Ricardo B %X

BACKGROUND: Intracellular neurofibrillary tangles are part of the core pathology of Alzheimer's disease (AD), which are mainly composed of hyperphosphorylated tau protein.

OBJECTIVES: The purpose of this study is to determine whether high molecular weight (HMW) or low molecular weight (LMW) tau protein levels, as well as the ratio HMW/LMW, present in platelets correlates with brain magnetic resonance imaging (MRI) structural changes in normal and cognitively impaired subjects.

METHODS: We examined 53 AD patients and 37 cognitively normal subjects recruited from two Memory Clinics at the Universidad de Chile. Tau levels in platelets were determined by immunoreactivity and the MRI scans were analyzed using voxel-based morphometry in 41 AD patients.

RESULTS: The HMW/LMW tau ratio was statistically different between controls and AD patients, and no associations were noted between HMW or LMW tau and MRI structures. In a multivariate analysis controlled for age and education level, the HMW/LMW tau ratio was associated with reduced volume in the left medial and right anterior cingulate gyri, right cerebellum, right thalamus (pulvinar), left frontal cortex, and right parahippocampal region.

CONCLUSIONS: This exploratory study showed that HMW/LMW tau ratio is significantly higher in AD patients than control subjects, and that it is associated with specific brain regions atrophy. Determination of peripheral markers of AD pathology can help understanding the pathophysiology of neurodegeneration in AD.

%B J Alzheimers Dis %V 55 %P 1595-1603 %G eng %N 4 %R 10.3233/JAD-160652 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tau Proteins Cross the Blood-Brain Barrier. %A Banks, William A %A Kovac, Andrej %A Majerova, Petra %A Bullock, Kristin M %A Shi, Min %A Zhang, Jing %X

Tauopathies are a hallmark of many neurodegenerative diseases, including Alzheimer's disease and traumatic brain injuries. It has been demonstrated that amyloid-beta peptides, alpha-synuclein, and prion proteins cross the blood-brain barrier (BBB), contributing to their abilities to induce disease. Very little is known about whether tau proteins can cross the BBB. Here we systematically characterized several key forms of tau proteins to cross the BBB, including Tau-441 (2N4R), Tau-410 (2N3R), truncated tau 151-391 (0N4R), and truncated tau 121-227. All of these tau proteins crossed the BBB readily and bidirectonally; however, only Tau-410 had a saturable component to its influx. The tau proteins also entered the blood after their injection into the brain, with Tau 121-227 having the slowest exit from brain. The tau proteins varied in regards to their enzymatic stability in brain and blood and in their peripheral pharmacokinetics. These results show that blood-borne tau proteins could contribute to brain tauopathies. The result also suggest that the CNS can contribute to blood levels of tau, raising the possibility that, as suggested for other misfolded proteins, blood levels of tau proteins could be used as a biomarker of CNS disease.

%B J Alzheimers Dis %V 55 %P 411-419 %8 2016 Sep 20 %G eng %N 1 %R 10.3233/JAD-160542 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tau Rather than TDP-43 Proteins are Potential Cerebrospinal Fluid Biomarkers for Frontotemporal Lobar Degeneration Subtypes: A Pilot Study. %A Kuiperij, H Bea %A Versleijen, Alexandra A M %A Beenes, Marijke %A Verwey, Nicolaas A %A Benussi, Luisa %A Paterlini, Anna %A Binetti, Giuliano %A Teunissen, Charlotte E %A Raaphorst, Joost %A Schelhaas, Helenius J %A Küsters, Benno %A Pijnenburg, Yolande A L %A Ghidoni, Roberta %A Verbeek, Marcel M %X

BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous disease both at the clinical, genetic, and pathobiological level. The underlying pathological spectrum (termed FTLD, frontotemporal lobar degeneration) is in most cases defined by accumulation of either tau (FTLD-tau) or TDP-43 proteins (FTLD-TDP). Biomarkers to differentiate these subtypes are not yet available, whereas these are essential requirements to study the natural course of disease and for homogeneous inclusion of patients in clinical studies.

OBJECTIVE: To study if a combination of total (t-) and phosphorylated (p-)tau, and t-TDP-43 and p-TDP-43 proteins in cerebrospinal fluid (CSF) is suitable to discriminate FTLD-tau and FTLD-TDP subtypes.

METHODS: We developed immunoassays for the quantification of t-TDP-43 and p-TDP-43 proteins and used commercially available assays for the quantification of t-tau and p-tau proteins. We quantified these proteins in ventricular CSF samples from neuropathologically defined FTLD-tau and FTLD-TDP cases to study the reflection of underlying brain pathology in CSF composition, and in lumbar CSF samples from FTLD-tau and FTLD-TDP patients to study the diagnostic potential of CSF biomarkers.

RESULTS: In ventricular CSF, t-TDP-43 and t-tau levels, when combined into one model, were significantly different between neuropathologically-defined FTLD-tau and FTLD-TDP cases. In a pilot study using lumbar CSF, the p-tau/t-tau ratio, but not t-TDP-43 levels, were significantly different between FTLD-TDP and FTLD-tau patients.

CONCLUSION: We conclude that with current available methods, CSF tau, rather than TDP-43 proteins, may have diagnostic value in the differentiation of FTLD patients with either tau or TDP-43 pathology.

%B J Alzheimers Dis %V 55 %P 585-595 %G eng %N 2 %R 10.3233/JAD-160386 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Temporal Order of Alzheimer's Disease-Related Cognitive Marker Changes in BLSA and WRAP Longitudinal Studies. %A Bilgel, Murat %A Koscik, Rebecca L %A An, Yang %A Prince, Jerry L %A Resnick, Susan M %A Johnson, Sterling C %A Jedynak, Bruno M %X

Investigation of the temporal trajectories of currently used neuropsychological tests is critical to identifying earliest changing measures on the path to dementia due to Alzheimer's disease (AD). We used the Progression Score (PS) method to characterize the temporal trajectories of measures of verbal memory, executive function, attention, processing speed, language, and mental status using data spanning normal cognition, mild cognitive impairment, and AD from 1,661 participants with a total of 7,839 visits (age at last visit 77.6 SD 9.2) in the Baltimore Longitudinal Study of Aging (BLSA) and 1510 participants with a total of 3,473 visits (age at last visit 59.5 SD 7.4) in the Wisconsin Registry for Alzheimer's Prevention (WRAP). This method aligns individuals in time based on the similarity of their longitudinal measurements to reveal temporal trajectories. As a validation of our methodology, we explored the associations between the individualized cognitive progression scores (Cog-PS) computed by our method and clinical diagnosis. Digit span tests were the first to show declines in both data sets, and were detected mainly among cognitively normal individuals. These were followed by tests of verbal memory, which were in turn followed by Trail Making Tests, Boston Naming Test, and Mini-Mental State Examination. Differences in Cog-PS across the clinical diagnosis and APOEɛ4 groups were statistically significant, highlighting the potential use of Cog-PS as individualized indicators of disease progression. Identifying cognitive measures that are changing in preclinical AD can lead to the development of novel cognitive tests that are finely tuned to detecting earliest changes.

%B J Alzheimers Dis %V 59 %P 1335-1347 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731452?dopt=Abstract %R 10.3233/JAD-170448 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Ten Challenges of the Amyloid Hypothesis of Alzheimer's Disease. %A Kepp, Kasper Planeta %X

The inability to effectively halt or cure Alzheimer's disease (AD), exacerbated by the recent failures of high-profile clinical trials, emphasizes the urgent need to understand the complex biochemistry of this major neurodegenerative disease. In this paper, ten central, current challenges of the major paradigm in the field, the amyloid hypothesis, are sharply formulated. These challenges together show that new approaches are necessary that address data heterogeneity, increase focus on the proteome level, use available human patient data more actively, account for the aging phenotype as a background model of the disease, unify our understanding of the interplay between genetic and non-genetic risk factors, and combine into one framework both the familial and sporadic forms of the disease.

%B J Alzheimers Dis %V 55 %P 447-457 %G eng %N 2 %R 10.3233/JAD-160550 %0 Journal Article %J J Alzheimers Dis %D 2017 %T TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5/p25, Attenuates Pathological Phenotypes and Restores Synaptic Function in CK-p25Tg Mice. %A Shukla, Varsha %A Seo, Jinsoo %A Binukumar, B K %A Amin, Niranjana D %A Reddy, Preethi %A Grant, Philip %A Kuntz, Susan %A Kesavapany, Sashi %A Steiner, Joseph %A Mishra, Santosh K %A Tsai, Li-Huei %A Pant, Harish C %X

It has been reported that cyclin-dependent kinase 5 (cdk5), a critical neuronal kinase, is hyperactivated in Alzheimer's disease (AD) and may be, in part, responsible for the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs). It has been proposed by several laboratories that hyperactive cdk5 results from the overexpression of p25 (a truncated fragment of p35, the normal cdk5 regulator), which, when complexed to cdk5, induces hyperactivity, hyperphosphorylated tau/NFTs, amyloid-β plaques, and neuronal death. It has previously been shown that intraperitoneal (i.p.) injections of a modified truncated 24-aa peptide (TFP5), derived from the cdk5 activator p35, penetrated the blood-brain barrier and significantly rescued AD-like pathology in 5XFAD model mice. The principal pathology in the 5XFAD mutant, however, is extensive amyloid plaques; hence, as a proof of concept, we believe it is essential to demonstrate the peptide's efficacy in a mouse model expressing high levels of p25, such as the inducible CK-p25Tg model mouse that overexpresses p25 in CamKII positive neurons. Using a modified TFP5 treatment, here we show that peptide i.p. injections in these mice decrease cdk5 hyperactivity, tau, neurofilament-M/H hyperphosphorylation, and restore synaptic function and behavior (i.e., spatial working memory, motor deficit using Rota-rod). It is noteworthy that TFP5 does not inhibit endogenous cdk5/p35 activity, nor other cdks in vivo suggesting it might have no toxic side effects, and may serve as an excellent therapeutic candidate for neurodegenerative disorders expressing abnormally high brain levels of p25 and hyperactive cdk5.

%B J Alzheimers Dis %V 56 %P 335-349 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28085018?dopt=Abstract %R 10.3233/JAD-160916 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Theobromine-Induced Changes in A1 Purinergic Receptor Gene Expression and Distribution in a Rat Brain Alzheimer's Disease Model. %A Mendiola-Precoma, Jesus %A Padilla, Karla %A Rodríguez-Cruz, Alfredo %A Berumen, Laura C %A Miledi, Ricardo %A García-Alcocer, Guadalupe %X

Dementia caused by Alzheimer's disease (AD) is mainly characterized by accumulation in the brain of extra- and intraneuronal amyloid-β (Aβ) and tau proteins, respectively, which selectively affect specific regions, particularly the neocortex and the hippocampus. Sporadic AD is mainly caused by an increase in apolipoprotein E, a component of chylomicrons, which are cholesterol transporters in the brain. Recent studies have shown that high lipid levels, especially cholesterol, are linked to AD. Adenosine is an atypical neurotransmitter that regulates a wide range of physiological functions by activating four P1 receptors (A1, A2A, A2B, and A3) and P2 purinergic receptors that are G protein-coupled. A1 receptors are involved in the inhibition of neurotransmitter release, which could be related to AD. The aim of the present work was to study the effects of a lard-enriched diet (LED) on cognitive and memory processes in adult rats (6 months of age) as well as the effect of theobromine on these processes. The results indicated that the fat-enriched diet resulted in a long-term deterioration in cognitive and memory functions. Increased levels of Aβ protein and IL-1β were also observed in the rats fed with a high-cholesterol diet, which were used to validate the AD animal model. In addition, the results of qPCR and immunohistochemistry indicated a decrease in gene expression and distribution of A1 purinegic receptor, respectively, in the hippocampus of LED-fed rats. Interestingly, theobromine, at both concentrations tested, restored A1 receptor levels and improved cognitive functions and Aβ levels for a dose of 30 mg/L drinking water.

%B J Alzheimers Dis %V 55 %P 1273-1283 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27792010?dopt=Abstract %R 10.3233/JAD-160569 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Therapeutics of Neurotransmitters in Alzheimer's Disease. %A Kandimalla, Ramesh %A Reddy, P Hemachandra %X

Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterized by the loss of memory, multiple cognitive impairments and changes in the personality and behavior. Several decades of intense research have revealed that multiple cellular changes are involved in disease process, including synaptic damage, mitochondrial abnormalities and inflammatory responses, in addition to formation and accumulation of amyloid-β (Aβ) and phosphorylated tau. Although tremendous progress has been made in understanding the impact of neurotransmitters in the progression and pathogenesis of AD, we still do not have a drug molecule associated with neurotransmitter(s) that can delay disease process in elderly individuals and/or restore cognitive functions in AD patients. The purpose of our article is to assess the latest developments in neurotransmitters research using cell and mouse models of AD. We also updated the current status of clinical trials using neurotransmitters' agonists/antagonists in AD.

%B J Alzheimers Dis %V 57 %P 1049-1069 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28211810?dopt=Abstract %R 10.3233/JAD-161118 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Three-Repeat Tau with Grain-Like Structures and Distribution in an 83-Year-Old Man. %A Kasahata, Naoki %A Sato, Tomohide %A Onishi, Iichiroh %A Kitagawa, Masanobu %A Uchihara, Toshiki %A Hirokawa, Katsuiku %X

We encountered an 83-year-old man with 3-repeat dominant grain-like tau deposition. Tau-positive lesions exhibited apparent similarity to argyrophilic grains in terms of their distribution in the ambient gyrus, amygdala, and dorsomedial temporal tip and the characteristic comma-like morphology. The abundant oligodendroglial tau immunoreactivities were 3-repeat dominant. Tuft-shaped astrocytes showed partial 3-repeat tau immnoreactivities. These grain-like structures, as well as tuft-shaped astrocytes and oligodendroglia, exhibited predominant 3-repeat tau immunoreactivity, suggesting that grain-like structures and their characteristic distribution are mutually linked and not unique to 4-repeat tau deposition. pTDP immunoreactivity, extensive macrophage infiltration, and spongiosis were associated with these 3-repeat tau deposits.

%B J Alzheimers Dis %V 58 %P 681-685 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453470?dopt=Abstract %R 10.3233/JAD-160672 %0 Journal Article %J J Alzheimers Dis %D 2017 %T TMEM230 Accumulation in Granulovacuolar Degeneration Bodies and Dystrophic Neurites of Alzheimer's Disease. %A Siedlak, Sandra L %A Jiang, Yinfei %A Huntley, Mikayla L %A Wang, Luwen %A Gao, Ju %A Xie, Fei %A Liu, Jingyi %A Su, Bo %A Perry, George %A Wang, Xinglong %X

Transmembrane Protein 230 (TMEM230) is a newly identified protein associated with Parkinson's disease (PD) found in Lewy bodies and Lewy neurites of patients with PD or dementia with Lewy body disease. However, TMEM230 has not yet been investigated in the most common neurodegenerative disorder, Alzheimer's disease (AD). Here, we demonstrate that the expression of TMEM230 is specifically increased in neurons in AD patients. Importantly, both granulovacuolar degeneration (GVD) and dystrophic neurites (DNs), two prominent characteristic pathological structures associated with AD, contain TMEM230 aggregates. TMEM230 immunoreactivity can be detected in neurofibrillary tangles-containing neurons and hyperphosphorylated tau positive DNs. TMEM230 accumulation is also noted around senile plaques. These findings identifying TMEM230 as a component of GVD and DNs suggest TMEM230 dysregulation as a likely mechanism playing an important role in the pathogenesis of AD.

%B J Alzheimers Dis %V 58 %P 1027-1033 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527219?dopt=Abstract %R 10.3233/JAD-170190 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tocotrienol-Rich Fraction Modulates Amyloid Pathology and Improves Cognitive Function in AβPP/PS1 Mice. %A Ibrahim, Nor Faeizah %A Yanagisawa, Daijiro %A Durani, Lina Wati %A Hamezah, Hamizah Shahirah %A Damanhuri, Hanafi Ahmad %A Wan Ngah, Wan Zurinah %A Tsuji, Mayumi %A Kiuchi, Yuji %A Ono, Kenjiro %A Tooyama, Ikuo %X

Alzheimer's disease (AD) is the most common cause of dementia. The cardinal neuropathological characteristic of AD is the accumulation of amyloid-β (Aβ) into extracellular plaques that ultimately disrupt neuronal function and lead to neurodegeneration. One possible therapeutic strategy therefore is to prevent Aβ aggregation. Previous studies have suggested that vitamin E analogs slow AD progression in humans. In the present study, we investigated the effects of the tocotrienol-rich fraction (TRF), a mixture of vitamin E analogs from palm oil, on amyloid pathology in vitro and in vivo. TRF treatment dose-dependently inhibited the formation of Aβ fibrils and Aβ oligomers in vitro. Moreover, daily TRF supplementation to AβPPswe/PS1dE9 double transgenic mice for 10 months attenuated Aβ immunoreactive depositions and thioflavin-S-positive fibrillar type plaques in the brain, and eventually improved cognitive function in the novel object recognition test compared with control AβPPswe/PS1dE9 mice. The present result indicates that TRF reduced amyloid pathology and improved cognitive functions, and suggests that TRF is a potential therapeutic agent for AD.

%B J Alzheimers Dis %V 55 %P 597-612 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716672?dopt=Abstract %R 10.3233/JAD-160685 %0 Journal Article %J J Alzheimers Dis %D 2017 %T TOMM40 and APOE Gene Expression and Cognitive Decline in Japanese Alzheimer's Disease Subjects. %A Mise, Ayano %A Yoshino, Yuta %A Yamazaki, Kiyohiro %A Ozaki, Yuki %A Sao, Tomoko %A Yoshida, Taku %A Mori, Takaaki %A Mori, Yoko %A Ochi, Shinichiro %A Iga, Jun-Ichi %A Ueno, Shu-Ichi %X

BACKGROUND: TOMM40 is located on chromosome 19, is in linkage disequilibrium with apolipoprotein E (APOE), andis reported in several genome-wide association studies to be associated with Alzheimer's disease (AD).

OBJECTIVE: Assess APOE and TOM40 and mitochondrial genes as blood biomarkers for AD.

METHODS: We examined TOMM40, PTEN-induced putative kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (PARK2), and APOE mRNA expression in relation to the methylation rates of CpG sites in the upstream region of TOMM40exon 1 in peripheral leukocytes and TOMM40523 polyT genotypes in 60 AD and age- and sex-matched control subjects.

RESULTS: TOMM40 mRNA expression was significantly lower in AD subjects (0.87±0.18 versus 1.0±0.23, p = 0.005), and PINK1 mRNA expression was higher in AD subjects (1.5±0.61 versus 1.0±0.52, p < 0.001). TOMM40 mRNA expression was significantly correlated with the Mini-Mental State Examination total score (r = 0.290, p = 0.027). There was no expressional change in peripheral APOE mRNA in either AD or control subjects (p = 0.32). Methylation rates in the upstream region of TOMM40exon 1 were not different between AD and control subjects (average rate: 1.37±0.99 versus 1.39±1.20, p = 0.885), and TOMM40523 polyT genotypes were also not different between AD and control subjects (p = 0.67).

CONCLUSION: TOMM40 mRNA expression was lower in AD subjects and was correlated with cognitive decline. Significant changes in both TOMM40 and PINK1 mRNA may be related to mitochondrial dysfunction.

%B J Alzheimers Dis %V 60 %P 1107-1117 %8 2017 %G eng %N 3 %R 10.3233/JAD-170361 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Topological Alterations and Symptom-Relevant Modules in the Whole-Brain Structural Network in Semantic Dementia. %A Ding, Junhua %A Chen, Keliang %A Zhang, Weibin %A Li, Ming %A Chen, Yan %A Yang, Qing %A Lv, Yingru %A Guo, Qihao %A Han, Zaizhu %X

BACKGROUND: Semantic dementia (SD) is characterized by a selective decline in semantic processing. Although the neuropsychological pattern of this disease has been identified, its topological global alterations and symptom-relevant modules in the whole-brain anatomical network have not been fully elucidated.

OBJECTIVE: This study aims to explore the topological alteration of anatomical network in SD and reveal the modules associated with semantic deficits in this disease.

METHODS: We first constructed the whole-brain white-matter networks of 20 healthy controls and 19 patients with SD. Then, the network metrics of graph theory were compared between these two groups. Finally, we separated the network of SD patients into different modules and correlated the structural integrity of each module with the severity of the semantic deficits across patients.

RESULTS: The network of the SD patients presented a significantly reduced global efficiency, indicating that the long-distance connections were damaged. The network was divided into the following four distinctive modules: the left temporal/occipital/parietal, frontal, right temporal/occipital, and frontal/parietal modules. The first two modules were associated with the semantic deficits of SD.

CONCLUSION: These findings illustrate the skeleton of the neuroanatomical network of SD patients and highlight the key role of the left temporal/occipital/parietal module and the left frontal module in semantic processing.

%B J Alzheimers Dis %V 59 %P 1283-1297 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731453?dopt=Abstract %R 10.3233/JAD-170449 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Toward the Automation of Diagnostic Conversation Analysis in Patients with Memory Complaints. %A Mirheidari, Bahman %A Blackburn, Daniel %A Harkness, Kirsty %A Walker, Traci %A Venneri, Annalena %A Reuber, Markus %A Christensen, Heidi %X

BACKGROUND: The early diagnosis of dementia is of great clinical and social importance. A recent study using the qualitative methodology of conversation analysis (CA) demonstrated that language and communication problems are evident during interactions between patients and neurologists, and that interactional observations can be used to differentiate between cognitive difficulties due to neurodegenerative disorders (ND) or functional memory disorders (FMD).

OBJECTIVE: This study explores whether the differential diagnostic analysis of doctor-patient interactions in a memory clinic can be automated.

METHODS: Verbatim transcripts of conversations between neurologists and patients initially presenting with memory problems to a specialist clinic were produced manually (15 with FMD, and 15 with ND). A range of automatically detectable features focusing on acoustic, lexical, semantic, and visual information contained in the transcripts were defined aiming to replicate the diagnostic qualitative observations. The features were used to train a set of five machine learning classifiers to distinguish between ND and FMD.

RESULTS: The mean rate of correct classification between ND and FMD was 93% ranging from 97% by the Perceptron classifier to 90% by the Random Forest classifier.Using only the ten best features, the mean correct classification score increased to 95%.

CONCLUSION: This pilot study provides proof-of-principle that a machine learning approach to analyzing transcripts of interactions between neurologists and patients describing memory problems can distinguish people with neurodegenerative dementia from people with FMD.

%B J Alzheimers Dis %V 58 %P 373-387 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28436388?dopt=Abstract %R 10.3233/JAD-160507 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Trajectories of Multidimensional Caregiver Burden in Chinese Informal Caregivers for Dementia: Evidence from Exploratory and Confirmatory Factor Analysis of the Zarit Burden Interview. %A Li, Dan %A Hu, Nan %A Yu, Yueyi %A Zhou, Aihong %A Li, Fangyu %A Jia, Jianping %X

BACKGROUND: Despite its popularity, the latent structure of 22-item Zarit Burden Interview (ZBI) remains unclear. There has been no study exploring how caregiver multidimensional burden changed.

OBJECTIVE: The aim of the work was to validate the latent structure of ZBI and to investigate how multidimensional burden evolves with increasing global burden.

METHODS: We studied 1,132 dyads of dementia patients and their informal caregivers. The caregivers completed the ZBI and a questionnaire regarding caregiving. The total sample was randomly split into two equal subsamples. Exploratory factor analysis (EFA) was performed in the first subsample. In the second subsample, confirmatory factor analysis (CFA) was conducted to validate models generated from EFA. The mean of weighted factor score was calculated to assess the change of dimension burden against the increasing ZBI total score.

RESULTS: The result of EFA and CFA supported that a five-factor structure, including role strain, personal strain, incompetency, dependency, and guilt, had the best goodness-of-fit. The trajectories of multidimensional burden suggested that three different dimensions (guilt, role strain and personal strain) became the main subtype of burden in sequence as the ZBI total score increased from mild to moderate. Factor dependency contributed prominently to the total burden in severe stage.

CONCLUSION: The five-factor ZBI is a psychometrically robust measure for assessing multidimensional burden in Chinese caregivers. The changes of multidimensional burden have deepened our understanding of the psychological characteristics of caregiving beyond a single total score and may be useful for developing interventions to reduce caregiver burden.

%B J Alzheimers Dis %V 59 %P 1317-1325 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28759966?dopt=Abstract %R 10.3233/JAD-170172 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Transactive DNA Binding Protein 43 Rather Than Other Misfolded Proteins in the Brain is Associated with Islet Amyloid Polypeptide in Pancreas in Aged Subjects with Diabetes Mellitus. %A Leino, Marina %A Popova, Svetlana N %A Alafuzoff, Irina %X

A link between diabetes mellitus (DM) related islet amyloid polypeptide (IAPP) and Alzheimer's disease (AD) related amyloid-β (Aβ) has been suggested in epidemiological and clinical studies. In 2017, proof for existing interaction between type 2 DM and AD on a molecular level was provided based on research carried out in experimental animal models. We assessed aging-related neurodegenerative lesions, i.e., misfolded proteins, associated with dementia such as hyperphosphorylated τ (HPτ), Aβ, α-synuclein (αS), and phosphorylated transactive DNA binding protein 43 (pTDP43) seen in the brain and IAPP seen in the pancreas in subjects with and without DM applying immunohistochemical techniques. HPτ in the brain and IAPP in the pancreas were observed in most subjects. The prevalence and the extent of all misfolded proteins increased with age but this increase was not influenced by DM. Interestingly the extent of misfolded proteins in the brain was higher in non-diabetics when compared with diabetics in demented. A significant correlation was observed between HPτ, Aβ, αS, and pTDP43, whereas IAPP showed no association with HPτ, Aβ, and αS. In subjects with DM, the extent of pTDP43 in brain correlated with the extent of IAPP in pancreas. Thus, there is no evidence of a link between AD-related pathology and DM in humans, whereas an association was found between pTDP43 and IAPP in DM. TDP43 is ubiquitously expressed in all organs but whether TDP43 is phosphorylated in other organs in DM or whether the phosphorylation of TDP43 is influenced by glucose metabolism is yet unknown.

%B J Alzheimers Dis %V 59 %P 43-56 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582864?dopt=Abstract %R 10.3233/JAD-170192 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Translational MRI Volumetry with NeuroQuant: Effects of Version and Normative Data on Relationships with Memory Performance in Healthy Older Adults and Patients with Mild Cognitive Impairment. %A Stelmokas, Julija %A Yassay, Lance %A Giordani, Bruno %A Dodge, Hiroko H %A Dinov, Ivo D %A Bhaumik, Arijit %A Sathian, K %A Hampstead, Benjamin M %X

NeuroQuant (NQ) is a fully-automated program that overcomes several existing limitations in the clinical translation of MRI-derived volumetry. The current study characterized differences between the original (NQ1) and an updated NQ version (NQ2) by 1) replicating previously identified relationships between neuropsychological test performance and medial temporal lobe volumes, 2) evaluating the level of agreement between NQ versions, and 3) determining if the addition of NQ2 age-/sex-based z-scores hold greater clinical utility for prediction of memory impairment than standard percent of intracranial volume (% ICV) values. Sixty-seven healthy older adults and 65 mild cognitive impairment patients underwent structural MRI and completed cognitive testing, including the Immediate and Delayed Memory indices from the Repeatable Battery for the Assessment of Neuropsychological Status. Results generally replicated previous relationships between key medial temporal lobe regions and memory test performance, though comparison of NQ regions revealed statistically different values that were biased toward one version or the other depending on the region. NQ2 hippocampal z-scores explained additional variance in memory performance relative to % ICV values. Findings indicate that NQ1/2 medial temporal lobe volumes, especially age- and sex-based z-scores, hold clinical value, though caution is warranted when directly comparing volumes across NQ versions.

%B J Alzheimers Dis %V 60 %P 1499-1510 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29060939?dopt=Abstract %R 10.3233/JAD-170306 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Transport of Non-Transferrin Bound Iron to the Brain: Implications for Alzheimer's Disease. %A Tripathi, Ajai K %A Karmakar, Shilpita %A Asthana, Abhishek %A Ashok, Ajay %A Desai, Vilok %A Baksi, Shounak %A Singh, Neena %X

A direct correlation between brain iron and Alzheimer's disease (AD) raises questions regarding the transport of non-transferrin-bound iron (NTBI), a toxic but less researched pool of circulating iron that is likely to increase due to pathological and/or iatrogenic systemic iron overload. Here, we compared the distribution of radiolabeled-NTBI (59Fe-NTBI) and transferrin-bound iron (59Fe-Tf) in mouse models of iron overload in the absence or presence of inflammation. Following a short pulse, most of the 59Fe-NTBI was taken up by the liver, followed by the kidney, pancreas, and heart. Notably, a strong signal of 59Fe-NTBI was detected in the brain ventricular system after 2 h, and the brain parenchyma after 24 h. 59Fe-Tf accumulated mainly in the femur and spleen, and was transported to the brain at a much slower rate than 59Fe-NTBI. In the kidney, 59Fe-NTBI was detected in the cortex after 2 h, and outer medulla after 24 hours. Most of the 59Fe-NTBI and 59Fe-Tf from the kidney was reabsorbed; negligible amount was excreted in the urine. Acute inflammation increased the uptake of 59Fe-NTBI by the kidney and brain from 2-24 hours. Chronic inflammation, on the other hand, resulted in sequestration of iron in the liver and kidney, reducing its transport to the brain. These observations provide direct evidence for the transport of NTBI to the brain, and reveal a complex interplay between inflammation and brain iron homeostasis. Further studies are necessary to determine whether transient increase in NTBI due to systemic iron overload is a risk factor for AD.

%B J Alzheimers Dis %V 58 %P 1109-1119 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550259?dopt=Abstract %R 10.3233/JAD-170097 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Treadmill Exercise Exerts Neuroprotection and Regulates Microglial Polarization and Oxidative Stress in a Streptozotocin-Induced Rat Model of Sporadic Alzheimer's Disease. %A Lu, Yujiao %A Dong, Yan %A Tucker, Donovan %A Wang, Ruimin %A Ahmed, Mohammad Ejaz %A Brann, Darrell %A Zhang, Quanguang %X

Recent work has suggested that exercise may be beneficial in preventing or ameliorating symptoms of several neurological disorders, although the mechanism is not entirely understood. The current study was designed to examine the potential beneficial effect of treadmill exercise upon cognitive function in a streptozotocin (STZ)-induced rat model of Alzheimer's disease (AD). Animals underwent treadmill exercise (30 min/day, 5 days/week) for 4 weeks after bilateral STZ intracerebroventricular injection (2.4 mg/kg). We demonstrated that treadmill exercise significantly attenuated STZ-induced neurodegeneration in the rat hippocampal CA1 region and strongly preserved hippocampal-dependent cognitive functioning. Further mechanistic investigation displayed a marked suppression of STZ-induced amyloid-β accumulation and tau phosphorylation. Intriguingly, treadmill exercise remarkably inhibited reactive gliosis following STZ insult and effectively shifted activated microglia from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype, which was correlated with a significantly reduced expression of pro-inflammatory mediators and a corresponding enhancement of anti-inflammatory cytokine expression in the hippocampus. Furthermore, treadmill exercise caused a robust suppression of oxidative damage as evidenced by significantly reduced peroxynitrite production, lipid peroxidation, and oxidized DNA damage. Finally, treadmill exercise strongly attenuated STZ-induced mitochondrial dysfunction manifested by a dramatically elevated intra-mitochondrial cytochrome c oxidase activity and ATP synthesis, and markedly inhibited neuronal apoptosis in the hippocampus. These findings demonstrate that treadmill exercise has a multifactorial effect to attenuate many of the pathological processes that play a key role in AD, and provide further support for the beneficial role of exercise as a potential therapeutic option in AD treatment.

%B J Alzheimers Dis %V 56 %P 1469-1484 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157094?dopt=Abstract %R 10.3233/JAD-160869 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Trehalose Improves Cognition in the Transgenic Tg2576 Mouse Model of Alzheimer's Disease. %A Portbury, Stuart D %A Hare, Dominic J %A Sgambelloni, Charlotte %A Perronnes, Kali %A Portbury, Ashley J %A Finkelstein, David I %A Adlard, Paul A %X

This study assessed the therapeutic utility of the autophagy enhancing stable disaccharide trehalose in the Tg2576 transgenic mouse model of Alzheimer's disease (AD) via an oral gavage of a 2% trehalose solution for 31 days. Furthermore, as AD is a neurodegenerative condition in which the transition metals, iron, copper, and zinc, are understood to be intricately involved in the cellular cascades leading to the defining pathologies of the disease, we sought to determine any parallel impact of trehalose treatment on metal levels. Trehalose treatment significantly improved performance in the Morris water maze, consistent with enhanced learning and memory. The improvement was not associated with significant modulation of full length amyloid-β protein precursor or other amyloid-β fragments. Trehalose had no effect on autophagy as assessed by western blot of the LC3-1 to LC3-2 protein ratio, and no alteration in biometals that might account for the improved cognition was observed. Biochemical analysis revealed a significant increase in the hippocampus of both synaptophysin, a synaptic vesicle protein and surrogate marker of synapses, and doublecortin, a reliable marker of neurogenesis. The growth factor progranulin was also significantly increased in the hippocampus and cortex with trehalose treatment. This study suggests that trehalose might invoke a suite of neuroprotective mechanisms that can contribute to improved cognitive performance in AD that are independent of more classical trehalose-mediated pathways, such as Aβ reduction and activation of autophagy. Thus, trehalose may have utility as a potential AD therapeutic, with conceivable implications for the treatment of other neurodegenerative disorders.

%B J Alzheimers Dis %V 60 %P 549-560 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869469?dopt=Abstract %R 10.3233/JAD-170322 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Trends, Predictors, and Outcomes of Healthcare Resources Used in Patients Hospitalized with Alzheimer's Disease with at Least One Procedure: The Nationwide Inpatient Sample. %A Beydoun, May A %A Gamaldo, Alyssa A %A Beydoun, Hind A %A Shaked, Danielle %A Zonderman, Alan B %A Eid, Shaker M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Female %K Health Resources %K Hospitalization %K Humans %K Inpatients %K Length of Stay %K Male %K Middle Aged %K Morbidity %K Outcome Assessment (Health Care) %K Predictive Value of Tests %K United States %X

We assessed trends, predictors and outcomes of resource utilization in hospital inpatient discharges with a principal diagnosis of Alzheimer's disease (AD) with at least one procedure. Using Nationwide Inpatient Sample data (NIS, 2002-2012), discharges primarily diagnosed with AD, aged ≥60 y and with ≥1 procedure, were selected (Weighted N = 92,300). Hospital resource utilization were assessed using ICD-9-CM codes, while hospitalization outcomes included total charges (TC, 2012$), length of stay (LOS, days), and mortality risk (MR, %). Brain and respiratory/gastrointestinal procedure utilization both dropped annually by 3-7%, while cardiovascular procedures/evaluations, blood evaluations, blood transfusion, and resuscitation ("CVD/Blood") as well as neurophysiological and psychological evaluation and treatment ("Neuro") procedures increased by 5-8%. Total charges, length of stay, and mortality risk were all markedly higher with use of respiratory/gastrointestinal procedures as opposed to being reduced with use of "Brain" procedures. Procedure count was positively associated with all three hospitalization outcomes. In sum, patterns of hospital resources that were used among AD inpatients changed over-time, and were associated with hospitalization outcomes such as total charges, length of stay, and mortality risk.

%B J Alzheimers Dis %V 57 %P 813-824 %8 2017 %G eng %N 3 %R 10.3233/JAD-161225 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Triceps and Subscapular Skinfold in Men Aged 40-65 and Dementia Prevalence 36 Years Later. %A Ravona-Springer, Ramit %A Schnaider-Beeri, Michal %A Goldbourt, Uri %K Adipose Tissue %K Aged %K Anthropometry %K Arm %K Body Mass Index %K Dementia %K Exercise %K Humans %K Israel %K Leisure Activities %K Longitudinal Studies %K Male %K Middle Aged %K Muscle, Skeletal %K Obesity %K Odds Ratio %K Prevalence %K Shoulder %K Skinfold Thickness %K Social Class %X

BACKGROUND: The relationship of obesity with risk for dementia is complex and may change with age.

OBJECTIVE: To analyze the relationship between measures of obesity at age 40-65 and dementia prevalence in survivors 36 years later.

METHODS: Obesity-related measures of triceps and subscapular skinfold thickness were assessed in 1963 in n = 9,760 men aged 40-65 participating in the Israel Ischemic Heart Disease study. Cognitive evaluation and assessment of dementia prevalence were performed in n = 1,643 participants of the original cohort who survived until 1999/2000 (age ≥76 years) and had anthropometric measures in 1963.

RESULTS: Age-adjusted prevalence of dementia in survivors in 1999/2000 by baseline triceps skinfold quintile was 20.5%, 21.2%, 17.6%, 15.6%, and 14.5%, respectively, from lowest to highest (p = 0.006 in trend test). Using logistic regression, a 6-mm increment of triceps skinfold was associated with an age and BMI-adjusted odds ratio of 0.81 (95% CI, 0.70-0.94) for dementia prevalence among survivors. Age-adjusted risk for dementia by subscapular skinfold quintile demonstrated 20.5%, 17.1%, 15.7%, 19.4%, and 18.1%, respectively, in groups of subjects by subscapular skinfold quintile from lowest to highest (p = 0.6 in trend test).

CONCLUSIONS: Lower triceps skinfold at age 40-65, reflecting diminished peripheral fat, was associated with higher dementia prevalence in late life, potentially suggesting a protective role of peripheral fat to brain health.

%B J Alzheimers Dis %V 57 %P 873-883 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304287?dopt=Abstract %R 10.3233/JAD-160786 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease. %A Liu, Collin Y %A Ohki, Yu %A Tomita, Taisuke %A Osawa, Satoko %A Reed, Bruce R %A Jagust, William %A Van Berlo, Victoria %A Jin, Lee-Way %A Chui, Helena C %A Coppola, Giovanni %A Ringman, John M %X

BACKGROUND: The presenilin-1 protein (PS1) is the catalytic unit of γ-secretase implicated in the production of abnormally long forms of amyloid-β (Aβ), including Aβ42, proteins thought critical in the pathogenesis of Alzheimer's disease (AD). In AD of autosomal dominant inheritance, the majority of pathogenic mutations have been found in the PSEN1 gene within which the location of the mutation can provide clues as to the mechanism of pathogenesis.

OBJECTIVE: To describe clinical features of two novel mutations in the transmembrane portion 1 (TMD-1) of PSEN1 as well as biochemical features in one and neuropathological findings in the other.

METHODS: Two index patients with young onset AD with an autosomal dominant pattern of inheritance underwent clinical and imaging assessments, as well as PSEN1 sequencing. Postmortem examination was completed in one patient. An artificial construct in which the P88L mutation was introduced was created to examine its effects on γ-secretase cleavage.

RESULTS: Two novel variants in TMD-1 (P88L and V89L) were identified in affected probands. The neuropathological findings of AD were confirmed in the V89L mutation. Both patients presented around age 40 with early short-term memory deficits followed by seizures and corticospinal tract signs. The P88L mutation additionally featured early myoclonus followed by Parkinsonism. The causal role of the P88L mutation is supported by demonstration that this mutation dramatically increased Aβ42 and decreased APP and Notch intracellular domain production in vitro.

CONCLUSION: Changes in a single amino acid in codons 88 and 89 of TMD-1 can result in young-onset AD. The TMD-1 of PS1 is a region important for the γ-secretase cleavage of Aβ.

%B J Alzheimers Dis %V 58 %P 1035-1041 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550247?dopt=Abstract %R 10.3233/JAD-161203 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Type 1 Diabetes Mellitus and Cognitive Impairments: A Systematic Review. %A Li, Wei %A Huang, Edgar %A Gao, Sujuan %X

Type 1 diabetes mellitus (T1DM) is a major subtype of diabetes and is usually diagnosed at a young age with insulin deficiency. The life expectancy of T1DM patients has increased substantially in comparison with that three decades ago due to the availability of exogenous insulin, though it is still shorter than that of healthy people. However, the relation remains unclear between T1DM and dementia as an aging-related disease. We conducted a systematic review of existing literature on T1DM and cognition impairments by carrying out searches in electronic databases Medline, EMBASE, and Google Scholar. We restricted our review to studies involving only human subjects and excluded studies on type 2 diabetes mellitus or non-classified diabetes. A meta-analysis was first performed on the relationship between T1DM and cognitive changes in youths and adults respectively. Then the review focused on the cognitive complications of T1DM and their relation with the characteristics of T1DM, glycemic control, diabetic complications, comorbidities, and others. First, age at onset, disease duration, and glycemic dysregulation were delineated for their association with cognitive changes. Then diabetic ketoacidosis, angiopathy, and neuropathy were examined as diabetic complications for their involvement in cognitive impairments. Lastly, body mass index and blood pressure were discussed for their relations with the cognitive changes. Future studies are needed to elucidate the pathogenesis of T1DM-related cognitive impairments or dementia.

%B J Alzheimers Dis %V 57 %P 29-36 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222533?dopt=Abstract %R 10.3233/JAD-161250 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Updating the Evidence on the Association between Serum Cholesterol and Risk of Late-Life Dementia: Review and Meta-Analysis. %A Anstey, Kaarin J %A Ashby-Mitchell, Kimberly %A Peters, Ruth %X

BACKGROUND: Cohort studies have reported that midlife high total serum cholesterol (TC) is associated with increased risk of Alzheimer's disease (AD) in late-life but findings have been based on few studies and previous reviews have been limited by a lack of compatible data.

OBJECTIVE: We synthesized all high quality data from cohort studies reporting on the association between total serum cholesterol measured and late-life cognitive outcomes including Alzheimer's disease (AD), vascular dementia (VaD), any dementia, mild cognitive impairment (MCI), and cognitive decline.

METHODS: The literature was searched up to October 2016 using a registered protocol. Thirty-four articles meeting study criteria were identified. Seventeen studies published from 1996 to 2014, including 23,338 participants were included in meta-analyses.

RESULTS: Relative risk of developing AD for adults with high TC in midlife was 2.14 (95% CI 1.33-3.44) compared with normal cholesterol. Individual studies that could not be pooled also reported high TC in midlife increased the risk of MCI and cognitive decline in late-life. High TC in late-life was not associated with MCI, AD, VaD, any dementia, or cognitive decline. Late-life measured HDL cholesterol and triglycerides were not associated with increased risk of VaD, and HDL was not associated with risk of MCI, AD, or any dementia. There were insufficient data to examine other cholesterol sub-fractions, sex differences, or APOE interactions.

CONCLUSIONS: Significant gaps in the literature regarding TC and late-life dementia remain. Evidence suggests that high midlife TC increases risk of late-life AD, and may correlate with the onset of AD pathology.

%B J Alzheimers Dis %V 56 %P 215-228 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911314?dopt=Abstract %R 10.3233/JAD-160826 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Upregulated Expression of Heparanase and Heparanase 2 in the Brains of Alzheimer's Disease. %A Garcia, Beatriz %A Martin, Carla %A Garcia-Suarez, Olivia %A Muniz-Alonso, Barbara %A Ordiales, Helena %A Fernandez-Menendez, Santiago %A Santos-Juanes, Jorge %A Lorente-Gea, Laura %A Castanon, Sonia %A Vicente-Etxenausia, Ikerne %A Pina Batista, Kelvin Manuel %A Ruiz-Diaz, Irune %A Caballero-Martinez, Maria Cristina %A Merayo-Lloves, Jesus %A Guerra-Merino, Isabel %A Quiros, Luis M %A Fernandez-Vega, Ivan %X

BACKGROUND: Heparan sulfate proteoglycans (HSPGs) promote amyloid-β peptide and tau fibrillization in Alzheimer's disease (AD) and provide resistance against proteolytic breakdown. Heparanase (HPSE) is the only enzyme that cleaves heparan sulfate (HS). Heparanase 2 (HPSE2) lacks HS-degrading activity, although it is able to interact with HS with high affinity.

OBJECTIVE: To analyze HPSE and HPSE2 expressions at different stages of AD.

METHODS: RT-PCR was used to analyze transcription levels of both heparanases at different stages of AD, and immunohistochemistry was performed to localize each one in different parts of the brain.

RESULTS: Both proteins appeared overexpressed at different stages of AD. Immunohistochemistry indicated that the presence of the heparanases was related to AD pathology, with intracellular deposits found in degenerated neurons. At the extracellular level, HPSE was observed only in neuritic plaques with a fragmented core, while HPSE2 appeared in those with compact cores as well.

CONCLUSION: Given the involvement of HSPGs in AD pathology, there would seem to be a relationship between the regulation of heparanase expression, the features of the disease, and a possible therapeutic alternative.

%B J Alzheimers Dis %V 58 %P 185-192 %8 2017 %G eng %N 1 %R 10.3233/JAD-161298 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Urine AD7c-NTP Predicts Amyloid Deposition and Symptom of Agitation in Patients with Alzheimer's Disease and Mild Cognitive Impairment. %A Zhang, Nan %A Zhang, Liling %A Li, Yan %A Gordon, Marc L %A Cai, Li %A Wang, Ying %A Xing, Mengya %A Cheng, Yan %X

BACKGROUND: Expression of neuronal thread protein (NTP), which is considered to be related to neuritic sprouting and neuronal death, may be elevated in brain tissue, cerebrospinal fluid, and even urine in patients with Alzheimer's disease (AD).

OBJECTIVE: In this study, we analyzed the correlation between urine AD-associated NTP (AD7c-NTP) level, and amyloid-β (Aβ) deposition, and clinical symptoms in AD and mild cognitive impairment (MCI).

METHODS: Twenty-two patients with mild to moderate AD and 8 subjects with MCI were recruited. Aβ deposition was measured with [11C]-labeled Pittsburgh compound B (PiB)-positron emission tomography (PET) in all participants. Urine AD7c-NTP levels were measured using enzyme-linked immunosorbent assay. Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory (NPI) were used to evaluate cognitive function and behavioral psychological symptoms, respectively.

RESULTS: Fourteen (63.6%) of AD patients and 2 (25.0%) of MCI subjects were Aβ positive on PiB-PET. There was a significant difference in urine AD7c-NTP level between Aβ positive (2.27±2.22 ng/ml) and negative (0.55±0.60 ng/ml) subjects (p = 0.018). Using 1.46 ng/ml as a cut-off value, 68.8% of Aβ positive subjects showed elevated urine AD7c-NTP level, and 92.9% of Aβ negative subjects showed normal urine AD7c-NTP level. There were no relationships between urine AD7c-NTP level and MMSE and total NPI scores. However, AD7c-NTP level positively correlated with agitation score on NPI.

CONCLUSIONS: Urine AD7c-NTP had high specificity and moderate sensitivity in predicting Aβ deposition among patients with cognitive impairment. Furthermore, urine AD7c-NTP level strongly correlated with the symptom of agitation.

%B J Alzheimers Dis %V 60 %P 87-95 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28777752?dopt=Abstract %R 10.3233/JAD-170383 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Urine Formaldehyde Predicts Cognitive Impairment in Post-Stroke Dementia and Alzheimer's Disease. %A Tong, Zhiqian %A Wang, Weishan %A Luo, Wenhong %A Lv, Jihui %A Li, Hui %A Luo, Hongjun %A Jia, Jianping %A He, Rongqiao %X

Although Alzheimer's disease (AD) was first described over 100 years ago, there is still no suitable biomarker for diagnosing AD in easily collectable samples (e.g., blood plasma, saliva, and urine). Here, we investigated the relationship between morning urine formaldehyde concentration and cognitive impairment in patients with post-stroke dementia (PSD) or AD in this cross-sectional survey for 7 years. Cognitive abilities of the study participants (n = 577, four groups: 231 controls, 61 stroke, 65 PSD, and 220 AD) were assessed by Mini-Mental State Examination (MMSE). Morning urine formaldehyde concentrations were measured by high performance liquid chromatography (HPLC). Gender- and age-matched participants were selected from the four groups (n = 42 in each group). Both semicarbazide-sensitive amine oxidase (SSAO, a formaldehyde-generating enzyme) and formaldehyde levels in the blood and urine were analyzed by using an enzyme-linked immunosorbent assay (ELISA) and HPLC, respectively. We found that morning urine formaldehyde levels were inversely correlated with MMSE scores. The threshold value (the best Cut-Off value) of formaldehyde concentration for predicting cognitive impairment was 0.0418 mM in patients with PSD (Sensitivity: 92.3%; Specificity: 77.1%), and 0.0449 mM in patients with AD (Sensitivity: 94.1%; Specificity: 81.8%), respectively. The results of biochemical analysis revealed that the observed increase in urine formaldehyde resulted from an overexpression of SSAO in the blood. The findings suggest that measuring the concentration of formaldehyde in overnight fasting urine could be used as a potentially noninvasive method for evaluating the likelihood of ensuing cognitive impairment or dementia.

%B J Alzheimers Dis %V 55 %P 1031-1038 %G ENG %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802225?dopt=Abstract %R 10.3233/JAD-160357 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Use of Analgesics (Opioids and Nonsteroidal Anti-Inflammatory Drugs) and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort. %A Dublin, Sascha %A Walker, Rod L %A Gray, Shelly L %A Hubbard, Rebecca A %A Anderson, Melissa L %A Yu, Onchee %A Montine, Thomas J %A Crane, Paul K %A Sonnen, Josh A %A Larson, Eric B %X

BACKGROUND: Opioids may influence the development of Alzheimer's disease (AD). Some studies have observed AD pathology in the brains of opioid abusers. No study has examined the association between prescription opioid use and dementia-related neuropathologic changes.

OBJECTIVE: To examine the relationship between prescription opioid or NSAID use and dementia-related neuropathologic changes.

METHODS: Within a community-based autopsy cohort (N = 420), we ascertained opioid and nonsteroidal anti-inflammatory drug (NSAID) use over a 10-year period from automated pharmacy data and calculated total standardized daily doses (TSDDs). A neuropathologist assessed outcomes including neuritic plaques, neurofibrillary tangles, and macroscopic infarcts. Outcome measures were dichotomized using established cutpoints. We used modified Poisson regression to calculate adjusted relative risks (RR) and 95% confidence intervals (CI), accounting for participant characteristics and using weighting to account for possible selection bias related to selection into the autopsy sample.

RESULTS: Heavier opioid exposure was not associated with greater neuropathologic changes. For neuritic plaques, the adjusted RR [95% CI] was 0.99 [0.64-1.47] for 91+ TSDDs of opioids versus little to no use, and for neurofibrillary tangles, 0.97 [0.49-1.78]. People with heavy NSAID use had higher risk of neuritic plaques (RR 1.39 [1.01-1.89]) than those with little to no use, as we have previously reported. Neither opioid nor NSAID use was associated with higher risk of macroscopic infarcts or with Lewy body disease.

CONCLUSION: Prescription opioid use is not associated with dementia-related neuropathologic changes, but heavy NSAID use may be. More research is needed examining chronic pain, its pharmacologic treatments, and neuropathologic changes.

%B J Alzheimers Dis %V 58 %P 435-448 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453469?dopt=Abstract %R 10.3233/JAD-160374 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Use of Music Playlists for People with Dementia: A Critical Synthesis. %A Garrido, Sandra %A Dunne, Laura %A Chang, Esther %A Perz, Janette %A Stevens, Catherine J %A Haertsch, Maggie %X

The use of pre-recorded music to ease behavioral and psychological symptoms associated with dementia is popular in health-care contexts in both formal music therapy settings and in non-therapist led interventions. However, further understanding of how non-therapist led interventions compare to therapist led interventions is needed. This paper reviews 28 studies that used pre-recorded music with people with dementia using a critical interpretive synthesis model. Results revealed that pre-recorded music can be effective in reducing a variety of affective and behavioral symptoms, in particular agitation, even where a trained music therapist is not present. However, the results are not universally positive, suggesting the need for further clarification of protocols for music use and closer investigation of variables that influence individual responseto music.

%B J Alzheimers Dis %V 60 %P 1129-1142 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984606?dopt=Abstract %R 10.3233/JAD-170612 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Using Drugs as Molecular Probes: A Computational Chemical Biology Approach in Neurodegenerative Diseases. %A Emon, Mohammad Asif Emran Khan %A Kodamullil, Alpha Tom %A Karki, Reagon %A Younesi, Erfan %A Hofmann-Apitius, Martin %X

Neurodegenerative diseases including Alzheimer's disease are complex to tackle because of the complexity of the brain, both in structure and function. Such complexity is reflected by the involvement of various brain regions and multiple pathways in the etiology of neurodegenerative diseases that render single drug target approaches ineffective. Particularly in the area of neurodegeneration, attention has been drawn to repurposing existing drugs with proven efficacy and safety profiles. However, there is a lack of systematic analysis of the brain chemical space to predict the feasibility of repurposing strategies. Using a mechanism-based, drug-target interaction modeling approach, we have identified promising drug candidates for repositioning. Mechanistic cause-and-effect models consolidate relevant prior knowledge on drugs, targets, and pathways from the scientific literature and integrate insights derived from experimental data. We demonstrate the power of this approach by predicting two repositioning candidates for Alzheimer's disease and one for amyotrophic lateral sclerosis.

%B J Alzheimers Dis %V 56 %P 677-686 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035920?dopt=Abstract %R 10.3233/JAD-160222 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Utility of Molecular and Structural Brain Imaging to Predict Progression from Mild Cognitive Impairment to Dementia. %A Lan, Martin J %A Ogden, R Todd %A Kumar, Dileep %A Stern, Yaakov %A Parsey, Ramin V %A Pelton, Gregory H %A Rubin-Falcone, Harry %A Pradhaban, Gnanavalli %A Zanderigo, Francesca %A Miller, Jeffrey M %A Mann, J John %A Devanand, D P %X

This project compares three neuroimaging biomarkers to predict progression to dementia in subjects with mild cognitive impairment (MCI). Eighty-eight subjects with MCI and 40 healthy controls (HCs) were recruited. Subjects had a 3T magnetic resonance imaging (MRI) scan, and two positron emission tomography (PET) scans, one with Pittsburgh compound B ([11C]PIB) and one with fluorodeoxyglucose ([18F]FDG). MCI subjects were followed for up to 4 y and progression to dementia was assessed on an annual basis. MCI subjects had higher [11C]PIB binding potential (BPND) than HCs in multiple brain regions, and lower hippocampus volumes. [11C]PIB BPND, [18F]FDG standard uptake value ratio (SUVR), and hippocampus volume were associated with time to progression to dementia using a Cox proportional hazards model. [18F]FDG SUVR demonstrated the most statistically significant association with progression, followed by [11C]PIB BPND and then hippocampus volume. [11C]PIB BPND and [18F]FDG SUVR were independently predictive, suggesting that combining these measures is useful to increase accuracy in the prediction of progression to dementia. Hippocampus volume also had independent predictive properties to [11C]PIB BPND, but did not add predictive power when combined with the [18F]FDG SUVR data. This work suggests that PET imaging with both [11C]PIB and [18F]FDG may help to determine which MCI subjects are likely to progress to AD, possibly directing future treatment options.

%B J Alzheimers Dis %V 60 %P 939-947 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984586?dopt=Abstract %R 10.3233/JAD-161284 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Utility of the Cognitive Function Instrument (CFI) to Detect Cognitive Decline in Non-Demented Older Adults. %A Li, Clara %A Neugroschl, Judith %A Luo, Xiaodong %A Zhu, Carolyn %A Aisen, Paul %A Ferris, Steven %A Sano, Mary %X

BACKGROUND: Subjective cognitive complaint is a sensitive marker of decline.

OBJECTIVE: This study aimed to (1) examine reliability of subjective cognitive complaint using the Cognitive Function Instrument (CFI), and (2) assess the utility of the CFI to detect cognitive decline in non-demented elders.

METHODS: Data from a four-year longitudinal study at multiple Alzheimer's Disease Cooperative Study (ADCS) sites were extracted (n = 644). Of these, 497 had Clinical Dementia Rating (CDR) global scores of 0 and 147 had a CDR of 0.5. Mean age and education were 79.5±3.6 and 15.0±3.1 years, respectively. All participants and their study partners completed the subject and study partner CFI yearly. Modified Mini-Mental State Exam (mMMSE) and Free and Cued Selective Reminding Test (FCSRT) were administered. Scores below the predetermined cut-off scores on either measure at annual visit were triggers for a full diagnostic evaluation. Cognitive decline was defined by the absence/presence of the trigger.

RESULTS: Three-month test retest reliability showed that inter-class coefficients for subject and study partner CFI were 0.76 and 0.78, respectively. Generalized estimating equation method revealed that both subject and study partner CFI change scores and scores from previous year were sensitive to cognitive decline in the CDR 0 group (p < 0.05). In the CDR 0.5 group, only the study partner CFI change score predicted cognitive decline (p < 0.05).

CONCLUSION: Cognitive decline was predicted differentially by CDR level with subject CFI scores providing the best prediction for those with CDR 0 while study partner CFI predicted best for those at CDR 0.5.

%B J Alzheimers Dis %V 60 %P 427-437 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28854503?dopt=Abstract %R 10.3233/JAD-161294 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Utilization of Robotic Pets in Dementia Care. %A Petersen, Sandra %A Houston, Susan %A Qin, Huanying %A Tague, Corey %A Studley, Jill %X

BACKGROUND: Behavioral problems may affect individuals with dementia, increasing the cost and burden of care. Pet therapy has been known to be emotionally beneficial for many years. Robotic pets have been shown to have similar positive effects without the negative aspects of traditional pets. Robotic pet therapy offers an alternative to traditional pet therapy.

OBJECTIVE: The study rigorously assesses the effectiveness of the PARO robotic pet, an FDA approved biofeedback device, in treating dementia-related symptoms.

METHODS: A randomized block design with repeated measurements guided the study. Before and after measures included reliable, valid tools such as: RAID, CSDD, GDS, pulse rate, pulse oximetry, and GSR. Participants interacted with the PARO robotic pet, and the control group received standard activity programs. Five urban secure dementia units comprised the setting.

RESULTS: 61 patients, with 77% females, average 83.4 years in age, were randomized into control and treatment groups. Compared to the control group, RAID, CSDD, GSR, and pulse oximetry were increased in the treatment group, while pulse rate, pain medication, and psychoactive medication use were decreased. The changes in GSR, pulse oximetry, and pulse rate over time were plotted for both groups. The difference between groups was consistent throughout the 12-week study for pulse oximetry and pulse rate, while GSR had several weeks when changes were similar between groups.

CONCLUSIONS: Treatment with the PARO robot decreased stress and anxiety in the treatment group and resulted in reductions in the use of psychoactive medications and pain medications in elderly clients with dementia.

%B J Alzheimers Dis %V 55 %P 569-574 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716673?dopt=Abstract %R 10.3233/JAD-160703 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Validation by Magnetic Resonance Imaging of the Diagnostic Potential of a Heptapeptide-Functionalized Imaging Probe Targeted to Amyloid-β and Able to Cross the Blood-Brain Barrier. %A André, Séverine %A Ansciaux, Emilie %A Saidi, Elamine %A Larbanoix, Lionel %A Stanicki, Dimitri %A Nonclercq, Denis %A Vander Elst, Luce %A Laurent, Sophie %A Muller, Robert N %A Burtea, Carmen %X

The diagnosis of Alzheimer's disease (AD) is a critical step in the management of patients. We have developed a non-invasive diagnosis tool based on magnetic resonance molecular imaging (MRMI) of amyloid-β peptide using ultra-small particles of iron oxide (USPIO) functionalized with a disulfide constrained cyclic heptapeptide (PHO) identified by phage display (USPIO-PHO). After previously demonstrating the optimal pharmacologic properties of USPIO-PHO and its capacity to cross the blood-brain barrier (BBB), the ability of USPIO-PHO to target amyloid plaques (AP) by MRMI has been validated in the present work on AD transgenic mice. The immunohistochemistry and immunofluorescent detection of USPIO-PHO on brain sections collected after in vivo MRMI studies enabled its colocalization with AP, confirming the BBB passage and specific targeting. The AP targeting by USPIO-PHO has been moreover corroborated by the good correlation between the number of AP detected with anti-amyloid β antibody and Perls'-DAB staining. Finally, the crossing mechanism of USPIO-PHO through the BBB was elucidated, revealing the involvement of non-degradation pathway of caveolae, while the control contrast agent USPIO-PEG was not endocytosed by the human brain endothelial cells.

%B J Alzheimers Dis %V 60 %P 1547-1565 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036827?dopt=Abstract %R 10.3233/JAD-170563 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Validation of a Latent Construct for Dementia in a Population-Wide Dataset from Singapore. %A Peh, Chao Xu %A Abdin, Edimansyah %A Vaingankar, Janhavi A %A Verma, Swapna %A Chua, Boon Yiang %A Sagayadevan, Vathsala %A Seow, Esmond %A Zhang, YunJue %A Shahwan, Shazana %A Ng, Li Ling %A Prince, Martin %A Chong, Siow Ann %A Subramaniam, Mythily %X

BACKGROUND: The latent variable δ has been proposed as a proxy for dementia. Previous validation studies have been conducted using convenience samples. It is currently unknown how δ performs in population-wide data.

OBJECTIVE: To validate δ in Singapore using population-wide epidemiological study data on persons aged 60 and above.

METHODS: δ was constructed using items from the Community Screening Instrument for Dementia (CSI'D) and World Health Organization Disability Assessment Schedule (WHODAS II). Confirmatory factor analysis (CFA) was conducted to examine δ model fit. Convergent validity was examined with the Clinical Dementia Rating scale (CDR) and GMS-AGECAT dementia. Divergent validity was examined with GMS-AGECAT depression.

RESULTS: The δ model demonstrated fit to the data, χ2(df) = 249.71(55), p < 0.001, CFI = 0.990, TLI = 0.997, RMSEA = 0.037. Latent variable δ was significantly associated with CDR and GMS-AGECAT dementia (range: β= 0.32 to 0.63), and was not associated with GMS-AGECAT depression. Compared to unadjusted models, δ model fit was poor when adjusted for age, gender, ethnicity, and education.

CONCLUSION: The study found some support for δ as a proxy for dementia in Singapore based on population data. Both convergent and divergent validity were established. In addition, the δ model structure appeared to be influenced by age, gender, ethnicity, and education covariates.

%B J Alzheimers Dis %V 55 %P 823-833 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802230?dopt=Abstract %R 10.3233/JAD-160575 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Validation of Suspected Somatic Single Nucleotide Variations in the Brain of Alzheimer's Disease Patients. %A Gomez-Ramos, Alberto %A Picher, Angel J %A García, Esther %A Garrido, Patricia %A Hernández, Félix %A Soriano, Eduardo %A Avila, Jesús %X

Next-generation sequencing techniques and genome-wide association study analyses have provided a huge amount of data, thereby enabling the identification of DNA variations and mutations related to disease pathogenesis. New techniques and software tools have been developed to improve the accuracy and reliability of this identification. Most of these tools have been designed to discover and validate single nucleotide variants (SNVs). However, in addition to germ-line mutations, human tissues bear genomic mosaicism, which implies that somatic events are present only in low percentages of cells within a given tissue, thereby hindering the validation of these variations using standard genetic tools. Here we propose a new method to validate some of these somatic mutations. We combine a recently developed software with a method that cuts DNA by using restriction enzymes at the sites of the variation. The non-cleaved molecules, which bear the SNV, can then be amplified and sequenced using Sanger's technique. This procedure, which allows the detection of alternative alleles present in as few as 10% of cells, could be of value for the identification and validation of low frequency somatic events in a variety of tissues and diseases.

%B J Alzheimers Dis %V 56 %P 977-990 %G eng %N 3 %R 10.3233/JAD-161053 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Validation of the Korean Version of the Lewy Body Composite Risk Score (K-LBCRS). %A Ryu, Hui Jin %A Kim, Minyoung %A Moon, Yeonsil %A Choi, Yeji %A Han, Jee-Young %A Galvin, James E %A Han, Seol-Heui %X

The Lewy body composite risk score (LBCRS) is a useful clinical screening tool to help determine whether the dementia is related to Lewy body pathology. The purpose of this study is to verify reliability, validity, and diagnostic usefulness of Korean version of LBCRS (K-LBCRS). CDR-sum of boxes, Mini-Mental State Examination, and standardized scales related to cognition, mood, behavior, and motor function were administered to a total of 107 subjects, including 30 dementia with Lewy bodies (DLB), 54 Alzheimer's disease (AD), and 23 cognitively normal elderly people and their collateral informants. Internal consistency of the K-LBCRS was good with Cronbach's alpha of 0.85, and concurrent validity was also satisfactory, with K-LBCRS correlating highly with CDR-SB and other scales. The test-retest reliability was very high with a Pearson correlation coefficient of 0.97. The mean scores of K-LBCRS were significantly different among three groups, with DLB (6.2±2.4), AD (1.4±1.3), and controls (0.3±0.6). We identified a cut-off score of 3 as best to differentiate between DLB and AD, having AUC of 0.97 (95% CI 0.94-1.00), sensitivity 97%, specificity 83%, positive predictive value 76%, negative predictive value 98%, which is the same score suggested in the original study. This study shows K-LBCRS as a new useful screening tool for Korean DLB patients in clinical settings.

%B J Alzheimers Dis %V 55 %P 1395-1401 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27834773?dopt=Abstract %R 10.3233/JAD-160463 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Validation of the Spanish Version of the LASSI-L for Diagnosing Mild Cognitive Impairment and Alzheimer's Disease. %A Matías-Guiu, Jordi A %A Curiel, Rosie E %A Rognoni, Teresa %A Valles-Salgado, María %A Fernández-Matarrubia, Marta %A Hariramani, Roshan %A Fernández-Castro, Alejandro %A Moreno-Ramos, Teresa %A Loewenstein, David A %A Matías-Guiu, Jorge %X

BACKGROUND: The Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L) is a novel cognitive test that measures recovery from proactive semantic interference, which may be an early cognitive marker of Alzheimer's disease (AD).

OBJECTIVE: To generate normative data for a Spaniard population and to validate the LASSI-L for the diagnosis of amnestic mild cognitive impairment (aMCI) and mild AD.

METHODS: We performed a cross-sectional study in which 97 healthy participants, 34 with aMCI, and 33 with mild AD were studied with LASSI-L and a comprehensive neuropsychological protocol. The overlapping strategy analysis was used to maximize the sample size and to provide age- and education-adjusted normative data using a logistic regression analysis.

RESULTS: Internal consistency was 0.932. Convergent validity with the Free and Cued Selective Reminding Test was moderate. LASSI-L raw scores were correlated with age and years of education, but not gender. The area under the curve for discriminating between healthy controls and aMCI was 0.909, and between healthy controls and mild AD was 0.986. LASSI-L sub-scores representing maximum storage capacity, recovery from proactive interference, and delayed recall yielded the highest diagnostic accuracy.

CONCLUSIONS: The LASSI-L is a reliable and valid test for the diagnosis of aMCI and mild AD. The age and education influences on the performance of the test and normative data are provided. LASSI-L merits further studies to evaluate its ability to detect preclinical AD and predict progression to aMCI and early dementia.

%B J Alzheimers Dis %V 56 %P 733-742 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983554?dopt=Abstract %R 10.3233/JAD-160866 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Validity of a Newly Developed Measure of Memory: Feasibility Study of the Virtual Environment Grocery Store. %A Parsons, Thomas D %A Barnett, Michael %X

Virtual reality-based neuropsychological assessments proffer the potential to address the limited ecological validity of pen-and-paper measures of memory. To investigate the construct validity of a newly developed virtual reality measure of memory, the Virtual Environment Grocery Store (VEGS), traditional neuropsychological measures of memory and executive functioning were administered to 48 older adults and 55 young adults. Performances on the VEGS memory tasks and the traditional neuropsychological assessments of memory were positively correlated, indicating that memory for VEGS content was similar to memory for traditional paper-and-pencil measures. The older adults performed significantly worse than young adults on the VEGS and the California Verbal Learning Test, but the DKEFS Color-Word Interference failed to differentiate the groups. Furthermore, significant differences were found between groups for the VEGS memory and multitasking measures. The VEGS has the advantage over traditional measures of providing objective measurement of individual components of memory in simulations of everyday activities.

%B J Alzheimers Dis %V 59 %P 1227-1235 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28759971?dopt=Abstract %R 10.3233/JAD-170295 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Varying Degrees of Temporoparietal Hypometabolism on FDG-PET Reveal Amyloid-Positive Logopenic Primary Progressive Aphasia is not a Homogeneous Clinical Entity. %A Krishnan, Kamini %A Machulda, Mary M %A Whitwell, Jennifer L %A Butts, Alissa M %A Duffy, Joseph R %A Strand, Edythe A %A Senjem, Matthew L %A Spychalla, Anthony J %A Jack, Clifford R %A Lowe, Val J %A Josephs, Keith A %X

BACKGROUND: The logopenic variant of primary progressive aphasia (lvPPA) manifests due to a breakdown of the language network with prominent hypometabolism of the left temporoparietal region. LvPPA is strongly associated with amyloid deposition, yet there is question as to whether it is a homogeneous clinical entity.

OBJECTIVE: This study investigated whether differences in temporoparietal metabolic patterns on 18F fludeoxyglucose positron emission tomography (FDG-PET) could elucidate brain regions preferentially affected in lvPPA.

METHOD: We used differences in FDG-PET metabolic z-scores relative to controls for means of left lateral temporal, left inferior parietal, and left superior parietal regions to classify 53 amyloid-positive lvPPA patients into temporal, parietal, or temporoparietal predominate groups. Clinical features and FDG-PET regions of hypometabolism outside of the temporoparietal region were then compared across the three groups; the latter using statistical parametric mapping.

RESULTS: Of the 53 lvPPA patients, 15 were classified as temporal, 14 as temporoparietal, and 22 as parietal predominate. There were no significant differences between the groups on demographic measures, language evaluation, or apolipoprotein E genotype. Compared to the other two groups, individuals with the parietal predominate pattern had extensive hypometabolism in left frontal lobe and the precuneus. Furthermore, this group had greater behavioral dyscontrol and deficits in executive function, visuospatial skills, visual memory retention, working memory, and cognitive flexibility (Bonferronip < 0.05).

CONCLUSIONS: This study demonstrates that there is clinical heterogeneity within amyloid-positive lvPPA. Patients with lvPPA with predominant parietal hypometabolism, unlike those with temporal or temporoparietal predominant hypometabolism, demonstrated widespread cognitive and behavioral changes.

%B J Alzheimers Dis %V 55 %P 1019-1029 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802232?dopt=Abstract %R 10.3233/JAD-160614 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Violation of Laws in Frontotemporal Dementia: A Multicenter Study in Japan. %A Shinagawa, Shunichiro %A Shigenobu, Kazue %A Tagai, Kenji %A Fukuhara, Ryuji %A Kamimura, Naoto %A Mori, Takaaki %A Yoshiyama, Kenji %A Kazui, Hiroaki %A Nakayama, Kazuhiko %A Ikeda, Manabu %X

Although violations of laws, such as shoplifting, are considered to be common in frontotemporal dementia (FTD) patients, there have been few studies on this subject and the frequencies and types of such violations have not been clarified. The objective of this study was to conduct a retrospective investigation of FTD patients in the psychiatry departments of multiple institutions to determine the types and frequencies of any law violations and compare them with those of AD patients. All patients were examined between January 2011 and December 2015 at the specialized dementia outpatient clinics of 10 facilities (5 psychiatry departments of university hospitals, 5 psychiatric hospitals). According to diagnostic criteria, 73 behavior variant FTD (bvFTD) patients, 84 semantic variant of primary progressive aphasia (svPPA) patients, and 255 age- and sex-matched AD subjects as the control group were selected. The findings revealed a higher rate of law violations in the bvFTD and svPPA patients before the initial consultation as compared to the AD group (bvFTD: 33%, svPPA: 21%, AD: 6%) and that many patients had been referred due to such violations. Laws had been broken 4 times or 5 or more times in several cases in the FTD group before the initial consultation. Regarding rates for different types of violation, in bvFTD subjects, the highest rate was for theft, followed by nuisance acts and hit and run. In svPPA, theft had the highest rate, followed by ignoring road signs. There was no gender difference in law violations but they were more frequent when the disease was severe at the initial consultation in the FTD group. As the rates of law violations after the initial consultation were lower than before it, interventions were considered to have been effective. These findings may be useful for future prevention as well as to the legal system.

%B J Alzheimers Dis %V 57 %P 1221-1227 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304308?dopt=Abstract %R 10.3233/JAD-170028 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Visit-to-Visit Blood Pressure Variability and Alzheimer's Disease: Links and Risks. %A Nagai, Michiaki %A Dote, Keigo %A Kato, Masaya %A Sasaki, Shota %A Oda, Noboru %A Kagawa, Eisuke %A Nakano, Yoshinori %A Yamane, Aya %A Higashihara, Tasuku %A Miyauchi, Shunsuke %A Tsuchiya, Akane %X

While hypertension has been shown to be a risk factor for vascular dementia, several studies have also demonstrated that hypertension also increases the risk of Alzheimer's disease (AD). Although the relationship between visit-to-visit blood pressure variability (VVV) and cognitive impairment, including AD, have been provided, the mechanisms remain poorly understood. This review paper focuses on the relationship of VVV with AD and summarizes the pathophysiology underlying that relationship, which appears to be mediated by arterial stiffness.

%B J Alzheimers Dis %V 59 %P 515-526 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598842?dopt=Abstract %R 10.3233/JAD-161172 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Visual Rating of Posterior Atrophy as a Marker of Progression to Dementia in Mild Cognitive Impairment Patients. %A Kim, Hang-Rai %A Park, Young Ho %A Jang, Jae-Won %A Park, So Young %A Wang, Min Jeong %A Baek, Min Jae %A Kim, Beom Joon %A Ahn, Soyeon %A Kim, SangYun %X

BACKGROUND: Although medial temporal atrophy (MTA) is a useful imaging marker of the progression to dementia in mild cognitive impairment (MCI), substantial numbers of MCI patients without MTA still progress to dementia.

OBJECTIVE: We investigated whether visual ratings of posterior atrophy (PA) on magnetic resonance imaging show independent predictive value for the progression to dementia in MCI patients.

METHODS: This was a retrospective cohort study of elderly patients who visited Seoul National University Bundang Hospital between 2004 and 2012. A total of 148 patients who were initially diagnosed with MCI were followed for up to 3 years (median 22 months) to determine whether they progressed to dementia. We used 4-point and 5-point visual rating scales to assess PA and MTA, respectively. PA and MTA scores were dichotomized into normal (no atrophy) or abnormal (atrophy) in each patient. We performed a Cox regression analysis to examine the hazard ratios (HRs) of PA and MTA for the progression to dementia with adjustment for age, APOEɛ4 allele status, and baseline Mini-Mental State Examination score.

RESULTS: Among the study population, 47 patients progressed to dementia. Visual assessment of the MRI scans revealed that 67 patients (45.3%) showed PA, whereas 85 patients (57.3%) showed MTA. The HRs with 95% confidence intervals for PA and MTA were 2.516 (1.244-5.091) and 4.238 (1.680-10.687), respectively. The predictive values of visually assessed PA and MTA remained significant, independent of the covariates.

CONCLUSION: Visual assessment of PA has independent predictive value for progression to dementia in MCI patients.

%B J Alzheimers Dis %V 55 %P 137-146 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636842?dopt=Abstract %R 10.3233/JAD-160339 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Visual Selective Attention Toward Novel Stimuli Predicts Cognitive Decline in Alzheimer's Disease Patients. %A Chau, Sarah A %A Herrmann, Nathan %A Sherman, Chelsea %A Chung, Jonathan %A Eizenman, Moshe %A Kiss, Alex %A Lanctôt, Krista L %X

BACKGROUND: Alzheimer's disease (AD) is associated with selective attention impairments, which could contribute to cognitive and functional deficits. Using visual scanning parameters, selective attention toward novel stimuli, or novelty preference, can be measured by a non-verbal, non-invasive method that may be of value in predicting disease progression.

OBJECTIVE: In this longitudinal study, we explored whether novelty preference can predict cognitive decline in AD patients.

METHODS: Mild to moderate AD patients viewed slides containing both novel and repeat images. The number of fixations, the average fixation time, and the relative fixation time on the two types of images were measured by an eye-tracking system. Novelty preference was estimated by the differences between the visual scanning parameters on novel and repeat images. Cognition and attention were assessed using the Standardized Mini-Mental Status Examination (sMMSE) and the Conners' Continuous Performance Test (CPT), respectively. Cognition was re-assessed every 6 months for up to 2 years.

RESULTS: Multivariate linear regressions of 32 AD patients (14 females, age = 77.9±7.8, baseline sMMSE = 22.2±4.4) indicated that reduced time spent on novel images (t = 2.78, p = 0.010) was also associated with greater decline in sMMSE scores (R2 = 0.41, Adjusted R2 = 0.35, F3,28 = 6.51, p = 0.002), adjusting for attention and baseline sMMSE.

CONCLUSION: These results suggest that novelty preference, measured by visual attention scanning technology, may reflect pathophysiological processes that could predict disease progression in the cognitively-impaired.

%B J Alzheimers Dis %V 55 %P 1339-1349 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27834775?dopt=Abstract %R 10.3233/JAD-160641 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Visuospatial Functioning in Cerebral Amyloid Angiopathy: A Pilot Study. %A Valenti, Raffaella %A Charidimou, Andreas %A Xiong, Li %A Boulouis, Gregoire %A Fotiadis, Panagiotis %A Ayres, Alison %A Riley, Grace %A Kuijf, Hugo J %A Reijmer, Yael D %A Pantoni, Leonardo %A Gurol, M Edip %A Davidsdottir, Sigurros %A Greenberg, Steven M %A Viswanathan, Anand %X

Cerebral amyloid angiopathy (CAA) is a contributor to cognitive impairment in the elderly. We hypothesized that the posterior cortical predilection of CAA would cause visual-processing impairment. We systematically evaluated visuospatial abilities in 22 non-demented CAA patients. Neurocognitive evaluation demonstrated visuoperceptual impairment (23% on Benton Facial Recognition Test [BFRT] and 13.6% on Benton Judgment of Line Orientation Test [BJLO]). BFRT was inversely correlated with white matter hyperintensities volume and BJLO with parietal cerebral microbleeds. This pilot study highlights the presence of visual-processing deficits in CAA. The impairment could be related to global disease severity in addition to local brain injury.

%B J Alzheimers Dis %V 56 %P 1223-1227 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222510?dopt=Abstract %R 10.3233/JAD-160927 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Vitamin D and the Risk of Dementia: The Rotterdam Study. %A Licher, Silvan %A de Bruijn, Renée F A G %A Wolters, Frank J %A Zillikens, M Carola %A Ikram, M Arfan %A Ikram, M Kamran %X

BACKGROUND: Vitamin D has gained interest as a potentially modifiable risk factor for dementia because of its putative neuroprotective effects. However, longitudinal studies examining the association between vitamin D and dementia have provided inconsistent results.

OBJECTIVE: To determine the relationship of serum vitamin D with prevalent and incident dementia in the general population.

METHODS: Within the prospective Rotterdam Study, we measured serum 25-hydroxyvitamin D concentrations between 1997 and 2001 using electrochemiluminescence-immunoassay in 6220 participants 55 years or older. We assessed dementia at baseline and continuously during follow-up until 1 January 2015. We used appropriate regression models to determine the relationship of vitamin D with prevalent and incident dementia, including Alzheimer's disease (AD). We adjusted models for age, sex, and season of blood collection. Additionally, we adjusted for ethnicity, education, cardiovascular risk factors, serum calcium, kidney function, depression, outdoor-activity and APOEɛ4 carriership.

RESULTS: At baseline, 127 of 6,220 participants had dementia, of whom 97 had AD. Lower vitamin D concentrations were associated with a non-significantly higher prevalence of dementia (adjusted OR, per SD decrease 1.20, 95% CI 0.95;1.52), but not with AD (adjusted OR: 0.97, 95% CI 0.74;1.29). Among 6,087 non-demented participants with 68,884 person-years of follow-up, 795 participants developed dementia, of whom 641 had AD. Lower vitamin D concentrations were associated with higher risk of dementia (adjusted HR, per SD decrease 1.11, 95% CI 1.02;1.20) and AD (adjusted HR: 1.13, 95% CI 1.03;1.24).

CONCLUSION: Lower serum vitamin D concentrations are associated with a higher incidence of dementia.

%B J Alzheimers Dis %V 60 %P 989-997 %8 2017 %G eng %N 3 %R 10.3233/JAD-170407 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Vitamin D Insufficiency and Cognitive Function Trajectories in Older Adults: The Rancho Bernardo Study. %A Laughlin, Gail A %A Kritz-Silverstein, Donna %A Bergstrom, Jaclyn %A Reas, Emilie T %A Jassal, Simerjot K %A Barrett-Connor, Elizabeth %A McEvoy, Linda K %X

BACKGROUND: Evidence of a role for vitamin D (VitD) in cognitive aging is mixed and based primarily on extreme VitD deficiency. We evaluated the association of VitD insufficiency with cognitive function in older, community-dwelling adults living in a temperate climate with year-round sunshine.

METHODS: A population-based longitudinal study of 1,058 adults (median age 75; 62% women) who had cognitive function assessed and serum levels of 25-hydroxyvitaminD (25OHD) measured in 1997-99 and were followed for up to three additional cognitive function assessments over a 12-year period.

RESULTS: Overall, 14% (n = 145) of participants had VitD insufficiency defined as 25OHD <30 ng/ml. Adjusting for age, sex, education, and season, VitD insufficiency was associated with poorer baseline performance on the Mini-Mental Status Exam (MMSE) (p = 0.013), Trails Making Test B (Trails B) (p = 0.015), Category Fluency (p = 0.006), and Long Term Retrieval (p = 0.019); differences were equivalent to 5 years of age. For those with VitD insufficiency, the odds of mildly impaired performance at baseline were 38% higher for MMSE (p = 0.08), 78% higher for Trails B (p = 0.017), and 2-fold higher for Category Fluency and Long Term Retrieval (both p = 0.001). VitD insufficiency was not related to the rate of cognitive decline on any test or the risk of developing impaired performance during follow-up.

CONCLUSION: In this population with little VitD deficiency, even moderately low VitD was associated with poorer performance on multiple domains of cognitive function. Low VitD did not predict 12-year cognitive decline. Clinical trials are essential to establish a causal link between VitD and cognitive well-being.

%B J Alzheimers Dis %V 58 %P 871-883 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505973?dopt=Abstract %R 10.3233/JAD-161295 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Voluptuary Habits and Risk of Frontotemporal Dementia: A Case Control Retrospective Study. %A Tremolizzo, Lucio %A Bianchi, Elisa %A Susani, Emanuela %A Pupillo, Elisabetta %A Messina, Paolo %A Aliprandi, Angelo %A Salmaggi, Andrea %A Cosseddu, Maura %A Pilotto, Andrea %A Borroni, Barbara %A Padovani, Alessandro %A Bonomini, Cristina %A Zanetti, Orazio %A Appollonio, Ildebrando %A Beghi, Ettore %A Ferrarese, Carlo %X

Alcohol, coffee, and tobacco consumption was assessed on 151 FTD outpatients and 151 matched controls in a multicenter retrospective case-control design. No association was found for smoking and coffee intake. The risk of FTD was decreased by alcohol consumption (adj. OR 0.30, 95% CI 0.14-0.63); risk reduction was significant in current alcohol consumers (adj. OR 0.22, 95% CI 0.10-0.51). The risk of FTD inversely correlated with the duration of exposure (adj. OR 0.88, 95% CI 0.81-0.95, for every 5 years of exposure increase). Retrospective information and the unknown amount of consumed alcohol are limits of the present work.

%B J Alzheimers Dis %V 60 %P 335-340 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28946566?dopt=Abstract %R 10.3233/JAD-170260 %0 Journal Article %J J Alzheimers Dis %D 2017 %T von Economo Neuron Density and Thalamus Volumes in Behavioral Deficits in Frontotemporal Dementia Cases with and without a C9ORF72 Repeat Expansion. %A Yang, Yue %A Halliday, Glenda M %A Hodges, John R %A Tan, Rachel H %X

BACKGROUND: The early and selective loss of von Economo neurons in the anterior cingulate cortex has been linked to behavioral deficits in frontotemporal dementia (FTD). Importantly, whether these neurons are also targeted in patients with the C9ORF72 repeat expansion has yet to be established. This is of particular interest given the recent evidence highlighting the thalamus rather than anterior cingulate cortex as a region of significant degeneration in patients with the C9ORF72 repeat expansion.

OBJECTIVE: To assess the von Economo neuron density and thalamus volumes in behavioral variant FTD (bvFTD) cases with the C9ORF72 repeat expansion, sporadic bvFTD, sporadic ALS, and controls.

METHODS: Volumetric and quantitative cell counting methods were employed to assess the von Economo neuron density and thalamus volumes in 37 pathologically-confirmed cases comprised of patients with bvFTD (n = 13) cases with the C9ORF72 repeat expansion (62% with psychosis), sporadic bvFTD (n = 8), sporadic amyotrophic lateral sclerosis (n = 7) and controls (n = 9).

RESULTS: von Economo neuron density was significantly reduced in sporadic bvFTD cases only. Thalamus degeneration was identified only in bvFTD cases with the C9ORF72 repeat expansion, and to a similar extent in cases with and without psychosis. No significant difference in von Economo neuron density or thalamus degeneration was seen between bvFTD cases with or without the C9ORF72 repeat expansion.

CONCLUSION: The present histological findings converge with neuroimaging results to corroborate the anterior cingulate cortex as a core region involved in sporadic bvFTD, and the thalamus as a major region targeted in patients with the C9ORF72 expansion.

%B J Alzheimers Dis %V 58 %P 701-709 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28482638?dopt=Abstract %R 10.3233/JAD-170002 %0 Journal Article %J J Alzheimers Dis %D 2017 %T What Can Quantitative Gait Analysis Tell Us about Dementia and Its Subtypes? A Structured Review. %A Mc Ardle, Ríona %A Morris, Rosie %A Wilson, Joanna %A Galna, Brook %A Thomas, Alan J %A Rochester, Lynn %X

Distinguishing dementia subtypes can be difficult due to similarities in clinical presentation. There is increasing interest in discrete gait characteristics as markers to aid diagnostic algorithms in dementia. This structured review explores the differences in quantitative gait characteristics between dementia and healthy controls, and between four dementia subtypes under single-task conditions: Alzheimer's disease (AD), dementia with Lewy bodies and Parkinson's disease dementia, and vascular dementia. Twenty-six papers out of an initial 5,211 were reviewed and interpreted using a validated model of gait. Dementia was associated with gait characteristics grouped by slower pace, impaired rhythm, and increased variability compared to normal aging. Only four studies compared two or more dementia subtypes. People with AD are less impaired in pace, rhythm, and variability domains of gait compared to non-AD dementias. Results demonstrate the potential of gait as a clinical marker to discriminate between dementia subtypes. Larger studies using a more comprehensive battery of gait characteristics and better characterized dementia sub-types are required.

%B J Alzheimers Dis %V 60 %P 1295-1312 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036826?dopt=Abstract %R 10.3233/JAD-170541 %0 Journal Article %J J Alzheimers Dis %D 2017 %T What Drives Country Differences in Cost of Alzheimer's Disease? An Explanation from Resource Use in the GERAS Study. %A Reed, Catherine %A Happich, Michael %A Argimon, Josep Maria %A Haro, Josep Maria %A Wimo, Anders %A Bruno, Giuseppe %A Dodel, Richard %A Jones, Roy W %A Vellas, Bruno %A Belger, Mark %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Caregivers %K Cohort Studies %K Cost of Illness %K Europe %K Female %K Health Resources %K Humans %K International Cooperation %K Male %K Surveys and Questionnaires %X

BACKGROUND: Country differences in resource use and costs of Alzheimer's disease (AD) may be driven by differences in health care systems and resource availability.

OBJECTIVE: To compare country resource utilization drivers of societal costs for AD dementia over 18 months.

METHODS: GERAS is an observational study in France (n = 419), Germany (n = 550), and the UK (n = 526). Resource use of AD patients and caregivers contributing to >1% of total societal costs (year 2010) was assessed for country differences, adjusting for participant characteristics.

RESULTS: Mean 18-month societal costs per patient were France €33,339, Germany €38,197, and UK €37,899 (£32,501). Caregiver time spent on basic and instrumental activities of daily living (ADL) contributed the most to societal costs (54% France, 64% Germany, 65% UK). Caregivers in France spent less time on ADL than UK caregivers and missed fewer work days than in other countries. Compared with other countries, patients in France used more community care services overall and were more likely to use home aid. Patients in Germany were least likely to use temporary accommodation or to be institutionalized at 18 months. UK caregivers spent the most time on instrumental ADL, UK patients used fewest outpatient resources, and UK patients/caregivers were most likely to receive financial support.

CONCLUSION: Caregiver time on ADL contributed the most to societal costs and differed across countries, possibly due to use of community care services and institutionalization. Other resources had different patterns of use across countries, reflecting country-specific health and social care systems.

%B J Alzheimers Dis %V 57 %P 797-812 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304285?dopt=Abstract %R 10.3233/JAD-160449 %0 Journal Article %J J Alzheimers Dis %D 2017 %T What is the Relationship between Health, Mood, and Mild Cognitive Impairment? %A Yates, Jennifer A %A Clare, Linda %A Woods, Robert T %X

Mild cognitive impairment (MCI) often co-exists with mood problems, and both cognitive functioning and mood are known to be linked with health. This study aims to investigate how health, mood, and cognitive impairment interact. Health is often assessed using a single proxy measure, but the use of a range of measures can provide a more informative picture and allows for combination into a comprehensive measure of health. We report an analysis of data from the Cognitive Function and Ageing Study Wales (CFAS Wales, N = 3,173), in which structured interviews with older people captured measures of cognition, mood, and health. Each measure of health was assessed independently in relation to cognition and mood, and then all measures were combined to form a latent health variable and tested using structural equation modeling (SEM). SEM confirmed the association between health and cognition, with depression acting as a mediator. All measures of health were individually associated with levels of anxiety and depression. Participants reporting mood problems were less likely to engage in physical activity and more likely to report poor or fair health, have more comorbid health conditions, use more services, and experience difficulties with instrumental activities of daily living. Perceived health was associated with cognitive status; participants with MCI were more likely to report fair or poor health than participants who were cognitively unimpaired. Careful intervention and encouragement to maintain healthy lifestyles as people age could help to reduce the risk of both mood problems and cognitive decline.

%B J Alzheimers Dis %V 55 %P 1183-1193 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27792011?dopt=Abstract %R 10.3233/JAD-160611 %0 Journal Article %J J Alzheimers Dis %D 2017 %T What is the Relationship of Traumatic Brain Injury to Dementia? %A Mendez, Mario F %K Apolipoprotein E4 %K Brain %K Brain Injuries, Traumatic %K Databases, Bibliographic %K Dementia %K Disease Progression %K Humans %K Neurodegenerative Diseases %K Risk Factors %X

There is a long history linking traumatic brain injury (TBI) with the development of dementia. Despite significant reservations, such as recall bias or concluding causality for TBI, a summary of recent research points to several conclusions on the TBI-dementia relationship. 1) Increasing severity of a single moderate-to-severe TBI increases the risk of subsequent Alzheimer's disease (AD), the most common type of dementia. 2) Repetitive, often subconcussive, mild TBIs increases the risk for chronic traumatic encephalopathy (CTE), a degenerative neuropathology. 3) TBI may be a risk factor for other neurodegenerative disorders that can be associated with dementia. 4) TBI appears to lower the age of onset of TBI-related neurocognitive syndromes, potentially adding "TBI cognitive-behavioral features". The literature further indicates several specific risk factors for TBI-associated dementia: 5) any blast or blunt physical force to the head as long as there is violent head displacement; 6) decreased cognitive and/or neuronal reserve and the related variable of older age at TBI; and 7) the presence of apolipoprotein E ɛ4 alleles, a genetic risk factor for AD. Finally, there are neuropathological features relating TBI with neurocognitive syndromes: 8) acute TBI results in amyloid pathology and other neurodegenerative proteinopathies; 9) CTE shares features with neurodegenerative dementias; and 10) TBI results in white matter tract and neural network disruptions. Although further research is needed, these ten findings suggest that dose-dependent effects of violent head displacement in vulnerable brains predispose to dementia; among several potential mechanisms is the propagation of abnormal proteins along damaged white matter networks.

%B J Alzheimers Dis %V 57 %P 667-681 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269777?dopt=Abstract %R 10.3233/JAD-161002 %0 Journal Article %J J Alzheimers Dis %D 2017 %T When Patient Engagement and Research Ethics Collide: Lessons from a Dementia Forum. %A Robillard, Julie M %A Feng, Tanya L %X

The importance of patient engagement in research has been gaining recognition since the turn of the 21st century. However, little is known about the perspectives of people with dementia on the process of discovery. To fill this gap and to inform priorities in patient engagement in the context of dementia research, the Clinic for Alzheimer Disease and Related Disorders at the University of British Columbia hosted an interactive session for members of the patient community and of the general public to share their views on various ethical aspects of the research process. Results from the session indicate that several current research ethics policies and norms in dementia research are not in line with participants' preferences. Here we discuss the importance of bridging the gap between researchers and patients and call for reforms in current standards of dementia research.

%B J Alzheimers Dis %V 59 %P 1-10 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550251?dopt=Abstract %R 10.3233/JAD-161285 %0 Journal Article %J J Alzheimers Dis %D 2017 %T White Matter Degradation is Associated with Reduced Financial Capacity in Mild Cognitive Impairment and Alzheimer's Disease. %A Gerstenecker, Adam %A Hoagey, David A %A Marson, Daniel C %A Kennedy, Kristen M %X

Financial capacity (FC) is a cognitively complex activity of daily living that declines in mild cognitive impairment (MCI) and Alzheimer's disease (AD), limiting an individual's ability to manage one's finances and function independently. The neural underpinnings of this decline in function are poorly understood but likely involve age-related and disease-related degradation across structural networks. The purpose of the current study was to determine if altered white matter integrity is associated with declining FC in persons with MCI and AD compared to older controls. Individuals with MCI due to AD (n = 31), mild dementia (n = 39), and cognitively healthy older adults (n = 60) were administered a neuropsychological battery including the FC Instrument, a performance-based measure of FC. All 130 participants also underwent diffusion tensor imaging (DTI) upon which tract-based spatial statistics were performed. Both FC and white matter integrity decreased in accordance with disease severity with little to no effect in healthy elderly, significant effects in MCI, and greater effects in AD. Regional white matter degradation (increased diffusivities and decreased fractional anisotropy) was associated with reduced FC in both MCI and AD groups even after controlling for age, education, and gender. Specifically, in MCI, decreased fractional anisotropy, but not increased diffusivities, was associated with poorer FC in widespread cingulo-parietal-frontal and temporo-occipital areas. In AD, rather than anisotropy, increased mean and axial diffusivities in anterior cingulate, callosum, and frontal areas associated with poorer FC. These findings suggest a severity gradient of white matter degradation across DTI metrics and AD stages that predict declining financial skill and knowledge.

%B J Alzheimers Dis %V 60 %P 537-547 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826185?dopt=Abstract %R 10.3233/JAD-170341 %0 Journal Article %J J Alzheimers Dis %D 2017 %T White Matter Hyperintensities Potentiate Hippocampal Volume Reduction in Non-Demented Older Individuals with Abnormal Amyloid-β. %A Freeze, Whitney M %A Jacobs, Heidi I L %A Gronenschild, Ed H %A Jansen, Jacobus F A %A Burgmans, Saartje %A Aalten, Pauline %A Clerx, Lies %A Vos, Stephanie J %A van Buchem, Mark A %A Barkhof, Frederik %A van der Flier, Wiesje M %A Verbeek, Marcel M %A Rikkert, Marcel Olde %A Backes, Walter H %A Verhey, Frans R %X

Cerebral small vessel disease (cSVD) and amyloid-β (Aβ) deposition often co-exist in (prodromal) dementia, and both types of pathology have been associated with neurodegeneration. We examined whether cSVD and Aβ have independent or interactive effects on hippocampal volume (HV) in a memory clinic population. We included 87 individuals with clinical diagnoses of Alzheimer's disease (AD) (n = 24), mild cognitive impairment (MCI) (n = 26), and subjective cognitive complaints (SCC) (n = 37). cSVD magnetic resonance imaging markers included white matter hyperintensity (WMH) volume, lacunar infarct presence, and microbleed presence. Aβ pathology was assessed as cerebrospinal fluid-derived Aβ1 - 42 levels and dichotomized into normal or abnormal, and HV was determined by manual volumetric measurements. A linear hierarchical regression approach was applied for the detection of additive or interaction effects between cSVD and Aβ on HV in the total participant group (n = 87) and in the non-demented group (including SCC and MCI individuals only, n = 63). The results revealed that abnormal Aβ and lacunar infarct presence were independently associated with lower HV in the non-demented individuals. Interestingly, Aβ and WMH pathology interacted in the non-demented individuals, such that WMH had a negative effect on HV in individuals with abnormal CSF Aβ42 levels, but not in individuals with normal CSF Aβ42 levels. These associations were not present when individuals with AD were included in the analyses. Our observations suggest that relatively early on in the disease process older individuals with abnormal Aβ levels are at an increased risk of accelerated disease progression when concomitant cSVD is present.

%B J Alzheimers Dis %V 55 %P 333-342 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662299?dopt=Abstract %R 10.3233/JAD-160474 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Young to Middle-Aged Dogs with High Amyloid-β Levels in Cerebrospinal Fluid are Impaired on Learning in Standard Cognition tests. %A Borghys, Herman %A Van Broeck, Bianca %A Dhuyvetter, Deborah %A Jacobs, Tom %A de Waepenaert, Katja %A Erkens, Tim %A Brooks, Melissa %A Thevarkunnel, Sandy %A Araujo, Joseph A %X

Understanding differences in Alzheimer's disease biomarkers before the pathology becomes evident can contribute to an improved understanding of disease pathogenesis and treatment. A decrease in amyloid-β (Aβ)42 in cerebrospinal fluid (CSF) is suggested to be a biomarker for Aβ deposition in brain. However, the relevance of CSF Aβ levels prior to deposition is not entirely known. Dogs are similar to man with respect to amyloid-β protein precursor (AβPP)-processing, age-related amyloid plaque deposition, and cognitive dysfunction. In the current study, we evaluated the relation between CSF Aβ42 levels and cognitive performance in young to middle-aged dogs (1.5-7 years old). Additionally, CSF sAβPPα and sAβPPβ were measured to evaluate AβPP processing, and CSF cytokines were measured to determine the immune status of the brain. We identified two groups of dogs showing consistently low or high CSF Aβ42 levels. Based on prior studies, it was assumed that at this age no cerebral amyloid plaques were likely to be present. The cognitive performance was evaluated in standard cognition tests. Low or high Aβ concentrations coincided with low or high sAβPPα, sAβPPβ, and CXCL-1 levels, respectively. Dogs with high Aβ concentrations showed significant learning impairments on delayed non-match to position (DNMP), object discrimination, and reversal learning compared to dogs with low Aβ concentrations. Our data support the hypothesis that high levels of CSF Aβ in dogs coincide with lower cognitive performance prior to amyloid deposition. Further experiments are needed to investigate this link, as well as the relevance with respect to Alzheimer's disease pathology progression.

%B J Alzheimers Dis %V 56 %P 763-774 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035921?dopt=Abstract %R 10.3233/JAD-160434 %0 Journal Article %J J Alzheimers Dis %D 2016 %T An 18-mer Peptide Derived from Prosaposin Ameliorates the Effects of Aβ1-42 Neurotoxicity on Hippocampal Neurogenesis and Memory Deficit in Mice. %A Gao, Hui-Ling %A Li, Cheng %A Nabeka, Hiroaki %A Shimokawa, Tetsuya %A Wang, Zhan-You %A Cao, Ya-Ming %A Matsuda, Seiji %X

The pathological hallmarks of Alzheimer's disease (AD) include amyloid-β (Aβ) accumulation, neurofibrillary tangle formation, synaptic dysfunction, and neuronal loss. The present study was performed to investigate the protective effects and mechanism of action of a prosaposin-derived 18-mer peptide (PS18: LSELIINNATEELLIKGL) on mice hippocampal progenitor cell proliferation, neurogenesis, and memory tasks after intracerebroventricular injection of Aβ1-42 peptide. Seven days after Aβ1-42 injection, significant proliferation of hippocampal progenitor cells and memory impairment were evident. Two weeks after Aβ1-42 peptide injection, elevated numbers of surviving 5-bromo-2-deoxyuridine cells and newly formed neurons were detected. Treatment with PS18 attenuated these effects evoked by Aβ1-42. Our data indicate that treatment with PS18 partially attenuated the increase in hippocampal neurogenesis caused by Aβ1-42-induced neuroinflammation and prevented memory deficits associated with increased numbers of activated glial cells. We observed an increase in ADAM10 and decreases in BACE1, PS1/2, and AβPP protein levels, suggesting that PS18 enhances the nonamyloidogenic AβPP cleavage pathway. Importantly, our results further showed that PS18 activated the PI3K/Akt pathway, phosphorylated GSK-3α/β, and, as a consequence, exerted a neuroprotective effect. In addition, PS18 showed a protective effect against Aβ1-42-induced neurotoxicity via suppression of the caspase pathway; upregulation of Bcl-2; downregulation of BAX, attenuating mitochondrial damage; and inhibition of caspase-3. These findings suggest that PS18 may provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative diseases, such as AD.

%B J Alzheimers Dis %V 53 %P 1173-92 %8 2016 Jun 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372641?dopt=Abstract %R 10.3233/JAD-160093 %0 Journal Article %J J Alzheimers Dis %D 2016 %T ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies. %A Boehm-Cagan, Anat %A Bar, Roni %A Liraz, Ori %A Bielicki, John K %A Johansson, Jan O %A Michaelson, Daniel M %X

The allele ɛ4 of apolipoprotein E (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD) and is therefore a promising therapeutic target. Human and animal model studies suggest that apoE4 is hypolipidated; accordingly, we have previously shown that the retinoid X receptor (RXR) agonist bexarotene upregulates ABCA1, the main apoE-lipidating protein, resulting in increased lipidation of apoE4, and the subsequent reversal of the pathological effects of apoE4, namely: accumulation of Aβ42 and hyperphosphorylated tau, as well as reduction in the levels of synaptic markers and cognitive deficits. Since the RXR system has numerous other targets, it is important to devise the means of activating ABCA1 selectively. We presently utilized CS-6253, a peptide shown to directly activate ABCA1 in vitro, and examined the extent to which it can affect the degree of lipidation of apoE4 in vivo and counteract the associated brain and behavioral pathologies. This revealed that treatment of young apoE4-targeted replacement mice with CS-6253 increases the lipidation of apoE4. This was associated with a reversal of the apoE4-driven Aβ42 accumulation and tau hyperphosphorylation in hippocampal neurons, as well as of the synaptic impairments and cognitive deficits. These findings suggest that the pathological effects of apoE4 in vivo are associated with decreased activation of ABCA1 and impaired lipidation of apoE4 and that the downstream brain-related pathology and cognitive deficits can be counteracted by treatment with the ABCA1 agonist CS-6253. These findings have important clinical ramifications and put forward ABCA1 as a promising target for apoE4-related treatment of AD.

%B J Alzheimers Dis %V 54 %P 1219-1233 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567858?dopt=Abstract %R 10.3233/JAD-160467 %0 Journal Article %J J Alzheimers Dis %D 2016 %T ABCA7 Genotypes Confer Alzheimer's Disease Risk by Modulating Amyloid-β Pathology. %A Zhao, Qing-Fei %A Wan, Yu %A Wang, Hui-Fu %A Sun, Fu-Rong %A Hao, Xiao-Ke %A Tan, Meng-Shan %A Tan, Chen-Chen %A Zhang, Dao-Qiang %A Tan, Lan %A Yu, Jin-Tai %X

ABCA7 gene has been identified as a strong genetic locus for Alzheimer's disease (AD) susceptibility in genome wide association studies (GWAS). However, the possible roles of ABCA7 variants in AD pathology were not specifically assessed. Using tagger methods, we extracted 15 targeted ABCA7 loci to investigate their associations with cerebrospinal fluid (CSF) and neuroimaging markers in Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Finally, although we did not detect any significant associations of previously published GWAS SNPs (rs3764650 and rs78117248) with all the CSF (Aβ1 - 42, T-tau, and P-tau) and neuroimaging markers, three other variants (rs3752242, rs3752240, and rs4147912) at ABCA7 loci were detected to show significant associations with amyloid deposition on AV-45 PET in brain. Moreover, haplotype and subgroup analysis confirmed these significant findings. Furthermore, there were no remarkable correlations between ABCA7 variants and neuronal degeneration biomarkers (elevated CSF tau, brain structure atrophy, and hypometabolism on imaging) in this study. Thus, our study suggested that ABCA7 genotypes contribute to the AD risk through involvement in amyloid-β deposition on in vivo imaging, but not in tau pathology, brain atrophy, or decreased glucose metabolism.

%B J Alzheimers Dis %V 52 %P 693-703 %8 2016 03 21 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003212?dopt=Abstract %R 10.3233/JAD-151005 %0 Journal Article %J J Alzheimers Dis %D 2016 %T ABCA7 Mediates Phagocytic Clearance of Amyloid-β in the Brain. %A Fu, YuHong %A Hsiao, Jen-Hsiang T %A Paxinos, George %A Halliday, Glenda M %A Kim, Woojin Scott %X

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and abnormal deposits of aggregated amyloid-β in the brain. Recent genome-wide association studies have revealed that ABCA7 is strongly associated with AD. In vitro evidence suggests that the role of ABCA7 is related to phagocytic activity. Deletion of ABCA7 in a mouse model of AD exacerbates cerebral amyloid-β plaque load. However, the biological role of ABCA7 in AD brain pathogenesis is unknown. We show that ABCA7 is highly expressed in microglia and when monocytes are differentiated into macrophages. We hypothesized that ABCA7 plays a protective role in the brain that is related to phagocytic clearance of amyloid-β. We isolated microglia and macrophages from Abca7-/- and wild type mice and tested them for their capacity to phagocytose amyloid-β oligomers. We found that the phagocytic clearance of amyloid-β was substantially reduced in both microglia and macrophages from Abca7-/- mice compared to wild type mice. Consistent with these results, in vivo phagocytic clearance of amyloid-β oligomers in the hippocampus was reduced in Abca7-/- mice. Furthermore, ABCA7 transcription was upregulated in AD brains and in amyloidogenic mouse brains specifically in the hippocampus as a response to the amyloid-β pathogenic state. Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD.

%B J Alzheimers Dis %V 54 %P 569-84 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472885?dopt=Abstract %R 10.3233/JAD-160456 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Aberrant Spontaneous Brain Activity in Patients with Mild Cognitive Impairment and concomitant Lacunar Infarction: A Resting-State Functional MRI Study. %A Ni, Ling %A Liu, Renyuan %A Yin, Zhenyu %A Zhao, Hui %A Nedelska, Zuzana %A Hort, Jakub %A Zhou, Fei %A Wu, Wenbo %A Zhang, Xin %A Li, Ming %A Yu, Haiping %A Zhu, Bin %A Xu, Yun %A Zhang, Bing %K Aged %K Aged, 80 and over %K Brain %K Brain Mapping %K Cognitive Dysfunction %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Rest %K Stroke, Lacunar %X

BACKGROUND: Lacunar infarctions (LI) have been associated with a cognitive decline and an increased risk of dementia. Whether and how the pattern of spontaneous brain activity in patients with mild cognitive impairment (MCI) differs in subjects with and without concomitant LI remains unclear.

OBJECTIVE: To compare the pattern of spontaneous brain activity in MCI patients with versus those without LI using resting-state functional magnetic resonance imaging (rs-fMRI).

METHODS: Forty-eight MCI patients, including 22 with LI [MCI-LI] and 26 without LI [MCI-no LI], and 28 cognitive normal subjects underwent rs-fMRI post-processed using regional homogeneity (ReHo) and the amplitude of low-frequency fluctuation (ALFF) methods.

RESULTS: Compared with cognitively normal subjects, the MCI-LI patients had decreased ReHo in the precuneus/cuneus (Pcu/CU) and insula; decreased ALFF in the Pcu/CU and frontal lobe; and increased ALFF and ReHo in the temporal lobe. While the MCI-no LI group had increased ReHo and ALFF in the bilateral hippocampus and parahippocampal gyrus, frontal lobe, and decreased ALFF and ReHo in the temporal lobe. Compared with the MCI-no LI patients, those with MCI-LI had decreased ALFF in the frontal lobe; decreased ReHo in the Pcu/CU and insula; and increased ALFF and ReHo in the temporal lobe (p <  0.05, AlphaSim corrected). In MCI-LI patients, the MOCA scores showed a relatively weak correlation with ALFF values in the medial frontal gyrus (r = 0.432, p = 0.045) (of borderline significance after Bonferroni correction).

CONCLUSIONS: The spontaneous brain activities in MCI-LI were distinct from MCI-no LI. The probable compensatory mechanism observed in MCI-no LI might be disrupted in MCI with LI due to vascular damage.

%B J Alzheimers Dis %V 50 %P 1243-54 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836013?dopt=Abstract %R 10.3233/JAD-150622 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Accurate Prediction of Conversion to Alzheimer's Disease using Imaging, Genetic, and Neuropsychological Biomarkers. %A Dukart, Juergen %A Sambataro, Fabio %A Bertolino, Alessandro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoproteins E %K Area Under Curve %K Brain %K Cognitive Dysfunction %K Disease Progression %K Female %K Fluorodeoxyglucose F18 %K Follow-Up Studies %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %K Prognosis %K Radiopharmaceuticals %K ROC Curve %K Sensitivity and Specificity %X

A variety of imaging, neuropsychological, and genetic biomarkers have been suggested as potential biomarkers for the identification of mild cognitive impairment (MCI) in patients who later develop Alzheimer's disease (AD). Here, we systematically evaluated the most promising combinations of these biomarkers regarding discrimination between stable and converter MCI and reflection of disease staging. Alzheimer's Disease Neuroimaging Initiative data of AD (n = 144), controls (n = 112), stable (n = 265) and converter (n = 177) MCI, for which apolipoprotein E status, neuropsychological evaluation, and structural, glucose, and amyloid imaging were available, were included in this study. Naïve Bayes classifiers were built on AD and controls data for all possible combinations of these biomarkers, with and without stratification by amyloid status. All classifiers were then applied to the MCI cohorts. We obtained an accuracy of 76% for discrimination between converter and stable MCI with glucose positron emission tomography as a single biomarker. This accuracy increased to about 87% when including further imaging modalities and genetic information. We also identified several biomarker combinations as strong predictors of time to conversion. Use of amyloid validated training data resulted in increased sensitivities and decreased specificities for differentiation between stable and converter MCI when amyloid was included as a biomarker but not for other classifier combinations. Our results indicate that fully independent classifiers built only on AD and controls data and combining imaging, genetic, and/or neuropsychological biomarkers can more reliably discriminate between stable and converter MCI than single modality classifiers. Several biomarker combinations are identified as strongly predictive for the time to conversion to AD.

%B J Alzheimers Dis %V 49 %P 1143-59 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599054?dopt=Abstract %R 10.3233/JAD-150570 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Activation of p53 in Down Syndrome and in the Ts65Dn Mouse Brain is Associated with a Pro-Apoptotic Phenotype. %A Tramutola, Antonella %A Pupo, Gilda %A Di Domenico, Fabio %A Barone, Eugenio %A Arena, Andrea %A Lanzillotta, Chiara %A Broekaart, Diede %A Blarzino, Carla %A Head, Elizabeth %A Butterfield, D Allan %A Perluigi, Marzia %K Acetylation %K Alzheimer Disease %K Animals %K Apoptosis %K Blotting, Western %K Disease Models, Animal %K Down Syndrome %K Female %K Frontal Lobe %K Humans %K Immunoprecipitation %K Male %K Mice, Inbred C3H %K Mice, Inbred C57BL %K Mice, Transgenic %K Middle Aged %K Phenotype %K Phosphorylation %K Tumor Suppressor Protein p53 %K Young Adult %X

Down syndrome (DS) is the most common genetic cause of intellectual disability, resulting from trisomy of chromosome 21. The main feature of DS neuropathology includes early onset of Alzheimer's disease (AD), with deposition of senile plaques and tangles. We hypothesized that apoptosis may be activated in the presence of AD neuropathology in DS, thus we measured proteins associated with upstream and downstream pathways of p53 in the frontal cortex from DS cases with and without AD pathology and from Ts65Dn mice, at different ages. We observed increased acetylation and phosphorylation of p53, coupled to reduced MDM2/p53 complex level and lower levels of SIRT1. Activation of p53 was associated with a number of targets (BAX, PARP1, caspase-3, p21, heat shock proteins, and PGC1α) that were modulated in both DS and DS/AD compared with age-matched controls. In particular, the most relevant changes (increased p-p53 and acetyl-p53 and reduced formation of MDM2/p53 complex) were found to be modified only in the presence of AD pathology in DS. In addition, a similar pattern of alterations in the p53 pathway was found in Ts65Dn mice. These results suggest that p53 may integrate different signals, which can result in a pro-apoptotic-phenotype contributing to AD neuropathology in people with DS.

%B J Alzheimers Dis %V 52 %P 359-71 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967221?dopt=Abstract %R 10.3233/JAD-151105 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Active Cigarette Smoking in Cognitively-Normal Elders and Probable Alzheimer's Disease is Associated with Elevated Cerebrospinal Fluid Oxidative Stress Biomarkers. %A Durazzo, Timothy C %A Korecka, Magdalena %A Trojanowski, John Q %A Weiner, Michael W %A O' Hara, Ruth %A Ashford, John W %A Shaw, Leslie M %X

Neurodegenerative diseases and chronic cigarette smoking are associated with increased cerebral oxidative stress (OxS). Elevated F2-isoprostane levels in biological fluid is a recognized marker of OxS. This study assessed the association of active cigarette smoking with F2-isoprostane in concentrations in cognitively-normal elders (CN), and those with mild cognitive impairment (MCI) and probable Alzheimer's disease (AD). Smoking and non-smoking CN (n = 83), MCI (n = 164), and probable AD (n = 101) were compared on cerebrospinal fluid (CSF) iPF2α-III and 8,12, iso-iPF2α-VI F2-isoprostane concentrations. Associations between F2-isoprostane levels and hippocampal volumes were also evaluated. In CN and AD, smokers had higher iPF2α-III concentration; overall, smoking AD showed the highest iPF2α-III concentration across groups. Smoking and non-smoking MCI did not differ on iPF2α-III concentration. No group differences were apparent on 8,12, iso-iPF2α-VI concentration, but across AD, higher 8,12, iso-iPF2α-VI level was related to smaller left and total hippocampal volumes. Results indicate that active cigarette smoking in CN and probable AD is associated with increased central nervous system OxS. Further investigation of factors mediating/moderating the absence of smoking effects on CSF F2-isoprostane levels in MCI is warranted. In AD, increasing magnitude of OxS appeared to be related to smaller hippocampal volume. This study contributes additional novel information to the mounting body of evidence that cigarette smoking is associated with adverse effects on the human central nervous system across the lifespan.

%B J Alzheimers Dis %V 54 %P 99-107 %8 2016 Jul 25 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472882?dopt=Abstract %R 10.3233/JAD-160413 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Activities of Daily Living and Depressive Symptoms in Patients with Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease. %A Stogmann, Elisabeth %A Moser, Doris %A Klug, Stefanie %A Gleiss, Andreas %A Auff, Eduard %A Dal-Bianco, Peter %A Pusswald, Gisela %A Lehrner, Johann %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Cognitive Dysfunction %K Depression %K Female %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Odds Ratio %K Perception %K Prospective Studies %X

BACKGROUND: Subjective cognitive decline (SCD) may be an early indicator for an increased risk of dementia. The exact definition of SCD remains unclear and has recently become a major research interest.

OBJECTIVES: To determine impairments in activities of daily living (ADL) and depressive symptoms in elderly individuals with SCD, mild cognitive impairment (MCI), and Alzheimer's disease (AD).

METHODS: We included 752 consecutive patients suffering from SCD, non-amnestic (naMCI) or amnestic MCI (aMCI), AD, and 343 healthy controls into this prospective cohort study. A neuropsychological test battery, B-ADL and BDI-II was performed.

RESULTS: SCD patients showed a decreased performance in ADL compared to controls. Performance in ADL declined concurrently with cognitive abilities along the controls-SCD-naMCI-aMCI-AD continuum. Individuals with cognitive complains, no matter if SCD, MCI, or AD patients, reported more often depressive symptoms compared to healthy controls without complaints. Within all five cognitive subgroups, patients with depressive symptoms reported more difficulties in ADL in comparison to patients without depressive symptoms. Adjusting for depressive symptoms, there was no significant group difference between the control versus the SCD group (OR 1.1, CI 0.6-1.7).

CONCLUSIONS: SCD is a heterogeneous clinical condition. Specific features such as slightly impaired ADL and depressive symptoms are associated with SCD. Clinical markers may serve as an indicator for preclinical AD and in combination with biomarkers guide to an early diagnosis of a progressive neurodegenerative disease.

%B J Alzheimers Dis %V 49 %P 1043-50 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26577522?dopt=Abstract %R 10.3233/JAD-150785 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory Clinic Patients in a Prospective Cohort. %A Handels, Ron L H %A Joore, Manuela A %A Vos, Stephanie J B %A Aalten, Pauline %A Ramakers, Inez H G B %A Rikkert, Marcel Olde %A Scheltens, Philip %A Jansen, Willemijn J %A Visser, Pieter-Jelle %A van Berckel, Bart M N %A van Domburg, Peter %A Smid, Machiel %A Hoff, Erik %A Hoogmoed, Jan %A Bouwman, Femke %A Claassen, Jurgen %A Leentjens, Albert F G %A Wolfs, Claire A G %A Severens, Johan L %A Verhey, Frans R J %X

BACKGROUND: Limited information is available on short-term prognosis of Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF) in addition to routine diagnostic workup.

OBJECTIVE: This study aims to investigate the added prognostic value of AD CSF biomarkers.

METHODS: In a prospective cohort study, clinical experts predicted cognitive and functional symptoms in 114 memory clinic patients by assessing comprehensive routine diagnostic test information (patient history, and physical, neurological, psychiatric, neuropsychological, and MRI examinations), without and with CSF biomarkers. The reference standard was the 'observed clinically relevant decline' using baseline and 1- and 2-year follow-up information.

RESULTS: Decline over a 2-year period was observed in 51% of all participants (3% in SMC, 48% in MCI, 90% in mild dementia). In the total sample, the accuracy of predicted decline did not differ significantly between routine assessment without (79% correctly predicted) and with (74% correctly predicted) CSF biomarkers. Subgroup analyses revealed 25 (83%) correct predictions in SMC, 30 (68%) in MCI, and 35 (88%) in dementia without the use of CSF; and 21 (70%), 27 (61%), and 36 (90%), respectively, with the use of CSF in addition to the routine assessment.

CONCLUSION: AD CSF biomarkers did not increase accuracy of 2-year prognosis of cognitive and functional decline when added to routine diagnostic workup. This suggests that the standard diagnostic workup without CSF biomarkers allows fairly accurate predictions for the short-term course of symptoms. Routine AD biomarkers in CSF have limited prognostic value over 2 years in persons with a suspected cognitive disorder.

%B J Alzheimers Dis %V 52 %P 875-85 %8 2016 Mar 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031483?dopt=Abstract %R 10.3233/JAD-151120 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Adenosine Type A2A Receptor in Peripheral Cell from Patients with Alzheimer's Disease, Vascular Dementia, and Idiopathic Normal Pressure Hydrocephalus: A New/Old Potential Target. %A Arosio, Beatrice %A Casati, Martina %A Gussago, Cristina %A Ferri, Evelyn %A Abbate, Carlo %A Scortichini, Valeria %A Colombo, Elena %A Rossi, Paolo Dionigi %A Mari, Daniela %X

As the European population gets older, the incidence of neurological disorders increases with significant impact on social costs. Despite differences in disease etiology, several brain disorders in the elderly (e.g., Alzheimer's disease, vascular dementia, normal pressure hydrocephalus) share dementia as a common clinical feature. The current treatment for the majority of these diseases is merely symptomatic and does not modify the course of the illness. Symptoms of normal pressure hydrocephalus are the only ones that can be modified if they are recognized in time and treated appropriately. Therefore, an important clinical strategy may be disclosed by pathogenic pathways that can be modified and to find drugs that can slow down or even arrest disease progression. Possibly a way to answer this question could be by re-examining all the molecules which have so far succeeded in improving many aspects of cognitive deterioration in some neurodegenerative conditions, that were not considered because of controversial opinions. The main purpose of this summary is to further substantiate the hypothesis that the pathway of adenosine type A2A receptor could be used as a potential target to develop new/old therapeutic strategies.

%B J Alzheimers Dis %V 54 %P 417-25 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497479?dopt=Abstract %R 10.3233/JAD-160324 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Administering Cognitive Tests Through Touch Screen Tablet Devices: Potential Issues. %A Jenkins, Amy %A Lindsay, Stephen %A Eslambolchilar, Parisa %A Thornton, Ian M %A Tales, Andrea %X

Mobile technologies, such as tablet devices, open up new possibilities for health-related diagnosis, monitoring, and intervention for older adults and healthcare practitioners. Current evaluations of cognitive integrity typically occur within clinical settings, such as memory clinics, using pen and paper or computer-based tests. In the present study, we investigate the challenges associated with transferring such tests to touch-based, mobile technology platforms from an older adult perspective. Problems may include individual variability in technical familiarity and acceptance; various factors influencing usability; acceptability; response characteristics and thus validity per se of a given test. For the results of mobile technology-based tests of reaction time to be valid and related to disease status rather than extraneous variables, it is imperative the whole test process is investigated in order to determine potential effects before the test is fully developed. Researchers have emphasized the importance of including the 'user' in the evaluation of such devices; thus we performed a focus group-based qualitative assessment of the processes involved in the administration and performance of a tablet-based version of a typical test of attention and information processing speed (a multi-item localization task), to younger and older adults. We report that although the test was regarded positively, indicating that using a tablet for the delivery of such tests is feasible, it is important for developers to consider factors surrounding user expectations, performance feedback, and physical response requirements and to use this information to inform further research into such applications.

%B J Alzheimers Dis %V 54 %P 1169-1182 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567875?dopt=Abstract %R 10.3233/JAD-160545 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Adults at Increased Alzheimer's Disease Risk Display Cognitive-Motor Integration Impairment Associated with Changes in Resting-State Functional Connectivity: A Preliminary Study. %A Hawkins, Kara M %A Sergio, Lauren E %X

BACKGROUND: Many neuroimaging parameters have demonstrated utility as biomarkers in preclinical AD, including resting-state functional connectivity in the default mode network. However, neuroimaging is not a practical, cost effective screening instrument.

OBJECTIVE: Here we investigate the relationship between performance on a cognitive-motor integration assessment and alterations in resting-state functional connectivity in an at-risk population.

METHODS: Three groups of ten adults (young: mean age = 26.6 ± 2.7, low AD risk: mean age = 58.7 ± 5.6, and high AD risk: mean age = 58.5 ± 6.9) performed a simple cognitive-motor integration task using a dual-touchscreen laptop and also underwent functional magnetic resonance imaging at rest.

RESULTS: We found poorer cognitive-motor integration performance in high AD risk participants, as well as an association with lower resting-state functional connectivity in this group.

CONCLUSION: These findings provide novel insight into underlying AD-related brain alterations associated with a behavioral assessment that can be easily administered clinically.

%B J Alzheimers Dis %V 53 %P 1161-72 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340846?dopt=Abstract %R 10.3233/JAD-151137 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Age and its association with low insulin and high amyloid-β peptides in blood. %A Li, Huajie %A Zhu, Haihao %A Wallack, Max %A Mwamburi, Mkaya %A Abdul-Hay, Samer O %A Leissring, Malcolm A %A Qiu, Wei Qiao %K Age Distribution %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Biomarkers %K Cognition Disorders %K Cross-Sectional Studies %K Female %K Humans %K Insulin %K Islet Amyloid Polypeptide %K Linear Models %K Male %K Middle Aged %K Multivariate Analysis %K Peptide Fragments %X

Age is the major risk factor for developing Alzheimer's disease (AD), and modifying age-related factors may help to delay the onset of the disease. The goal of this study was to investigate the relationship between age and the metabolic factors related to the risk of developing AD. The concentrations of insulin, amylin, and amyloid-β peptide (Aβ) in plasma were measured. We further measured the activity of serum Aβ degradation by using fluorescein- and biotin-labeled Aβ40. Apolipoprotein E4 allele (ApoE4) and cognitive impairment were characterized. Subjects were divided into three age groups: 60-70, 70-80, and ≥80 years old. We found that the older the subjects, the lower the concentration of insulin (p = 0.001) and the higher the concentration of Aβ1-40 (p = 0.004) in plasma. However, age was not associated with the concentration of another pancreatic peptide, amylin, and only marginally with Aβ1-42. These relationships remained in the absence of diabetes, cardiovascular disease, and stroke, and regardless of the presence of ApoE4 and cognitive impairment. Both age and ApoE4 were inversely associated with, while insulin was positively associated with, the activities of Aβ degradation in serum. Our study suggested that low concentration of insulin and high concentration of Aβ40 are aging factors related to the risk of AD.

%B J Alzheimers Dis %V 49 %P 129-37 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444783?dopt=Abstract %R 10.3233/JAD-150428 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Age-Dependent Regulation of the Blood-Brain Barrier Influx/Efflux Equilibrium of Amyloid-β Peptide in a Mouse Model of Alzheimer's Disease (3xTg-AD). %A Do, Tuan Minh %A Dodacki, Agnès %A Alata, Wael %A Calon, Frederic %A Nicolic, Sophie %A Scherrmann, Jean-Michel %A Farinotti, Robert %A Bourasset, Fanchon %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K ATP Binding Cassette Transporter, Sub-Family G, Member 1 %K ATP Binding Cassette Transporter, Sub-Family G, Member 2 %K ATP-Binding Cassette Transporters %K Biological Transport %K Blood-Brain Barrier %K Brain %K Carbon Isotopes %K Cholesterol %K Disease Models, Animal %K Humans %K Lipoproteins %K Mice %K Mice, Transgenic %K P-Glycoproteins %K Peptide Fragments %K Receptors, LDL %K Sucrose %K Tritium %K Tumor Suppressor Proteins %X

The involvement of transporters located at the blood-brain barrier (BBB) has been suggested in the control of cerebral Aβ levels, and thereby in Alzheimer's disease (AD). However, little is known about the regulation of these transporters at the BBB in animal models of AD. In this study, we investigated the BBB expression of Aβ influx (Rage) and efflux (Abcb1-Abcg2-Abcg4-Lrp-1) transporters and cholesterol transporter (Abca1) in 3-18-month-old 3xTg-AD and control mice. The age-dependent effect of BBB transporters regulation on the brain uptake clearance (Clup) of [3H]cholesterol and [3H]Aβ1 - 40 was then evaluated in these mice, using the in situ brain perfusion technique. Our data suggest that transgenes expression led to the BBB increase in Aβ influx receptor (Rage) and decrease in efflux receptor (Lrp-1). Our data also indicate that mice have mechanisms counteracting this increased net influx. Indeed, Abcg4 and Abca1 are up regulated in 3- and 3/6-month-old 3xTg-AD mice, respectively. Our data show that the balance between the BBB influx and efflux of Aβ is maintained in 3 and 6-month-old 3xTg-AD mice, suggesting that Abcg4 and Abca1 control the efflux of Aβ through the BBB by a direct (Abcg4) or indirect (Abca1) mechanism. At 18 months, the BBB Aβ efflux is significantly increased in 3xTg-AD mice compared to controls. This could result from the significant up-regulation of both Abcg2 and Abcb1 in 3xTg-AD mice compared to control mice. Thus, age-dependent regulation of several Aβ and cholesterol transporters at the BBB could ultimately limit the brain accumulation of Aβ.

%B J Alzheimers Dis %V 49 %P 287-300 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484906?dopt=Abstract %R 10.3233/JAD-150350 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Age-Related Changes in the Synaptic Density of Amyloid-β Protein Precursor and Secretases in the Human Cerebral Cortex. %A Pliássova, Anna %A Canas, Paula M %A Xavier, Ana Carolina %A da Silva, Beatriz S %A Cunha, Rodrigo A %A Agostinho, Paula %X

Amyloid-β protein precursor (AβPP) is involved in synaptic formation and function. In the human cingulate cortex, AβPP was preferentially located in the presynaptic active zone as in rodents, indicating a preserved subsynaptic AβPP distribution across species and brain regions. Synaptic AβPP immunoreactivity was decreased with aging in cortical samples collected from autopsies of males (20-80 years), whereas the synaptic levels of α-secretase (ADAM10) and β-secretase (BACE1) did not significantly change. Decreased AβPP levels may be related to lower allostasis of synapses in the aged brain and their greater susceptibility to dysfunction characteristic of the onset of neurodegenerative disorders.

%B J Alzheimers Dis %V 52 %P 1209-14 %8 2016 Apr 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104908?dopt=Abstract %R 10.3233/JAD-160213 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Age-Related Effects of the Apolipoprotein E Gene on Brain Function. %A Matura, Silke %A Prvulovic, David %A Hartmann, Daniel %A Scheibe, Monika %A Sepanski, Beate %A Butz, Marius %A Oertel-Knöchel, Viola %A Knöchel, Christian %A Karakaya, Tarik %A Fußer, Fabian %A Hattingen, Elke %A Pantel, Johannes %X

The apolipoprotein E (ApoE) ɛ4 allele is a well-established genetic risk factor for sporadic Alzheimer's disease. Some evidence suggests a negative role of the ApoE ɛ4 allele for cognitive performance in late life, while beneficial effects on cognition have been shown in young age. We investigated age-related effects of the ApoE gene on brain function by assessing cognitive performance, as well as functional activation patterns during retrieval of Face-Name pairs in a group of young (n = 50; age 26.4±4.6 years, 25 ɛ4 carriers) and old (n = 40; age 66.1±7.0 years, 20 ɛ4 carriers) participants. A cross-sectional factorial design was used to examine the effects of age, ApoE genotype, and their interaction on both cognitive performance and the blood oxygenation level dependent (BOLD) brain response during retrieval of Face-Name pairs. While there were no genotype-related differences in cognitive performance, we found a significant interaction of age and ApoE genotype on task-related activation bilaterally in anterior cingulate gyrus and superior frontal gyrus, as well as left and right insula. Old age was associated with increased activity in ɛ4 carriers. The increased BOLD response in old ɛ4 carriers during retrieval could indicate a neurocognitive disadvantage associated with the ɛ4 allele with increasing age. Furthermore, recruitment of neuronal resources resulted in enhanced memory performance in young ɛ4 carriers, pointing to a better neurofunctional capacity associated with the ApoE4 genotype in young age.

%B J Alzheimers Dis %V 52 %P 317-31 %8 2016 03 16 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003211?dopt=Abstract %R 10.3233/JAD-150990 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Aging as a Precipitating Factor in Chronic Restraint Stress-Induced Tau Aggregation Pathology, and the Protective Effects of Rosmarinic Acid. %A Shan, Ye %A Wang, Dan-Dan %A Xu, Yu-Xia %A Wang, Chu %A Cao, Lan %A Liu, Yun-Sheng %A Zhu, Cui-Qing %K Aging %K Animals %K Antioxidants %K Brain %K Cinnamates %K Corticotropin-Releasing Hormone %K Depsides %K Disease Models, Animal %K HEK293 Cells %K HSP90 Heat-Shock Proteins %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Microscopy, Immunoelectron %K NIMA-Interacting Peptidylprolyl Isomerase %K Peptidylprolyl Isomerase %K Phosphorylation %K Precipitating Factors %K Receptors, Corticotropin %K Restraint, Physical %K Stress, Psychological %K tau Proteins %K Transfection %X

Stress is an important risk factor of Alzheimer's disease (AD). It has been evidenced that stress could induce tau phosphorylation and increase tau insolubility in brain; however, little is known about the interactional effect of stress with aging on tauopathy. Therefore, we explored the effects of aging on stress-induced tauopathy and the potential mechanism in mouse model of chronic restraint stress (CRS). Here we found that in general, the level of phosphorylated tau (P-tau) was higher in brain of middle-aged mice than that in adult mice under physiological conditions. CRS-induced tau phosphorylation and its insolubility were more prominent in middle-aged mice. The increase of AT8-labeled insoluble P-tau was dramatic in middle-aged mice, which was highly ubiquitinated but did not form PHF structures. The levels of chaperones were relatively lower in middle-aged mice brain; CRS further reduced the expression, especially for HDJ2/HSP40. CRS also suppressed the expression of Pin1, the peptidylprolyl cis/trans isomerase, in middle-aged mice but not in adult mice. Downregulation of HSP40 or Pin1 caused an increase of transfected extraneous tau in 293 cells. Rosmarinic acid (RA) could effectively suppress the elevation of P-tau and insoluble P-tau formation induced by CRS, and reversed the abnormal changes of chaperones and Pin1 particularly in middle-aged mice. Taken together, our findings provided evidence that aging could be a promoting factor in stress-induced tauopathy, which was relevant with malregulation of chaperones and Pin1, and RA might be a promising beneficial agent for stress-induced tauopathy.

%B J Alzheimers Dis %V 49 %P 829-44 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26577520?dopt=Abstract %R 10.3233/JAD-150486 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Aging Enables Ca2+ Overload and Apoptosis Induced by Amyloid-β Oligomers in Rat Hippocampal Neurons: Neuroprotection by Non-Steroidal Anti-Inflammatory Drugs and R-Flurbiprofen in Aging Neurons. %A Calvo-Rodríguez, María %A García-Durillo, Mónica %A Villalobos, Carlos %A Núñez, Lucía %X

The most important risk factor for Alzheimer's disease (AD) is aging. Neurotoxicity in AD has been linked to dyshomeostasis of intracellular Ca2+ induced by small aggregates of the amyloid-β peptide 1-42 (Aβ42 oligomers). However, how aging influences susceptibility to neurotoxicity induced by Aβ42 oligomers is unknown. In this study, we used long-term cultures of rat hippocampal neurons, a model of neuronal in vitro aging, to investigate the contribution of aging to Ca2+ dishomeostasis and neuron cell death induced by Aβ42 oligomers. In addition, we tested whether non-steroidal anti-inflammatory drugs (NSAIDs) and R-flurbiprofen prevent apoptosis acting on subcellular Ca2+ in aged neurons. We found that Aβ42 oligomers have no effect on young hippocampal neurons cultured for 2 days in vitro (2 DIV). However, they promoted apoptosis modestly in mature neurons (8 DIV) and these effects increased dramatically after 13 DIV, when neurons display many hallmarks of in vivo aging. Consistently, cytosolic and mitochondrial Ca2+ responses induced by Aβ42 oligomers increased dramatically with culture age. At low concentrations, NSAIDs and the enantiomer R-flurbiprofen lacking anti-inflammatory activity prevent Ca2+ overload and neuron cell death induced by Aβ42 oligomers in aged neurons. However, at high concentrations R-flurbiprofen induces apoptosis. Thus, Aβ42 oligomers promote Ca2+ overload and neuron cell death only in aged rat hippocampal neurons. These effects are prevented by low concentrations of NSAIDs and R-flurbiprofen acting on mitochondrial Ca2+ overload.

%B J Alzheimers Dis %V 54 %P 207-21 %8 2016 Jul 22 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27447424?dopt=Abstract %R 10.3233/JAD-151189 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Alcohol Consumption and Incident Dementia: Evidence from the Sydney Memory and Ageing Study. %A Heffernan, Megan %A Mather, Karen A %A Xu, Jing %A Assareh, Amelia A %A Kochan, Nicole A %A Reppermund, Simone %A Draper, Brian %A Trollor, Julian N %A Sachdev, Perminder %A Brodaty, Henry %X

Alcohol consumption is a potentially modifiable risk factor for dementia, but the literature is not completely consistent. This inconsistency may be partly due to an interaction with the apolipoprotein E (APOE) genotype, an established risk factor for Alzheimer's dementia. The aim of this study was to examine whether alcohol consumption is associated with incident dementia or decline in specific cognitive domains over 4 years, and if this effect is modified by APOEɛ4 status. Non-demented community dwelling older adults (70-90 years) from an ongoing longitudinal study were assessed for cognitive impairment in attention/processing speed, language, executive function, visuospatial ability, and memory. Incident dementia was diagnosed according to DSM-IV criteria. Compared to those who did not drink in the previous 12 months, neither low consumption (HR 0.64 95% CI 0.3-1.4) or risky consumption (HR 0.58 95% CI 0.2-1.5) was associated with incident dementia. Carriers of the APOEɛ4 allele were more likely to develop dementia, but there was no significant interaction with alcohol consumption.

%B J Alzheimers Dis %V 52 %P 529-38 %8 2016 Mar 29 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031466?dopt=Abstract %R 10.3233/JAD-150537 %0 Journal Article %J J Alzheimers Dis %D 2016 %T All Is Not Lost: Positive Behaviors in Alzheimer's Disease and Behavioral-Variant Frontotemporal Dementia with Disease Severity. %A Midorikawa, Akira %A Leyton, Cristian E %A Foxe, David %A Landin-Romero, Ramon %A Hodges, John R %A Piguet, Olivier %X

BACKGROUND: Anecdotal evidence indicates that some patients with dementia exhibit novel or increased positive behaviors, such as painting or singing, after the disease onset. Due to the lack of objective measures, however, the frequency and nature of these changes has not been formally investigated.

OBJECTIVE: This study aimed to systematically identify changes in these behaviors in the two most common younger-onset dementia syndromes: Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD).

METHODS: Sixty-three caregivers of patients with dementia (32 caregivers of AD patients and 31 caregivers of bvFTD patients) participated in the study. Caregivers rated the presence and frequency of positive and negative behavior changes after the onset of dementia using the Hypersensory and Social/Emotional Scale (HSS) questionnaire, focusing on three domains: sensory processing, cognitive skills, and social/emotional processing. Six composites scores were obtained reflecting these three domains (two composite scores for each domain). Differences across scores and ratios of increased and decreased behaviors were analyzed between AD and bvFTD, at different disease severity levels.

RESULTS: After disease onset, significant changes in the sensory processing domain were observed across disease severity levels, particularly in AD. Composite scores of the other domains did not change significantly. Importantly, however, some novel or increased positive behaviors were present in between 10% (Music activities) and 70% (Hypersensitivity) of AD and bvFTD patients, regardless of disease severity.

CONCLUSIONS: We provide the first systematic investigation of positive behaviors in AD and bvFTD. The newly developed HSS questionnaire is a valid measure to characterize changes and progression of positive behaviors in patients with dementia.

%B J Alzheimers Dis %V 54 %P 549-58 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472884?dopt=Abstract %R 10.3233/JAD-160440 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Alterations in Phase-Related Prefrontal Activation During Cognitive Tasks and Nicotinic α4β2 Receptor Availability in Alzheimer's Disease. %A Oboshi, Yumi %A Kikuchi, Mitsuru %A Terada, Tatsuhiro %A Yoshikawa, Etsuji %A Bunai, Tomoyasu %A Ouchi, Yasuomi %X

BACKGROUND: Evidence shows that the cholinergic system plays an important role in regulating working memory and that working memory-related prefrontal activation decreases with age and neuronal degeneration, such as Alzheimer's disease (AD). However, the relation between attention-related α4β2 nicotinic cholinergic function and task-induced prefrontal activation especially time course-related activation remains to be explored.

OBJECTIVE: We aimed to elucidate the relationship between changes in task-induced oxy-hemoglobin concentration (cerebral blood flow, CBF) in the prefrontal cortex and the availability of α4β2 nicotinic receptors in the brain of AD patients in light of their task performance.

METHODS: Eleven mild-to-moderate AD patients and eleven normal elderly subjects underwent the near-infrared spectroscopy during easy and difficult working memory tasks for estimating prefrontal CBF changes and positron emission tomography with the α4β2 tracer [18F]2FA-85380 ([18F]2FA) for measuring the α4β2 nicotinic receptor binding.

RESULTS: Significant correlations between mean oxy-hemoglobin concentration in the channels with significant [group] main effects and prefrontal [18F]2FA binding were observed during the early easy task period in the normal group and during the late difficult task in the AD group. In addition, those prefrontal CBF responses were significantly correlated with not correct performance but the execution time to spend.

CONCLUSION: The α4β2 nicotinic acetylcholine receptors in the prefrontal cortex play an important role in increasing prefrontal activation when attending to novel stimuli, irrespective of the accuracy of the outcome. A delay in the cholinergic-induced increase in prefrontal activation in AD patients might explain their delayed responses in the cognitive task.

%B J Alzheimers Dis %V 53 %P 817-30 %8 2016 May 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258412?dopt=Abstract %R 10.3233/JAD-151165 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Alterations in the Levels of Amyloid-β, Phospholipid Hydroperoxide, and Plasmalogen in the Blood of Patients with Alzheimer's Disease: Possible Interactions between Amyloid-β and These Lipids. %A Yamashita, Shinji %A Kiko, Takehiro %A Fujiwara, Hironori %A Hashimoto, Michio %A Nakagawa, Kiyotaka %A Kinoshita, Mikio %A Furukawa, Katsutoshi %A Arai, Hiroyuki %A Miyazawa, Teruo %K Aged %K Amyloid beta-Peptides %K Female %K Humans %K Hydrogen Peroxide %K Male %K Phosphatidylcholines %K Plasmalogens %X

Aside from accumulation of amyloid-β (Aβ) peptide in the brain, Alzheimer's disease (AD) has been reported as being associated with peroxidation of major phospholipids (e.g., phosphatidylcholine (PtdCho)) and degradation of antioxidative phospholipids (e.g., ethanolamine plasmalogen (PlsEtn)). In addition to its presence in the brain, Aβ is also found in blood; however, there is still little information about the levels of PtdCho hydroperoxide (PCOOH) and PlsEtn in the blood of patients with AD. In this study, by assuming a possible interaction among Aβ, PCOOH, and PlsEtn in blood circulation, we evaluated the levels of these molecules and correlations in blood samples that had been obtained from our former AD study for PCOOH measurement (Kiko et al., J Alzheimers Dis28, 593-600, 2012). We found that when compared to controls, plasma from patients with AD showed lower concentrations of PlsEtn species, especially PlsEtn bearing the docosahexaenoic acid (DHA) moiety. In addition, lower PlsEtn and higher PCOOH levels were observed in red blood cells (RBCs) of patients with AD. In both AD and control blood samples, RBC PCOOH levels tended to correlate with plasma levels of Aβ40, and each PlsEtn species showed different correlations with plasma Aβ. These results, together with in vitro data suggesting Aβ aggregation due to a decrease in levels of PlsEtn having DHA, led us to deduce that Aβ is involved in alterations in levels of PCOOH and PlsEtn species observed in the blood of patients with AD.

%B J Alzheimers Dis %V 50 %P 527-37 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682681?dopt=Abstract %R 10.3233/JAD-150640 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Altered Affective Evaluations of Smells in Alzheimer's Disease. %A Joussain, Pauline %A Bessy, Marion %A Fournel, Arnaud %A Ferdenzi, Camille %A Rouby, Catherine %A Delphin-Combe, Floriane %A Krolak-Salmon, Pierre %A Bensafi, Moustafa %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Case-Control Studies %K Emotions %K Female %K Humans %K Male %K Mood Disorders %K Odorants %K Olfaction Disorders %K Psychiatric Status Rating Scales %K Smell %K Surveys and Questionnaires %X

BACKGROUND: Studies of olfaction in Alzheimer's disease (AD) mainly focused on deficits in odor detection and identification, with very few investigations of olfactory emotional changes and their consequences for hedonics.

OBJECTIVE: The aim of the present study was to characterize affective evaluations of odors in AD patients.

METHODS: To this end, 20 AD patients and 20 matched controls were tested. Participants were screened for odor detection and identification ability and then asked to rate the intensity, pleasantness, and edibility of 20 odorants.

RESULTS: Results showed that, overall, AD patients had lower detection ability and perceived all odors as weaker than controls. As expected, they had lower identification ability on both cued and non-cued tasks. In addition, when smelling pleasant odors, patients had significantly lower hedonic ratings than controls (p <  0.02), whereas no group difference was found for neutral or unpleasant odors (p >  0.05 in both cases). Moreover, an analysis combining both intensity and pleasantness ratings showed that whereas intensity increased as a function of pleasantness and unpleasantness in controls, this quadratic relationship was not observed in AD patients.

CONCLUSIONS: The study suggests that the simplest categorization criteria of odors (intensity and hedonic valence) are impaired in AD patients (especially for pleasant odors).

%B J Alzheimers Dis %V 49 %P 433-41 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484905?dopt=Abstract %R 10.3233/JAD-150332 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Altered Brain Activities Associated with Neural Repetition Effects in Mild Cognitive Impairment Patients. %A Yu, Jing %A Li, Rui %A Jiang, Yang %A Broster, Lucas S %A Li, Juan %X

Older adults with mild cognitive impairment (MCI) manifest impaired explicit memory. However, studies on implicit memory such as repetition effects in persons with MCI have been limited. In the present study, 17 MCI patients and 16 healthy normal controls (NC) completed a modified delayed-match-to-sample task while undergoing functional magnetic resonance imaging. We aim to examine the neural basis of repetition; specifically, to elucidate whether and how repetition-related brain responses are altered in participants with MCI. When repeatedly rejecting distracters, both NC and MCI showed similar behavioral repetition effects; however, in both whole-brain and region-of-interest analyses of functional data, persons with MCI showed reduced repetition-driven suppression in the middle occipital and middle frontal gyrus. Further, individual difference analysis found that activation in the left middle occipital gyrus was positively correlated with rejecting reaction time and negatively correlated with accuracy rate, suggesting a predictor of repetition behavioral performance. These findings provide new evidence to support the view that neural mechanisms of repetition effect are altered in MCI who manifests compensatory repetition-related brain activities along with their neuropathology.

%B J Alzheimers Dis %V 53 %P 693-704 %8 2016 May 11 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27176074?dopt=Abstract %R 10.3233/JAD-160086 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Altered Energy Metabolism Pathways in the Posterior Cingulate in Young Adult Apolipoprotein E ɛ4 Carriers. %A Perkins, Michelle %A Wolf, Andrew B %A Chavira, Bernardo %A Shonebarger, Daniel %A Meckel, J P %A Leung, Lana %A Ballina, Lauren %A Ly, Sarah %A Saini, Aman %A Jones, T Bucky %A Vallejo, Johana %A Jentarra, Garilyn %A Valla, Jon %X

The APOE gene, encoding apolipoprotein E, is the primary genetic risk factor for late-onset Alzheimer's disease (AD). Apolipoprotein E ɛ4 allele (APOE4) carriers have alterations in brain structure and function (as measured by brain imaging) even as young adults. Examination of this population is valuable in further identifying details of these functional changes and their association with vulnerability to AD decades later. Previous work demonstrates functional declines in mitochondrial activity in the posterior cingulate cortex, a key region in the default mode network, which appears to be strongly associated with functional changes relevant to AD risk. Here, we demonstrate alterations in the pathways underlying glucose, ketone, and mitochondrial energy metabolism. Young adult APOE4 carriers displayed upregulation of specific glucose (GLUT1 & GLUT3) and monocarboxylate (MCT2) transporters, the glucose metabolism enzyme hexokinase, the SCOT & AACS enzymes involved in ketone metabolism, and complexes I, II, and IV of the mitochondrial electron transport chain. The monocarboxylate transporter (MCT4) was found to be downregulated in APOE4 carriers. These data suggest that widespread dysregulation of energy metabolism in this at-risk population, even decades before possible disease onset. Therefore, these findings support the idea that alterations in brain energy metabolism may contribute significantly to the risk that APOE4 confers for AD.

%B J Alzheimers Dis %V 53 %P 95-106 %8 2016 Apr 23 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128370?dopt=Abstract %R 10.3233/JAD-151205 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Altered Executive Function in Pre-Mild Cognitive Impairment. %A Seo, Eun Hyun %A Kim, Hoowon %A Lee, Kun Ho %A Choo, Il Han %X

BACKGROUND: For the early detection of Alzheimer's disease (AD), there is increasing interest in pre-mild cognitive impairment (pre-MCI).

OBJECTIVE: We explored the neuropsychological characteristics in a group of pre-MCI and cognitively normal (CN) elderly individuals, with the aim of providing measures sensitive to cognitive change in pre-MCI.

METHODS: We included 188 CN elderly and 77 individuals with pre-MCI. All participants underwent comprehensive clinical and neuropsychological assessment. We compared 17 cognitive tests between the CN and pre-MCI groups by using one-way ANOVAs with false discovery rate correction for multiple comparisons. Pearson's correlations were also obtained between episodic memory and executive function tests in the pre-MCI group.

RESULTS: The pre-MCI group showed significantly lower scores for visual immediate recall, fluency tests, and Stroop color naming in the color-word incongruent condition than the CN group (p < 0.05). Most of these executive function measures were significantly correlated with episodic memory (p < 0.05). There were no significant group-differences in other tests assessing attention, verbal memory, visuospatial ability, and language.

CONCLUSION: Our findings indicate that poor executive function especially demanding inhibition and goal-directed behaviors within time limit could be the characteristics of the very early cognitive sign in the course of AD.

%B J Alzheimers Dis %V 54 %P 933-940 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567814?dopt=Abstract %R 10.3233/JAD-160052 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Altered sense of humor in dementia. %A Clark, Camilla N %A Nicholas, Jennifer M %A Gordon, Elizabeth %A Golden, Hannah L %A Cohen, Miriam H %A Woodward, Felix J %A Macpherson, Kirsty %A Slattery, Catherine F %A Mummery, Catherine J %A Schott, Jonathan M %A Rohrer, Jonathan D %A Warren, Jason D %K Aged %K Alzheimer Disease %K Case-Control Studies %K Cognition Disorders %K Emotions %K Female %K Frontotemporal Dementia %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Primary Progressive Nonfluent Aphasia %K Psychiatric Status Rating Scales %K Surveys and Questionnaires %X

Sense of humor is potentially relevant to social functioning in dementias, but has been little studied in these diseases. We designed a semi-structured informant questionnaire to assess humor behavior and preferences in patients with behavioral variant frontotemporal dementia (bvFTD; n = 15), semantic dementia (SD; n = 7), progressive nonfluent aphasia (PNFA; n = 10), and Alzheimer's disease (AD; n = 16) versus healthy age-matched individuals (n = 21). Altered (including frankly inappropriate) humor responses were significantly more frequent in bvFTD and SD (all patients) than PNFA or AD (around 40% of patients). All patient groups liked satirical and absurdist comedy significantly less than did healthy controls. This pattern was reported premorbidly for satirical comedy in bvFTD, PNFA, and AD. Liking for slapstick comedy did not differ between groups. Altered sense of humor is particularly salient in bvFTD and SD, but also frequent in AD and PNFA. Humor may be a sensitive probe of social cognitive impairment in dementia, with diagnostic, biomarker and social implications.

%B J Alzheimers Dis %V 49 %P 111-9 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444779?dopt=Abstract %R 10.3233/JAD-150413 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Altered Topology in Information Processing of a Narrated Story in Older Adults with Mild Cognitive Impairment. %A Yogev-Seligmann, Galit %A Oren, Noga %A Ash, Elissa L %A Hendler, Talma %A Giladi, Nir %A Lerner, Yulia %X

The ability to store, integrate, and manipulate information declines with aging. These changes occur earlier, faster, and to a greater degree as a result of neurodegeneration. One of the most common and early characteristics of cognitive decline is difficulty with comprehension of information. The neural mechanisms underlying this breakdown of information processing are poorly understood. Using functional MRI and natural stimuli (e.g., stories), we mapped the neural mechanisms by which the human brain accumulates and processes information with increasing duration and complexity in participants with amnestic mild cognitive impairment (aMCI) and healthy older adults. To explore the mechanisms of information processing, we measured the reliability of brain responses elicited by listening to different versions of a narrated story created by segmenting the story into words, sentences, and paragraphs and then scrambling the segments. Comparing healthy older adults and participants with aMCI revealed that in both groups, all types of stimuli similarly recruited primary auditory areas. However, prominent differences between groups were found at the level of processing long and complex stimuli. In healthy older adults, parietal and frontal regions demonstrated highly synchronized responses in both the paragraph and full story conditions, as has been previously reported in young adults. Participants with aMCI, however, exhibited a robust functional shift of long time scale processing to the pre- and post-central sulci. Our results suggest that participants with aMCI experienced a functional shift of higher order auditory information processing, possibly reflecting a functional response to concurrent or impending neuronal or synaptic loss. This observation might assist in understanding mechanisms of cognitive decline in aMCI.

%B J Alzheimers Dis %V 53 %P 517-33 %8 2016 May 03 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163799?dopt=Abstract %R 10.3233/JAD-150845 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Alzheimer's and Parkinson's Diseases: Expected Economic Impact on Europe-A Call for a Uniform European Strategy. %A Maresova, Petra %A Klimova, Blanka %A Novotny, Michal %A Kuca, Kamil %X

The purpose of this study is to analyze the economic burden of persons with Alzheimer's disease (AD) and Parkinson's disease (PD) in Europe. On the basis of available data about the number of persons with dementia, their prevalence, and treatment and care costs, a mean cost burden is estimated for the year of 2030 and for the year of 2050 in Europe. The method of retrospective analysis of available sources was used; furthermore, analysis of database data such as WHO and Eurostat, which provide information about the number of older people and people with dementia; and specification of direct and indirect medical and nonmedical costs of patients with AD and PD from current studies was also used. The findings of this study confirm that the number of patients affected with AD and PD, as well as annual costs of the treatment and care of these patients, in the selected European countries are rapidly growing. The cost burden of both AD and PD in the selected European countries rises year by year, and by 2050, the cost burden of both diseases in fact will be almost two times higher in comparison with the year of 2010. In 2050, the overall mean cost burden is estimated to reach 357 billion Euros. The European Union calls for a joint initiative in the development of a uniformed strategic plan in the fight against dementia.

%B J Alzheimers Dis %V 54 %P 1123-1133 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567862?dopt=Abstract %R 10.3233/JAD-160484 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Alzheimer's Disease: Assessing the Role of Spirochetes, Biofilms, the Immune System, and Amyloid-β with Regard to Potential Treatment and Prevention. %A Allen, Herbert B %X

Alzheimer's disease (AD) is an infectious disease caused by spirochetes, and these spirochetes form biofilms, which attract the innate immune system. The innate immune system first responder, Toll-like receptor 2, generates both NF-κB and TNF-α which try to kill the spirochetes in the biofilm, but cannot penetrate the "slime". NF-κB is also responsible for the generation of amyloid-β (Aβ) which itself is anti-microbial. Aβ cannot penetrate the biofilm either, and its accumulation leads to destruction of the cerebral neurocircuitry. Treatment with penicillin (as in tertiary syphilis, the comparator to AD) is outlined; a biofilm dispersing agent may need to be added to the protocol.

%B J Alzheimers Dis %V 53 %P 1271-6 %8 2016 Jun 27 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372648?dopt=Abstract %R 10.3233/JAD-160388 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Alzheimer's Disease Risk Genes and Lipid Regulators. %A El Gaamouch, Farida %A Jing, Ping %A Xia, Jiahong %A Cai, Dongming %X

Brain lipid homeostasis plays an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. Aggregation of amyloid-β peptide is one of the major events in AD. The complex interplay between lipids and amyloid-β accumulation has been intensively investigated. The proportions of lipid components including phospholipids, sphingolipids, and cholesterol are roughly similar across different brain regions under physiological conditions. However, disruption of brain lipid homeostasis has been described in AD and implicated in disease pathogenesis. Moreover, studies suggest that analysis of lipid composition in plasma and cerebrospinal fluid could improve our understanding of the disease development and progression, which could potentially serve as disease biomarkers and prognostic indicators for AD therapies. Here, we summarize the functional roles of AD risk genes and lipid regulators that modulate brain lipid homeostasis including different lipid species, lipid complexes, and lipid transporters, particularly their effects on amyloid processing, clearance, and aggregation, as well as neuro-toxicities that contribute to AD pathogenesis.

%B J Alzheimers Dis %V 53 %P 15-29 %8 2016 Apr 23 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128373?dopt=Abstract %R 10.3233/JAD-160169 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Amyloid-Related Imaging Abnormalities (ARIA) in Immunotherapy Trials for Alzheimer's Disease: Need for Prognostic Biomarkers? %A Piazza, Fabrizio %A Winblad, Bengt %X

At the 8th International Conference on Clinical Trials in Alzheimer's Disease held November 5-7, 2015 in Barcelona, Spain, promising data were presented on two candidate Alzheimer's disease immunotherapeutic agents, gantenerumab and aducanumab. Trial results demonstrated that the implementation of cerebrospinal fluid and Aβ-PET biomarkers improves trial enrichment and outcome, which has led to a change in targeting strategy as clinical trials would be conducted with earlier, even presymptomatic, stages of the disease. Promising findings of outcomes, as measured by Aβ-PET and cerebrospinal fluid tau and P-tau, were, nevertheless, associated with antibody dose-dependent increased risk of severe adverse effects, specifically amyloid-related imaging abnormalities (ARIA). Aducanumab was associated with concomitant time-, dose-, and APOE-related incidence of ARIA in more than one-half of the patients within the high-dose arm. The future challenge will thus be to find biomarkers more favorably balanced between effective dosing of antibody to remove Aβ versus dosing to limit deleterious side effects. Interest was shown by Roche and Biogen, which promoted high-dose phase 3 trials. However, this generated some concerns related to a reasonable expected further increase in the incidence of severe side effects. What has been learned is challenging primary industry strategies for following-up and monitoring safety and effectiveness of anti-Aβ antibodies in clinical trials. Here, we debate the issue of what is an acceptable balance of treatment side effects, i.e., therapeutic-induced ARIA, versus the positive prospects. Indeed, implementation of biomarkers for ARIA might increase value and reduce waste in the design of immunotherapy trials of Alzheimer's disease.

%B J Alzheimers Dis %V 52 %P 417-20 %8 2016 Mar 29 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031492?dopt=Abstract %R 10.3233/JAD-160122 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Amyloid-β Increases Activity of Proteasomes Capped with 19S and 11S Regulators. %A Morozov, Alexey V %A Kulikova, Alexandra A %A Astakhova, Tatiana M %A Mitkevich, Vladimir A %A Burnysheva, Ksenia M %A Adzhubei, Alexei A %A Erokhov, Pavel A %A Evgen'ev, Michail B %A Sharova, Natalia P %A Karpov, Vadim L %A Makarov, Alexander A %X

Accumulation of amyloid-β (Aβ) in neurons accompanies Alzheimer's disease progression. In the cytoplasm Aβ influences activity of proteasomes, the multisubunit protein complexes that hydrolyze the majority of intracellular proteins. However, the manner in which Aβ affects the proteolytic activity of proteasomes has not been established. In this study the effect of Aβ42 and Aβ42 with isomerized Asp7 on activity of different forms of proteasomes has been analyzed. It has been shown that Aβ peptides efficiently reduce activity of the 20S proteasomes, but increase activity of the 20S proteasomes capped with the 19S and/or 11S regulators. Modulation of proteasome activity is mainly determined by the C-terminal segment of Aβ (amino acids 17-42). This study demonstrated an important role of proteasome regulators in the interplay between Aβ and the proteasomes.

%B J Alzheimers Dis %V 54 %P 763-76 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567864?dopt=Abstract %R 10.3233/JAD-160491 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Amyloid-β Reduces Exosome Release from Astrocytes by Enhancing JNK Phosphorylation. %A Abdullah, Mohammad %A Takase, Hiroshi %A Nunome, Mari %A Enomoto, Hiroyuki %A Ito, Jin-Ichi %A Gong, Jian-Sheng %A Michikawa, Makoto %X

Exosomes are small extracellular vesicles secreted by variety of cell types such as neurons, astrocytes, and oligodendrocytes. It is suggested that exosomes play essential role in the maintenance of the neuronal functions and also in the clearance of amyloid-β (Aβ) from the brain. Aβ is well known to cause neuronal cell death, whereas little is known about its effect on astrocytes. In this study, we examined the effect of Aβ on release of exosomes from astrocytes in culture. We analyzed release of exosomes and apoE, both of which are known to remove/clear Aβ from the brain, in the culture medium of astrocytes. We found that exosome and apoE-HDL were successfully separated by density gradient ultracentrifugation demonstrated by distribution of their specific markers, flotillin and HSP90, and cholesterol, and morphological analysis using electron microscopy. Exosome release was significantly reduced by Aβ1-42 treatment in cultured astrocytes accompanied by an increased JNK phosphorylation. Whereas, apoE-HDL release remained unchanged. A JNK inhibitor restored the decreased levels of exosome release induced by Aβ treatment to levels similar to those of control, suggesting that Aβ1-42 inhibits exosome release via stimulation of JNK signal pathway. Because exosomes are shown to remove Aβ in the brain, our findings suggest that increased Aβ levels in the brain may impair the exosome-mediated Aβ clearance pathway.

%B J Alzheimers Dis %V 53 %P 1433-41 %8 2016 Jul 02 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392863?dopt=Abstract %R 10.3233/JAD-160292 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Analysis of Cerebrospinal Fluid and [11C]PIB PET Biomarkers for Alzheimer's Disease with Updated Protocols. %A Wang, Min Jeong %A Yi, SangHak %A Han, Jee-Young %A Park, So Young %A Jang, Jae-Won %A Chun, In Kook %A Giau, Vo Van %A Bagyinszky, Eva %A Lim, Kun Taek %A Kang, Sung Min %A An, Seong Soo A %A Park, Young Ho %A Youn, Young Chul %A Kim, SangYun %X

BACKGROUND: Recently, a Korean research group suggested a consensus protocol, based on the Alzheimer's Disease Neuroimaging Initiative study protocol but with modifications for minimizing the confounding factors, for the evaluation of cerebrospinal fluid (CSF) biomarkers.

OBJECTIVE: Here, we analyzed fluid and imaging biomarkers of Alzheimer's disease (AD) in Korean population. We used the updated protocol to propose a more accurate CSF biomarker value for the diagnosis of AD.

METHODS: Twenty-seven patients with AD and 30 cognitively normal controls (NC) were enrolled. CSF was collected from 55 subjects (patients with AD = 26, NC = 29) following the Korea consensus protocol. CSF biomarkers were measured using the INNO-BIA AlzBio3 immunoassay, and Pittsburgh compound B (PIB) positron emission tomography (PET) scans were also performed.

RESULTS: The cutoff values of CSF amyloid beta 1-42 (Aβ42), total tau (t-Tau), and phosphorylated tau (p-Tau) proteins were 357.1 pg/ml, 83.35 pg/ml, and 38.00 pg/ml, respectively. The cutoff values of CSF t-Tau/Aβ42 and p-Tau/Aβ42 ratio- were 0.210 (sensitivity 100%, specificity 86.21%) and 0.1350 (sensitivity 88.46%, specificity of 92.86%). The concordance rate with PIB-PET was higher using the CSF t-Tau/Aβ42 ratio (κ= 0.849, CI 0.71-0.99) than CSF Aβ42 alone (κ= 0.703, CI 0.51-0.89).

CONCLUSIONS: Here, we improved controversial factors associated with the previous CSF study protocol and suggested a new cutoff value for the diagnosis of AD. Our results showed good diagnostic performance for differentiation of AD. Thus, we expect our findings could be a cornerstone in the establishment and clinical application of biomarkers for AD diagnosis.

%B J Alzheimers Dis %V 52 %P 1403-13 %8 2016 May 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163824?dopt=Abstract %R 10.3233/JAD-160143 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Analysis of the MIRIAD Data Shows Sex Differences in Hippocampal Atrophy Progression. %A Ardekani, Babak A %A Convit, Antonio %A Bachman, Alvin H %K Alzheimer Disease %K Atrophy %K Disease Progression %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %X

BACKGROUND: Hippocampus (HC) atrophy is a hallmark of early Alzheimer's disease (AD). Atrophy rates can be measured by high-resolution structural MRI. Longitudinal studies have previously shown sex differences in the progression of functional and cognitive deficits and rates of brain atrophy in early AD dementia. It is important to corroborate these findings on independent datasets.

OBJECTIVE: To study temporal rates of HC atrophy over a one-year period in probable AD patients and cognitively normal (CN) subjects by longitudinal MRI scans obtained from the Minimal Interval Resonance Imaging in AD (MIRIAD) database.

METHODS: We used a novel algorithm to compute an index of hippocampal (volumetric) integrity (HI) at baseline and one-year follow-up in 43 mild-moderate probable AD patients and 22 CN subjects in MIRIAD. The diagnostic power of longitudinal HI measurement was assessed using a support vector machines (SVM) classifier.

RESULTS: The HI was significantly reduced in the AD group (p <  10(-20)). In addition, the annualized percentage rate of reduction in HI was significantly greater in the AD group (p <  10(-13)). Within the AD group, the annual reduction of HI in women was significantly greater than in men (p = 0.008). The accuracy of SVM classification between AD and CN subjects was estimated to be 97% by 10-fold cross-validation.

CONCLUSION: In the MIRIAD patients with probable AD, the HC atrophies at a significantly faster rate in women as compared to men. Female sex is a risk factor for faster descent into AD. The HI measure has potential for AD diagnosis, as a biomarker of AD progression and a therapeutic target in clinical trials.

%B J Alzheimers Dis %V 50 %P 847-57 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836168?dopt=Abstract %R 10.3233/JAD-150780 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Anemia and Mild Cognitive Impairment in the German General Population. %A Dlugaj, Martha %A Winkler, Angela %A Weimar, Christian %A Dürig, Jan %A Broecker-Preuss, Martina %A Dragano, Nico %A Moebus, Susanne %A Jöckel, Karl-Heinz %A Erbel, Raimund %A Eisele, Lewin %K Aged %K Aged, 80 and over %K Anemia %K Cognitive Dysfunction %K Cohort Studies %K Executive Function %K Female %K Follow-Up Studies %K Germany %K Humans %K Male %K Memory %K Middle Aged %K Neuropsychological Tests %K Prevalence %K Speech Perception %X

There is increasing evidence that anemia is associated with cognitive impairment. Therefore, the aim of the study was to examine the cross-sectional association of anemia as well as the persistence of anemia over the last five years with mild cognitive impairment (MCI) and MCI subtypes (amnestic/non-amnestic MCI (aMCI/naMCI)). Out of 4,157 participants (50% men, 50-80 years) of the second examination (t1) of a cohort study (baseline (t0) 2000-2003), we included 4,033 participants with available hemoglobin information and complete cognitive assessment. Anemia was defined as hemoglobin <13 g/dl in men (n = 84) and <12 g/dl in women (n = 79). Group comparisons were used to compare the cognitive subtests. To determine the association of MCI with anemia at t1, with anemia five years prior to the cognitive assessment (t0) and anemia at both time points, we used logistic regression models and included 579 participants with MCI and 1,438 cognitively normal participants out of the total cohort. Anemic participants showed lower performances in verbal memory and executive functions. The fully adjusted odds ratios (OR) for MCI, aMCI, and naMCI in anemic versus non-anemic participants were 1.92 (95% -CI, 1.09-3.39), 1.96 (1.00-3.87), and 1.88 (0.91-3.87). Anemia at both times points showed a non-significant association with naMCI (OR 3.74, 0.94-14.81, fully adjusted). Our results suggest that anemia is associated with an increased risk of MCI independent of traditional cardiovascular risk factors. The association of anemia and MCI has important clinical relevance, because many causes of anemia can be treated effectively.

%B J Alzheimers Dis %V 49 %P 1031-42 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599053?dopt=Abstract %R 10.3233/JAD-150434 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Anthocyanins Protect SK-N-SH Cells Against Acrolein-Induced Toxicity by Preserving the Cellular Redox State. %A Belkacemi, Abdenour %A Ramassamy, Charles %K Acrolein %K Anthocyanins %K Antioxidants %K Cell Death %K Cell Line, Tumor %K Dose-Response Relationship, Drug %K Glutathione %K Humans %K Neuroprotective Agents %K NF-kappa B %K Oxidation-Reduction %K Oxidative Stress %K Reactive Oxygen Species %K Src Homology 2 Domain-Containing, Transforming Protein 1 %X

In Alzheimer's disease (AD) and in mild cognitive impairment (MCI) patients, by-products of lipid peroxidation such as acrolein accumulated in vulnerable regions of the brain. We have previously shown that acrolein is a highly reactive and neurotoxic aldehyde and its toxicity involves the alteration of several redox-sensitive pathways. Recently, protein-conjugated acrolein in cerebrospinal fluid has been proposed as a biomarker to distinguish between MCI and AD. With growing evidence of the early involvement of oxidative stress in AD etiology, one would expect that a successful therapy should prevent brain oxidative damage. In this regard, several studies have demonstrated that polyphenol-rich extracts exert beneficial effect on cognitive impairment and oxidative stress. We have recently demonstrated the efficacy of an anthocyanin formulation (MAF14001) against amyloid-β-induced oxidative stress. The aim of this study is to investigate the neuroprotective effect of MAF14001 as a mixture of anthocyanins, a particular class of polyphenols, against acrolein-induced oxidative damage in SK-N-SH neuronal cells. Our results demonstrated that MAF14001, from 5μM, was able to efficiently protect SK-N-SH cells against acrolein-induced cell death. MAF14001 was able to lower reactive oxygen species and protein carbonyl levels induced by acrolein. Moreover, MAF1401 prevented glutathione depletion and positively modulated, in the presence of acrolein, some oxidative stress-sensitive pathways including the transcription factors NF-κB and Nrf2, the proteins γ-GCS and GSK3β, and the protein adaptator p66Shc. Along with its proven protective effect against amyloid-β toxicity, these results demonstrate that MAF14001 could target multiple mechanisms and could be a promising agent for AD prevention.

%B J Alzheimers Dis %V 50 %P 981-98 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890747?dopt=Abstract %R 10.3233/JAD-150770 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Anti-Amyloid-β Monoclonal Antibody 4G8 Recognizes a Generic Sequence-Independent Epitope Associated with α-Synuclein and Islet Amyloid Polypeptide Amyloid Fibrils. %A Hatami, Asa %A Monjazeb, Sanaz %A Glabe, Charles %K alpha-Synuclein %K Alzheimer Disease %K Amyloid beta-Peptides %K Antibodies, Monoclonal %K Brain %K Epitopes %K Humans %K Islet Amyloid Polypeptide %X

Recently we reported that several monoclonal antibodies that recognize linear segments of amyloid-β (Aβ) also recognize amyloid fibrils, but not monomers of unrelated sequences, indicating that recognition of a linear sequence segment is not a reliable indicator of sequence specificity. We asked whether any of the commonly used commercially available Aβ antibodies also recognize fibrils of unrelated sequence. Here we report that 4G8, which recognizes residues 18-23 of the Aβ sequence and is widely believed to be sequence-specific, also recognizes fibrils formed from α-synuclein and islet amyloid polypeptide (IAPP). The recognition of amyloid fibrils is aggregation-dependent because 4G8 does not recognize α-synuclein or IAPP monomer. 4G8 also stains fibrillar α-synuclein aggregates in human multiple system atrophy brain where it colocalizes with anti-α-synuclein monoclonal antibody LB509 immunoreactivity. We also found that LB509 recognizes Aβ fibrils, but not monomer, indicating that generic epitope-reactive antibodies are also produced in response to α-synuclein immunization. Taken together, our results indicate that generic fibril conformational epitope specificity may be a pervasive property among monoclonal antibodies raised against amyloid-forming antigens and that the specificity of their immunoreactivity should be rigorously established and otherwise interpreted with caution.

%B J Alzheimers Dis %V 50 %P 517-25 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682688?dopt=Abstract %R 10.3233/JAD-150696 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease. %A Gomar, Jesus J %A Conejero-Goldberg, Concepcion %A Davies, Peter %A Goldberg, Terry E %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Atrophy %K Brain %K Disease Progression %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Prodromal Symptoms %K Regression Analysis %K Statistics, Nonparametric %K tau Proteins %X

BACKGROUND: The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood.

OBJECTIVE: To examine dynamic interrelationships between Aβ42 and tau in preclinical AD.

METHODS: We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18).

RESULTS: In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p <  0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau.

CONCLUSIONS: The evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.

%B J Alzheimers Dis %V 51 %P 1085-97 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967213?dopt=Abstract %R 10.3233/JAD-150937 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Antioxidants Rescue Mitochondrial Transport in Differentiated Alzheimer's Disease Trans-Mitochondrial Cybrid Cells. %A Yu, Qing %A Fang, Du %A Swerdlow, Russell Howard %A Yu, Haiyang %A Chen, John Xi %A Yan, Shirley ShiDu %X

Mitochondrial dysfunction and axonal degeneration are early pathological features of Alzheimer's disease (AD)-affected brains. The underlying mechanisms and strategies to rescue it have not been well elucidated. Here, we evaluated axonal mitochondrial transport and function in AD subject-derived mitochondria. We analyzed mitochondrial transport and kinetics in human trans-mitochondrial "cybrid" (cytoplasmic hybrid) neuronal cells whose mitochondria were derived from platelets of patients with sporadic AD and compared these AD cybrid cell lines with cybrid cell lines whose mitochondria were derived from age-matched, cognitively normal subjects. Human AD cybrid cell lines, when induced to differentiate, developed stunted projections. Mitochondrial transport and function within neuronal processes/axons was altered in AD-derived mitochondria. Antioxidants reversed deficits in axonal mitochondrial transport and function. These findings suggest that antioxidants may be able to mitigate the consequences of AD-associated mitochondrial dysfunction. The present study provides evidence of the cause/effect of AD specific mitochondrial defects, which significantly enhances our understanding of the AD pathogenesis and exploring the effective therapeutic strategy for AD.

%B J Alzheimers Dis %V 54 %P 679-90 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567872?dopt=Abstract %R 10.3233/JAD-160532 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Antioxidative and Neuroprotective Effects of Curcumin in an Alzheimer's Disease Rat Model Co-Treated with Intracerebroventricular Streptozotocin and Subcutaneous D-Galactose. %A Huang, Han-Chang %A Zheng, Bo-Wen %A Guo, Yu %A Zhao, Jian %A Zhao, Jiang-Yan %A Ma, Xiao-Wei %A Jiang, Zhao-Feng %X

Epidemiological data imply links between the increasing incidences of Alzheimer's disease (AD) and type 2 diabetes mellitus. In this study, an AD rat model was established by combining treatments with intracerebroventricular streptozotocin (icv-STZ) and subcutaneous D-galactose, and the effects of curcumin on depressing AD-like symptoms were investigated. In the AD model group, rats were treated with icv-STZ in each hippocampus with 3.0 mg/kg of bodyweight once and then were subcutaneously injected with D-galactose daily (125 mg/kg of bodyweight) for 7 weeks. In the curcumin-protective group, after icv-STZ treatment, rats were treated with D-galactose (the same as in the AD model group) and intraperitoneally injected with curcumin daily (10 mg/kg of bodyweight) for 7 weeks. Vehicle-treated rats were treated as control. Compared with the vehicle control, the amount of protein carbonylation and glutathione in liver, as well as malondialdehyde in serum, were upregulated but glutathione peroxidase activity in blood was downregulated in the AD model group. The shuttle index and locomotor activity of rats in the AD model group were decreased compared with the vehicle control group. Furthermore, AD model rats showed neuronal damage and neuron loss with formation of amyloid-like substances and neurofibrillary tangles, and the levels of both β-cleavage of AβPP and phosphorylation of tau (Ser396) were significantly increased compared with the vehicle control group. Notably, compared with the AD model group, oxidative stress was decreased and the abilities of active avoidance and locomotor activity were improved, as well as attenuated neurodegeneration, in the curcumin-protective group. These results imply the applications of this animal model for AD research and of curcumin in the treatment of AD.

%B J Alzheimers Dis %V 52 %P 899-911 %8 2016 Apr 05 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060945?dopt=Abstract %R 10.3233/JAD-150872 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Anti-Prion Antibody 15B3 Detects Toxic Amyloid-β Oligomers. %A Stravalaci, Matteo %A Tapella, Laura %A Beeg, Marten %A Rossi, Alessandro %A Joshi, Pooja %A Pizzi, Erika %A Mazzanti, Michele %A Balducci, Claudia %A Forloni, Gianluigi %A Biasini, Emiliano %A Salmona, Mario %A Diomede, Luisa %A Chiesa, Roberto %A Gobbi, Marco %X

15B3 is a monoclonal IgM antibody that selectively detects pathological aggregates of the prion protein (PrP). We report the unexpected finding that 15B3 also recognizes oligomeric but not monomeric forms of amyloid-β (Aβ)42, an aggregating peptide implicated in the pathogenesis of Alzheimer's disease (AD). The 15B3 antibody: i) inhibits the binding of synthetic Aβ42 oligomers to recombinant PrP and neuronal membranes; ii) prevents oligomer-induced membrane depolarization; iii) antagonizes the inhibitory effects of oligomers on the physiological pharyngeal contractions of the nematode Caenorhabditis elegans; and iv) counteracts the memory deficits induced by intracerebroventricular injection of Aβ42 oligomers in mice. Thus this antibody binds to pathologically relevant forms of Aβ, and offers a potential research, diagnostic, and therapeutic tool for AD.

%B J Alzheimers Dis %V 53 %P 1485-97 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392850?dopt=Abstract %R 10.3233/JAD-150882 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Anti-Viral Properties of Amyloid-β Peptides. %A Bourgade, Karine %A Dupuis, Gilles %A Frost, Eric H %A Fülöp, Tamás %X

Amyloid-β (Aβ) peptides generated by the amyloidogenic pathway of amyloid-β protein precursor processing contribute significantly to neurodegeneration characteristic of Alzheimer's disease (AD). The involvement of Aβ peptides in the etiology of AD remains a subject of debate. Data published in the last 6 years by three different groups have added a new twist by revealing that Aβ peptides could act as antimicrobial peptides (AMP) in in vitro assays against some common and clinically relevant microorganisms, inhibit replication of seasonal and pandemic strains of influenza A and HSV-1 virus. These observations are of significance with respect to the notion that pathogens may be important contributors to the development of AD, particularly in the case of herpes simplex virus (HSV) infection, which often resides in the same cerebral sites where AD arises. Here, we review the data that support the interpretation that Aβ peptides behave as AMP, with an emphasis on studies concerning HSV-1 and a putative molecular mechanism that suggests that interactions between Aβ peptides and the HSV-1 fusogenic protein gB lead to impairment of HSV-1 infectivity by preventing the virus from fusing with the plasma membrane. A number of avenues for future research are suggested.

%B J Alzheimers Dis %V 54 %P 859-878 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392871?dopt=Abstract %R 10.3233/JAD-160517 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Apathy and Attentional Biases in Alzheimer's Disease. %A Chau, Sarah A %A Chung, Jonathan %A Herrmann, Nathan %A Eizenman, Moshe %A Lanctôt, Krista L %K Aged %K Alzheimer Disease %K Apathy %K Attentional Bias %K Cognition %K Cross-Sectional Studies %K Emotions %K Eye Movement Measurements %K Eye Movements %K Female %K Humans %K Linear Models %K Male %K Neuropsychological Tests %K Photic Stimulation %K Severity of Illness Index %K Social Perception %X

BACKGROUND: Apathy, one of the most prevalent neuropsychiatric symptoms in Alzheimer's disease (AD), can be difficult to assess as cognition deteriorates. There is a need for more objective assessments that do not rely on patient insight, communicative capacities, or caregiver observation.

OBJECTIVE: We measured visual scanning behavior, using an eye-tracker, to explore attentional bias in the presence of competing stimuli to assess apathy in AD patients.

METHODS: Mild-to-moderate AD patients (Standardized Mini-Mental Status Examination, sMMSE >10) were assessed for apathy (Neuropsychiatric Inventory [NPI] apathy, Apathy Evaluation Scale [AES]). Participants were presented with 16 slides, each containing 4 images of different emotional themes (2 neutral, 1 social, 1 dysphoric). The duration of time spent, and fixation frequency on images were measured.

RESULTS: Of the 36 AD patients (14 females, age = 78.2±7.8, sMMSE = 22.4±3.5) included, 17 had significant apathy (based on NPI apathy ≥4) and 19 did not. These groups had comparable age and sMMSE. Repeated-measures analysis of covariance models, controlling for total NPI, showed group (apathetic versus non-apathetic) by image (social versus dysphoric) interactions for duration (F(1,32) = 4.31, p = 0.046) and fixation frequency (F(1,32) = 11.34, p = 0.002). Apathetic patients demonstrated reduced duration and fixation frequency on social images compared with non-apathetic patients. Additionally, linear regression models suggest that more severe apathy predicted decreasing fixation frequency on social images (R2 = 0.26, Adjusted R2 = 0.19, F(3,32) = 3.65, p = 0.023).

CONCLUSION: These results suggest that diminished attentional bias toward social-themed stimuli is a marker of apathy in AD. Measurements of visual scanning behavior may have the potential to predict and monitor treatment response in apathy.

%B J Alzheimers Dis %V 51 %P 837-46 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890774?dopt=Abstract %R 10.3233/JAD-151026 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Apo J and Apo D: Complementary or Antagonistic Roles in Alzheimer's Disease? %A Del Valle, Eva %A Navarro, Ana %A Martínez-Pinilla, Eva %A Torices, Silvia %A Tolivia, Jorge %X

Apolipoprotein D (Apo D) and Apolipoprotein J (Apo J) are among the only nine apolipoproteins synthesized in the nervous system. Apart from development, these apolipoproteins are implicated in the normal aging process as well as in different neuropathologies as Alzheimer's disease (AD), where a neuroprotective role has been postulated. Different authors have proposed that Apo D and Apo J could be biomarkers for AD but as far as we know, there are no studies about the relationship between them as well as their expression pattern along the progression of the disease. In this paper, using double immunohistochemistry techniques, we have demonstrated that Apo D is mainly located in glial cells while Apo J expression preferentially occurs in neurons; both proteins are also present in AD diffuse and mature senile plaques but without signal overlap. In addition, we have observed that Apo J and Apo D immunostaining shows a positive correlation with the progression of the disease and the Braak's stages. These results suggest complementary and cell-dependent neuroprotective roles for each apolipoprotein during AD progress.

%B J Alzheimers Dis %V 53 %P 639-50 %8 2016 May 17 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27197790?dopt=Abstract %R 10.3233/JAD-160032 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Apolipoprotein E Related Co-Morbidities and Alzheimer's Disease. %A Singhrao, Sim K %A Harding, Alice %A Chukkapalli, Sasanka %A Olsen, Ingar %A Kesavalu, Lakshmyya %A Crean, StJohn %K Aging %K Alzheimer Disease %K Animals %K Apolipoprotein E4 %K Cardiovascular Diseases %K Comorbidity %K Diabetes Mellitus, Type 2 %K Humans %K Mice %K Periodontal Diseases %X

The primary goal of advancement in clinical services is to provide a health care system that enhances an individual's quality of life. Incidence of diabetes mellitus, cardiovascular disease, and associated dementia coupled with the advancing age of the population, have led to an increase in the worldwide challenge to the healthcare system. In order to overcome these challenges, prior knowledge of common, reliable risk factors and their effectors is essential. Oral health constitutes one such relatively unexplored but indispensable risk factor for aforementioned co-morbidities, in the form of poor oral hygiene and tooth loss during aging. Behavioral traits such as low education, smoking, poor diet, neglect of oral health, lack of exercise, and hypertension are few of the risk factors that are shared commonly among these conditions. In addition, common genetic susceptibility traits such as the apolipoprotein E gene, together with an individual's lifestyle can also influence the development of co-morbidities such as periodontitis, atherosclerosis/stroke, diabetes, and Alzheimer's disease. This review specifically addresses the susceptibility of apolipoprotein E gene allele 4 as the plausible commonality for the etiology of co-morbidities that eventually result from periodontal diseases and ultimately progress to dementia.

%B J Alzheimers Dis %V 51 %P 935-48 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923007?dopt=Abstract %R 10.3233/JAD150690 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Apolipoprotein ɛ4 is Associated with Dementia and Cognitive Impairment Predominantly Due to Alzheimer's Disease and Not with Vascular Cognitive Impairment: A Singapore-Based Cohort. %A Chai, Yuek Ling %A Yeo, Hazel Kai-Hui %A Wang, Jiehao %A Hilal, Saima %A Ikram, Mohammad Kamran %A Venketasubramanian, Narayanaswamy %A Wong, Boon-Seng %A Chen, Christopher Li-Hsian %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Apolipoprotein E4 %K Cognition Disorders %K Cohort Studies %K Dementia %K Female %K Genetic Association Studies %K Genotype %K Humans %K Male %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Singapore %K Vascular Diseases %X

BACKGROUND AND OBJECTIVE: While the association for apolipoprotein ɛ4 allele (APOE4) with Alzheimer's disease (AD) has been consistently confirmed, the association with vascular cognitive impairment (VCI) is unclear. We therefore explored the relationship of APOE with both AD and cerebrovascular disease (CeVD) by examining the prevalence of APOE4 in AD, AD with CeVD and vascular dementia (VaD), as well as in cognitive impairment no dementia (CIND) with and without CeVD.

METHODS: We performed a case-control study with subjects recruited from memory clinics and the community. All subjects underwent standardized brain neuroimaging, clinical and neuropsychological assessments, following which they were classified using research criteria.

RESULTS: A total of 411 subjects; 92 controls with no cognitive impairment (NCI), 77 CIND without CeVD, 87 CIND with CeVD, 55 AD without CeVD, 68 AD with CeVD, and 32 VaD patients were recruited. Compared to NCI (16.3%), the prevalence of APOE4 carriers was significantly higher only in CIND (37.7%) and AD in the absence of CeVD (45.5%), but not in the three subgroups of VCI, namely CIND with CeVD (20.7%), AD with CeVD (27.9%) and VaD (25.0%). Logistic regression analyses also showed that APOE4 carriers were more likely to have CIND without CeVD (Odds Ratio [OR]: 3.34; 95% Confidence Interval [CI]: 1.59-7.03) and AD without CeVD (OR: 7.21; 95% CI: 2.74-18.98), but no such association was observed in the VCI subgroups.

CONCLUSION: APOE4 is significantly associated with dementia and CIND due to AD pathology, but not with VCI.

%B J Alzheimers Dis %V 51 %P 1111-8 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923016?dopt=Abstract %R 10.3233/JAD-150902 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Application of the IWG-2 Diagnostic Criteria for Alzheimer's Disease to the ADNI. %A Wang, Hui-Fu %A Tan, Lan %A Cao, Lei %A Zhu, Xi-Chen %A Jiang, Teng %A Tan, Meng-Shan %A Liu, Ying %A Wang, Chong %A Tsai, Richard M %A Jia, Jian-Ping %A Yu, Jin-Tai %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid Precursor Protein Secretases %K Aspartic Acid Endopeptidases %K Cognitive Dysfunction %K Databases, Factual %K Disease Progression %K Female %K Humans %K Longitudinal Studies %K Male %K Multicenter Studies as Topic %K Neuroimaging %K Psychiatric Status Rating Scales %K tau Proteins %X

BACKGROUND: The International Working Group (IWG) recently proposed the revised diagnostic criteria for Alzheimer's disease (AD) to define and refine several types of AD, and to reclassify AD-related biomarkers into diagnostic and progression markers, but its performance is not known.

OBJECTIVE: This study was designed to describe the application of the revised IWG criteria in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and to ascertain whether diagnostic and progression markers show significant differences in their relationships to AD severity and progression.

METHODS: Based on the requirements of the refined criteria, 857 ADNI subjects with memory evaluation and at least one pathophysiological marker (CSF or amyloid imaging biomarkers) were eligible and reclassified in this study, and we calculated the associations of diagnostic (CSF and amyloid PET) and progression markers (MRI and fluorodeoxyglucose-PET) with AD severity and progression respectively.

RESULTS: The majority (84.2% ) of ADNI AD group (n = 117) and 173 MCI (37.4% ) subjects in ADNI met the definition of typical AD; and 105 cognitively normal (41.0% ) individuals were diagnosed as asymptomatic AD. Furthermore, diagnostic and progression markers showed significant differences when correlated to AD severity and progression.

CONCLUSION: A large proportion of AD dementia subjects were categorized as typical AD, and the revised criteria could identify typical AD from MCI status as well as asymptomatic AD at the asymptomatic stage. Moreover, the significant differences between diagnostic and progression markers further supported the new biomarkers categorization in the refined criteria.

%B J Alzheimers Dis %V 51 %P 227-36 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836176?dopt=Abstract %R 10.3233/JAD-150824 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Approaches to Increasing Ethical Compliance in China with Drug Trial Standards of Practice. %A Rosenberg, Jacob %X

Zeng et al.'s Ethics Review highlights some of the challenges associated with clinical research in China. They found that only a minority of published clinical trials of anti-dementia drugs reported that they fulfilled the basic ethical principles as outlined in the Declaration of Helsinki. With recent reports of scientific misconduct from China, there is an urgent need to find approaches to compel researchers to adhere to ethical research practices. This problem does not call for a simple solution, but if forces are joined with governmental regulations, education in ethics issues for medical researchers, and strong reinforcement by Chinese journal editors not to publish studies with these flaws, then research ethics and publication standards will probably improve. Other solutions to foster ethical practice of drug trials are discussed including Chinese initiatives directed at managing conflict of interest from the pharmaceutical industry and educating clinical researchers.

%B J Alzheimers Dis %V 52 %P 825-7 %8 2016 Mar 29 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031489?dopt=Abstract %R 10.3233/JAD-151196 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Aquaporin-4 and Alzheimer's Disease. %A Yang, Canhong %A Huang, Xiaomin %A Huang, Xiaoyu %A Mai, Hantao %A Li, Jie %A Jiang, Tao %A Wang, Xiaofeng %A Lü, Tianming %X

Alzheimer's disease (AD) is the most common form of dementia. Although the pathogenesis of AD remains unclear, AD is thought to result from an imbalance in the production and clearance of amyloid-β protein (Aβ). Aquaporin-4 (AQP4) is the major aquaporin in the mammalian brain, is mostly expressed on astrocytic endfeet, and functions as a water transporter. However, the distribution and expression of AQP4 are altered in both AD clinical populations and animal models. Recent studies have revealed that AQP4 is important to the clearance of Aβ in brain via lymphatic clearance, transcytotic delivery, and glial degradation, as well as to the synaptic function. Thus, AQP4 likely plays an important role in the pathogenesis of AD. Further studies would provide new targets for prevention, ultimately leading to improved treatment options for AD.

%B J Alzheimers Dis %V 52 %P 391-402 %8 2016 Mar 25 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031475?dopt=Abstract %R 10.3233/JAD-150949 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Artificial Neural Networks Link One-Carbon Metabolism to Gene-Promoter Methylation in Alzheimer's Disease. %A Grossi, Enzo %A Stoccoro, Andrea %A Tannorella, Pierpaola %A Migliore, Lucia %A Coppedè, Fabio %X

BACKGROUND: There is increasing interest in DNA methylation studies in Alzheimer's disease (AD), but little is still known concerning the relationship between gene-promoter methylation and circulating biomarkers of one-carbon metabolism in patients.

OBJECTIVE: To detect the connections among circulating folate, homocysteine (hcy) and vitamin B12 levels and promoter methylation levels of PSEN1, BACE1, DNMT1, DNMT3A, DNMT3B, and MTHFR genes in blood DNA.

METHODS: We applied a data mining system called Auto Contractive Map to an existing database of 100 AD and 100 control individuals.

RESULTS: Low vitamin B12 was linked to the AD condition, to low folates, and to high hcy. Low PSEN1 methylation was linked to low folate levels as well as to low promoter methylation of BACE1 and DNMTs genes. Low hcy was linked to controls, to high folates and vitamin B12, as well as to high methylation levels of most of the studied genes.

CONCLUSIONS: The present pilot study suggests that promoter methylation levels of the studied genes are linked to circulating levels of folates, hcy, and vitamin B12.

%B J Alzheimers Dis %V 53 %P 1517-22 %8 2016 Jul 01 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392858?dopt=Abstract %R 10.3233/JAD-160210 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Assessment and Reporting of Driving Fitness in Patients with Dementia in Clinical Practice: Data from SveDem, the Swedish Dementia Registry. %A Lovas, Joel %A Fereshtehnejad, Seyed-Mohammad %A Cermakova, Pavla %A Lundberg, Catarina %A Johansson, Björn %A Johansson, Kurt %A Winblad, Bengt %A Eriksdotter, Maria %A Religa, Dorota %X

BACKGROUND: Driving constitutes a very important aspect of daily life and is dependent on cognitive functions such as attention, visuo-spatial skills and memory, which are often compromised in dementia. Therefore, the driving fitness of patients with dementia needs to be addressed by physicians and those that are deemed unfit should not be allowed to continue driving.

OBJECTIVE: We aimed at investigating to what extent physicians assess driving fitness in dementia patients and determinant factors for revoking of their licenses.

METHODS: This study includes 15113 patients with newly diagnosed dementia and driver's license registered in the Swedish Dementia Registry (SveDem). The main outcomes were reporting to the licensing authority and making an agreement about driving eligibility with the patients.

RESULTS: Physicians had not taken any action in 16% of dementia patients, whereas 9% were reported to the authority to have their licenses revoked. Males (OR = 3.04), those with an MMSE score between 20-24 (OR = 1.35) and 10-19 (OR = 1.50), patients with frontotemporal (OR = 3.09) and vascular dementia (OR = 1.26) were more likely to be reported to the authority.

CONCLUSION: For the majority of patients with dementia, driving fitness was assessed. Nevertheless, physicians did not address the issue in a sizeable proportion of dementia patients. Type of dementia, cognitive status, age, sex and burden of comorbidities are independent factors associated with the assessment of driving fitness in patients with dementia. Increased knowledge on how these factors relate to road safety may pave the way for more specific guidelines addressing the issue of driving in patients with dementia.

%B J Alzheimers Dis %V 53 %P 631-8 %8 2016 May 05 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163829?dopt=Abstract %R 10.3233/JAD-160254 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association between Antipsychotic Drugs and Mortality in Older Persons with Alzheimer's Disease: A Systematic Review and Meta-Analysis. %A Zhai, Yaoming %A Yin, Song %A Zhang, Dongfeng %X

Antipsychotic drugs have been inconsistently associated with death risk of Alzheimer's disease (AD) patients. Herein we review and quantitatively summarize the evidence from epidemiological studies. Pertinent studies were identified by searching PubMed and Cochrane Library Register of Controlled Trials through 20 December 2015. The DerSimonian and Laird random effect model was adopted as the pooling method. Twelve studies from nine articles with 11,463 participants were included. The pooled RR of observational studies was 1.36 (95% CI, 0.83-2.24; I2 = 94.9%) for antipsychotic drugs users versus individuals who were not exposed to antipsychotic drugs. When the three studies that were key contributors to the high heterogeneity were excluded, the pooled RR was 2.08 (95% CI 1.39 to 3.13). The result of one double-blind randomized clinical trial indicated that antipsychotic drugs nearly doubled the risk of death in AD patients. In conclusion, there is no evidence of absence of association between antipsychotic drugs' use with death risk of AD patients. Careful assessments of potential benefits and risks should be made before prescribing antipsychotics for treatment of psychosis symptoms and behavioral problems of AD patients.

%B J Alzheimers Dis %V 52 %P 631-9 %8 2016 Mar 31 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031490?dopt=Abstract %R 10.3233/JAD-151207 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association between Cerebrospinal Fluid Biomarkers for Alzheimer's Disease, APOE Genotypes and Auditory Verbal Learning Task in Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease. %A Mandecka, Monika %A Budziszewska, Magdalena %A Barczak, Anna %A Pepłońska, Beata %A Chodakowska-Żebrowska, Małgorzata %A Filipek-Gliszczyńska, Anna %A Nesteruk, Marta %A Styczyńska, Maria %A Barcikowska, Maria %A Gabryelewicz, Tomasz %X

In the course of Alzheimer's disease (AD), early pathological changes in the brain start decades before any clinical manifestation. The concentration levels of AD cerebrospinal fluid (CSF) biomarkers, such as amyloid-β1-42 (Aβ1-42), total tau (T-tau), and phosphorylated tau (P-tau), may reflect a cerebral pathology facilitating an early diagnosis of the disease and predicting a cognitive deterioration. The aim of this study was to estimate the prevalence of AD CSF biomarkers in those individuals with a subjective cognitive decline (SCD), a mild cognitive impairment (MCI), and Alzheimer's dementia (AD-D), together with the relationships between the biomarkers, an APOE ɛ4 presence, and a verbal episodic memory performance. We included 252 patients from the memory clinic with a diagnosis of SCD (n = 85), MCI (n = 87), and AD-D (n = 80). A verbal episodic memory performance level was assessed and was based on a delayed recall trial from the 10-word list of an auditory verbal learning task (AVLT). We found that the patients with more severe cognitive impairments had significantly lower levels of Aβ1-42 and higher levels of T-tau and P-tau. This pattern was also typical for the APOE ɛ4 carriers, who had lower levels of Aβ1-42 than the noncarriers in the AD-D and MCI groups. The levels of T-tau and P-tau were significantly higher in the APOE ɛ4 carriers than in the noncarriers, but only in the MCI patients. The AVLT performance in the whole study samples was predicted by age, Aβ1-42, and the T-tau CSF biomarkers, but not by the APOE genotyping.

%B J Alzheimers Dis %V 54 %P 157-68 %8 2016 Jul 29 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472875?dopt=Abstract %R 10.3233/JAD-160176 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association between Coffee Consumption and Incident Risk of Disabling Dementia in Elderly Japanese: The Ohsaki Cohort 2006 Study. %A Sugiyama, Kemmyo %A Tomata, Yasutake %A Kaiho, Yu %A Honkura, Kenji %A Sugawara, Yumi %A Tsuji, Ichiro %K Aged %K Aged, 80 and over %K Coffee %K Dementia %K Female %K Health Surveys %K Humans %K Incidence %K Japan %K Male %K Prospective Studies %K Risk Factors %X

Epidemiological studies of the association between coffee consumption and dementia have yielded inconsistent results. Therefore, we investigated the association between coffee consumption and incident risk of dementia in an elderly Japanese population. 23,091 subjects aged ≥65 y living in Ohsaki City, northeastern Japan, responded to the baseline survey in 2006. Of these, we analyzed 13,137 subjects who gave informed consent and were not disabled at baseline. The outcome was the incidence of disabling dementia defined by usage of the Long-term Care Insurance database. We used the Cox proportional hazards regression model for multivariate analysis. During 5.7 y of follow-up period, we identified 1,107 cases of incident dementia. Overall, coffee consumption was significantly associated with a lower risk of incident dementia. The multivariate-adjusted HRs for the incidence of dementia according to coffee consumption categories (never, occasionally, 1-2 cups/d, and ≥3 cups/d) were 1.00, 0.73 (95% CI, 0.62-0.86), 0.72 (95% CI, 0.61-0.84), and 0.82 (95% CI, 0.65-1.02; p for trend = 0.009), respectively. In addition, this significant inverse association was more remarkable among women, non-smokers, and non-drinkers. Coffee consumption is significantly associated with a lower risk of incident dementia.

%B J Alzheimers Dis %V 50 %P 491-500 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682686?dopt=Abstract %R 10.3233/JAD-150693 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Association Between Plasma Ceramides and Sphingomyelins and Risk of Alzheimer's Disease Differs by Sex and APOE in the Baltimore Longitudinal Study of Aging. %A Mielke, Michelle M %A Haughey, Norman J %A Han, Dingfen %A An, Yang %A Bandaru, Veera Venkata Ratnam %A Lyketsos, Constantine G %A Ferrucci, Luigi %A Resnick, Susan M %X

BACKGROUND: Cellular and animal studies demonstrated relationships between sphingolipid metabolism and Alzheimer's disease (AD) pathology. High blood ceramide levels have been shown to predict cognitive impairment and AD, but these studies had small sample sizes and did not assess differences in risk by sex or APOE genotype.

OBJECTIVE: To determine whether plasma ceramides and sphingomyelins were associated with risk of AD, and whether the association varied by sex and APOE genotype.

METHODS: Participants included 626 men and 366 women, aged 55 years and older, enrolled in the Baltimore Longitudinal Study of Aging. Plasma ceramides and sphingomyelins were determined using quantitative analyses performed on a high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometer. Cox proportional hazards models, stratified by sex, were used to examine the relationship of plasma ceramides and sphingomyelins with risk of AD over a mean (SD) follow-up of 15.0 (7.0) years for men and 13.1 (5.9) years for women.

RESULTS: Among men, the highest tertile of most ceramides and sphingomyelins were associated with an increased risk of AD. Among women, there were no associations between any of the ceramides and risk of AD. In contrast, women in the highest tertile of most sphingomyelins had a reduced risk of AD, which was most pronounced among APOE ɛ4 carriers.

CONCLUSION: These results provide further evidence for the role of sphingolipid metabolism in AD and highlight the importance of considering sex and APOE genotype in assessing this relationship.

%B J Alzheimers Dis %V 60 %P 819-828 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035934?dopt=Abstract %R 10.3233/JAD-160925 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Association Between Retinal Neuronal Layer and Brain Structure is Disrupted in Patients with Cognitive Impairment and Alzheimer's Disease. %A Liu, Siwei %A Ong, Yi-Ting %A Hilal, Saima %A Loke, Yng Miin %A Wong, Tien Y %A Chen, Christopher Li-Hsian %A Cheung, Carol Y %A Zhou, Juan %X

Both healthy and pathological aging due to Alzheimer's disease (AD) are associated with decreased brain grey matter volume (GMV) and disrupted white matter (WM) microstructure. Thinner macular ganglion cell-inner plexiform layer (GC-IPL) measured by spectral-domain optical coherence tomography has been reported in patients with AD and mild cognitive impairment. Emerging evidence suggested a link between thinner GC-IPL and lower GMV in subjects with no dementia using region-of-interest-based approach. However, it remains unknown whether GC-IPL thickness is associated with brain WM microstructure and how such association differed between normal and cognitively impaired subjects. Here, for subjects with no cognitive impairment (NCI), thinner GC-IPL was associated with lower WM microstructure integrity in the superior longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tracts, anterior thalamic radiation, and cingulum regions, while it was weakly associated with lower GMV in visual cortex and cerebellum. Nevertheless, these retina-brain associations were disrupted in the presence of cognitive impairment. Correlations between GMV and GC-IPL were lost in patients with cognitive impairment but no dementia (CIND) and AD patients. GC-IPL was related to WM microstructural disruption in similar regions with decreased significance. In contrast, lower WM microstructure integrity in the fornix showed a trend of correlation with thinner GC-IPL in both CIND and AD but not NCI. Collectively, our findings suggest the possible physiological retina-brain relationship in healthy aging, which might be disrupted by disease-induced changes in patients with cognitive impairment. Longitudinal study with larger patient sample should follow to confirm the disease mechanism behind these retina-brain relationship changes.

%B J Alzheimers Dis %V 54 %P 585-95 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567815?dopt=Abstract %R 10.3233/JAD-160067 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association Between Serum Ceruloplasmin Specific Activity and Risk of Alzheimer's Disease. %A Siotto, Mariacristina %A Simonelli, Ilaria %A Pasqualetti, Patrizio %A Mariani, Stefania %A Caprara, Deborah %A Bucossi, Serena %A Ventriglia, Mariacarla %A Molinario, Rossana %A Antenucci, Mirca %A Rongioletti, Mauro %A Rossini, Paolo Maria %A Squitti, Rosanna %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Area Under Curve %K Biomarkers %K Blood Chemical Analysis %K Ceruloplasmin %K Copper %K Female %K Genotype %K Genotyping Techniques %K Humans %K Logistic Models %K Male %K Multivariate Analysis %K Prognosis %K Risk %K ROC Curve %K Sensitivity and Specificity %K Transferrin %X

Meta-analyses demonstrate copper involvement in Alzheimer's disease (AD), and the systemic ceruloplasmin status in relation to copper is an emerging issue. To deepen this matter, we evaluated levels of ceruloplasmin concentration, ceruloplasmin activity, ceruloplasmin specific activity (eCp/iCp), copper, non-ceruloplasmin copper iron, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype in a sample of 84 AD patients and 58 healthy volunteers. From the univariate logistic analyses we found that ceruloplasmin concentration, eCp/iCp, copper, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype were significantly associated with the probability of AD. In the multivariable logistic regression analysis, we selected the best subset of biological predictors by the forward stepwise procedure. The analysis showed a decrease of the risk of having AD for eCp/iCp (p = 0.001) and an increase of this risk for non-ceruloplasmin copper (p = 0.008), age (p = 0.001), and APOE-ɛ4 allele (p <  0.001). The estimated model showed a good power in discriminating AD patients from healthy controls (area under curve: 88% ; sensitivity: 66% ; specificity 93%). These data strength the breakdown of copper homeostasis and propose eCp/iCp as a reliable marker of ceruloplasmin status.

%B J Alzheimers Dis %V 50 %P 1181-9 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836154?dopt=Abstract %R 10.3233/JAD-150611 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association Between Smoking and Cholinergic Basal Forebrain Volume in Healthy Aging and Prodromal and Dementia Stages of Alzheimer's Disease. %A Teipel, Stefan %A Grothe, Michel J %X

BACKGROUND: Smoking has been found associated with decreased cerebral volumes in healthy adults and in various neuropsychiatric disorders.

OBJECTIVE: We aimed to determine whether chronic nicotine exposure through smoking is associated with reduced volume of cortically projecting cholinergic basal forebrain nuclei in healthy aging, mild cognitive impairment (MCI), and dementia stages of Alzheimer's disease (AD).

METHODS: We retrieved cross-sectional data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database including 179 cognitively normal elderly subjects, 270 subjects with early stage MCI, 136 subjects in later, more advanced, stage of MCI, and 86 subjects in dementia stages of AD. We determined the association between past or current smoking versus lifetime non-smoker status on the volumes of the basal forebrain determined from volumetric MRI scans. Hippocampus volume was used as a control region. Significant effects were controlled for mediating or moderating effects of respiratory and cardiovascular morbidity.

RESULTS: In cognitively healthy individuals and early MCI, past or current smoking was significantly associated with smaller basal forebrain volume. This effect was independent from age, sex, or cardiovascular or respiratory morbidity. Hippocampus volume was not associated with smoking. In late MCI and AD dementia, smoking was not associated with basal forebrain or hippocampus volumes.

CONCLUSIONS: Our findings suggest that chronic nicotine exposure through smoking may lead to atrophy of cholinergic input areas of the basal forebrain. This effect may account for an increased risk of AD dementia onset with smoking by exhausting the cholinergic system reserve capacity.

%B J Alzheimers Dis %V 52 %P 1443-51 %8 2016 Apr 12 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079707?dopt=Abstract %R 10.3233/JAD-151100 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Butyrylcholinesterase-K Allele and Apolipoprotein E ɛ4 Allele with Cognitive Decline in Dementia with Lewy Bodies and Alzheimer's Disease. %A Vijayaraghavan, Swetha %A Darreh-Shori, Taher %A Rongve, Arvid %A Berge, Guro %A Sando, Sigrid B %A White, Linda R %A Auestad, Bjørn H %A Witoelar, Aree %A Andreassen, Ole A %A Ulstein, Ingun D %A Aarsland, Dag %K Aged %K Aged, 80 and over %K Alleles %K Alzheimer Disease %K Apolipoprotein E4 %K Butyrylcholinesterase %K Cognition %K Disease Progression %K Female %K Gene Frequency %K Genotype %K Humans %K Lewy Body Disease %K Male %K Neuropsychological Tests %X

BACKGROUND: A common polymorphism of the butyrylcholinesterase gene, the K-variant (BCHE-K) is associated with reduced butyrylcholinesterase (BuChE) activity. Insufficient studies exist regarding the frequency and role of BCHE-K in dementias.

OBJECTIVE: To determine the association of BCHE-K and APOEɛ4 with diagnosis and rate of cognitive decline in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) patients.

METHODS: Genomic DNA from 368 subjects (108 AD, 174 DLB, and 86 controls) from two routine clinical cohort studies in Norway; DemVest and TrønderBrain, were genotyped for BCHE-K and APOEɛ4. The mild dementia DemVest subjects received annual Mini-Mental State Examination assessments for five years.

RESULTS: BCHE-K frequency was lower in DLB (33.9% ; p <  0.01) than in control subjects (51.2%), and was numerically lower in AD as well (38.9% ; p = 0.11). More rapid cognitive decline was associated with the APOEɛ4 genotype, but not with the BCHE-K genotype. In an exploratory analysis of patients who completed all five follow-up visits, there was greater cognitive decline in BCHE-K carriers in the presence of the APOEɛ4 allele than in the absence of these polymorphisms.

CONCLUSION: BCHE-K is associated with a reduced risk for AD and DLB whereas APOEɛ4 is associated with more rapid cognitive decline. The greater cognitive decline in individuals with both APOEɛ4 and BCHE-K alleles require prospective confirmation in well-controlled trials.

%B J Alzheimers Dis %V 50 %P 567-76 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757188?dopt=Abstract %R 10.3233/JAD-150750 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Coffee Consumption with MRI Markers and Cognitive Function: A Population-Based Study. %A Araújo, Larissa Fortunato %A Mirza, Saira Saeed %A Bos, Daniel %A Niessen, Wiro J %A Barreto, Sandhi Maria %A van der Lugt, Aad %A Vernooij, Meike W %A Hofman, Albert %A Tiemeier, Henning %A Ikram, M Arfan %X

BACKGROUND: Coffee is one of the most widely consumed beverages worldwide and has been of considerable interest in research on cognition and dementia.

OBJECTIVE: To investigate the effect of coffee on preclinical brain MRI markers of dementia and cognitive performance.

METHODS: In 2,914 participants from the population-based Rotterdam Study (mean age: 59.3±7.2 years, 55% females), we assessed coffee consumption, performed brain MRI, and assessed cognition at baseline. To study cognitive change, cognitive assessment was repeated after 5 years of follow-up. Coffee consumption was analyzed continuously (per cup increase) and in categories (0-1, >1-3, >3 cups/day). Using logistic and linear regression, associations of coffee consumption with lacunar infarcts and brain tissue volumes on MRI, and cognitive performance (cross-sectional and longitudinal) were investigated, adjusting for relevant confounders.

RESULTS: We found that higher coffee consumption was associated with a lower prevalence of lacunar infarcts [odds ratio per cup increase: 0.88 (95% CI:0.79;0.98)], and smaller hippocampal volume [difference: -0.01 (95% CI:-0.02;0.00)]. Also, we found that the highest category of coffee consumption was associated with better performance on the Letter Digit Substitution Task [difference: 1.13(95% CI:0.39;1.88)], Word Fluency test [0.74(95% CI:0.04,1.45)], Stroop interference task [1.82(95% CI:0.23;3.41)], and worse performance on the 15-Word Learning test delayed recall [-0.38(95% CI:-0.74;-0.02)]. These associations were not found when cognition was analyzed longitudinally.

CONCLUSION: We found complex associations between coffee consumption, brain structure, and cognition. Higher coffee consumption was cross-sectionally associated with a lower occurrence of lacunar infarcts and better executive function, but also with smaller hippocampal volume and worse memory function.

%B J Alzheimers Dis %V 53 %P 451-61 %8 2016 May 03 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163820?dopt=Abstract %R 10.3233/JAD-160116 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Frontotemporal Dementia GWAS Loci with Late-Onset Alzheimer's Disease in a Northern Han Chinese Population. %A Tan, Chen-Chen %A Wan, Yu %A Tan, Meng-Shan %A Zhang, Wei %A Wang, Zi-Xuan %A Sun, Fu-Rong %A Miao, Dan %A Tan, Lan %A Yu, Jin-Tai %K Age of Onset %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Asian Continental Ancestry Group %K Case-Control Studies %K China %K Female %K Frontotemporal Dementia %K Gene Frequency %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Genotyping Techniques %K Humans %K Linkage Disequilibrium %K Male %K Mental Status Schedule %K Polymorphism, Single Nucleotide %X

BACKGROUND: Both Alzheimer's disease (AD) and frontotemporal dementia (FTD) are a class of neurodegenerative diseases. Strong similarities in cerebrospinal fluid biomarker, imaging markers, and disease progression profiles suggest that some or most of the pathophysiology is shared between AD and FTD. A recent large genome-wide association study reported several single nucleotide polymorphisms (SNPs) at the RAB38, RAB38/CTSC, HLA-DRA/HLA-DRB5, and BTNL2 in association with FTD.

OBJECTIVE: To explore whether these SNPs are associated with AD risk.

METHODS: We conducted a case-control study to investigate the association of FTD-associated loci in 2338 Han Chinese subjects.

RESULTS: We observed significant differences in genotype distributions of rs302668 (pc = 0.025), rs9268877 (pc = 0.025), rs9268856 (p <  0.001), and rs1980493 (pc = 0.045) between cases and controls. The SNPs rs16913634 for RAB38/CTSC was unrelated to LOAD risk (p = 0.088).

CONCLUSION: The SNPs rs302668 in RAB38, rs9268877 and rs9268856 polymorphism in HLA-DRA/HLA-DRB5, and rs1980493 polymorphism in BTNL2 might play a role in the susceptibility to late-onset AD in the Han Chinese population.

%B J Alzheimers Dis %V 52 %P 43-50 %8 2016 02 26 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967218?dopt=Abstract %R 10.3233/JAD-151073 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Physical Function with Clinical and Subclinical Brain Disease: The Framingham Offspring Study. %A Camargo, Erica C %A Weinstein, Galit %A Beiser, Alexa S %A Tan, Zaldy S %A DeCarli, Charles %A Kelly-Hayes, Margaret %A Kase, Carlos %A Murabito, Joanne M %A Seshadri, Sudha %X

BACKGROUND: Handgrip strength and gait speed are simple measures of physical capability and have been associated with current and future health outcomes. However, studies on their associations with brain structure and function in middle-aged adults are lacking.

OBJECTIVE: To assess the relationship of fast-paced walking speed and handgrip strength with risk of dementia, Alzheimer's disease (AD), and stroke, as well as the cross-sectional associations with cognitive and brain magnetic resonance imaging (MRI) measures in a middle-aged community sample.

METHODS: Framingham Offspring (n = 2,176; mean age 62, 54% female) had physical function, brain MRI, and cognitive evaluations between 1999 and 2005 and were followed-up for incident dementia AD and stroke until 11 years later. We related walking speed and handgrip strength to incident dementia, AD, and stroke using Cox models, and to brain and cognitive measures using multivariable linear and logistic regression. Models were adjusted for age, sex, education, and vascular risk factors.

RESULTS: Slow walking and weak handgrip were associated with more than 2.5-fold increase in risk of AD. Weaker handgrip was associated with an increased risk of incident stroke (HR 1.74, 95% CI: 1.12-2.70/SDU, p = 0.01) in persons ≥65 years. Both measures were associated with lower total brain volume and poorer performance on tests of visual memory, language, executive function, and visuoperceptual function. Slower gait was also related to poorer verbal memory, and weaker handgrip to poorer abstraction.

CONCLUSION: Tests of walking speed and handgrip strength may serve as clinical markers of brain structure and function and may improve dementia risk prediction.

%B J Alzheimers Dis %V 53 %P 1597-608 %8 2016 Jul 14 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27540965?dopt=Abstract %R 10.3233/JAD-160229 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Plasma Aβ40 Peptides, But Not Aβ42, with Coronary Artery Disease and Diabetes Mellitus. %A Roeben, Benjamin %A Maetzler, Walter %A Vanmechelen, Eugeen %A Schulte, Claudia %A Heinzel, Sebastian %A Stellos, Konstantinos %A Godau, Jana %A Huber, Heiko %A Brockmann, Kathrin %A Wurster, Isabel %A Gaenslen, Alexandra %A Grüner, Eva %A Niebler, Raphael %A Eschweiler, Gerhard W %A Berg, Daniela %X

BACKGROUND/OBJECTIVE: Plasma levels of amyloid-beta (Aβ) 1-40 peptide have been proposed to be associated with cardiovascular mortality in patients with coronary artery disease (CAD). Therefore, we aimed to investigate the association of plasma Aβ levels with CAD, cardiovascular risk factors (CVRF), and APOE genotype in non-demented elderly individuals.

METHODS: Plasma Aβ1 - 40 and Aβ1 - 42 levels of 526 individuals (mean age of 63.0±7.3 years) were quantified with the INNO-BIA plasma Aβ forms assay based on multiplextrademark technique. APOE genotype was determined with an established protocol. Presence of CAD and CVRFs were ascertained using a questionnaire and/or medical records.

RESULTS: Plasma Aβ1 - 40 levels were significantly higher in individuals with CAD (p = 0.043) and, independently, in individuals with diabetes mellitus (DM) type 2 (p = 0.001) while accounting for age- and gender-effects. Plasma Aβ1 - 42 levels were higher in APOEɛ4 carriers (p = 0.004), but were neither relevantly associated with CAD nor with any CVRF. Plasma Aβ1 - 40 showed no association with APOE genotype.

DISCUSSION: Our findings argue for an association of circulating plasma Aβ1 - 40 peptides with incident CAD and DM. Further investigations are needed to entangle the role of Aβ1 - 40 role in the pathophysiology of cardiovascular disease independent of its known role in Alzheimer's disease.

%B J Alzheimers Dis %V 52 %P 161-9 %8 2016 03 16 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003209?dopt=Abstract %R 10.3233/JAD-150575 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Platelet Serotonin Levels in Alzheimer's Disease with Clinical and Cerebrospinal Fluid Markers. %A Tajeddinn, Walid %A Fereshtehnejad, Seyed-Mohammad %A Seed Ahmed, Mohammed %A Yoshitake, Takashi %A Kehr, Jan %A Shahnaz, Tasmin %A Milovanovic, Micha %A Behbahani, Homira %A Höglund, Kina %A Winblad, Bengt %A Cedazo-Minguez, Angel %A Jelic, Vesna %A Järemo, Petter %A Aarsland, Dag %X

INTRODUCTION: Serotonin (5-HT) is involved in the pathology of Alzheimer's disease (AD).

OBJECTIVE: We aimed to measure 5-HT level in platelets in AD and explore its association with cerebrospinal fluid (CSF), AD biomarkers (amyloid-β 1-42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau)), and clinical symptoms.

METHODS: 15 patients with AD and 20 patients with subjective cognitive impairment (SCI) were included. 5-HT metabolites were measured, in a specific fraction, using high performance liquid chromatography with electrochemical detection (HPLC-ECD).

RESULTS: Significantly lower 5-HT concentrations were observed in AD patients compared to SCI patients both after normalization against total protein (p = 0.008) or platelet count (p = 0.019). SCI patients with lower 5-HT level have higher AD CSF biomarkers, total tau (p = 0.026) and tau/Aβ42 ratio (p = 0.001), compared to those with high 5-HT levels.

CONCLUSION: AD patients have reduced platelet 5-HT levels. In SCI, lower 5-HT content was associated with a higher AD-CSF biomarker burden.

%B J Alzheimers Dis %V 53 %P 621-30 %8 2016 May 04 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163811?dopt=Abstract %R 10.3233/JAD-160022 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Serum Vitamin D with the Risk of Incident Dementia and Subclinical Indices of Brain Aging: The Framingham Heart Study. %A Karakis, Ioannis %A Pase, Matthew P %A Beiser, Alexa %A Booth, Sarah L %A Jacques, Paul F %A Rogers, Gail %A DeCarli, Charles %A Vasan, Ramachandran S %A Wang, Thomas J %A Himali, Jayandra J %A Annweiler, Cedric %A Seshadri, Sudha %K Adult %K Aging %K Brain %K Cohort Studies %K Dementia %K Female %K Humans %K Incidence %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Multivariate Analysis %K Neuropsychological Tests %K Regression Analysis %K Risk %K Sensitivity and Specificity %K Vitamin D %X

BACKGROUND: Identifying nutrition- and lifestyle-based risk factors for cognitive impairment and dementia may aid future primary prevention efforts.

OBJECTIVE: We aimed to examine the association of serum vitamin D levels with incident all-cause dementia, clinically characterized Alzheimer's disease (AD), MRI markers of brain aging, and neuropsychological function.

METHODS: Framingham Heart Study participants had baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations measured between 1986 and 2001. Vitamin D status was considered both as a continuous variable and dichotomized as deficient (<10 ng/mL), or at the cohort-specific 20th and 80th percentiles. Vitamin D was related to the 9-year risk of incident dementia (n = 1663), multiple neuropsychological tests (n = 1291) and MRI markers of brain volume, white matter hyperintensities and silent cerebral infarcts (n = 1139).

RESULTS: In adjusted models, participants with vitamin D deficiency (n = 104, 8% of the cognitive sample) displayed poorer performance on Trail Making B-A (β= -0.03 to -0.05±0.02) and the Hooper Visual Organization Test (β= -0.09 to -0.12±0.05), indicating poorer executive function, processing speed, and visuo-perceptual skills. These associations remained when vitamin D was examined as a continuous variable or dichotomized at the cohort specific 20th percentile. Vitamin D deficiency was also associated with lower hippocampal volumes (β= -0.01±0.01) but not total brain volume, white matter hyperintensities, or silent brain infarcts. No association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized AD.

CONCLUSIONS: In this large community-based sample, low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function.

%B J Alzheimers Dis %V 51 %P 451-61 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890771?dopt=Abstract %R 10.3233/JAD-150991 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Associations between a Capsaicin-Rich Diet and Blood Amyloid-β Levels and Cognitive Function. %A Liu, Cheng-Hui %A Bu, Xian-Le %A Wang, Jun %A Zhang, Tao %A Xiang, Yang %A Shen, Lin-Lin %A Wang, Qing-Hua %A Deng, Bo %A Wang, Xin %A Zhu, Chi %A Yao, Xiu-Qing %A Zhang, Meng %A Zhou, Hua-Dong %A Wang, Yan-Jiang %X

BACKGROUND: Capsaicin-rich diets are common worldwide. Capsaicin has been shown to have favorable effects on various diseases including atherosclerosis, cardiovascular diseases, stroke, obesity, hypertension, cancer, and gastrointestinal and inflammatory diseases. The impact of capsaicin on Alzheimer's disease (AD), which is the most common form of dementia in the elderly, remains unknown.

OBJECTIVE: To investigate the correlations of capsaicin intake with cognition and blood markers of AD.

METHODS: A total of 338 participants aged 40 years or older were enrolled from communities. Dietary habits regarding chili pepper consumption were collected using a Food Frequency Questionnaire (FFQ). Cognitive function was measured using the Chinese version of the Mini-Mental State Examination (MMSE). Blood amyloid-β (Aβ)40 and Aβ42 were measured with ELISA kits.

RESULTS: In univariate analysis, MMSE scores (r = 0.209, p < 0.001), serum Aβ40 levels (r = -0.149, p = 0.006), the ratio of Aβ42/Aβ40 (r = 0.11, p = 0.043) and total serum Aβ levels (r = -0.097, p = 0.075), but not serum Aβ42 levels (r = 0.17, p = 0.757), were significantly correlated with total capsaicin diet scores. In multivariate analysis, total capsaicin diet scores were positively associated with MMSE scores and inversely associated with serum Aβ40 levels, and total serum Aβ levels, but not serum Aβ42 levels and the ratio of Aβ42/Aβ40, after adjustment for age, gender, educational level, smoking history, alcohol consumption, body mass index (BMI) and comorbidities.

CONCLUSION: These findings suggest that a capsaicin-rich diet may exert favorable effects on AD blood biomarkers and cognitive function in middle-aged and elderly adults.

%B J Alzheimers Dis %V 52 %P 1081-8 %8 2016 Apr 08 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079706?dopt=Abstract %R 10.3233/JAD-151079 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Associations between Neuropsychiatric Symptoms and Cerebral Amyloid Deposition in Cognitively Impaired Elderly People. %A Bensamoun, David %A Guignard, Renaud %A Furst, Ansgar J %A Derreumaux, Alexandre %A Manera, Valeria %A Darcourt, Jacques %A Benoit, Michel %A Robert, Philippe H %A David, Renaud %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloidogenic Proteins %K Cerebral Cortex %K Cognition Disorders %K Cohort Studies %K Female %K Fluorodeoxyglucose F18 %K Humans %K Male %K Mental Status Schedule %K Mood Disorders %K Neuropsychological Tests %K Positron-Emission Tomography %X

BACKGROUND: Neuropsychiatric symptoms, also known as behavioral and psychological symptoms of dementia (BPSD), affect the majority of patients with dementia, and result in a greater cognitive and functional impairment.

OBJECTIVE: To investigate associations between BPSD and amyloid cerebral deposition as measured by 18F-Florbetapir-PET quantitative uptake in elderly subjects with and without cognitive impairment.

METHODS: Participants with cognitive impairment [mild cognitive impairment (MCI) or Alzheimer's disease (AD)] and healthy controls (HC) from the ADNI cohort (Alzheimer Disease Neuroimaging Initiative) who underwent an 18F-florbetapir PET scan between May 2010 and March 2014 were included. Clinical assessments included the Clinical Dementia Rating, the Mini-Mental State Examination (MMSE), and the Neuropsychiatric Inventory. Freesurfer software was used to extract PET counts based on T1-based structural ROI (frontal, cingulate, parietal, and temporal). Spearman's partial correlation scores between BPSD severity and regional amyloid uptake were calculated.

RESULTS: Data for 657 participants [age = 72.6 (7.19); MMSE = 27.4 (2.67)] were analyzed, including 230 HC [age = 73.1 (6.02); MMSE = 29 (1.21)], 308 MCI [age = 71.5 (7.44); MMSE = 28.0 (1.75)], and 119 AD subjects [age = 74.7 (8.05); MMSE = 23.1 (2.08)]. Considering all diagnostic groups together, positive significant correlations were found between anxiety and 18F-florbetapir uptake in the frontal (r = 0.102; p = 0.009), cingulate (r = 0.083; p = 0.034), and global cerebral uptake (r = 0.099; p = 0.011); between irritability and frontal (r = 0.089; p = 0.023), cingulate (r = 0.085; p = 0.030), parietal (r = 0.087; p = 0.025), and global cerebral uptake (r = 0.093; p = 0.017); in the MCI subgroup, between anxiety and frontal (r = 0.126; p = 0.03) and global uptake (r = 0.14; p = 0.013); in the AD subgroup, between irritability and parietal uptake (r = 0.201; p = 0.03).

CONCLUSION: Anxiety and irritability are associated with greater amyloid deposition in the neurodegenerative process leading to AD.

%B J Alzheimers Dis %V 49 %P 387-98 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484900?dopt=Abstract %R 10.3233/JAD-150181 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Associations between Performance on an Abbreviated CogState Battery, Other Measures of Cognitive Function, and Biomarkers in People at Risk for Alzheimer's Disease. %A Racine, Annie M %A Clark, Lindsay R %A Berman, Sara E %A Koscik, Rebecca L %A Mueller, Kimberly D %A Norton, Derek %A Nicholas, Christopher R %A Blennow, Kaj %A Zetterberg, Henrik %A Jedynak, Bruno %A Bilgel, Murat %A Carlsson, Cynthia M %A Christian, Bradley T %A Asthana, Sanjay %A Johnson, Sterling C %X

It is not known whether computerized cognitive assessments, like the CogState battery, are sensitive to preclinical cognitive changes or pathology in people at risk for Alzheimer's disease(AD). In 469 late middle-aged participants from the Wisconsin Registry for Alzheimer's Prevention(mean age 63.8±7 years at testing; 67% female; 39% APOE4+), we examined relationships between a CogState abbreviated battery(CAB) of seven tests and demographic characteristics, traditional paper-based neuropsychological tests as well as a composite cognitive impairment index, cognitive impairment status(determined by consensus review), and biomarkers for amyloid and tau(CSF phosphorylated-tau/Aβ42 and global PET-PiB burden) and neural injury(CSF neurofilament light protein). CSF and PET-PiB were collected in n = 71 and n = 91 participants, respectively, approximately four years prior to CAB testing. For comparison, we examined three traditional tests of delayed memory in parallel. Similar to studies in older samples, the CAB was less influenced by demographic factors than traditional tests. CAB tests were generally correlated with most paper-based cognitive tests examined and mapped onto the same cognitive domains. Greater composite cognitive impairment index was associated with worse performance on all CAB tests. Cognitively impaired participants performed significantly worse compared to normal controls on all but one CAB test. Poorer One Card Learning test performance was associated with higher levels of CSF phosphorylated-tau/Aβ42. These results support the use of the CogState battery as measures of early cognitive impairment in studies of people at risk for AD.

%B J Alzheimers Dis %V 54 %P 1395-1408 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589532?dopt=Abstract %R 10.3233/JAD-160528 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Associations between Serum Omega-3 Fatty Acid Levels and Cognitive Functions among Community-Dwelling Octogenarians in Okinawa, Japan: The KOCOA Study. %A Nishihira, Junko %A Tokashiki, Takashi %A Higashiuesato, Yasushi %A Willcox, Donald Craig %A Mattek, Nora %A Shinto, Lynne %A Ohya, Yusuke %A Dodge, Hiroko H %K Age Factors %K Aged, 80 and over %K Arachidonic Acid %K Blood Chemical Analysis %K Cognition %K Cross-Sectional Studies %K Educational Status %K Fatty Acids, Omega-3 %K Female %K Humans %K Japan %K Logistic Models %K Male %K Mental Status Schedule %K Obesity %K Prospective Studies %K Sex Factors %X

BACKGROUND: Epidemiological studies have found frequent consumption of fatty fish is protective against cognitive decline. However, the association between circulating omega-3 polyunsaturated fatty acid (PUFA) levels and cognitive functions among the oldest old is not well known.

OBJECTIVE: To examine the association between serum PUFA levels and cognitive function among community-dwelling, non-demented elderly aged over 80 years old.

METHODS: The data came from the Keys to Optimal Cognitive Aging (KOCOA) study; an ongoing cohort of relatively healthy volunteers aged over 80 years old, living in Okinawa, Japan. One hundred eighty five participants (mean age 84.1±3.4 years) assessed in 2011 who were free from frank dementia (defined as Clinical Dementia Rating <1.0) were used for the current cross-sectional study. We examined whether serum omega-3 PUFAs (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), arachidonic acid (AA), EPA/AA ratio, DHA/AA ratio, and DHA+EPA are associated with (1) age and (2) global cognitive function (Japanese MMSE) and executive function (Verbal Fluency Letter). Data was analyzed univariately by t-test and multivariately by cumulative logistic regression models controlling for age, gender, years of education, obesity, hypertension, diabetes, and dyslipidemia.

RESULTS: Serum DHA levels decreased with increasing age (p = 0.04). Higher global cognitive function was associated with higher levels of serum EPA (p = 0.03) and DHA + EPA (p = 0.03) after controlling for confounders.

CONCLUSIONS: Higher serum EPA and DHA + EPA levels were independently associated with better scores on global cognitive function among the oldest old, free from dementia. Longitudinal follow-up studies are warranted.

%B J Alzheimers Dis %V 51 %P 857-66 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890763?dopt=Abstract %R 10.3233/JAD-150910 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Astrocytes release HspB1 in response to amyloid-β exposure in vitro. %A Nafar, Firoozeh %A Williams, J Bradley %A Mearow, Karen M %K Amyloid beta-Peptides %K Animals %K Astrocytes %K Cells, Cultured %K HSP27 Heat-Shock Proteins %K Protein Transport %K Rats %X

Although heat shock proteins are thought to function primarily as intracellular chaperones, the release and potential extracellular functions of heat shock proteins have been the focus of an increasing number of studies. Our particular interest is HspB1 (Hsp25/27) and as astrocytes are an in vivo source of HspB1 it is a reasonable possibility they could release HspB1 in response to local stresses. Using primary cultures of rat cortical astrocytes, we investigated the extracellular release of HspB1 with exposure to amyloid-β (Aβ). In order to assess potential mechanisms of release, we cotreated the cells with compounds that can modulate protein secretion including Brefeldin A, Methyl β-cyclodextrin, and MAP kinase inhibitors. Exposure to Aβ (0.1, 1.0, 2.0 μM) for 24-48 h resulted in a selective release of HspB1 that was insensitive to BFA treatment; none of the other inhibitors had any detectable influence. Protease protection assays indicated that some of the released HspB1 was associated with a membrane bound fraction, and analysis of exosomal preparations indicated the presence of HspB1 in exosomes. Finally, immunoprecipitation experiments demonstrated that the extracellular HspB1 was able to interact with extracellular Aβ. In summary, Aβ can stimulate release of HspB1 from astrocytes, this release is insensitive to Golgi or lipid raft disruption, and HspB1 can be found either free in the medium or associated with exosomes. This release suggests that there is a potential for extracellular HspB1 to be able to bind and sequester extracellular Aβ.

%B J Alzheimers Dis %V 49 %P 251-63 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444769?dopt=Abstract %R 10.3233/JAD-150317 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Astrocytic GluN2A and GluN2B Oppose the Synaptotoxic Effects of Amyloid-β1-40 in Hippocampal Cells. %A Li, Yan %A Chang, Lirong %A Song, Yizhi %A Gao, Xianghong %A Roselli, Francesco %A Liu, Jinping %A Zhou, Wei %A Fang, Yuan %A Ling, Wei %A Li, Hui %A Almeida, Osborne F X %A Wu, Yan %X

Early-stage Alzheimer's disease (AD) is characterized by synaptic dysfunction, a phenomenon in which soluble oligomers of amyloid-beta (Aβ) and N-methyl-D-aspartate receptor (NMDAR) are implicated. Here, we demonstrated that astrocytes express NMDARs and therefore have the potential to modulate the synaptotoxic actions of Aβ. We found that specific pharmacological antagonism of two of the major NMDAR subunits, GluN2A and GluN2B, exacerbates Aβ-induced synaptotoxicity suggesting, for the first time, that astrocytic GluN2A and GluN2B mediate synaptoprotection. From the perspective of the pathogenic mechanisms of Alzheimer's disease, in which Aβ and NMDAR play significant roles, these observations are striking since neuronal GluN2A and GluN2B are well known modulators of neurodegeneration. We did initial studies to understand the basis for the differential effects of astrocytic and neuronal GluN2A and GluN2B in the promotion of synapse survival, and identified a neurotrophin produced by astrocytes, nerve growth factor β (β-NGF), as a likely mediator of the synaptoprotective effects of astrocytic GluN2A and GluN2B activation. The results presented suggest that astrocytes may be suitable druggable targets for the prevention and/or delay of the synaptic loss that occurs during early stages of AD.

%B J Alzheimers Dis %V 54 %P 135-48 %8 2016 Aug 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497478?dopt=Abstract %R 10.3233/JAD-160297 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Atrophy in Alzheimer's Disease and Semantic Dementia: An ALE Meta-Analysis of Voxel-Based Morphometry Studies. %A Chapleau, Marianne %A Aldebert, Joséphine %A Montembeault, Maxime %A Brambati, Simona M %X

BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) and semantic dementia (SD) have distinct episodic memory profiles despite the hippocampal atrophy that characterizes both diseases. The aim of this study was to delineate the pattern of gray matter (GM) atrophy associated with AD and SD as well as any differences in these patterns by pooling together the results of previous voxel-based morphometry (VBM) studies.Methods/Overview: We conducted a meta-analysis of VBM studies that investigated GM atrophy in AD patients versus controls (CTRLs) and in SD patients versus CTRLs using the activation likelihood estimation (ALE) approach. Our systematic review allowed us to identify 63 VBM studies.

RESULTS: The results confirmed that in addition to the classical cortical pattern of atrophy involving posterior medial and lateral regions in AD and the anterior lateral temporal lobes in SD, both AD and SD patients are characterized by bilateral atrophy of the hippocampus. Furthermore, in SD, the hippocampal atrophy was limited to the anterior portion of the hippocampus, while in AD, both the anterior and posterior parts of the hippocampus exhibited atrophy. When we compared the foci identified in the studies that compared AD patients versus CTRLs with those identified in the studies that compared SD patients versus CTRLs, we observed that the atrophy in the posterior hippocampus and precuneus was more severe in AD.

CONCLUSION: These results support theories that propose that the deficits observed in AD result from damage to the episodic memory network, which involves the posterior hippocampus and posterior medial brain regions. However, sparing of the posterior hippocampus in SD could explain the absence of episodic memory deficits in this population.

%B J Alzheimers Dis %V 54 %P 941-955 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567843?dopt=Abstract %R 10.3233/JAD-160382 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Attitudes and Perceptions of Research in Aging and Dementia in an Urban Minority Population. %A Neugroschl, Judith %A Sewell, Margaret %A De La Fuente, Angelica %A Umpierre, Mari %A Luo, Xiaodong %A Sano, Mary %X

In dementia trials, minority participation is low. We assessed attitudes toward research in a community based urban poor minority sample of elderly adults attending senior center talks using the 7-item Research Attitudes Questionnaire (RAQ). Presentations on cognitive aging were given at senior centers, and 123 attendees completed the RAQ-7. On trust and safety questions, a significant minority (42-48%) responded neutrally or negatively. Encouragingly, on questions concerning the importance of research, 72-81% answered positively. More work can be done to capitalize on these findings to engage and foster trust, and this can be a focus of outreach.

%B J Alzheimers Dis %V 53 %P 69-72 %8 2016 Apr 23 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128368?dopt=Abstract %R 10.3233/JAD-151072 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Autobiographical Memory Performance in Alzheimer's Disease Depends on Retrieval Frequency. %A Müller, Stephan %A Mychajliw, Christian %A Reichert, Carolin %A Melcher, Tobias %A Leyhe, Thomas %X

Alzheimer's disease (AD) is characterized by memory disturbances primarily caused by pathogenic mechanisms affecting medial temporal lobe structures. As proposed by current theories of memory formation, this decrease is mediated by the age of the acquired knowledge. However, they cannot fully explain specific patterns of retrograde amnesia in AD. In the current study we examined an alternative approach and investigated whether the extent and severity of retrograde amnesia in AD is mediated by the frequency of memory retrieval or whether it depends on the mere age of knowledge. We compared recall of autobiographical incidents from three life periods in patients with amnestic mild cognitive impairment (aMCI), patients with early dementia of Alzheimer type (eDAT), and healthy control (HC) individuals using the Autobiographical Memory Interview. Retrieval frequency was operationalized by a paired comparison analysis. In contrast to HC individuals, recall of autobiographical incidents was impaired in patients with aMCI and eDAT following Ribot's gradient, with a reduced memory loss for remote compared to more recent life events. However, there was a strong effect of retrieval frequency on memory performance with frequently retrieved incidents memorized in more detail than less frequently retrieved episodes. Remote memories were recalled more often than recent ones. These findings suggest that more frequently retrieved autobiographical memories generally become more independent of the hippocampal complex and might thus be better protected against early hippocampal damage related to AD. Hence, the extent of retrograde amnesia in AD appears mainly mediated by the frequency of memory retrieval, which could plausibly explain why cognitive activity can effectively delay the onset of memory decline in AD.

%B J Alzheimers Dis %V 52 %P 1215-25 %8 2016 Apr 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104895?dopt=Abstract %R 10.3233/JAD-151071 %0 Journal Article %J J Alzheimers Dis %D 2016 %T AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders. %A Ivachtchenko, Alexandre V %A Lavrovsky, Yan %A Okun, Ilya %X

Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2-2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41-3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer's disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis.

%B J Alzheimers Dis %V 53 %P 583-620 %8 2016 May 25 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27232215?dopt=Abstract %R 10.3233/JAD-151146 %0 Journal Article %J J Alzheimers Dis %D 2016 %T AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics. %A Eketjäll, Susanna %A Janson, Juliette %A Kaspersson, Karin %A Bogstedt, Anna %A Jeppsson, Fredrik %A Fälting, Johanna %A Haeberlein, Samantha Budd %A Kugler, Alan R %A Alexander, Robert C %A Cebers, Gvido %K Administration, Oral %K Amyloid beta-Peptides %K Amyloid Precursor Protein Secretases %K Animals %K Blood Chemical Analysis %K Blood-Brain Barrier %K Brain %K Dogs %K Dose-Response Relationship, Drug %K Drug Evaluation, Preclinical %K Enzyme Inhibitors %K Female %K Guinea Pigs %K Humans %K Imidazoles %K Kinetics %K Male %K Mice, Inbred C57BL %K Peptide Fragments %K Spiro Compounds %X

A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-β peptide (Aβ) concentrations, plays a key role in the pathogenesis of Alzheimer's disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-β protein precursor (AβPP) to Aβ peptides, with the soluble N terminal fragment of AβPP (sAβPPβ) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of Aβ. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Aβ. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.

%B J Alzheimers Dis %V 50 %P 1109-23 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890753?dopt=Abstract %R 10.3233/JAD-150834 %0 Journal Article %J J Alzheimers Dis %D 2016 %T AβPP/PS1 Transgenic Mice Show Sex Differences in the Cerebellum Associated with Aging. %A Ordoñez-Gutierrez, Lara %A Fernandez-Perez, Ivan %A Herrera, Jose Luis %A Anton, Marta %A Benito-Cuesta, Irene %A Wandosell, Francisco %X

Cerebellar pathology has been related to presenilin 1 mutations in certain pedigrees of familial Alzheimer's disease. However, cerebellum tissue has not been intensively analyzed in transgenic models of mutant presenilins. Furthermore, the effect of the sex of the mice was not systematically analyzed, despite the fact that important gender differences in the evolution of the disease in the human population have been described. We analyzed whether the progression of amyloidosis in a double transgenic mouse, AβPP/PS1, is susceptible to aging and differentially affects males and females. The accumulation of amyloid in the cerebellum differentially affects males and females of the AβPP/PS1 transgenic line, which was found to be ten-fold higher in 15-month-old females. Amyloid-β accumulation was more evident in the molecular layer of the cerebellum, but glia reaction was only observed in the granular layer of the older mice. The sex divergence was also observed in other neuronal, survival, and autophagic markers. The cerebellum plays an important role in the evolution of the pathology in this transgenic mouse model. Sex differences could be crucial for a complete understanding of this disease. We propose that the human population could be studied in this way. Sex-specific treatment strategies in human populations could show a differential response to the therapeutic approach.

%B J Alzheimers Dis %V 54 %P 645-56 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567877?dopt=Abstract %R 10.3233/JAD-160572 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Bacterial Amyloid and DNA are Important Constituents of Senile Plaques: Further Evidence of the Spirochetal and Biofilm Nature of Senile Plaques. %A Miklossy, Judith %X

It has long been known that spirochetes form clumps or micro colonies in vitro and in vivo. Cortical spirochetal colonies in syphilitic dementia were considered as reproductive centers for spirochetes. Historic and recent data demonstrate that senile plaques in Alzheimer's disease (AD) are made up by spirochetes. Spirochetes, are able to form biofilm in vitro. Senile plaques are also reported to contain elements of biofilm constituents. We expected that AβPP and Aβ (the main components of senile plaques) also occur in pure spirochetal biofilms, and bacterial DNA (an important component of biofilm) is also present in senile plaques. Histochemical, immunohistochemical, and in situ hybridization techniques and the TUNEL assay were used to answer these questions. The results obtained demonstrate that Aβ and DNA, including spirochete-specific DNA, are key components of both pure spirochetal biofilms and senile plaques in AD and confirm the biofilm nature of senile plaques. These results validate validate previous observations that AβPP and/or an AβPP-like amyloidogenic protein are an integral part of spirochetes, and indicate that bacterial and host derived Aβ are both constituents of senile plaques. DNA fragmentation in senile plaques further confirms their bacterial nature and provides biochemical evidence for spirochetal cell death. Spirochetes evade host defenses, locate intracellularly, form more resistant atypical forms and notably biofilms, which contribute to sustain chronic infection and inflammation and explain the slowly progressive course of dementia in AD. To consider co-infecting microorganisms is equally important, as multi-species biofilms result in a higher resistance to treatments and a more severe dementia.

%B J Alzheimers Dis %V 53 %P 1459-73 %8 2016 Jun 13 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27314530?dopt=Abstract %R 10.3233/JAD-160451 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Bacterial Component to Alzheimer's-Type Dementia Seen via a Systems Biology Approach that Links Iron Dysregulation and Inflammagen Shedding to Disease. %A Pretorius, Etheresia %A Bester, Janette %A Kell, Douglas B %X

The progression of Alzheimer's disease (AD) is accompanied by a great many observable changes, both molecular and physiological. These include oxidative stress, neuroinflammation, and (more proximal to cognitive decline) the death of neuronal and other cells. A systems biology approach seeks to organize these observed variables into pathways that discriminate those that are highly involved (i.e., causative) from those that are more usefully recognized as bystander effects. We review the evidence that iron dysregulation is one of the central causative pathway elements here, as this can cause each of the above effects. In addition, we review the evidence that dormant, non-growing bacteria are a crucial feature of AD, that their growth in vivo is normally limited by a lack of free iron, and that it is this iron dysregulation that is an important factor in their resuscitation. Indeed, bacterial cells can be observed by ultrastructural microscopy in the blood of AD patients. A consequence of this is that the growing cells can shed highly inflammatory components such as lipopolysaccharides (LPS). These too are known to be able to induce (apoptotic and pyroptotic) neuronal cell death. There is also evidence that these systems interact with elements of vitamin D metabolism. This integrative systems approach has strong predictive power, indicating (as has indeed been shown) that both natural and pharmaceutical iron chelators might have useful protective roles in arresting cognitive decline, and that a further assessment of the role of microbes in AD development is more than highly warranted.

%B J Alzheimers Dis %V 53 %P 1237-56 %8 2016 Jun 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340854?dopt=Abstract %R 10.3233/JAD-160318 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Behavioral and Electrophysiological Correlates of Memory Binding Deficits in Patients at Different Risk Levels for Alzheimer's Disease. %A Pietto, Marcos %A Parra, Mario A %A Trujillo, Natalia %A Flores, Facundo %A García, Adolfo M %A Bustin, Julian %A Richly, Pablo %A Manes, Facundo %A Lopera, Francisco %A Ibáñez, Agustín %A Baez, Sandra %X

Deficits in visual short-term memory (VSTM) binding have been proposed as an early and specific marker for Alzheimer's disease (AD). However, no studies have explored the neural correlates of this domain in clinical categories involving prodromal stages with different risk levels of conversion to AD. We assessed underlying electrophysiological modulations in patients with mild cognitive impairment (MCI), patients in the MCI stages of familial AD carrying the mutation E280A of the presenilin-1 gene (MCI-FAD), and healthy controls. Moreover, we compared the behavioral performance and neural correlates of both patient groups. Participants completed a change-detection VSTM task assessing recognition of changes between shapes or shape-color bindings, presented in two consecutive arrays (i.e., study and test) while event related potentials (ERPs) were recorded. Changes always occurred in the test array and consisted of new features replacing studied features (shape-only) or features swapping across items (shape-color binding). Both MCI and MCI-FAD patients performed worse than controls in the shape-color binding condition. Early electrophysiological activity (100-250 ms) was significantly reduced in both clinical groups, particularly over fronto-central and parieto-occipital regions. However, shape-color binding performance and their reduced neural correlates were similar between MCI and MCI-FAD. Our results support the validity of the VSTM binding test and their neural correlates in the early detection of AD and highlight the importance of studies comparing samples at different risk for AD conversion. The combined analysis of behavioral and ERP data gleaned with the VSTM binding task can offer a valuable memory biomarker for AD.

%B J Alzheimers Dis %V 53 %P 1325-40 %8 2016 Jun 30 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372640?dopt=Abstract %R 10.3233/JAD-160056 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Beneficial Effects of an Integrated Psychostimulation Program in Patients with Alzheimer's Disease. %A Ibarria, Marta %A Alegret, Montserrat %A Valero, Sergi %A Morera, Amèrica %A Guitart, Marina %A Cañabate, Pilar %A Moreno, Mariola %A Lara, Susana %A Diego, Susana %A Hernández, Joan %A Tantinyá, Natàlia %A Vera, Maribel %A Hernandez, Isabel %A Becker, James T %A Ruiz, Agustin %A Boada, Merce %A Tárraga, Lluís %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cholinesterase Inhibitors %K Cognition %K Combined Modality Therapy %K Disease Progression %K Female %K Humans %K Male %K Neuropsychological Tests %K Psychotherapy %K Severity of Illness Index %K Treatment Outcome %X

BACKGROUND: The existing pharmacological treatments for Alzheimer's disease (AD) can only slow the progression of symptoms or delay admission to long-term care facilities. The beneficial effects of non-drug treatments are poorly studied.

OBJECTIVE: To describe the effects of an Integrated Psychostimulation Program (IPP) in patients with mild-moderate AD treated with acetylcholinesterase inhibitors; and to identify factors related to greater benefit of the IPP.

METHODS: 206 patients (mean age = 75.9 years; MMSE = 19.6) were evaluated before starting the IPP and 3, 6, 9, and 12 months later. Measures included: Mini-Mental State Examination (MMSE), Cognitive Subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog), Rapid Disability Rating Scale (RDRS-2), and Neuropsychiatric Inventory Questionnaire (NPI-Q).

RESULTS: Patients remained cognitively stable (MMSE/ADAS-Cog) for more than 6 months and significantly worsened at 9-month and 12-month follow-ups, without clinically significant functional changes (RDRS-2) or psychiatric symptoms(NPI-Q). The mean annual change on MMSE and ADAS-Cog were 2.06 and 3.56 points, respectively, lower than the annual decline demonstrated previously in similar patients (2.4 and 4.5, respectively). 42.7% of patients maintained or improved global cognitive scores between baseline and 12-month follow-up. The patients who maintained cognitive functions were older than those who did not (77.5 versus 74.7 years).

CONCLUSIONS: The IPP may be an effective treatment to maintain cognition, functionality, and psychiatric symptoms in AD patients pharmacologically treated, and older age seems to increase beneficial effects of IPP.

%B J Alzheimers Dis %V 50 %P 559-66 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757182?dopt=Abstract %R 10.3233/JAD-150455 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Best Linear Unbiased Prediction of Individual Polygenic Susceptibility to Sporadic Vascular Dementia. %A Lee, Chaeyoung %X

Genetic factors of sporadic vascular dementia have been quite limitedly understood. Many underlying polygenes are suspected to contribute to susceptibility to sporadic vascular dementia as a typical complex disease although they have not been identified from genome-wide association studies. This study suggests a stochastic prediction of individual polygenetic susceptibility to sporadic vascular dementia using best linear unbiased prediction in a mixed model framework. The prediction shows a relative degree of individual genetic susceptibility to the disease that reflects its integrative polygenetic factors across the genome. The estimate should take into account heritability and the prevalence of sporadic vascular dementia to cope with the disease. This offers a model for application of a genetic blueprint for a complex disease to personalized preventive medicine.

%B J Alzheimers Dis %V 53 %P 1115-9 %8 2016 May 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258425?dopt=Abstract %R 10.3233/JAD-160391 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Better Objective Sleep Quality in Older Adults with High Subjective Memory Decline. %A Cavuoto, Marina G %A Ong, Ben %A Pike, Kerryn E %A Nicholas, Christian L %A Bei, Bei %A Kinsella, Glynda J %X

BACKGROUND: Sleep disturbance is implicated in memory function across normal aging and neurodegenerative disease. Furthermore, there is mounting evidence to suggest that high levels of subjective memory decline (SMD) may signal very early neurodegenerative changes associated with Alzheimer's disease (AD). This view prompts research examining the relationship between SMD and other risk factors for cognitive decline, including sleep disturbance.

OBJECTIVE: To determine whether objective and subjective indices of sleep predict SMD in older adults.

METHODS: 181 community-based older adults were divided into groups of high and low SMD based on their responses to the Memory Assessment Complaint Questionnaire (MAC-Q). They undertook two weeks of objective sleep monitoring (actigraphy), and completed a subjective sleep quality assessment using the Pittsburgh Sleep Quality Index.

RESULTS: Hierarchical logistic regression indicated that after controlling for demographics and mood, objective sleep quality predicted high SMD group status (ΔNagelkerke R2 = 0.07, χ2 = 9.80 (3), p = 0.020), while subjective sleep quality did not. Contrary to expectation, however, less sleep disruption predicted high SMD.

CONCLUSION: These unexpected results may suggest a non-linear trajectory between sleep and memory decline in aging. The findings are discussed in relation to previous research, which taken together, may indicate compensatory sleep patterns of reduced sleep disruption in people with high levels of SMD. These preliminary findings suggest the utility of including analysis of sleep behavior in further longitudinal research of this at-risk group of older people.

%B J Alzheimers Dis %V 53 %P 943-53 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340849?dopt=Abstract %R 10.3233/JAD-160187 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Biochemical and Radiological Markers of Alzheimer's Disease Progression. %A Dziedzic, Tomasz %A Pera, Joanna %A Klimkowicz-Mrowiec, Aleksandra %A Mroczko, Barbara %A Slowik, Agnieszka %K Alzheimer Disease %K Biomarkers %K Disease Progression %K Humans %K Neuroimaging %K Radionuclide Imaging %X

Alzheimer's disease (AD) is a neurodegenerative, inevitably progressive disease with a rate of cognitive, functional, and behavioral decline that varies highly from patient to patient. Although several clinical predictors of AD progression have been identified, to our mind in clinical practice there is a lack of a reliable biomarker that enables one to stratify the risk of deterioration. Identification of biomarkers that allow the monitoring of AD progression could change the way physicians and caregivers make treatment decisions. This review summarizes the results of studies on potential biochemical and radiological markers related to AD progression.

%B J Alzheimers Dis %V 50 %P 623-44 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757184?dopt=Abstract %R 10.3233/IFS-150578 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Bioenergetic Impairment in Animal and Cellular Models of Alzheimer's Disease: PARP-1 Inhibition Rescues Metabolic Dysfunctions. %A Martire, Sara %A Fuso, Andrea %A Mosca, Luciana %A Forte, Elena %A Correani, Virginia %A Fontana, Mario %A Scarpa, Sigfrido %A Maras, Bruno %A d'Erme, Maria %X

Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer's disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose. In this paper, we demonstrate that a mitochondrial dysfunction occurs in Alzheimer's transgenic mice TgCRND8, in SH-SY5Y treated with amyloid-beta and in 7PA2 cells. Moreover, PARP-1 activation contributes to the functional energetic decline affecting cytochrome oxidase IV protein levels, oxygen consumption rates, and membrane potential, resulting in cellular bioenergetic deficit. We also observed, for the first time, an increase of pyruvate kinase 2 expression, suggesting a modulation of the glycolytic pathway by PARP-1. PARP-1 inhibitors are able to restore both mitochondrial impairment and pyruvate kinase 2 expression. The overall data here presented indicate a pivotal role for this enzyme in the bioenergetic network of neuronal cells and open new perspectives for investigating molecular mechanisms underlying energy charge decline in Alzheimer's disease. In this scenario, PARP-1 inhibitors might represent a novel therapeutic intervention to rescue cellular energetic metabolism.

%B J Alzheimers Dis %V 54 %P 307-24 %8 2016 Aug 10 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567805?dopt=Abstract %R 10.3233/JAD-151040 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Biofunctionalized Silica Nanoparticles: Standards in Amyloid-β Oligomer-Based Diagnosis of Alzheimer's Disease. %A Hülsemann, Maren %A Zafiu, Christian %A Kühbach, Katja %A Lühmann, Nicole %A Herrmann, Yvonne %A Peters, Luriano %A Linnartz, Christina %A Willbold, Johannes %A Kravchenko, Kateryna %A Kulawik, Andreas %A Willbold, Sabine %A Bannach, Oliver %A Willbold, Dieter %X

Amyloid-β (Aβ) oligomers represent a promising biomarker for the early diagnosis of Alzheimer's disease (AD). However, state-of-the-art methods for immunodetection of Aβ oligomers in body fluids show a large variability and lack a reliable and stable standard that enables the reproducible quantitation of Aβ oligomers. At present, the only available standard applied in these assays is based on a random aggregation process of synthetic Aβ and has neither a defined size nor a known number of epitopes. In this report, we generated a highly stable standard in the size range of native Aβ oligomers that exposes a defined number of epitopes. The standard consists of a silica nanoparticle (SiNaP), which is functionalized with Aβ peptides on its surface (Aβ-SiNaP). The different steps of Aβ-SiNaP synthesis were followed by microscopic, spectroscopic and biochemical analyses. To investigate the performance of Aβ-SiNaPs as an appropriate standard in Aβ oligomer immunodetection, Aβ-SiNaPs were diluted in cerebrospinal fluid and quantified down to a concentration of 10 fM in the sFIDA (surface-based fluorescence intensity distribution analysis) assay. This detection limit corresponds to an Aβ concentration of 1.9 ng l-1 and lies in the sensitivity range of currently applied diagnostic tools based on Aβ oligomer quantitation. Thus, we developed a highly stable and well-characterized standard for the application in Aβ oligomer immunodetection assays that finally allows the reproducible quantitation of Aβ oligomers down to single molecule level and provides a fundamental improvement for the worldwide standardization process of diagnostic methods in AD research.

%B J Alzheimers Dis %V 54 %P 79-88 %8 2016 Jul 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472876?dopt=Abstract %R 10.3233/JAD-160253 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Biomarker Exposure-Response Analysis in Mild-To-Moderate Alzheimer's Disease Trials of Bapineuzumab. %A Russu, Alberto %A Samtani, Mahesh N %A Xu, Steven %A Adedokun, Omoniyi J %A Lu, Ming %A Ito, Kaori %A Corrigan, Brian %A Raje, Sangeeta %A Liu, Enchi %A Brashear, H Robert %A Styren, Scot %A Hu, Chuanpu %X

BACKGROUND: Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer's disease (AD) patients.

OBJECTIVE: To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling.

METHODS: Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance imaging. Bapineuzumab or placebo was administered as a 1-hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE*E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers.

RESULTS: Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE*E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected.

CONCLUSIONS: Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated.

%B J Alzheimers Dis %V 53 %P 535-46 %8 2016 May 03 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163805?dopt=Abstract %R 10.3233/JAD-151065 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Biomarkers Differentiating Dementia with Lewy Bodies from Other Dementias: A Meta-Analysis. %A Mishima, Aki %A Nihashi, Takashi %A Ando, Yoshio %A Kawai, Hisashi %A Kato, Takashi %A Ito, Kengo %A Terasawa, Teruhiko %K Biomarkers %K Dementia %K Diagnosis, Differential %K Humans %K Lewy Bodies %K PubMed %K Radionuclide Imaging %K Retrospective Studies %X

BACKGROUND: Several nuclear imaging and cerebrospinal fluid (CSF) biomarkers are under investigation, aimed at facilitating the differential diagnosis of dementias.

OBJECTIVE: To quantitatively synthesize data on test performance in differentiating dementia with Lewy bodies (DLB) from other dementias.

METHODS: We searched PubMed (January 2000- March 2015) for English-language publications that assessed a selected set of five imaging and three CSF biomarkers for this purpose. We meta-analyzed measures of agreement between biomarker results and clinical diagnosis.

RESULTS: Forty-five publications were eligible. The majority of evidence was based on studies that enrolled representative disease populations. For differentiating between DLB and Alzheimer's disease (AD) or other dementias, metaiodobenzylguanidine scintigraphy and dopamine transporter (DAT) single photon emission computed tomography (SPECT) showed, respectively, excellent (summary kappa = 0.85; 95% confidence interval [95% CI], 0.74-0.96) and good (summary kappa = 0.71; 95% CI, 0.43-0.99) agreement. Metaiodobenzylguanidine scintigraphy appeared superior to fluorodeoxyglucose- positron emission tomography (summary kappa = 0.53; 95% CI, 0.36-0.69) and cerebral blood flow SPECT (summary kappa = 0.40; 95% CI, 0.33-0.47). For differentiating DLB from AD, CSF t-tau levels (summary kappa = 0.68; 95% CI, 0.55-0.82) performed comparably to metaiodobenzylguanidine scintigraphy and DAT SPECT. Sparse direct comparative evidence failed to corroborate these indirect comparisons.

CONCLUSION: Metaiodobenzylguanidine scintigraphy and DAT SPECT are highly concordant with clinical diagnosis in differentiating DLB from other dementias. However, given the limitations in the study design, the applicability of these results to real-world differential diagnosis remains unclear. Prospective studies targeting patients with atypical presentations that adopt gold standard tests would reliably estimate the true test performance of these promising biomarkers.

%B J Alzheimers Dis %V 50 %P 161-74 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639967?dopt=Abstract %R 10.3233/JAD-150675 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Blockade of the Interaction of Calcineurin with FOXO in Astrocytes Protects Against Amyloid-β-Induced Neuronal Death. %A Fernandez, Ana M %A Hervas, Ruben %A Dominguez-Fraile, Manuel %A Garrido, Victoria Navarro %A Gomez-Gutierrez, Patricia %A Vega, Miguel %A Vitorica, Javier %A Perez, Juan J %A Torres Aleman, Ignacio %X

Astrocytes actively participate in neuro-inflammatory processes associated to Alzheimer's disease (AD), and other brain pathologies. We recently showed that an astrocyte-specific intracellular signaling pathway involving an interaction of the phosphatase calcineurin with the transcription factor FOXO3 is a major driver in AD-associated pathological inflammation, suggesting a potential new druggable target for this devastating disease. We have now developed decoy molecules to interfere with calcineurin/FOXO3 interactions, and tested them in astrocytes and neuronal co-cultures exposed to amyloid-β (Aβ) toxicity. We observed that interference of calcineurin/FOXO3 interactions exerts a protective action against Aβ-induced neuronal death and favors the production of a set of growth factors that we hypothesize form part of a cytoprotective pathway to resolve inflammation. Furthermore, interference of the Aβ-induced interaction of calcineurin with FOXO3 by decoy compounds significantly decreased amyloid-β protein precursor (AβPP) synthesis, reduced the AβPP amyloidogenic pathway, resulting in lower Aβ levels, and blocked the expression of pro-inflammatory cytokines TNFα and IL-6 in astrocytes. Collectively, these data indicate that interrupting pro-inflammatory calcineurin/FOXO3 interactions in astrocytes triggered by Aβ accumulation in brain may constitute an effective new therapeutic approach in AD. Future studies with intranasal delivery, or brain barrier permeable decoy compounds, are warranted.

%B J Alzheimers Dis %V 52 %P 1471-8 %8 2016 Apr 12 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079728?dopt=Abstract %R 10.3233/JAD-160149 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly. %A Westwood, Sarah %A Leoni, Emanuela %A Hye, Abdul %A Lynham, Steven %A Khondoker, Mizanur R %A Ashton, Nicholas J %A Kiddle, Steven J %A Baird, Alison L %A Sainz-Fuertes, Ricardo %A Leung, Rufina %A Graf, John %A Hehir, Cristina Tan %A Baker, David %A Cereda, Cristina %A Bazenet, Chantal %A Ward, Malcolm %A Thambisetty, Madhav %A Lovestone, Simon %X

Increasingly, clinical trials for Alzheimer's disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p <  0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q <  0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature.

%B J Alzheimers Dis %V 52 %P 561-72 %8 2016 Mar 29 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031486?dopt=Abstract %R 10.3233/JAD-151155 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Blood-Borne Activity-Dependent Neuroprotective Protein (ADNP) is Correlated with Premorbid Intelligence, Clinical Stage, and Alzheimer's Disease Biomarkers. %A Malishkevich, Anna %A Marshall, Gad A %A Schultz, Aaron P %A Sperling, Reisa A %A Aharon-Peretz, Judith %A Gozes, Illana %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Chi-Square Distribution %K Cognitive Dysfunction %K Cohort Studies %K Female %K Homeodomain Proteins %K Humans %K Independent Living %K Intelligence %K Male %K Mental Status Schedule %K Middle Aged %K Nerve Tissue Proteins %K Peptide Fragments %K RNA, Messenger %K tau Proteins %X

Biomarkers for Alzheimer's disease (AD) are vital for disease detection in the clinical setting. Discovered in our laboratory, activity-dependent neuroprotective protein (ADNP) is essential for brain formation and linked to cognitive functions. Here, we revealed that blood borne expression of ADNP and its paralog ADNP2 is correlated with premorbid intelligence, AD pathology, and clinical stage. Age adjustment showed significant associations between: 1) higher premorbid intelligence and greater serum ADNP, and 2) greater cortical amyloid and lower ADNP and ADNP2 mRNAs. Significant increases in ADNP mRNA levels were observed in patients ranging from mild cognitive impairment (MCI) to AD dementia. ADNP2 transcripts showed high correlation with ADNP transcripts, especially in AD dementia lymphocytes. ADNP plasma/serum and lymphocyte mRNA levels discriminated well between cognitively normal elderly, MCI, and AD dementia participants. Measuring ADNP blood-borne levels could bring us a step closer to effectively screening and tracking AD.

%B J Alzheimers Dis %V 50 %P 249-60 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639975?dopt=Abstract %R 10.3233/JAD-150799 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Brain Amyloid-β Plays an Initiating Role in the Pathophysiological Process of the PS1V97L-Tg Mouse Model of Alzheimer's Disease. %A Wang, Wei %A Lu, Lu %A Wu, Qiao-Qi %A Jia, Jian-Ping %X

Amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, and neuroinflammation are major pathophysiological events in Alzheimer's disease (AD). However, the relationships among these processes and which first exerts an effect are unknown. In the present study, we investigated age-dependent behavioral changes and the sequential pathological progression from the brain to the periphery in AD transgenic (PS1V97L-Tg) mice and their wild-type littermates. We discovered that the brain Aβ significantly increased at 6 months old, the increased brain Aβ caused memory dysfunction, and the ability of Aβ to induce tau hyperphosphorylation might be due to oxidative stress and neuroinflammatory reactions. The levels of Aβ42, total tau (t-tau), oxidative stress parameters, and proinflammatory cytokines in plasma can be used to differentiate between PS1V97L-Tg mice and their wild-type littermates at different time points. Collectively, our findings support the hypothesis that Aβ is a trigger among these pathophysiological processions and show that plasma biomarkers can reflect the condition of the AD brain.

%B J Alzheimers Dis %V 52 %P 1089-99 %8 2016 Apr 12 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079718?dopt=Abstract %R 10.3233/JAD-160004 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Brain Atrophy of Secondary REM-Sleep Behavior Disorder in Neurodegenerative Disease. %A Kim, Hee-Jin %A Im, Hyung Kyun %A Kim, Juhan %A Han, Jee-Young %A de Leon, Mony %A Deshpande, Anup %A Moon, Won-Jin %X

BACKGROUND: Rapid eye movement sleep behavior disorder (RBD) may present as an early manifestation of an evolving neurodegenerative disorder with alpha-synucleinopathy.

OBJECTIVE: We investigated that dementia with RBD might show distinctive cortical atrophic patterns.

METHODS: A total of 31 patients with idiopathic Parkinson's disease (IPD), 23 with clinically probable Alzheimer's disease (AD), and 36 healthy controls participated in this study. Patients with AD and IPD were divided into two groups according to results of polysomnography and rated with a validated Korean version of the RBD screening questionnaire (RBDSQ-K), which covers the clinical features of RBD. Voxel-based morphometry was adapted for detection of regional brain atrophy among groups of subjects.

RESULTS: Scores on RBDSQ-K were higher in the IPD group (3.54 ± 2.8) than in any other group (AD, 2.94 ± 2.4; healthy controls, 2.31 ± 1.9). Atrophic changes according to RBDSQ-K scores were characteristically in the posterior part of the brain and brain stem, including the hypothalamus and posterior temporal region including the hippocampus and bilateral occipital lobe. AD patients with RBD showed more specialized atrophic patterns distributed in the posterior and inferior parts of the brain including the bilateral temporal and occipital cortices compared to groups without RBD. The IPD group with RBD showed right temporal cortical atrophic changes.

CONCLUSION: The group of patients with neurodegenerative diseases and RBD showed distinctive brain atrophy patterns, especially in the posterior and inferior cortices. These results suggest that patients diagnosed with clinically probable AD or IPD might have mixed pathologies including α-synucleinopathy.

%B J Alzheimers Dis %V 52 %P 1101-9 %8 2016 Apr 05 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060938?dopt=Abstract %R 10.3233/JAD-151197 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Brain Metabolism Correlates of the Free and Cued Selective Reminding Test in Mild Cognitive Impairment. %A Caffarra, Paolo %A Ghetti, Caterina %A Ruffini, Livia %A Spallazzi, Marco %A Spotti, Annamaria %A Barocco, Federica %A Guzzo, Caterina %A Marchi, Massimo %A Gardini, Simona %K Aged %K Brain %K Cognitive Dysfunction %K Cues %K Female %K Fluorodeoxyglucose F18 %K Humans %K Male %K Memory Disorders %K Memory, Episodic %K Mental Recall %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %X

Free and Cued Selective Reminding Test (FCSRT) measures immediate and delayed episodic memory and cueing sensitivity and is suitable to detect prodromal Alzheimer's disease (AD). The present study aimed at investigating the segregation effect of FCSRT scores on brain metabolism of memory-related structures, usually affected by AD pathology, in the Mild Cognitive Impairment (MCI) stage. A cohort of forty-eight MCI patients underwent FCSRT and 18F-FDG-PET. Multiple regression analysis showed that Immediate Free Recall correlated with brain metabolism in the bilateral anterior cingulate and delayed free recall with the left anterior cingulate and medial frontal gyrus, whereas semantic cueing sensitivity with the left posterior cingulate. FCSRT in MCI is associated with neuro-functional activity of specific regions of memory-related structures connected to hippocampal formation, such as the cingulate cortex, usually damaged in AD.

%B J Alzheimers Dis %V 51 %P 27-31 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836012?dopt=Abstract %R 10.3233/JAD-150418 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Brain Serotonergic and Noradrenergic Deficiencies in Behavioral Variant Frontotemporal Dementia Compared to Early-Onset Alzheimer's Disease. %A Vermeiren, Yannick %A Janssens, Jana %A Aerts, Tony %A Martin, Jean-Jacques %A Sieben, Anne %A Van Dam, Debby %A De Deyn, Peter P %X

Routinely prescribed psychoactive drugs in behavioral variant frontotemporal dementia (FTD) for improvement of (non)cognitive symptoms are primarily based on monoamine replacement or augmentation strategies. These were, however, initially intended to symptomatically treat other degenerative, behavioral, or personality disorders, and thus lack disease specificity. Moreover, current knowledge on brain monoaminergic neurotransmitter deficiencies in this presenile disorder is scarce, particularly with reference to changes in Alzheimer's disease (AD). The latter hence favors neurochemical comparison studies in order to elucidate the monoaminergic underpinnings of FTD compared to early-onset AD, which may contribute to better pharmacotherapy. Therefore, frozen brain samples, i.e., Brodmann area (BA) 6/8/9/10/11/12/22/24/46, amygdala, and hippocampus, of 10 neuropathologically confirmed FTD, AD, and control subjects were analyzed by means of reversed-phase high-performance liquid chromatography. Levels of serotonergic, dopaminergic, and noradrenergic compounds were measured. In nine brain areas, serotonin (5-HT) concentrations were significantly increased in FTD compared to AD patients, while 5-hydroxyindoleacetic acid/5-HT ratios were decreased in eight regions, also compared to controls. Furthermore, in all regions, noradrenaline (NA) levels were significantly higher, and 3-methoxy-4-hydroxyphenylglycol/NA ratios were significantly lower in FTD than in AD and controls. Contrarily, significantly higher dopamine (DA) levels and reduced homovanillic acid/DA ratios were only found in BA12 and BA46. Results indicate that FTD is defined by distinct serotonergic and noradrenergic deficiencies. Additional research regarding the interactions between both monoaminergic networks is required. Similarly, clinical trials investigating the effects of 5-HT1A receptor antagonists or NA-modulating agents, such as α1/2/β1-blockers, seem to have a rationale and should be considered.

%B J Alzheimers Dis %V 53 %P 1079-96 %8 2016 Jun 15 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27314528?dopt=Abstract %R 10.3233/JAD-160320 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Brain-Specific Basal and Novelty-Induced Alternations in PI3K-Akt and MAPK/ERK Signaling in a Middle-Aged AβPP/PS1 Mouse Model of Alzheimer's Disease. %A Guillot, Florence %A Kemppainen, Susanna %A Lavasseur, Gregoire %A Miettinen, Pasi O %A Laroche, Serge %A Tanila, Heikki %A Davis, Sabrina %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Disease Models, Animal %K Gene Expression Regulation %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mitogen-Activated Protein Kinase Kinases %K Mutation %K Oncogene Protein v-akt %K Phosphatidylinositol 3-Kinases %K Presenilin-1 %K Signal Transduction %X

Although it is well established that insulin/IGF and BDNF signaling are dysfunctionally regulated in Alzheimer's disease, there are very few studies documenting changes in major target proteins in different murine models of the disease. We investigated a panel of proteins in the PI3K-Akt and MAPK/ERK cascades in parietal cortex, dentate gyrus and CA1 in 13-month-old AβPP/PS1 transgenic mice to determine whether amyloid pathology is associated with basal dysregulation of these proteins or following exposure to novelty. The most striking effect we found was that there was little common regulation of proteins either by pathology alone or exposure to novelty across the three structures, suggesting dysfunctional mechanisms that occur simultaneously have important structure specificity. CA1 shared certain dysfunctional regulation of proteins in the MAPK/ERK cascade, but shared dysfunctional regulation of the PI3K/Akt cascade with the dentate gyrus. Changes in ERK/CREB in transgenic mice did not result in coordinated dysfunction of the downstream transcription factor, Egr1, as it was overexpressed in a normal manner following exposure to novelty. In the PI3K-Akt cascade, there was a flagrant increase in the levels of proteins associated with inflammation, such as NFκB, and structure specific regulation of proteins associated with autophagy, such as mTOR and FOXO1 and lack of regulation of Beclin-1. Finally, Beclin-1 was increased by novelty in wild-type mice but deficient in transgenic mice. Results are interpreted in terms of structure-specific dysfunctional regulation of signaling mechanisms associated with Alzheimer's disease.

%B J Alzheimers Dis %V 51 %P 1157-73 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923018?dopt=Abstract %R 10.3233/JAD-150926 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Breakdown of the Cerebrovasculature and Blood-Brain Barrier: A Mechanistic Link Between Diabetes Mellitus and Alzheimer's Disease. %A Goldwaser, Eric L %A Acharya, Nimish K %A Sarkar, Abhirup %A Godsey, George %A Nagele, Robert G %X

Alzheimer's disease (AD) and diabetes mellitus (DM) are among the most pervasive and devastating disorders that afflict people throughout the world. Although typically associated with older demographics, recent epidemiologic studies have reported parallel trends in decreasing age of onset and increasing incidence of these conditions. Promising research continues to implicate the cerebrovasculature and blood-brain barrier (BBB) as playing key roles in AD pathoetiology. Similarly, complications accompanying DM, such as diabetic nephropathy/retinopathy, cardiovascular disease, and stroke, have been rooted in vascular compromise. Not surprisingly, DM is now considered a major risk factor for AD. The purpose of this review is to highlight investigations into the role of the cerebrovasculature in the development and progression of AD. We give particular attention to studies on humans and a variety of animal model systems that have demonstrated a link between BBB dysfunction and pathological changes in the brain consistent with aging and AD. Together, these studies suggest that the vascular complications associated with chronic, poorly managed DM can lead to subclinical BBB breakdown that precedes and drives the pathological changes progressing to symptomatic AD, providing a common mechanistic thread connecting these two disorders. Furthermore, this emphasizes the need to focus on the vasculature as a potential therapeutic target with the intent of limiting BBB breakdown involved in disease initiation and progression. In conclusion, AD may be more than just an associated comorbidity of DM, and instead another manifestation of the underlying vascular pathology that is common to both.

%B J Alzheimers Dis %V 54 %P 445-56 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497477?dopt=Abstract %R 10.3233/JAD-160284 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Bridging Integrator 1 (BIN1) Genotypes Mediate Alzheimer's Disease Risk by Altering Neuronal Degeneration. %A Wang, Hui-Fu %A Wan, Yu %A Hao, Xiao-Ke %A Cao, Lei %A Zhu, Xi-Chen %A Jiang, Teng %A Tan, Meng-Shan %A Tan, Lin %A Zhang, Dao-Qiang %A Tan, Lan %A Yu, Jin-Tai %K Adaptor Proteins, Signal Transducing %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Brain %K Databases, Factual %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Genetic Predisposition to Disease %K Glucose %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Nerve Degeneration %K Nuclear Proteins %K Polymorphism, Single Nucleotide %K Positron-Emission Tomography %K Risk %K tau Proteins %K Tumor Suppressor Proteins %X

BACKGROUND: Bridging integrator 1 (BIN1) has been identified as one of the most associated loci for Alzheimer's disease (AD), and recently was reported to modulate tau pathology to mediate AD in vitro. However, the effects of BIN1 on the AD related biomarkers in AD continuum were not specifically assessed.

OBJECTIVE: We explored the effects of BIN1 loci on AD specific biomarkers (CSF proteins, brain structures, glucose and amyloid-β (Aβ) metabolisms) to investigate the role BIN1 in AD pathogenesis.

METHODS: We calculated the associations of BIN1 loci with these markers at baseline and follow-up in multiple linear models in 812 ADNI subjects.

RESULTS: BIN1 loci were significantly associated with the levels of T-tau (rs744373: pc = 0.047, rs13031703: pc = 0.042) and P-tau (rs744373: pc = 0.044, rs13031703: pc = 0.019), but not with Aβ in CSF test. BIN1 genotypes were strongly related to atrophy of hippocampus (rs7561528: pc = 0.011), CA1 (rs1469980: pc = 0.029) and parahippocampus (rs72838284, pc = 0.017) on MRI, and to glucose metabolism on FDG-PET, but not to Aβ deposition on AV45-PET imaging. Furthermore, haplotype and subgroup analysis confirmed these significant findings. In addition, the loci associated with these markers were also identified to influence the risk for AD in the meta-analysis of 74 046 European individuals.

CONCLUSION: This study supported that BIN1 contributes to the risk of AD by altering neural degeneration (abnormal tau, brain atrophy and glucose metabolism) but not Aβ pathology.

%B J Alzheimers Dis %V 52 %P 179-90 %8 2016 03 15 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003210?dopt=Abstract %R 10.3233/JAD-150972 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Brief Computerized Paired Associate Test for the Detection of Mild Cognitive Impairment in Community-Dwelling Older Adults. %A Curiel, Rosie E %A Crocco, Elizabeth %A Rosado, Marian %A Duara, Ranjan %A Greig, Maria T %A Raffo, Arlene %A Loewenstein, David A %X

BACKGROUND: Semantic memory interference has been found to be a predictive cognitive marker of incipient AD. This is relevant given that developing assessment paradigms to identify subtle cognitive and functional deficits is a priority in preclinical Alzheimer's disease research.

OBJECTIVE: To examine the utility of a novel computerized paired associate test in distinguishing between mild cognitive impairment (MCI) and cognitively normal (CN) groups of older adults residing in the community.

METHODS: Participants that were CN (n = 64) or MCI (n = 34) were administered the Miami Test of Semantic Interference and Learning (MITSI-L). This novel instrument is a brief, computerized paired associate test that measured the strength of memory binding of semantically related word pairs and introduced a proactive semantic interference condition which required participants to make different associations between semantically similar targets. A series of ANOVAs explored differences on MITSI-L performance. Logistic regression and receiver operator curves (ROC) analyses were employed to further determine discriminative validity.

RESULTS: MCI participants had lower scores on all indices relative to CN elders. A composite of two subscores correctly classified 85.3% of MCI and 84.4% of CN participants. Area under the ROC was higher relative to the MMSE, immediate memory for passages, and several subtests of a sensitive memory measure, the LASSI-L.

CONCLUSIONS: The MITSI-L is a computerized test that can successfully differentiate MCI from CN participants. Area under the ROC curve exceeded that of global mental status and other memory measures. The effectiveness of the MITSI-L in detecting MCI, and its brief administration and portability render it worthy of further research.

%B J Alzheimers Dis %V 54 %P 793-9 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567839?dopt=Abstract %R 10.3233/JAD-160370 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Butyrylcholinesterase K and Apolipoprotein E-ɛ4 Reduce the Age of Onset of Alzheimer's Disease, Accelerate Cognitive Decline, and Modulate Donepezil Response in Mild Cognitively Impaired Subjects. %A De Beaumont, Louis %A Pelleieux, Sandra %A Lamarre-Théroux, Louise %A Dea, Doris %A Poirier, Judes %X

BACKGROUND: Genetic heterogeneity in amnestic mild cognitively impaired (aMCI) subjects could lead to variations in progression rates and response to cholinomimetic agents. Together with the apolipoprotein E4 (APOE-ɛ4) gene, butyrylcholinesterase (BCHE) has become recently one of the few Alzheimer's disease (AD) susceptibility genes with distinct pharmacogenomic properties.

OBJECTIVE: To validate candidate genes (APOE/BCHE) which display associations with age of onset of AD and donepezil efficacy in aMCI subjects.

METHODS: Using the Petersen et al. (2005) study on vitamin E and donepezil efficacy in aMCI, we contrasted the effects of BCHE and APOE variants on donepezil drug response using the Alzheimer's Disease Assessment Score-Cognition (ADAS-Cog) scale. Independently, we assessed the effects of APOE/BCHE genotypes on age of onset and cortical choline acetyltransferase activity in autopsy-confirmed AD and age-matched control subjects.

RESULTS: Statistical analyses revealed a significant earlier age of onset in AD for APOE-ɛ4, BCHE-K*, and APOE-ɛ4/BCHE-K* carriers. Among the carriers of APOE-ɛ4 and BCHE-K*, the benefit of donepezil was evident at the end of the three-year follow-up. The responder's pharmacogenomic profile is consistent with reduced brain cholinergic activity measured in APOE-ɛ4 and BCHE-K* positive subjects.

CONCLUSIONS: APOE-ɛ4 and BCHE-K* positive subjects display an earlier age of onset of AD, an accelerated cognitive decline and a greater cognitive benefits to donepezil therapy. These results clearly emphasize the necessity of monitoring potential pharmacogenomic effects in this population of subjects, and suggest enrichment strategies for secondary prevention trials involving prodromal AD subjects.

%B J Alzheimers Dis %V 54 %P 913-922 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567841?dopt=Abstract %R 10.3233/JAD-160373 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cannabinoid Receptor 2 Participates in Amyloid-β Processing in a Mouse Model of Alzheimer's Disease but Plays a Minor Role in the Therapeutic Properties of a Cannabis-Based Medicine. %A Aso, Ester %A Andrés-Benito, Pol %A Carmona, Margarita %A Maldonado, Rafael %A Ferrer, Isidre %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Cannabidiol %K Cognition %K Disease Models, Animal %K Dronabinol %K Humans %K Male %K Medical Marijuana %K Memory %K Mice, Inbred C57BL %K Mice, Transgenic %K Nootropic Agents %K Presenilin-1 %K Random Allocation %K Receptor, Cannabinoid, CB2 %K tau Proteins %K Treatment Outcome %X

The endogenous cannabinoid system represents a promising therapeutic target to modify neurodegenerative pathways linked to Alzheimer's disease (AD). The aim of the present study was to evaluate the specific contribution of CB2 receptor to the progression of AD-like pathology and its role in the positive effect of a cannabis-based medicine (1:1 combination of Δ9-tetrahidrocannabinol and cannabidiol) previously demonstrated to be beneficial in the AβPP/PS1 transgenic model of the disease. A new mouse strain was generated by crossing AβPP/PS1 transgenic mice with CB2 knockout mice. Results show that lack of CB2 exacerbates cortical Aβ deposition and increases the levels of soluble Aβ40. However, CB2 receptor deficiency does not affect the viability of AβPP/PS1 mice, does not accelerate their memory impairment, does not modify tau hyperphosphorylation in dystrophic neurites associated to Aβ plaques, and does not attenuate the positive cognitive effect induced by the cannabis-based medicine in these animals. These findings suggest a minor role for the CB2 receptor in the therapeutic effect of the cannabis-based medicine in AβPP/PS1 mice, but also constitute evidence of a link between CB2 receptor and Aβ processing.

%B J Alzheimers Dis %V 51 %P 489-500 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890764?dopt=Abstract %R 10.3233/JAD-150913 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Capillary amyloid-β protein deposition in a population-based study (Vantaa 85+). %A Mäkelä, Mira %A Paetau, Anders %A Polvikoski, Tuomo %A Myllykangas, Liisa %A Tanskanen, Maarit %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Autopsy %K Capillaries %K Cerebral Amyloid Angiopathy %K Female %K Finland %K Genotype %K Humans %K Immunohistochemistry %K Logistic Models %K Male %K Multivariate Analysis %K Occipital Lobe %K Prospective Studies %K Severity of Illness Index %X

BACKGROUND: Capillary amyloid-β (capAβ) deposition in the cerebral cortex is the neuropathological feature providing the basis for categorizing cerebral amyloid angiopathy (CAA) into two distinct types, CAA-Type1 with capAβ and CAA-Type2 without capAβ.

OBJECTIVE: We investigated the neuropathological and clinical characteristics of capAβ deposition in a prospective population-based study.

METHODS: Vantaa 85+ includes 601 individuals aged ≥85 years, of which 300 were studied clinically and neuropathologically. 278 subjects were analyzed for the apolipoprotein E (APOE) genotype. The diagnosis of capAβ was determined using immunohistochemistry against Aβ, and of CAA using Congo red confirmed by Aβ immunohistochemistry, both analyzed in six brain areas. The severity of capAβ was graded semi-quantitatively, and the severity of CAA was based on the percentage of affected vessels. Alzheimer's disease (AD)-type neuropathology (CERAD score and Braak stage) was analyzed using standard methods.

RESULTS: CAA-Type1 was present in 86/300, CAA-Type2 in 135/300, and 79/300 had no CAA. CapAβ was most frequent in the occipital lobe (79/86). CAA-Type1 was associated with the severity of CAA (p <  0.001), dementia (p <  0.001), severe AD-type neuropathology (p-value 0.09 for CERAD C and 0.017 for Braak stages V-VI), and APOE ɛ4 allele carrier status (p <  0.001).

CONCLUSIONS: This population-based study confirmed the presence of distinct CAA-Type1 and its association with the severity of CAA, severe AD-type neuropathology, and the APOE ɛ4 carrier status. Both the severity and localization of the deposition seemed to determine the clinical significance of capAβ.

%B J Alzheimers Dis %V 49 %P 149-57 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444758?dopt=Abstract %R 10.3233/JAD-150241 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebral Amyloid Angiopathy (CAA)-Related Inflammation: Comparison of Inflammatory CAA and Amyloid-β-Related Angiitis. %A Chu, Shuguang %A Xu, Feijia %A Su, Ya %A Chen, Hong %A Cheng, Xin %K Apolipoproteins E %K Cerebral Amyloid Angiopathy %K Headache %K Humans %K Inflammation %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Seizures %K Vasculitis, Central Nervous System %X

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a relatively rare syndrome of reversible encephalopathy and could be divided into two subtypes of inflammatory CAA (ICAA) and amyloid-β-related angiitis (ABRA) according to histopathology. We present a case of pathologically proved ABRA with partial seizures and headache, and a focal lesion in the right temporal lobes on magnetic resonance imaging. Summarized from previous 139 ABRA and ICAA cases, ABRA is preferred when the lesion is enhanced on MRI and requires combination drug therapy, while ICAA is highly suspected with ApoE genotype of ɛ4/ɛ4. More clinical markers for diagnosis of CAA-ri warrant further researches.

%B J Alzheimers Dis %V 51 %P 525-32 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890776?dopt=Abstract %R 10.3233/JAD-151036 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebral Arterial Occlusion Did Not Promote the Prevalence of Cerebral Amyloid Angiopathy. %A Honda, Kazuhiro %X

BACKGROUND: An impairment of amyloid-β (Aβ) clearance has been suggested in Alzheimer's disease. Perivascular drainage along cerebrovascular vessels is considered an important amyloid clearance pathway.

OBJECTIVE: This study examined the effect of reduced arterial pulsation that could cause an impairment in cerebral amyloid drainage on the prevalence of cortical microbleeds (CMBs), a surrogate marker for cerebral amyloid angiopathy (CAA).

METHODS: Patients who lost depiction of either side of the carotid artery or the middle cerebral artery on magnetic resonance angiography were studied. Those who showed acute cerebral infarction or a previous cortical cerebral infarction were excluded. The number of CMBs was counted on the occluded and non-occluded sides of the brain in each subject. The number of subjects who showed more CMBs on the occluded side of the brain was compared with the number of subjects who showed more CMBs on the non-occluded side of the brain.

RESULTS: Twenty-eight patients were studied. The extent of lacunar infarction and white matter lesions was not different, irrespective of the occluded vessels or the distribution of CMBs. The prevalence of CMBs was not different between the occluded and non-occluded sides of the brain.

CONCLUSION: In this cross-sectional study, reduction of arterial pulsation was not associated with a higher prevalence of CAA. Therefore, reduced arterial pulsation alone may not be enough to promote CAA.

%B J Alzheimers Dis %V 54 %P 269-74 %8 2016 Aug 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497483?dopt=Abstract %R 10.3233/JAD-160499 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebral Glucose Metabolism is Associated with Verbal but not Visual Memory Performance in Community-Dwelling Older Adults. %A Gardener, Samantha L %A Sohrabi, Hamid R %A Shen, Kai-Kai %A Rainey-Smith, Stephanie R %A Weinborn, Michael %A Bates, Kristyn A %A Shah, Tejal %A Foster, Jonathan K %A Lenzo, Nat %A Salvado, Olivier %A Laske, Christoph %A Laws, Simon M %A Taddei, Kevin %A Verdile, Giuseppe %A Martins, Ralph N %X

Increasing evidence suggests that Alzheimer's disease (AD) sufferers show region-specific reductions in cerebral glucose metabolism, as measured by [18F]-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET). We investigated preclinical disease stage by cross-sectionally examining the association between global cognition, verbal and visual memory, and 18F-FDG PET standardized uptake value ratio (SUVR) in 43 healthy control individuals, subsequently focusing on differences between subjective memory complainers and non-memory complainers. The 18F-FDG PET regions of interest investigated include the hippocampus, amygdala, posterior cingulate, superior parietal, entorhinal cortices, frontal cortex, temporal cortex, and inferior parietal region. In the cohort as a whole, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in both the left hippocampus and right amygdala. There were no associations observed between global cognition, delayed recall in logical memory, or visual reproduction and 18F-FDG PET SUVR. Following stratification of the cohort into subjective memory complainers and non-complainers, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in the right amygdala in those with subjective memory complaints. There were no significant associations observed in non-memory complainers between 18F-FDG PET SUVR in regions of interest and cognitive performance. We observed subjective memory complaint-specific associations between 18F-FDG PET SUVR and immediate verbal memory performance in our cohort, however found no associations between delayed recall of verbal memory performance or visual memory performance. It is here argued that the neural mechanisms underlying verbal and visual memory performance may in fact differ in their pathways, and the characteristic reduction of 18F-FDG PET SUVR observed in this and previous studies likely reflects the pathophysiological changes in specific brain regions that occur in preclinical AD.

%B J Alzheimers Dis %V 52 %P 661-72 %8 2016 Mar 31 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031482?dopt=Abstract %R 10.3233/JAD-151084 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebral Microbleeds and Cerebrovascular Reactivity in the General Population: The EDAN Study. %A Akoudad, Saloua %A Gurol, M Edip %A Fotiadis, Panagiotis %A Koudstaal, Peter J %A Hofman, Albert %A Ikram, M Arfan %A Greenberg, Steven M %A Vernooij, Meike W %X

BACKGROUND: In patients with symptomatic cerebral amyloid angiopathy (CAA), cerebrovascular reactivity to visual stimuli is reduced. Lobar microbleeds are a diagnostic hallmark of CAA, but are also highly prevalent in asymptomatic individuals. Recent data suggest that the latter group might have CAA.

OBJECTIVE: We investigated whether cerebrovascular reactivity is impaired in asymptomatic individuals with lobar microbleeds.

METHODS: From the population-based Rotterdam Study, we invited 35 participants with lobar microbleeds and 15 age-matched controls (all≥55 years) for functional MRI (fMRI) as part of the Early Detection of Angiopathy Network (EDAN) Study. Cerebrovascular reactivity parameters (i.e., amplitude and time to peak responses) were assessed in response to visual stimulation using fMRI. Student's t-test and linear regression were used to compare fMRI parameters in participants with and without microbleeds.

RESULTS: Amplitude and time to peak responses did not differ between participants with and without microbleeds (respectively, p = 0.179 and p = 0.555). Participants with microbleeds had slightly higher amplitude responses compared to participants without microbleeds. After excluding individuals with mixed microbleeds (i.e., lobar and non-lobar microbleeds), we found no significant difference in cerebrovascular reactivity for persons with a single microbleed or multiple microbleeds compared to persons without microbleeds.

CONCLUSIONS: In the general population, lobar microbleeds may not relate to impaired cerebrovascular reactivity. In asymptomatic individuals, lobar microbleeds may either reflect less advanced CAA pathology insufficient to cause functional vascular impairment, or reflect vascular pathology other than CAA.

%B J Alzheimers Dis %V 53 %P 497-503 %8 2016 May 04 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163807?dopt=Abstract %R 10.3233/JAD-151130 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebral Small Vessel Disease and Motoric Cognitive Risk Syndrome: Results from the Kerala-Einstein Study. %A Wang, Nan %A Allali, Gilles %A Kesavadas, Chandrasekharan %A Noone, Mohan L %A Pradeep, Vayyattu G %A Blumen, Helena M %A Verghese, Joe %K Aged %K Brain %K Cerebral Small Vessel Diseases %K Cognition Disorders %K Female %K Humans %K Image Processing, Computer-Assisted %K India %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Risk Factors %K Stroke, Lacunar %K White Matter %X

BACKGROUND: The contribution of cerebral small vessel disease to cognitive decline, especially in non-Caucasian populations, is not well established.

OBJECTIVE: We examined the relationship between cerebral small vessel disease and motoric cognitive risk syndrome (MCR), a recently described pre-dementia syndrome, in Indian seniors.

METHODS: 139 participants (mean age 66.6 ± 5.4 y, 33.1% female) participating in the Kerala-Einstein study in Southern India were examined in a cross-sectional study. The presence of cerebral small vessel disease (lacunar infarcts and cerebral microbleeds (CMB)) and white matter hyperintensities on MRI was ascertained by raters blinded to clinical information. MCR was defined by the presence of cognitive complaints and slow gait in older adults without dementia or mobility disability.

RESULTS: Thirty-eight (27.3%) participants met MCR criteria. The overall prevalence of lacunar infarcts and CMB was 49.6% and 9.4% , respectively. Lacunar infarcts in the frontal lobe, but no other brain regions, were associated with MCR even after adjusting for vascular risk factors and presence of white matter hyperintensities (adjusted Odds Ratio (aOR): 4.67, 95% CI: 1.69-12.94). Frontal lacunar infarcts were associated with slow gait (aOR: 3.98, 95% CI: 1.46-10.79) and poor performance on memory test (β: -1.24, 95% CI: -2.42 to -0.05), but not with cognitive complaints or non-memory tests. No association of CMB was found with MCR, individual MCR criterion or cognitive tests.

CONCLUSIONS: Frontal lacunar infarcts are associated with MCR in Indian seniors, perhaps, by contributing to slow gait and poor memory function.

%B J Alzheimers Dis %V 50 %P 699-707 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757037?dopt=Abstract %R 10.3233/JAD-150523 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebral White Matter Changes on Therapeutic Response to Rivastigmine in Alzheimer's Disease. %A Ho, Bo-Lin %A Kao, Yi-Hui %A Chou, Mei-Chuan %A Yang, Yuan-Han %X

BACKGROUND: Rivastigmine has been approved in the treatment of Alzheimer's disease (AD) patients as it can inhibit acetyl- and butyryl-cholinesterase and provide neuroprotective effects involving the synapses. White matter changes (WMCs) are frequently observed in AD, and clinical-pathological correlations imply their possible impacts on cognitive function by interference with cortical and subcortical neuronal pathways.

OBJECTIVE: To evaluate the therapeutic effects of rivastigmine in AD patients with cerebral WMCs.

METHODS: Clinically diagnosed AD patients from Kaohsiung Municipal Ta-Tung hospital were recruited together with their cranial magnetic resonance imaging and a series of annual psychometric tests, including Mini-Mental State Examination (MMSE) and sum of boxes of clinical dementia rating scale (CDR-SB). WMCs were rated through the modified Fazekas scale for the periventricular and deep WMCs.

RESULTS: In total, 87 AD patients treated with rivastigmine were enrolled. Patients at severe stage of WMCs, compared to mild stage ones, had significant improvement evaluated by MMSE (periventricular WMCs, p = 0.025; deep WMCs, p = 0.030), but not CDR-SB. Compared to the worsening group, the clinically improving group had a significant higher ratio of pre-existing hypertension in terms of cognitive performance [p = 0.016, odds ratio (OR) = 3.48, 95% CI = 1.25-10.34], while having younger age (p = 0.043, OR = 0.11, 95% CI = 0.01-1.12) in terms of global status.

CONCLUSION: Rivastigmine may provide better benefits in cognitive function, but not global status, for AD patients with more advanced WMCs. The detailed mechanisms still have to be determined in future studies.

%B J Alzheimers Dis %V 54 %P 351-7 %8 2016 Aug 10 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567838?dopt=Abstract %R 10.3233/JAD-160364 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Alzheimer's Disease Biomarkers Across the Spectrum of Lewy Body Diseases: Results from a Large Multicenter Cohort. %A van Steenoven, Inger %A Aarsland, Dag %A Weintraub, Daniel %A Londos, Elisabet %A Blanc, Frédéric %A van der Flier, Wiesje M %A Teunissen, Charlotte E %A Mollenhauer, Brit %A Fladby, Tormod %A Kramberger, Milica G %A Bonanni, Laura %A Lemstra, Afina W %X

BACKGROUND: Concomitant Alzheimer's disease (AD) pathology is observed in Lewy body diseases (LBD), but the clinical impact is unknown. Only a few biomarker studies in LBD exist and have included small cohorts from single centers.

OBJECTIVE: We aimed to evaluate the prevalence of abnormal cerebrospinal fluid (CSF) AD biomarkers across the spectrum of LBD in a large multicenter cohort and to assess whether an AD biomarker profile was associated with demographic and clinical differences in dementia with Lewy bodies (DLB).

METHODS: We included 375 DLB patients, 164 Parkinson's disease (PD) patients without dementia, and 55 PD patients with dementia (PDD) from 10 centers. CSF amyloid-beta42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) values were dichotomized as abnormal or normal according to locally available cut-off values. A CSF AD profile was defined as abnormal Aβ42 combined with abnormal t-tau and/or p-tau.

RESULTS: A substantial proportion of DLB patients had abnormal values for CSF Aβ42, t-tau, and p-tau, while abnormal values were uncommon in PD without dementia. Patients with PDD had values in between. A CSF AD profile was observed in 25% of DLB patients, compared with only 9% of PDD and 3% of PD without dementia. Within DLB, patients with a CSF AD profile were older, more often female, performed worse on the Mini-Mental State Examination, and had shorter disease duration compared with patients with normal CSF.

CONCLUSION: A CSF AD profile is more common in DLB compared with PDD and PD, and is associated with more severe cognitive impairment in DLB.

%B J Alzheimers Dis %V 54 %P 287-95 %8 2016 Aug 18 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567832?dopt=Abstract %R 10.3233/JAD-160322 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Cerebral Amyloid Angiopathy-Related Inflammation. %A Renard, Dimitri %A Wacongne, Anne %A Ayrignac, Xavier %A Charif, Mahmoud %A Fourcade, Genevieve %A Azakri, Souhayla %A Le Floch, Anne %A Bouly, Stephane %A Marelli, Cecilia %A Arquizan, Caroline %A Hirtz, Christophe %A Gabelle, Audrey %A Thouvenot, Eric %A Lehmann, Sylvain %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cerebral Amyloid Angiopathy %K Female %K Humans %K Inflammation %K Male %K Middle Aged %K Retrospective Studies %K tau Proteins %X

BACKGROUND: Decreased cerebrospinal fluid (CSF) amyloid-β 1-40 (Aβ40) and amyloid-β 1-42 (Aβ42) and increased total and phosphorylated tau (t-tau, p-tau) concentrations have been described in cerebral amyloid angiopathy (CAA).

OBJECTIVE: Our aim was to analyze these biomarkers in patients with CAA-related inflammation (CAA-I).

METHODS: We prospectively recruited nine patients with acute phase CAA-I fulfilling Chung criteria. CSF was analyzed for t-tau, p-tau, Aβ42, and Aβ40. Data were compared to controls (n = 14), patients with Alzheimer's disease (AD, n = 42), CAA (n = 10), and primary angiitis of the central nervous system (PACNS, n = 3).

RESULTS: For the CAA-I group, statistically significant differences were: lower Aβ42 (p = 0.00053) compared to the control group; lower t-tau (p = 0.018), p-tau (p <  0.001), and Aβ40 (p <  0.001) compared to AD; lower Aβ42 (p = 0.027) compared to CAA; lower Aβ42 (p = 0.012) compared to PACNS. Nearly significantly lower Aβ40 (p = 0.051) and higher t-tau (p = 0.051) were seen in CAA-I compared to controls.

CONCLUSION: CSF biomarkers profile similar to that of CAA was observed in CAA-I (with even lower levels of Aβ42 compared to CAA). Based on our findings, high p-tau seems more specific for AD, whereas low Aβ42 differentiates CAA-I from CAA, PACNS, and controls, and low Aβ40 differentiates CAA-I from AD.

%B J Alzheimers Dis %V 50 %P 759-64 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757185?dopt=Abstract %R 10.3233/JAD-150621 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Isolated Supratentorial Cortical Superficial Siderosis. %A Renard, Dimitri %A Gabelle, Audrey %A Hirtz, Christophe %A Demattei, Christophe %A Thouvenot, Eric %A Lehmann, Sylvain %X

We evaluated cerebrospinal fluid amyloid-β 1-40 (Aβ40), amyloid-β 1-42 (Aβ42), total and phosphorylated-tau (t-tau and p-tau) in patients with symptomatic isolated cortical supratentorial superficial siderosis (SS), by prospectively recruiting ten patients with SS in the absence of pre-existing cognitive dysfunction, and comparing biomarkers with lobar hematoma cerebral amyloid angiopathy patients (LH-CAA, n = 13), Alzheimer's disease patients (AD, n = 42), and controls (n = 16). Compared to controls, SS patients showed statistically significant higher t-tau (p = 0.019) and lower Aβ42 (p = 0.0084). Compared to other groups, SS showed statistically significant lower t-tau, p-tau, and Aβ40 compared to AD (p = 0.0063, p = 0.0004, and p = 0022, respectively), and higher p-tau compared to LH-CAA (p = 0.012).

%B J Alzheimers Dis %V 54 %P 1291-1295 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567848?dopt=Abstract %R 10.3233/JAD-160400 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Anti-Amyloid-β Autoantibodies and Amyloid PET in Cerebral Amyloid Angiopathy-Related Inflammation. %A Carmona-Iragui, María %A Fernández-Arcos, Ana %A Alcolea, Daniel %A Piazza, Fabrizio %A Morenas-Rodriguez, Estrella %A Antón-Aguirre, Sofía %A Sala, Isabel %A Clarimón, Jordi %A Dols-Icardo, Oriol %A Camacho, Valle %A Sampedro, Frederic %A Munuera, Josep %A Nuñez-Marin, Fidel %A Lleo, Alberto %A Fortea, Juan %A Gómez-Ansón, Beatriz %A Blesa, Rafael %K Aged %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoproteins E %K Autoantibodies %K Cerebral Amyloid Angiopathy %K Ethylene Glycols %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Meningoencephalitis %K Peptide Fragments %K Positron-Emission Tomography %K Statistics, Nonparametric %K tau Proteins %X

We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) treated with corticosteroids. Patients presented with focal symptomatology and cognitive impairment. MRI revealed cortical microbleeds and asymmetrical hyperintense white matter lesions (WML). Cerebrospinal fluid (CSF) biomarker analyses showed increased anti-Aβ autoantibodies, t-Tau, and p-Tau and decreased Aβ40 and Aβ42. After treatment, focal symptomatology disappeared, and WML and anti-Aβ autoantibodies decreased. The APOEɛ4 allele was overrepresented. Florbetapir-PET showed cortical deposition with lower retention in swollen areas. In the case of suspected CAA-ri, both CSF anti-Aβ autoantibodies levels and Florbetapir-PET could provide highly useful data to guide the correct diagnosis.

%B J Alzheimers Dis %V 50 %P 1-7 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639966?dopt=Abstract %R 10.3233/JAD-150614 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Biomarkers and Reserve Variables as Predictors of Future "Non-Cognitive" Outcomes of Alzheimer's Disease. %A Ingber, Adam P %A Hassenstab, Jason %A Fagan, Anne M %A Benzinger, Tammie L S %A Grant, Elizabeth A %A Holtzman, David M %A Morris, John C %A Roe, Catherine M %X

BACKGROUND: The influence of reserve variables and Alzheimer's disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on "non-cognitive" outcomes, including functional abilities and mood.

OBJECTIVE: We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior.

METHODS: Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal at baseline (Clinical Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants.

RESULTS: Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers.

CONCLUSIONS: The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD.

%B J Alzheimers Dis %V 52 %P 1055-64 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104893?dopt=Abstract %R 10.3233/JAD-150478 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Biomarkers in Highly Exposed PM2.5 Urbanites: The Risk of Alzheimer's and Parkinson's Diseases in Young Mexico City Residents. %A Calderón-Garcidueñas, Lilian %A Avila-Ramírez, José %A Calderón-Garcidueñas, Ana %A González-Heredia, Tonatiuh %A Acuña-Ayala, Hilda %A Chao, Chih-Kai %A Thompson, Charles %A Ruiz-Ramos, Rubén %A Cortés-González, Victor %A Martínez-Martínez, Luz %A García-Pérez, Mario Alberto %A Reis, Jacques %A Mukherjee, Partha S %A Torres-Jardón, Ricardo %A Lachmann, Ingolf %X

Exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with Alzheimer's disease (AD) risk, while Mn toxicity induces parkinsonism. Mexico City Metropolitan Area (MCMA) children have pre- and postnatal sustained and high exposures to PM2.5, O3, polycyclic aromatic hydrocarbons, and metals. Young MCMA residents exhibit frontal tau hyperphosphorylation and amyloid-β (Aβ)1 - 42 diffuse plaques, and aggregated and hyperphosphorylated α-synuclein in olfactory nerves and key brainstem nuclei. We measured total prion protein (TPrP), total tau (T-tau), tau phosphorylated at threonine 181 (P-Tau), Aβ1-42, α-synuclein (t-α-syn and d-α-synuclein), BDNF, insulin, leptin, and/or inflammatory mediators, in 129 normal CSF samples from MCMA and clean air controls. Aβ1-42 and BDNF concentrations were significantly lower in MCMA children versus controls (p = 0.005 and 0.02, respectively). TPrP increased with cumulative PM2.5 up to 5 μg/m3 and then decreased, regardless of cumulative value or age (R2 = 0.56). TPrP strongly correlated with T-Tau and P-Tau, while d-α-synuclein showed a significant correlation with TNFα, IL10, and IL6 in MCMA children. Total synuclein showed an increment in childhood years related to cumulated PM2.5, followed by a decrease after age 12 years (R2 = 0.47), while d-α-synuclein exhibited a tendency to increase with cumulated PM2.5 (R2 = 0.30). CSF Aβ1-42, BDNF, α-synuclein, and TPrP changes are evolving in young MCMA urbanites historically showing underperformance in cognitive processes, odor identification deficits, downregulation of frontal cellular PrP, and neuropathological AD and PD hallmarks. Neuroprotection of young MCMA residents ought to be a public health priority.

%B J Alzheimers Dis %V 54 %P 597-613 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567860?dopt=Abstract %R 10.3233/JAD-160472 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Fatty Acid-Binding Protein 3 is Related to Dementia Development in a Population-Based Sample of Older Adult Women Followed for 8 Years. %A Bjerke, Maria %A Kern, Silke %A Blennow, Kaj %A Zetterberg, Henrik %A Waern, Margda %A Börjesson-Hanson, Anne %A Östling, Svante %A Kern, Jürgen %A Skoog, Ingmar %K Aged %K Aged, 80 and over %K Albumins %K Amyloid beta-Peptides %K Community Health Planning %K Dementia %K Fatty Acid-Binding Proteins %K Female %K Humans %K Longitudinal Studies %K Peptide Fragments %K Sweden %K tau Proteins %X

BACKGROUND: Increased fatty acid-binding protein 3 (FABP-3) levels have been reported in neurodegenerative diseases, including Alzheimer's disease (AD). Cerebrospinal fluid (CSF) FABP-3 has therefore been proposed as a putative marker for dementia. Population-based studies examining whether CSF FABP-3 predicts later development of dementia are lacking.

OBJECTIVE: The aim of this study was to examine CSF levels of FABP-3 in relation to later development of dementia in elderly women and in relation to Aβ42, T-tau, P-tau181, and CSF: serum albumin ratio.

METHODS: 86 non-demented women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-93. CSF-FABP-3, Aβ42, T-tau, P-tau181, and the CSF: serum albumin ratio were measured at baseline. Participants were examined with a neuropsychiatric exam at baseline and at follow-up in 2000. Dementia was diagnosed in accordance with DSM-III-R criteria.

RESULTS: Between 1992 and 2000, 8 women developed dementia (4 AD, 3 vascular dementia, 1 mixed vascular dementia and AD). Higher levels of CSF-FABP-3 at baseline were related to development of dementia (OR 1.36 CI [1.05-1.76] p = 0.022) and the subtype AD (OR 1.38 CI [1.06-1.82), p = 0.019) during follow-up. FABP-3 correlated with CSF T-tau (r = 0.88, p <  0.001), P-tau181 (r = 0.619, p <  0.001), and CSF:serum albumin ratio (r = 0.233, p = 0.031), but not with Aβ42 (r = -0.08, p = 0.444)CONCLUSION:CSF FABP-3 may be an early marker for later development of dementia, probably related to neuronal degeneration, but independent of Aβ metabolism.

%B J Alzheimers Dis %V 49 %P 733-41 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484922?dopt=Abstract %R 10.3233/JAD-150525 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Markers of Alzheimer's Disease Pathology and Microglial Activation are Associated with Altered White Matter Microstructure in Asymptomatic Adults at Risk for Alzheimer's Disease. %A Melah, Kelsey E %A Lu, Sharon Yuan-Fu %A Hoscheidt, Siobhan M %A Alexander, Andrew L %A Adluru, Nagesh %A Destiche, Daniel J %A Carlsson, Cynthia M %A Zetterberg, Henrik %A Blennow, Kaj %A Okonkwo, Ozioma C %A Gleason, Carey E %A Dowling, N Maritza %A Bratzke, Lisa C %A Rowley, Howard A %A Sager, Mark A %A Asthana, Sanjay %A Johnson, Sterling C %A Bendlin, Barbara B %K Adipokines %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Chemokine CCL2 %K Chitinase-3-Like Protein 1 %K Diffusion Tensor Imaging %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Lectins %K Male %K Microglia %K Middle Aged %K Peptide Fragments %K tau Proteins %K White Matter %X

BACKGROUND: The immune response in Alzheimer's disease (AD) involves activation of microglia which may remove amyloid-β (Aβ). However, overproduction of inflammatory compounds may exacerbate neural damage in AD. AD pathology accumulates years before diagnosis, yet the extent to which neuroinflammation is involved in the earliest disease stages is unknown.

OBJECTIVE: To determine whether neuroinflammation exacerbates neural damage in preclinical AD.

METHODS: We utilized cerebrospinal fluid (CSF) and magnetic resonance imaging collected in 192 asymptomatic late-middle-aged adults (mean age = 60.98 years). Neuroinflammatory markers chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) in CSF were utilized as markers of neuroinflammation. Neural cell damage was assessed using CSF neurofilament light chain protein (NFL), CSF total tau (T-Tau), and neural microstructure assessed with diffusion tensor imaging (DTI). With regard to AD pathology, CSF Aβ42 and tau phosphorylated at threonine 181 (P-Tau181) were used as markers of amyloid and tau pathology, respectively. We hypothesized that higher YKL-40 and MCP-1 in the presence of AD pathology would be associated with higher NFL, T-Tau, and altered microstructure on DTI.

RESULTS: Neuroinflammation was associated with markers of neural damage. Higher CSF YKL-40 was associated with both higher CSF NFL and T-Tau. Inflammation interacted with AD pathology, such that greater MCP-1 and lower Aβ42 was associated with altered microstructure in bilateral frontal and right temporal lobe and that greater MCP-1 and greater P-Tau181 was associated with altered microstructure in precuneus.

CONCLUSION: Inflammation may play a role in neural damage in preclinical AD.

%B J Alzheimers Dis %V 50 %P 873-86 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836182?dopt=Abstract %R 10.3233/JAD-150897 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Cerebrospinal Fluid Neurogranin/BACE1 Ratio is a Potential Correlate of Cognitive Decline in Alzheimer's Disease. %A De Vos, Ann %A Struyfs, Hanne %A Jacobs, Dirk %A Fransen, Erik %A Klewansky, Tom %A De Roeck, Ellen %A Robberecht, Caroline %A Van Broeckhoven, Christine %A Duyckaerts, Charles %A Engelborghs, Sebastiaan %A Vanmechelen, Eugeen %X

BACKGROUND: In diagnosing Alzheimer's disease (AD), ratios of cerebrospinal fluid (CSF) biomarkers, such as CSF Aβ1-42/tau, have an improved diagnostic performance compared to the single analytes, yet, still a limited value to predict cognitive decline. Since synaptic dysfunction/loss is closely linked to cognitive impairment, synaptic proteins are investigated as candidate CSF AD progression markers.

OBJECTIVE: We studied CSF levels of the postsynaptic protein neurogranin and protein BACE1, predominantly localized presynaptically, and their relation to CSF total-tau, Aβ1-42, Aβ1-40, and Aβ1-38. All six analytes were considered as single parameters as well as ratios.

METHODS: Every ELISA involved was based on monoclonal antibodies, including the BACE1 and neurogranin immunoassay. The latter specifically targets neurogranin C-terminally truncated at P75, a more abundant species of the protein in CSF. We studied patients with MCI due to AD (n = 38) and 50 dementia due to AD patients, as well as age-matched cognitively healthy elderly (n = 20). A significant subset of the patients was followed up by clinical and neuropsychological (MMSE) examinations for at least one year.

RESULTS: The single analytes showed statistically significant differences between the clinical groups, but the ratios of analytes indeed had a higher diagnostic performance. Furthermore, only the ratio of CSF neurogranin trunc P75/BACE1 was significantly correlated with the yearly decline in MMSE scores in patients with MCI and dementia due to AD, pointing toward the prognostic value of the ratio.

CONCLUSION: This is the first study demonstrating that the CSF neurogranin trunc P75/BACE1 ratio, reflecting postsynaptic/presynaptic integrity, is related to cognitive decline.

%B J Alzheimers Dis %V 53 %P 1523-38 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392859?dopt=Abstract %R 10.3233/JAD-160227 %0 Journal Article %J J Alzheimers Dis %D 2016 %T CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atrophy in Alzheimer's Disease and Cerebrovascular Disease. %A Shankle, William R %A Hara, Junko %A Barrentine, Lori W %A Curole, Melanie V %X

We examined whether using a medical food therapy for hyperhomocysteinemia (HHcy) in patients with Alzheimer's disease (AD) or cognitive impairment due to cerebrovascular disease (CVD) with Cerefolin®/CerefolinNAC® (CFLN: L-methylfolate, methylcobalamin, and N-acetyl-cysteine) slowed regional brain atrophy. Thirty HHcy patients with AD and related disorders (ADRD) received CFLN (HHcy+CFLN: duration [μ ±  σ] = 18.6±16.1 months); a sub-sample of this group did not receive CFLN for varying periods of time (HHcy+NoCFLN: duration [μ ±  σ] = 12.6±5.6 months). Thirty-seven NoHHcy patients with ADRD did not receive CFLN (NoHHcy+NoCFLN: duration [μ ±  σ] = 13.3±17.7 months). No participant took supplemental B vitamins. Regional brain volumes were measured at baseline and end of study, and covariate-adjusted rates of hippocampal, cortical, and forebrain parenchymal (includes white matter) atrophy were predicted. The HHcy+CFLN group's hippocampal and cortical atrophy adjusted rates were 4.25 and 11.2 times slower than those of the NoHHcy+NoCFLN group (p < 0.024). The HHcy+CFLN group's forebrain parenchyma atrophy rate was significantly slower only for CVD; the rate of slowing was proportional to the degree of homocysteine lowering (p < 0.0001). CFLN was associated with significantly slowed hippocampal and cortical atrophy rates in ADRD patients with HHcy, and forebrain parenchymal atrophy rates in CVD patients with HHcy. The present results should be further validated.

%B J Alzheimers Dis %V 54 %P 1073-1084 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567825?dopt=Abstract %R 10.3233/JAD-160241 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Changes in Brain Volume with Bapineuzumab in Mild to Moderate Alzheimer's Disease. %A Novak, Gerald %A Fox, Nick %A Clegg, Shona %A Nielsen, Casper %A Einstein, Steven %A Lu, Yuan %A Tudor, Iulia Cristina %A Gregg, Keith %A Di, Jianing %A Collins, Peter %A Wyman, Bradley T %A Yuen, Eric %A Grundman, Michael %A Brashear, H Robert %A Liu, Enchi %K Aged %K Alzheimer Disease %K Antibodies, Monoclonal, Humanized %K Apolipoprotein E4 %K Brain %K Double-Blind Method %K Female %K Heterozygote %K Humans %K Least-Squares Analysis %K Magnetic Resonance Imaging %K Male %K Nootropic Agents %K Organ Size %K Severity of Illness Index %K Treatment Outcome %X

BACKGROUND: Bapineuzumab, an anti-amyloid-β monoclonal antibody, was evaluated in two placebo-controlled trials in APOE*ɛ4 carriers and noncarriers, respectively, with Alzheimer's disease.

OBJECTIVES: A volumetric magnetic resonance imaging substudy was performed to determine if bapineuzumab altered brain volume rate of change.

METHODS: Bapineuzumab dosages included 0.5 mg/kg in carriers and 0.5 or 1.0 mg/kg in noncarriers, every 13 weeks for 78 weeks. Volumetric outcomes included annualized brain, ventricular, and mean hippocampal boundary shift integrals (BBSI; VBSI; HBSI) up to Week 71. Treatment differences were estimated using mixed models for repeated measures.

RESULTS: For BBSI and HBSI, there were no significant treatment-related differences within either study, but, compared to pooled carriers and noncarriers receiving placebo, noncarriers receiving1.0 mg/kg bapineuzumab had greater increases in these measures. Bapineuzumab-treated patients showed significantly greater VBSI rates compared with placebo for 0.5 mg/kg in carriers and 1.0 mg/kg (but not 0.5 mg/kg) in noncarriers.

CONCLUSIONS: Bapineuzumab produced an increase in ventricular volume compared with placebo. Etiology for this increase is unclear but may be related to amyloid-β clearance or its consequences.

%B J Alzheimers Dis %V 49 %P 1123-34 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639957?dopt=Abstract %R 10.3233/JAD-150448 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Changes in Frailty Predict Changes in Cognition in Older Men: The Honolulu-Asia Aging Study. %A Armstrong, Joshua J %A Godin, Judith %A Launer, Lenore J %A White, Lon R %A Mitnitski, Arnold %A Rockwood, Kenneth %A Andrew, Melissa K %X

BACKGROUND: As cognitive decline mostly occurs in late life, where typically it co-exists with many other ailments, it is important to consider frailty in understanding cognitive change.

OBJECTIVE: Here, we examined the association of change in frailty status with cognitive trajectories in a well-studied cohort of older Japanese-American men.

METHODS: Using the prospective Honolulu-Asia Aging Study (HAAS), 2,817 men of Japanese descent were followed (aged 71-93 at baseline). Starting in 1991 with follow-up health assessments every two to three years, cognition was measured using the Cognitive Abilities Screening Instrument (CASI). For this study, health data was used to construct an accumulation of deficits frailty index (FI). Using six waves of data, multilevel growth curve analyses were constructed to examine simultaneous changes in cognition in relation to changes in FI, controlling for baseline frailty, age, education, and APOE-ɛ4 status.

RESULTS: On average, CASI scores declined by 2.0 points per year (95% confidence interval 1.9-2.1). Across six waves, each 10% within-person increase in frailty from baseline was associated with a 5.0 point reduction in CASI scores (95% confidence interval 4.7-5.2). Baseline frailty and age were associated both with lower initial CASI scores and with greater decline across the five follow-up assessments (p < 0.01).

DISCUSSION: Cognition is adversely affected by impaired health status in old age. Using a multidimensional measure of frailty, both baseline status and within-person changes in frailty were predictive of cognitive trajectories.

%B J Alzheimers Dis %V 53 %P 1003-13 %8 2016 Jun 15 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27314525?dopt=Abstract %R 10.3233/JAD-151172 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Changes in Neural Connectivity and Memory Following a Yoga Intervention for Older Adults: A Pilot Study. %A Eyre, Harris A %A Acevedo, Bianca %A Yang, Hongyu %A Siddarth, Prabha %A Van Dyk, Kathleen %A Ercoli, Linda %A Leaver, Amber M %A Cyr, Natalie St %A Narr, Katherine %A Baune, Bernhard T %A Khalsa, Dharma S %A Lavretsky, Helen %X

BACKGROUND: No study has explored the effect of yoga on cognitive decline and resting-state functional connectivity.

OBJECTIVES: This study explored the relationship between performance on memory tests and resting-state functional connectivity before and after a yoga intervention versus active control for subjects with mild cognitive impairment (MCI).

METHODS: Participants ( ≥ 55 y) with MCI were randomized to receive a yoga intervention or active "gold-standard" control (i.e., memory enhancement training (MET)) for 12 weeks. Resting-state functional magnetic resonance imaging was used to map correlations between brain networks and memory performance changes over time. Default mode networks (DMN), language and superior parietal networks were chosen as networks of interest to analyze the association with changes in verbal and visuospatial memory performance.

RESULTS: Fourteen yoga and 11 MET participants completed the study. The yoga group demonstrated a statistically significant improvement in depression and visuospatial memory. We observed improved verbal memory performance correlated with increased connectivity between the DMN and frontal medial cortex, pregenual anterior cingulate cortex, right middle frontal cortex, posterior cingulate cortex, and left lateral occipital cortex. Improved verbal memory performance positively correlated with increased connectivity between the language processing network and the left inferior frontal gyrus. Improved visuospatial memory performance correlated inversely with connectivity between the superior parietal network and the medial parietal cortex.

CONCLUSION: Yoga may be as effective as MET in improving functional connectivity in relation to verbal memory performance. These findings should be confirmed in larger prospective studies.

%B J Alzheimers Dis %V 52 %P 673-84 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060939?dopt=Abstract %R 10.3233/JAD-150653 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Changes in Neuropsychiatric Inventory Associated with Semagacestat Treatment of Alzheimer's Disease. %A Rosenberg, Paul B %A Lanctôt, Krista L %A Herrmann, Nathan %A Mintzer, Jacobo E %A Porsteinsson, Anton P %A Sun, Xiaoying %A Raman, Rema %X

BACKGROUND: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD).

OBJECTIVE: We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS).

METHODS: 1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline.

RESULTS: Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased.

CONCLUSION: In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD.

%B J Alzheimers Dis %V 54 %P 373-81 %8 2016 Aug 10 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567808?dopt=Abstract %R 10.3233/JAD-151113 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Changes of Cerebral Perfusion and Functional Brain Network Organization in Patients with Mild Cognitive Impairment. %A Lou, Wutao %A Shi, Lin %A Wong, Adrian %A Chu, Winnie C W %A Mok, Vincent C T %A Wang, Defeng %X

Disruptions of the functional brain network and cerebral blood flow (CBF) have been revealed in patients with mild cognitive impairment (MCI). However, the neurophysiological mechanism of hypoperfusion as well as the reorganization of the intrinsic whole brain network due to the neuropathology of MCI are still unclear. In this study, we aimed to investigate the changes of CBF and the whole brain network organization in MCI by using a multimodal MRI approach. Resting state ASL MRI and BOLD MRI were used to evaluate disruptions of CBF and underlying functional connectivity in 27 patients with MCI and 35 cognitive normal controls (NC). The eigenvector centrality mapping (ECM) was used to assess the whole brain network reorganization in MCI, and a seed-based ECM approach was proposed to reveal the contributions of the whole brain network on the ECM alterations. Significantly decreased perfusion in the posterior parietal cortex as well as its connectivity within the default mode network and occipital cortex were found in the MCI group compared to the NC group. The ECM analysis revealed decreased EC in the middle cingulate cortex, parahippocampal gyrus, medial frontal gyrus, and increased EC in the right calcarine sulcus, superior temporal gyrus, and supplementary motor area in the MCI group. The results of this study indicate that there are deficits in cerebral blood flow and functional connectivity in the default mode network, and that sensory-processing networks might play a compensatory role to make up for the decreased connections in MCI.

%B J Alzheimers Dis %V 54 %P 397-409 %8 2016 Aug 10 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567823?dopt=Abstract %R 10.3233/JAD-160201 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Characteristics of Alzheimer's Disease Patients with Severe Executive Disorders. %A Godefroy, Olivier %A Bakchine, Serge %A Verny, Marc %A Delabrousse-Mayoux, Jean-Philippe %A Roussel, Martine %A Pere, Jean-Jacques %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Caregivers %K Cost of Illness %K Executive Function %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Prevalence %K Severity of Illness Index %K Treatment Outcome %X

BACKGROUND: Executive dysfunctions in Alzheimer's disease (AD) have been assessed using variable batteries and/or in selected populations.

OBJECTIVE: The primary objective of this observational study was to determine the prevalence and severity of executive dysfunction in AD patients using a previously validated battery. The secondary objective was to determine the characteristics including treatment outcomes of AD patients with severe executive dysfunction.

METHODS: The study included AD patients with mild-to-moderate dementia aged 60 or over, consulting in various clinical settings including memory clinics and requiring the introduction of an antidementia drug. Executive dysfunction was examined using a validated, shortened executive battery.

RESULTS: 381 patients were included. Executive dysfunctions were observed in 88.2% of the patients (95% CI: 84.9-91.4) and were severe (defined as ≥2/3 impaired scores) in 80.4% (95% CI: 76.9-84.8). Global hypoactivity with apathy was more frequent (p = 0.0001) than impairment in executive function tests. The 308 patients with severe executive dysfunction were older (p = 0.003) and had more severe dementia (p = 0.0001). Similarly, in the subset of 257 patients with mild dementia, individuals with severe executive dysfunction were older (p = 0.003) and had more severe dementia. Global hypoactivity was independently associated with difficulties in IADL and a higher caregiver burden (p = 0.0001 for both). The severity of executive dysfunction did not significantly influence the patients' outcomes at 6 months.

CONCLUSIONS: Executive dysfunction is a very common disorder in a representative population of patients with mild-to-moderate AD. It was independently correlated with impaired autonomy and increased caregiver burden but did not significantly influence treatment outcomes.

%B J Alzheimers Dis %V 51 %P 815-25 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890770?dopt=Abstract %R 10.3233/JAD-150971 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Characterization of Alzheimer's Disease and Mild Cognitive Impairment in Older Adults in Panama. %A Villarreal, Alcibiades E %A Grajales, Shantal %A O'Bryant, Sid E %A Edwards, Melissa %A López, Lineth %A Montalván, Astevia %A Britton, Gabrielle B %X

Research on age-related cognitive impairment is scarce in Central America. We report factors associated with cognitive impairment among a sample of older adults in Panama diagnosed with Alzheimer's disease (AD, n = 31), mild cognitive impairment (MCI, n = 43), or no cognitive impairment (controls, n = 185). Apolipoprotein E (ApoE) genotype was assessed in a subset of cases (n = 135). Age (OR = 2.53, 95% CI = 1.03-6.17) and ApoE ɛ4 (OR = 5.14, 95% CI = 2.11-12.52) were significantly related to cognitive impairment (AD/MCI combined). Results underscore the potential of genetic screening in Panama for identifying those at risk of dementia.

%B J Alzheimers Dis %V 54 %P 897-901 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567849?dopt=Abstract %R 10.3233/JAD-160402 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Characterization of Amyloid-β Deposits in Bovine Brains. %A Vallino Costassa, Elena %A Fiorini, Michele %A Zanusso, Gianluigi %A Peletto, Simone %A Acutis, Pierluigi %A Baioni, Elisa %A Maurella, Cristiana %A Tagliavini, Fabrizio %A Catania, Marcella %A Gallo, Marina %A Faro, Monica Lo %A Chieppa, Maria Novella %A Meloni, Daniela %A D'Angelo, Antonio %A Paciello, Orlando %A Ghidoni, Roberta %A Tonoli, Elisa %A Casalone, Cristina %A Corona, Cristiano %K Aging %K Amyloid beta-Peptides %K Animals %K Apolipoproteins E %K Blotting, Western %K Brain %K Cattle %K Extracellular Space %K Gene Frequency %K Genotyping Techniques %K Glial Fibrillary Acidic Protein %K Immunohistochemistry %K Intracellular Space %K Neuroglia %K Neurons %K Polymorphism, Genetic %K Presenilin-1 %K Presenilin-2 %K Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization %X

Amyloid-β (Aβ) deposits are seen in aged individuals of many mammalian species that possess the same aminoacid sequence as humans. This study describes Aβ deposition in 102 clinically characterized cattle brains from animals aged 0 to 20 years. Extracellular and intracellular Aβ deposition was detected with 4G8 antibody in the cortex, hippocampus, and cerebellum. X-34 staining failed to stain Aβ deposits, indicating the non β-pleated nature of these deposits. Western blot analysis and surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry revealed in Tris, Triton, and formic acid fractions the presence of different Aβ peptides, characterized mainly by C-terminally truncated forms. Exploration of the genetic variability of APOE, PSEN1, and PSEN2 genes involved in Alzheimer's disease pathogenesis revealed several previously unreported polymorphisms. This study demonstrates certain similarities between Aβ deposition patterns exhibited in cattle brains and those in the human brain in early stages of aging. Furthermore, the identification of the same Aβ peptides reported in humans, but unable to form aggregates, supports the hypothesis that cattle may be protected against amyloid plaque formation.

%B J Alzheimers Dis %V 51 %P 875-87 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890772?dopt=Abstract %R 10.3233/JAD-151007 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Characterizing Aging, Mild Cognitive Impairment, and Dementia with Blood-Based Biomarkers and Neuropsychology. %A Kleinschmidt, Martin %A Schoenfeld, Robby %A Göttlich, Claudia %A Bittner, Daniel %A Metzner, Jürgen Erich %A Leplow, Bernd %A Demuth, Hans-Ulrich %K Activities of Daily Living %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Aging %K Amyloid beta-Peptides %K Analysis of Variance %K Apolipoproteins E %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Cross-Sectional Studies %K Cytokines %K Dementia %K Female %K Humans %K Male %K Memory Disorders %K Middle Aged %K Neuropsychological Tests %K Young Adult %X

BACKGROUND: Current treatment in Alzheimer's disease (AD) is initiated at a stage where the brain already has irreversible structural deteriorations. Therefore, the concept of treatment prior to obvious cognitive deficits has become widely accepted, and simple biochemical tests to discriminate normal aging from prodromal or demented stages are now common practice.

OBJECTIVE: The objective of the study was the differentiation of controls, mild cognitive impairment (MCI) and AD patients by novel blood-based assays in combination with neuropsychological tests.

METHODS: In a cross-sectional study, 143 subjects aged 18 to 85 years were recruited. All participants were classified by a comprehensive neuropsychological assessment. Blood samples were analyzed for several amyloid-β (Aβ) species, pro-inflammatory markers, anti-Aβ autoantibodies, and ApoE allele status, respectively.

RESULTS: Plasma Aβ1-42 was significantly decreased in MCI and AD compared to age-matched controls, whereas Aβ1-40 did not differ, but increases with age in healthy controls. The Aβ1-42 to Aβ1-40 ratio was stepwise decreased from age-matched controls via MCI to AD, and shows a clear correlation with memory scores. Reduced Aβ1-42 and Aβ1-42 to Aβ1-40 ratio have strongly correlated with carrying ApoE ɛ4 allele. Autoantibodies against pyroglutamate-modified Aβ, but only a certain subclass, were significantly decreased in AD compared to MCI and age-matched controls, whereas autoantibodies against the unmodified N-terminus of Aβ did not differ.

CONCLUSION: Comprehensive sample preparation and assay standardization enable reliable usage of plasma Aβ for diagnosis of MCI and AD. Anti-pGlu-Aβ autoantibodies correlate with cognition, but not with ApoE, supporting the associated plasma Aβ analysis with additional and independent information.

%B J Alzheimers Dis %V 50 %P 111-26 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639953?dopt=Abstract %R 10.3233/JAD-143189 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Characterizing White Matter Tract Degeneration in Syndromic Variants of Alzheimer's Disease: A Diffusion Tensor Imaging Study. %A Madhavan, Ajay %A Schwarz, Christopher G %A Duffy, Joseph R %A Strand, Edythe A %A Machulda, Mary M %A Drubach, Daniel A %A Kantarci, Kejal %A Przybelski, Scott A %A Reid, Robert I %A Senjem, Matthew L %A Gunter, Jeffrey L %A Apostolova, Liana G %A Lowe, Val J %A Petersen, Ronald C %A Jack, Clifford R %A Josephs, Keith A %A Whitwell, Jennifer L %K Aged %K Alzheimer Disease %K Aniline Compounds %K Anisotropy %K Aphasia, Primary Progressive %K Case-Control Studies %K Diffusion Tensor Imaging %K Female %K Humans %K Image Processing, Computer-Assisted %K Male %K Middle Aged %K Nerve Fibers, Myelinated %K Neurodegenerative Diseases %K Neuropsychological Tests %K Positron-Emission Tomography %K Psychiatric Status Rating Scales %K Retrospective Studies %K Thiazoles %K White Matter %X

BACKGROUND: Different clinical syndromes can arise from Alzheimer's disease (AD) neuropathology, including dementia of the Alzheimer's type (DAT), logopenic primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA).

OBJECTIVE: To assess similarities and differences in patterns of white matter tract degeneration across these syndromic variants of AD.

METHODS: Sixty-four subjects (22 DAT, 24 lvPPA, and 18 PCA) that had diffusion tensor imaging and showed amyloid-β deposition on PET were assessed in this case-control study. A whole-brain voxel-based analysis was performed to assess differences in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity across groups.

RESULTS: All three groups showed overlapping diffusion abnormalities in a network of tracts, including fornix, corpus callosum, posterior thalamic radiations, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and uncinate fasciculus. Subtle regional differences were also observed across groups, with DAT particularly associated with degeneration of fornix and cingulum, lvPPA with left inferior fronto-occipital fasciculus and uncinate fasciculus, and PCA with posterior thalamic radiations, superior longitudinal fasciculus, posterior cingulate, and splenium of the corpus callosum.

CONCLUSION: These findings show that while each AD phenotype is associated with degeneration of a specific structural network of white matter tracts, striking spatial overlap exists among the three network patterns that may be related to AD pathology.

%B J Alzheimers Dis %V 49 %P 633-43 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484918?dopt=Abstract %R 10.3233/JAD-150502 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Chocolate Consumption is Associated with a Lower Risk of Cognitive Decline. %A Moreira, Afonso %A Diógenes, Maria José %A de Mendonça, Alexandre %A Lunet, Nuno %A Barros, Henrique %X

Cocoa-related products like chocolate have taken an important place in our food habits and culture. In this work, we aim to examine the relationship between chocolate consumption and cognitive decline in an elderly cognitively healthy population. In the present longitudinal prospective study, a cohort of 531 participants aged 65 and over with normal Mini-Mental State Examination (MMSE; median 28) was selected. The median follow-up was 48 months. Dietary habits were evaluated at baseline. The MMSE was used to assess global cognitive function at baseline and at follow-up. Cognitive decline was defined by a decrease ≥ 2 points in the MMSE score between evaluations. Relative risk (RR) and 95% confidence interval (95% CI) estimates were adjusted for age, education, smoking, alcohol drinking, body mass index, hypertension, and diabetes. Chocolate intake was associated with a lower risk of cognitive decline (RR = 0.59, 95% CI 0.38-0.92). This protective effect was observed only among subjects with an average daily consumption of caffeine lower than 75 mg (69% of the participants; RR = 0.50, 95% CI 0.31-0.82). To our knowledge, this is the first prospective cohort study to show an inverse association between regular long-term chocolate consumption and cognitive decline in humans.

%B J Alzheimers Dis %V 53 %P 85-93 %8 2016 May 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163823?dopt=Abstract %R 10.3233/JAD-160142 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cholesterol, 24-Hydroxycholesterol, and 27-Hydroxycholesterol as Surrogate Biomarkers in Cerebrospinal Fluid in Mild Cognitive Impairment and Alzheimer's Disease: A Meta-Analysis. %A Wang, Hua-Long %A Wang, Yan-Yong %A Liu, Xin-Gang %A Kuo, Sheng-Han %A Liu, Na %A Song, Qiao-Yun %A Wang, Ming-Wei %K Alzheimer Disease %K Cholesterol %K Cognitive Dysfunction %K Databases, Bibliographic %K Humans %K Hydroxycholesterols %X

Abnormal cholesterol metabolism is an established feature of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) is the fluid surrounding the central nervous system, and the protein and lipid content alterations in the CSF could be biomarkers for degenerative changes in the brain. The laboratory diagnosis of AD is limited to the analysis of three biomarkers in CSF: Aβ42, total tau, and phospho-tau. The purpose of this analysis is to systematically analyze the available data describing the biomarkers of cholesterol and its metabolites in the CSF of subjects with AD. MEDLINE, EMBASE, and the Cochrane Central database were systematically queried to collect studies that have evaluated the markers of cholesterol and its metabolites in the CSF of subjects with mild cognitive impairment (MCI) or AD and age-matched controls. Analysis of the published data shows that the levels of cholesterol are increased in MCI subjects; 24-hydroxycholesterol and 27-hydroxycholesterol are elevated in AD and MCI subjects compared to controls. There is a significant dysfunction of cholesterol metabolism in the CSF of AD subjects. This analysis indicates that in addition to the available biomarkers in the CSF, such as Aβ42, total tau, and phospho-tau, 24-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol appear to be sensitive biomarkers for the evaluation of MCI and AD.

%B J Alzheimers Dis %V 51 %P 45-55 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836015?dopt=Abstract %R 10.3233/JAD-150734 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cholesteryl Ester Transfer Protein Intimately Involved in Dyslipidemia-Related Susceptibility to Cognitive Deficits in Type 2 Diabetic Patients. %A Sun, Jie %A Cai, Rongrong %A Huang, Rong %A Wang, Pin %A Tian, Sai %A Sun, Haixia %A Xia, Wenqing %A Wang, Shaohua %X

BACKGROUND: Cholesteryl ester transfer protein (CETP) is involved in diabetic dyslipidemia.

OBJECTIVE: We aim to test the hypothesis that CETP might be of importance in mediating dyslipidemia-related susceptibility to cognitive deficits in diabetic patients.

METHODS: We recruited 190 type 2 diabetic patients and divided them into two groups according to the Montreal Cognitive Assessment (MoCA) score. The association between CETP and cognitive decline was analyzed with logistic regression and stratification.

RESULTS: There were 110 diabetic patients with mild cognition impairment (MCI) and 80 healthy cognition subjects as controls. Dyslipidemia is more common among diabetic patients with MCI; they had a significant increase of serum CETP concentrations, which was negatively correlated with MoCA (r = -0.638; p < 0.001). Negative correlations were also found between the serum CETP concentration with the Auditory Verbal Learning Test (r = -0.266; p = 0.008), indicating memory deficit. Logistic regression analysis revealed that CETP concentration was an independent factor of diabetic MCI (p < 0.001). Further stratification study showed that high serum levels of CETP was an independent risk factor of MCI in diabetic patients with a low density lipoproteins level ≥2.59 mmol/L, or high density lipoproteins level ≤1.0 mmol/L for men and ≤1.3 mmol/L for women, or TG level ≥1.7 mmol/L, after adjusting for age, sex, education, and glucose control (all ps < 0.05).

CONCLUSIONS: CETP was intimately involved in dyslipidemia-related susceptibility to cognitive decline, especially memory function in type 2 diabetic patients.

%B J Alzheimers Dis %V 54 %P 175-84 %8 2016 Aug 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497473?dopt=Abstract %R 10.3233/JAD-160053 %0 Journal Article %J J Alzheimers Dis %D 2016 %T CHRNA7 Gene and Response to Cholinesterase Inhibitors in an Italian Cohort of Alzheimer's Disease Patients. %A Clarelli, Ferdinando %A Mascia, Elisabetta %A Santangelo, Roberto %A Mazzeo, Salvatore %A Giacalone, Giacomo %A Galimberti, Daniela %A Fusco, Federica %A Zuffi, Marta %A Fenoglio, Chiara %A Franceschi, Massimo %A Scarpini, Elio %A Forloni, Gianluigi %A Magnani, Giuseppe %A Comi, Giancarlo %A Albani, Diego %A Martinelli Boneschi, Filippo %X

Previous studies suggest that genetic variants in CHRNA7, which encodes for the major subunit of the acetylcholine receptor (α7-nAChR), are associated with the clinical response to cholinesterase inhibitors (ChEI) in Alzheimer's disease (AD) patients. We sought to replicate the association of two SNPs in the CHRNA7 gene, rs6494223 and rs8024987, with response to ChEI treatment in an Italian cohort of 169 AD patients, further extending the study to gene-level analysis. None of the tested variants was associated with clinical response. However, rs6494223 showed a consistent effect direction (OR = 1.4; p = 0.17), which after meta-analysis with previous study yielded a significant result (OR = 1.57, p = 0.02, I2 = 0%).

%B J Alzheimers Dis %V 52 %P 1203-8 %8 2016 Apr 16 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104904?dopt=Abstract %R 10.3233/JAD-160074 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Chronic Cerebral Hypoperfusion Accelerates Alzheimer's Disease Pathology with Cerebrovascular Remodeling in a Novel Mouse Model. %A Zhai, Yun %A Yamashita, Toru %A Nakano, Yumiko %A Sun, Zhuoran %A Shang, Jingwei %A Feng, Tian %A Morihara, Ryuta %A Fukui, Yusuke %A Ohta, Yasuyuki %A Hishikawa, Nozomi %A Abe, Koji %X

Recently, aging societies have been showing an increasingly strong relationship between Alzheimer's disease (AD) and chronic cerebral hypoperfusion (HP). In the present study, we created a new mouse model for AD with HP, and investigated its clinical and pathological characteristics. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral HP. In contrast to simple APP23 mice, cerebral HP exacerbated motor and cognitive dysfunctions with white matter lesions and meningo-parenchymal amyloid-β (Aβ) burdens. Strong cerebrovascular inflammation and severe amyloid angiopathy with cerebrovascular remodeling were also observed in APP23 + HP mouse brains. An acetylcholinesterase inhibitor galantamine improved such clinical dysfunctions, retrieved above neuropathological characteristics, and enhanced nicotinic acetylcholine receptor (nAChR)-binding activity. The present study demonstrates that chronic cerebral HP enhanced cognitive/motor dysfunctions with parenchymal/cerebrovascular Aβ accumulation and cerebrovascular remodeling. These neuropathological abnormalities were greatly ameliorated by galantamine treatment associated with nAChR-mediated neuroprotection by allosterically potentiating ligand action.

%B J Alzheimers Dis %V 53 %P 893-905 %8 2016 Jun 13 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27314529?dopt=Abstract %R 10.3233/JAD-160345 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Chronic Obstructive Pulmonary Disease as a Risk Factor for Cognitive Dysfunction: A Meta-Analysis of Current Studies. %A Zhang, Ximeng %A Cai, Xiaoying %A Shi, Xiaolei %A Zheng, Zhenyang %A Zhang, Aiwu %A Guo, Junliang %A Fang, Yannan %K Cognitive Dysfunction %K Humans %K Pulmonary Disease, Chronic Obstructive %K Risk Factors %X

Cognitive dysfunction has been shown to be associated with many risk factors, such as smoking, diabetes, and body mass index. Chronic obstructive pulmonary disease (COPD), a common disease within the elderly population, has also been found to be related to cognitive decline. However, whether COPD is a risk factor of cognitive dysfunction is not well established. The purpose of this meta-analysis is to investigate the role COPD plays in cognitive dysfunction. PubMed, Cochrane library and Web of Science databases were searched. Three cohort studies and eleven cross-sectional studies were found to be eligible. According to our results, COPD patients had a higher risk of cognitive dysfunction than controls (OR [odds ratio]: 1.72; 95% CI, 1.12-2.65; p = 0.01). The exacerbation of COPD was strongly correlated with cognitive decline. COPD patients performed worse than controls on the Mini- Mental State Examination test, but the results were not statistically significant (OR: -0.79; 95% CI, [-1.78, 0.19]; p = 0.11). Thus, more attention should be given to the occurrence of cognitive decline in COPD patients. The prevention and control of COPD exacerbation are critical.

%B J Alzheimers Dis %V 52 %P 101-11 %8 2016 02 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967208?dopt=Abstract %R 10.3233/JAD-150735 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Chronic Sleep Deprivation Exacerbates Learning-Memory Disability and Alzheimer's Disease-Like Pathologies in AβPP(swe)/PS1(ΔE9) Mice. %A Qiu, Hongyan %A Zhong, Rujia %A Liu, Hui %A Zhang, Feng %A Li, Song %A Le, Weidong %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Apoptosis %K Brain %K Cognition Disorders %K Disease Models, Animal %K Humans %K In Situ Nick-End Labeling %K Learning Disorders %K Mice %K Mice, Transgenic %K Mitochondrial Diseases %K Mutation %K Phosphorylation %K Plaque, Amyloid %K Presenilin-1 %K Reversal Learning %K Sleep Deprivation %K tau Proteins %X

Recently, there is an increasing concern over the association between sleep disorders and Alzheimer's disease (AD). Clinical observations have reported that chronic sleep deprivation (SD) may serve as a risk factor for AD. However, the pathological evidence for this assumption is still lacking. In the present study, we examined the potential impacts of chronic SD on learning-memory and AD-related pathologies in AβPP(swe)/PS1(ΔE9) transgenic (TG) mice and their wild-type (WT) littermates. Results indicated that mice (both TG and WT) exposed to 2-month SD showed an altered amyloid-β protein precursor processing, an elevated level of phosphorylated tau protein, and impaired cognitive performance as compared to non-sleep deprivation (NSD) controls. Moreover, the SD-treated TG mice exhibited more amyloid-β(1-42) production and developed more senile plaques in the cortex and hippocampus than NSD-treated TG mice. In addition, SD caused a striking neuronal mitochondrial damage, caspase cascade activation, and neuronal apoptosis in the hippocampus of both TG and WT mice. More importantly, all these behavioral, neuropathological, and biochemical changes induced by chronic SD were long lasting and were irreversible during a 3-month normal housing condition. Collectively, these results indicate that chronic SD impairs learning and memory, exacerbates AD pathologies, and aggravates the mitochondria-mediated neuronal apoptosis in a long-lasting manner. Our findings provide important experimental evidence to prove that chronic SD is a risk factor for AD.

%B J Alzheimers Dis %V 50 %P 669-85 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757041?dopt=Abstract %R 10.3233/JAD-150774 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Chronic Stress Aggravates Cognitive Impairment and Suppresses Insulin Associated Signaling Pathway in APP/PS1 Mice. %A Han, Bing %A Yu, Lulu %A Geng, Yuan %A Shen, Li %A Wang, Hualong %A Wang, Yanyong %A Wang, Jinhua %A Wang, Mingwei %X

Differences in brain function are a central determinant of individual variability in the stress response. Brain dysfunction, resulting from aging, illness, or genetic mutations, could reduce the tolerance of glucocorticoid stress hormones. When glucocorticoids exceed tolerable limits in the brain, especially in the hippocampus, this state can cause or aggravate structural or functional damage. However, the underlying mechanisms are not well understood. This study investigated the effects of chronic unpredictable mild stress (CUMS) in APP/PS1 and control mice. We showed that 4 weeks of CUMS exposure increased the levels of glucocorticoids, reduced glucocorticoids receptor expression, and promoted senile plaque deposition, neuronal injury, and cognitive impairment in APP/PS1 mice compared to controls. The phosphorylation of insulin receptor, insulin receptor substrate 1 and associated signaling pathways (Akt, mTOR, p70S6K, ERK1/2, and PTEN) were decreased in hippocampus in APP/PS1 mice compared to control mice, while no changes were found in GSK3 and TSC2 phosphorylation. Furthermore, insulin and Akt/mTOR signaling pathways were further decreased in APP/PS1 mice after CUMS, which may be related to the activation of the stress-activated protein kinase JNK, while no alterations in the levels of phosphorylated ERK1/2, GSK3, PTEN, or TSC2 were observed. These results suggest that chronic stress may affect the insulin and Akt/mTOR pathway, accelerating the progression of Alzheimer's disease in vulnerable individuals.

%B J Alzheimers Dis %V 53 %P 1539-52 %8 2016 Jul 02 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392857?dopt=Abstract %R 10.3233/JAD-160189 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Chronic Traumatic Encephalopathy Presenting as Alzheimer's Disease in a Retired Soccer Player. %A Grinberg, Lea T %A Anghinah, Renato %A Nascimento, Camila Fernandes %A Amaro, Edson %A Leite, Renata P %A Martin, Maria da Graça M %A Naslavsky, Michel S %A Takada, Leonel T %A Filho, Wilson Jacob %A Pasqualucci, Carlos A %A Nitrini, Ricardo %X

The relationship between soccer and chronic traumatic encephalopathy (CTE) is not well established. We report clinicopathological correlations in an 83-year-old retired center-back soccer player, with no history of concussion, manifesting typical Alzheimer-type dementia. Examination revealed mixed pathology including widespread CTE, moderate Alzheimer's disease, hippocampal sclerosis, and TDP-43 proteinopathy. This case adds to a few CTE cases described in soccer players. Furthermore, it corroborates that CTE may present clinically as typical Alzheimer-type dementia. Further studies investigating the extent to which soccer is a risk for CTE are needed.

%B J Alzheimers Dis %V 54 %P 169-74 %8 2016 Jul 29 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472879?dopt=Abstract %R 10.3233/JAD-160312 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cigarette Smoke-Induced Alterations in Frontal White Matter Lipid Profiles Demonstrated by MALDI-Imaging Mass Spectrometry: Relevance to Alzheimer's Disease. %A Nunez, Kavin %A Kay, Jared %A Krotow, Alexander %A Tong, Ming %A Agarwal, Amit R %A Cadenas, Enrique %A de la Monte, Suzanne M %K Aldehydes %K Analysis of Variance %K Animals %K Dinoprost %K Disease Models, Animal %K Enzyme-Linked Immunosorbent Assay %K Frontal Lobe %K Lipid Metabolism %K Male %K Mice %K Phospholipids %K Principal Component Analysis %K Protein Carbonylation %K Smoking %K Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization %K Substance Withdrawal Syndrome %K White Matter %X

BACKGROUND: Meta-analysis has shown that smokers have significantly increased risks for Alzheimer's disease (AD), and neuroimaging studies showed that smoking alters white matter (WM) structural integrity.

OBJECTIVE: Herein, we characterize the effects of cigarette smoke (CS) exposures and withdrawal on WM myelin lipid composition using matrix assisted laser desorption and ionization-imaging mass spectrometry (MALDI-IMS).

METHODS: Young adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). Frontal lobe WM was examined for indices of lipid and protein oxidation and lipid profile alterations by MALDI-IMS. Lipid ions were identified by MS/MS with the LIPID MAPS prediction tools database. Inter-group comparisons were made using principal component analysis and R-generated heatmap.

RESULTS: CS increased lipid and protein adducts such that higher levels were present in CS8 compared with CS4 samples. CS8 + R reversed CS8 effects and normalized the levels of oxidative stress. MALDI-IMS demonstrated striking CS-associated alterations in WM lipid profiles characterized by either reductions or increases in phospholipids (phosphatidylinositol, phosphatidylserine, phosphatidylcholine, or phosphatidylethanolamine) and sphingolipids (sulfatides), and partial reversal of CS's inhibitory effects with recovery. The heatmap hierarchical dendrogram and PCA distinguished CS exposure, duration, and withdrawal effects on WM lipid profiles.

CONCLUSION: CS-mediated WM degeneration is associated with lipid peroxidation, protein oxidative injury, and alterations in myelin lipid composition, including shifts in phospholipids and sphingolipids needed for membrane integrity, plasticity, and intracellular signaling. Future goals are to delineate WM abnormalities in AD using MALDI-IMS, and couple the findings with MRI-mass spectroscopy to improve in vivo diagnostics and early detection of brain biochemical responses to treatment.

%B J Alzheimers Dis %V 51 %P 151-63 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836183?dopt=Abstract %R 10.3233/JAD-150916 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer's Disease Mouse Model. %A LeVault, Kelsey R %A Tischkau, Shelley A %A Brewer, Gregory J %K Age Factors %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Analysis of Variance %K Animals %K Brain %K Chromatography, High Pressure Liquid %K Chronobiology Disorders %K Disease Models, Animal %K Gene Expression Regulation %K Glutathione %K Glutathione Disulfide %K Humans %K Memory Disorders %K Mice %K Mice, Transgenic %K Mutation %K NADP %K Nitric Oxide Synthase Type II %K Oxidation-Reduction %X

It is unclear whether pre-symptomatic Alzheimer's disease (AD) causes circadian disruption or whether circadian disruption accelerates AD pathogenesis. In order to examine the sensitivity of learning and memory to circadian disruption, we altered normal lighting phases by an 8 h shortening of the dark period every 3 days (jet lag) in the APPSwDI NOS2-/- model of AD (AD-Tg) at a young age (4-5 months), when memory is not yet affected compared to non-transgenic (non-Tg) mice. Analysis of activity in 12-12 h lighting or constant darkness showed only minor differences between AD-Tg and non-Tg mice. Jet lag greatly reduced activity in both genotypes during the normal dark time. Learning on the Morris water maze was significantly impaired only in the AD-Tg mice exposed to jet lag. However, memory 3 days after training was impaired in both genotypes. Jet lag caused a decrease of glutathione (GSH) levels that tended to be more pronounced in AD-Tg than in non-Tg brains and an associated increase in NADH levels in both genotypes. Lower brain GSH levels after jet lag correlated with poor performance on the maze. These data indicate that the combination of the environmental stress of circadian disruption together with latent stress of the mutant amyloid and NOS2 knockout contributes to cognitive deficits that correlate with lower GSH levels.

%B J Alzheimers Dis %V 49 %P 301-16 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484899?dopt=Abstract %R 10.3233/JAD-150026 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Circulating microRNAs as Biomarkers of Alzheimer's Disease: A Systematic Review. %A Wu, Helen Zong Ying %A Ong, Kwok Leung %A Seeher, Katrin %A Armstrong, Nicola J %A Thalamuthu, Anbupalam %A Brodaty, Henry %A Sachdev, Perminder %A Mather, Karen %K Alzheimer Disease %K Biomarkers %K Databases, Bibliographic %K Humans %K MicroRNAs %X

BACKGROUND: In recent years, microRNAs (miRNA), a class of non-coding RNA known to regulate protein expression post-transcriptionally, have been recognized as novel biomarkers of diseases.

OBJECTIVE: In this systematic review, we identify miRNAs that are differentially expressed in Alzheimer's disease (AD) and/or mild cognitive impairment (MCI) and evaluate their accuracy as potential blood biomarkers.

METHODS: Eligible studies of miRNAs in peripheral blood distinguishing patients with AD or MCI from cognitively normal controls were identified through standardized search strategies in Medline, PubMed, and Embase. MiRNAs that were differentially expressed were identified and where available their sensitivity and specificity for AD or MCI extracted from the retrieved studies.

RESULTS: Eighteen studies investigated the diagnostic value of miRNAs as peripheral biomarkers of AD/MCI. Twenty miRNAs were significantly upregulated and 32 miRNAs downregulated in AD compared to controls in ten AD studies. Nine miRNAs were consistently dysregulated in more than one study. Of the 8 MCI studies, only one miRNA, miR-132, was consistently upregulated in three independent studies. Of the studies that reported diagnostic accuracy data, the majority of miRNA panels and individual miRNAs had a sensitivity and specificity greater than 0.75.

CONCLUSION: Individual studies suggest that miRNAs can differentiate patients with AD/MCI from cognitively normal controls with modest accuracy. However, the literature is constrained by methodological differences between studies, with few studies assessing the same miRNAs. To become potential biomarkers for AD, further studies with standardized study designs for replication and validation are required. Results from this review may help researchers select candidate miRNAs for further investigation.

%B J Alzheimers Dis %V 49 %P 755-66 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484928?dopt=Abstract %R 10.3233/JAD-150619 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Classification of Neuropsychiatric Symptoms Requiring Antipsychotic Treatment in Patients with Alzheimer's Disease: Analysis of the CATIE-AD Study. %A Nagata, Tomoyuki %A Shinagawa, Shunichiro %A Nakajima, Shinichiro %A Plitman, Eric %A Mihashi, Yukiko %A Hayashi, Shogo %A Mimura, Masaru %A Nakayama, Kazuhiko %K Aged %K Aged, 80 and over %K Aggression %K Alzheimer Disease %K Antipsychotic Agents %K Apathy %K Cluster Analysis %K Female %K Humans %K Male %K Psychiatric Status Rating Scales %K Psychomotor Agitation %K Psychotic Disorders %K Retrospective Studies %K Severity of Illness Index %X

BACKGROUND: The Neuropsychiatric Inventory (NPI) comprises 12 items, which were conventionally determined by psychopathological symptoms of patients with dementia. The clinical rating scales with structured questionnaires have been useful to evaluate neuropsychiatric symptoms (NPSs) of patients with dementia over the past twenty year.

OBJECTIVE: The aim of this study was to classify the conventional NPSs in patients with Alzheimer's disease (AD) requiring antipsychotic treatment for their NPSs into distinct clusters to simplify assessment of these numerous symptoms.

METHODS: Twelve items scores (product of severity and frequency of each symptom) in the NPI taken from the baseline visit were classified into subgroups by principle component analysis using data from 421 outpatients with AD enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) Phase 1. Chi square tests were conducted to examine the co-occurrence of the subgroups.

RESULTS: We found four distinct clusters: aggressiveness (agitation and irritabilities), apathy and eating problems (apathy and appetite/eating disturbance), psychosis (delusions and hallucinations), and emotion and disinhibition (depression, euphoria, and disinhibition). Anxiety, aberrant motor behavior, and sleep disturbance were not included by these clusters. Apathy and eating problems, and emotion and disinhibition co-occurred (p = 0.002), whereas aggressiveness and psychosis occurred independent of the other clusters.

CONCLUSIONS: Four distinct category clusters were identified from NPSs in patients with AD requiring antipsychotic treatment. Future studies should investigate psychosocial backgrounds or risk factors of each distinct cluster, in addition to their longitudinal course over treatment intervention.

%B J Alzheimers Dis %V 50 %P 839-45 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836181?dopt=Abstract %R 10.3233/JAD-150869 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clearing Amyloid-β through PPARγ/ApoE Activation by Genistein is a Treatment of Experimental Alzheimer's Disease. %A Bonet-Costa, Vicent %A Herranz-Pérez, Vicente %A Blanco-Gandía, MariCarmen %A Mas-Bargues, Cristina %A Inglés, Marta %A Garcia-Tarraga, Patricia %A Rodriguez-Arias, Marta %A Miñarro, Jose %A Borras, Consuelo %A Garcia-Verdugo, Jose Manuel %A Viña, Jose %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Apolipoproteins E %K Astrocytes %K Avoidance Learning %K Brain %K Cells, Cultured %K Disease Models, Animal %K Female %K Genistein %K Habituation, Psychophysiologic %K Maze Learning %K Mice, Inbred C57BL %K Mice, Transgenic %K Neuroprotective Agents %K Nootropic Agents %K Olfactory Perception %K Plaque, Amyloid %K PPAR gamma %K Recognition (Psychology) %K Tetrahydronaphthalenes %X

Amyloid-β (Aβ) clearance from brain, which is decreased in Alzheimer's disease, is facilitated by apolipoprotein E (ApoE). ApoE is upregulated by activation of the retinoid X receptor moiety of the RXR/PPARγ dimeric receptor. Genistein, a non-toxic, well-tested, and inexpensive drug activates the other moiety of the receptor PPARγ. Treatment of an Alzheimer's disease mouse model with genistein results in a remarkable and rapid improvement in various parameters of cognition, such as hippocampal learning, recognition memory, implicit memory, and odor discrimination. This is associated with a lowering of Aβ levels in brain, in the number and the area of amyloid plaques (confirmed in vivo by positron emission tomography) as well as in microglial reactivity. Finally, incubation of primary astrocytes with genistein results in a PPARγ-mediated increased release of ApoE. Our results strongly suggest that controlled clinical trials should be performed to test the effect of genistein as treatment of human Alzheimer's disease.

%B J Alzheimers Dis %V 51 %P 701-11 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890773?dopt=Abstract %R 10.3233/JAD-151020 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clinical and Demographic Factors Associated with the Cognitive and Emotional Efficacy of Regular Musical Activities in Dementia. %A Särkämö, Teppo %A Laitinen, Sari %A Numminen, Ava %A Kurki, Merja %A Johnson, Julene K %A Rantanen, Pekka %K Aged %K Aged, 80 and over %K Analysis of Variance %K Caregivers %K Case-Control Studies %K Cognition Disorders %K Dementia %K Executive Function %K Female %K Follow-Up Studies %K Humans %K Male %K Memory, Short-Term %K Middle Aged %K Mood Disorders %K Music Therapy %K Neuropsychological Tests %K Orientation %K Outcome Assessment (Health Care) %K Psychiatric Status Rating Scales %K Quality of Life %X

Recent evidence suggests that music-based interventions can be beneficial in maintaining cognitive, emotional, and social functioning in persons with dementia (PWDs). Our aim was to determine how clinical, demographic, and musical background factors influence the cognitive and emotional efficacy of caregiver-implemented musical activities in PWDs. In a randomized controlled trial, 89 PWD-caregiver dyads received a 10-week music coaching intervention involving either singing or music listening or standard care. Extensive neuropsychological testing and mood and quality of life (QoL) measures were performed before and after the intervention (n = 84) and six months later (n = 74). The potential effects of six key background variables (dementia etiology and severity, age, care situation, singing/instrument playing background) on the outcome of the intervention were assessed. Singing was beneficial especially in improving working memory in PWDs with mild dementia and in maintaining executive function and orientation in younger PWDs. Music listening was beneficial in supporting general cognition, working memory, and QoL especially in PWDs with moderate dementia not caused by Alzheimer's disease (AD) who were in institutional care. Both music interventions alleviated depression especially in PWDs with mild dementia and AD. The musical background of the PWD did not influence the efficacy of the music interventions. Our findings suggest that clinical and demographic factors can influence the cognitive and emotional efficacy of caregiver-implemented musical activities and are, therefore, recommended to take into account when applying and developing the intervention to achieve the greatest benefit.

%B J Alzheimers Dis %V 49 %P 767-81 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519435?dopt=Abstract %R 10.3233/JAD-150453 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clinical Application of Automatic Segmentation of Medial Temporal Lobe Subregions in Prodromal and Dementia-Level Alzheimer's Disease. %A Gertje, Eske Christiane %A Pluta, John %A Das, Sandhitsu %A Mancuso, Lauren %A Kliot, Dasha %A Yushkevich, Paul %A Wolk, David %X

BACKGROUND: Volumetry of medial temporal lobe (MTL) structures to diagnose Alzheimer's disease (AD) in its earliest symptomatic stage could be of great importance for interventions or disease modifying pharmacotherapy.

OBJECTIVE: This study aimed to demonstrate the first application of an automatic segmentation method of MTL subregions in a clinical population. Automatic segmentation of magnetic resonance images (MRIs) in a research population has previously been shown to detect evidence of neurodegeneration in MTL subregions and to help discriminate AD and mild cognitive impairment (MCI) from a healthy comparison group.

METHODS: Clinical patients were selected and T2-weighted MRI scan quality was checked. An automatic segmentation method of hippocampal subfields (ASHS) was applied to scans of 67 AD patients, 38 amnestic MCI patients, and 57 healthy controls. Hippocampal subfields, entorhinal cortex (ERC), and perirhinal cortex were automatically labeled and subregion volumes were compared between groups.

RESULTS: One fourth of all scans were excluded due to bad scan quality. There were significant volume reductions in all subregions, except BA36, in aMCIs (p < 0.001), most prominently in Cornu Ammonis 1 (CA1) and ERC, and in all subregions in AD. However, sensitivity of CA1 and ERC hardly differed from sensitivity of WH in aMCI and AD.

CONCLUSION: Applying automatic segmentation of MTL subregions in a clinical setting as a potential biomarker for prodromal AD is feasible, but issues of image quality due to motion remain to be addressed. CA1 and ERC provided strongest group discrimination in differentiating aMCIs from controls, but discriminatory power of different subfields was low overall.

%B J Alzheimers Dis %V 54 %P 1027-1037 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567809?dopt=Abstract %R 10.3233/JAD-160014 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clinical Conversion or Reversion of Mild Cognitive Impairment in Community versus Hospital Based Studies: GDEMCIS (Gwangju Dementia and Mild Cognitive Impairment Study) and CREDOS (Clinical Research Center for Dementia of South Korea). %A Roh, Hyun Woong %A Hong, Chang Hyung %A Lee, Yunhwan %A Lee, Kang Soo %A Chang, Ki Jung %A Kang, Dae Ryong %A Lee, Jung-Dong %A Choi, Seong Hye %A Kim, Seong Yoon %A Na, Duk L %A Seo, Sang Won %A Kim, Doh Kwan %A Back, Joung Hwan %A Chung, Young Ki %A Lim, Ki Young %A Noh, Jai Sung %A Son, Sang Joon %X

BACKGROUND: In keeping with increasing interest in dementia, few recent studies suggest that clinical course of mild cognitive impairment vary across different studies with hospital-based subjects showing higher rates of conversion than community-based subjects.

OBJECTIVE: The main objective of the present study was to assess whether the clinical conversion or reversion rates differ according to recruitment source.

METHODS: The baseline study subjects comprised of patients who were diagnosed with mild cognitive impairment in community-based GDEMCIS or hospital-based CREDOS. The two studies had nearly the same protocol and were performed over a similar period. We used propensity score matching for baseline comparability. After that, Cox proportional hazards regression analyses were conducted to estimate the hazard ratios and 95% confidence intervals of clinical conversion or reversion.

RESULTS: Based on 89 GDEMCIS subjects, 1 : 4 propensity score matching was conducted and 356 CREDOS subjects were selected. After adjusting for covariates including baseline demographics, comorbidity, depression, disability, and neuropsychological result, Cox proportional hazard regression analysis for time to clinical conversion indicated that recruitment from hospital-based CREDOS exhibited hazard ratio of 2.13 (95% CI, 1.08-4.21), as compared to recruitment from community-based GDEMCIS. Similarly, Cox proportional hazard regression analysis for time to reversion indicated that recruitment from hospital-based CREDOS exhibited hazard ratio of 0.34 (95% CI, 0.20-0.59), as compared to recruitment from community-based GDEMCIS.

CONCLUSION: The present study demonstrated that even after the matching process and adjustments for baseline covariates, recruitment source greatly affected the course of mild cognitive impairment.

%B J Alzheimers Dis %V 53 %P 463-73 %8 2016 May 03 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163831?dopt=Abstract %R 10.3233/JAD-160341 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clinical Dementia Rating Scale Detects White Matter Changes in Older Adults at Risk for Alzheimer's Disease. %A Chang, Yu-Ling %A Yen, Yu-Shiuan %A Chen, Ta-Fu %A Yan, Sui-Hing %A Tseng, Wen-Yih Isaac %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Cognition Disorders %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Memory %K Middle Aged %K Neuropsychological Tests %K Risk Factors %K White Matter %X

This study investigated the putative changes in regional gray matter and cingulum bundle segments in mild cognitive impairment (MCI) by using two diagnostic criteria. Participants comprised 50 older adults with MCI and 22 healthy older controls (HC). The older adults with MCI were further divided into two groups defined by a global Clinical Dementia Rating (CDR) score of 0.5 and with (the CDR/NPT MCI group) or without (the CDR MCI group) objective cognitive impairments determined using neuropsychological tests (NPTs). Comparable regional gray matter integrity was observed among the three groups. However, the integrity of the right inferior segment of the cingulum bundle in the two MCI groups was more reduced than that in the HC group, and the CDR/NPT MCI group exhibited additional disruption in the left inferior cingulum bundle. The results also demonstrated that neuropsychological measures have greater predictive value for changes in white matter beyond the contribution of an informant-based instrument alone. Overall, the findings confirm the utility of informant-based assessment in detecting microstructural brain changes in high-risk older adults, even before objective cognitive impairment is evident. The findings also suggest that combining the neuropsychological measures with the informant-based assessment provided the greatest predictive value in assessing white matter disruption. The essential role of the white matter measurement as a biomarker for detecting individuals at a high risk of developing dementia was highlighted.

%B J Alzheimers Dis %V 50 %P 411-23 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639963?dopt=Abstract %R 10.3233/JAD-150599 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clinical Impact of a Second FDG-PET in Atypical/Unclear Dementia Syndromes. %A Bergeron, David %A Beauregard, Jean-Mathieu %A Guimond, Jean %A Fortin, Marie-Pierre %A Houde, Michèle %A Poulin, Stéphane %A Verret, Louis %A Bouchard, Rémi W %A Laforce, Robert %K Adult %K Brain %K Dementia %K Diagnosis, Differential %K Female %K Fluorodeoxyglucose F18 %K Humans %K Male %K Middle Aged %K Positron-Emission Tomography %K Radiopharmaceuticals %K Retrospective Studies %X

Diagnosis of atypical/unclear dementia is often difficult and this delays treatment initiation. Several authors have shown that beyond standard dementia workup, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) reduces the number of unclear diagnoses, leads to earlier treatment, and has a beneficial impact on families. However, it is not uncommon that the FDG-PET findings are equivocal in this setting. For those cases, a repeat FDG-PET may clarify the diagnosis and prevent treatment delay. We retrospectively assessed the clinical impact of a repeat FDG-PET in 59 patients with atypical/unclear dementia syndromes and inconclusive initial FDG-PET. Changes in primary diagnosis, diagnostic confidence, and management following the second FDG-PET were examined. Conducting a second FDG-PET reduced the number of unclear diagnoses from 80% to 34% , led to diagnostic change in 24% of cases, and treatment modification in 22% of patients. Overall, the clinical impact was higher when initial diagnostic confidence was low and the second FDG-PET repeated ≥12 months after the first one. In tertiary care memory clinic settings, when diagnostic incertitude persists despite extensive evaluation and an equivocal FDG-PET, repeating the FDG-PET 12 months later can greatly clarify the diagnosis and improve management.

%B J Alzheimers Dis %V 49 %P 695-705 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484904?dopt=Abstract %R 10.3233/JAD-150302 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clinical Utility of Amyloid PET Imaging in the Differential Diagnosis of Atypical Dementias and Its Impact on Caregivers. %A Bensaïdane, Mohamed Reda %A Beauregard, Jean-Mathieu %A Poulin, Stéphane %A Buteau, François-Alexandre %A Guimond, Jean %A Bergeron, David %A Verret, Louis %A Fortin, Marie-Pierre %A Houde, Michèle %A Bouchard, Rémi W %A Soucy, Jean-Paul %A Laforce, Robert %X

Recent studies have supported a role for amyloid positron emission tomography (PET) imaging in distinguishing Alzheimer's disease (AD) pathology from other pathological protein accumulations leading to dementia. We investigated the clinical utility of amyloid PET in the differential diagnosis of atypical dementia cases and its impact on caregivers. Using the amyloid tracer 18F-NAV4694, we prospectively scanned 28 patients (mean age 59.3 y, s.d. 5.8; mean MMSE 21.4, s.d. 6.0) with an atypical dementia syndrome. Following a comprehensive diagnostic workup (i.e., history taking, neurological examination, blood tests, neuropsychological evaluation, MRI, and FDG-PET), no certain diagnosis could be arrived at. Amyloid PET was then conducted and classified as positive or negative. Attending physicians were asked to evaluate whether this result led to a change in diagnosis or altered management. They also reported their degree of confidence in the diagnosis. Caregivers were met after disclosure of amyloid PET results and completed a questionnaire/interview to assess the impact of the scan. Our cohort was evenly divided between positive (14/28) and negative (14/28) 18F-NAV4694 cases. Amyloid PET resulted in a diagnostic change in 9/28 cases (32.1%: 17.8% changed from AD to non-AD, 14.3% from non-AD to AD). There was a 44% increase in diagnostic confidence. Altered management occurred in 71.4% (20/28) of cases. Knowledge of amyloid status improved caregivers' outcomes in all domains (anxiety, depression, disease perception, future anticipation, and quality of life). This study suggests a useful additive role for amyloid PET in atypical cases with an unclear diagnosis beyond the extensive workup of a tertiary memory clinic. Amyloid PET increased diagnostic confidence and led to clinically significant alterations in management. The information gained from that test was well received by caregivers and encouraged spending quality time with their loved ones.

%B J Alzheimers Dis %V 52 %P 1251-62 %8 2016 Apr 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104896?dopt=Abstract %R 10.3233/JAD-151180 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clinical utility of the informant AD8 as a dementia case finding instrument in primary healthcare. %A Chan, Qun Lin %A Xu, Xin %A Shaik, Muhammad Amin %A Chong, Steven Shih Tsze %A Hui, Richard Jor Yeong %A Chen, Christopher Li-Hsian %A Dong, YanHong %K Aged %K Aged, 80 and over %K Dementia %K Female %K Humans %K Language %K Logistic Models %K Male %K Mass Screening %K Middle Aged %K Neuropsychological Tests %K Primary Health Care %K Reproducibility of Results %K ROC Curve %K Sensitivity and Specificity %K Singapore %K Surveys and Questionnaires %X

The informant AD8 has excellent discriminant ability for dementia case finding in tertiary healthcare settings. However, its clinical utility for dementia case finding at the forefront of dementia management, primary healthcare, is unknown. Therefore, we recruited participants from two primary healthcare centers in Singapore and measured their performance on the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), and a local formal neuropsychological battery, in addition to the AD8. Logistic regression was conducted to examine the associations between demographic factors and dementia. Area under the receiver operating characteristics (ROC) curve analysis was used to establish the optimal cut-off points for dementia case finding. Of the 309 participants recruited, 243 (78.7%) had CDR = 0, 22 (7.1%) CDR = 0.5, and 44 (14.2%) CDR ≥1. Age was strongly associated with dementia, and the optimal age for dementia case finding in primary healthcare settings was ≥75 years. In this age group, the AD8 has excellent dementia case finding capability and was superior to the MMSE and equivalent to the MoCA [AD8 AUC (95% CI): 0.95 (0.91-0.99), cut-off: ≥3, sensitivity: 0.90, specificity: 0.88, PPV: 0.79 and NPV: 0.94; MMSE AUC (95% CI): 0.87 (0.79-0.94), p = 0.04; MoCA AUC (95% CI): 0.88 (0.82-0.95), p = 0.06]. In conclusion, the AD8 is well suited for dementia case finding in primary healthcare settings.

%B J Alzheimers Dis %V 49 %P 121-7 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444776?dopt=Abstract %R 10.3233/JAD-150390 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Cognitive Change Index as a Measure of Self and Informant Perception of Cognitive Decline: Relation to Neuropsychological Tests. %A Rattanabannakit, Chatchawan %A Risacher, Shannon L %A Gao, Sujuan %A Lane, Kathleen A %A Brown, Steven A %A McDonald, Brenna C %A Unverzagt, Frederick W %A Apostolova, Liana G %A Saykin, Andrew J %A Farlow, Martin R %K Adult %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cognitive Dysfunction %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Perception %K Self Report %X

BACKGROUND: The perception of cognitive decline by individuals and those who know them well ("informants") has been inconsistently associated with objective cognitive performance, but strongly associated with depressive symptoms.

OBJECTIVE: We investigated associations of self-report, informant-report, and discrepancy between self- and informant-report of cognitive decline obtained from the Cognitive Change Index (CCI) with cognitive test performance and self-reported depressive symptoms.

METHODS: 267 participants with normal cognition, mild cognitive impairment (MCI), or mild dementia were included from a cohort study and memory clinic. Association of test performance and self-rated depression (Geriatric Depression Scale, GDS) with CCI scores obtained from subjects (CCI-S), their informants (CCI-I), and discrepancy scores between subjects and informants (CCI-D; CCI-S minus CCI-I) were analyzed using correlation and analysis of covariance (ANCOVA) models.

RESULTS: CCI-S and CCI-I scores showed high internal consistency (Cronbach alpha 0.96 and 0.98, respectively). Higher scores on CCI-S and CCI-I, and lower scores on the CCI-D, were associated with lower performance on various cognitive tests in both univariate and in ANCOVA models adjusted for age, gender, and education. Adjustment for GDS slightly weakened the relationships between CCI and test performance but most remained significant.

CONCLUSION: Self- and informant-report of cognitive decline, as measured by the CCI, show moderately strong relationships with objective test performance independent of age, gender, education, and depressive symptoms. The CCI appears to be a valid cross-sectional measure of self and informant perception of cognitive decline across the continuum of functioning. Studies are needed to address the relationship of CCI scores to longitudinal outcome.

%B J Alzheimers Dis %V 51 %P 1145-55 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923008?dopt=Abstract %R 10.3233/JAD-150729 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Impairment after Mild Stroke: Development and Validation of the SIGNAL2 Risk Score. %A Kandiah, Nagaendran %A Chander, Russell Jude %A Lin, Xuling %A Ng, Aloysius %A Poh, Yen Yeong %A Cheong, Chin Yee %A Cenina, Alvin Rae %A Assam, Pryseley Nkouibert %K Aged %K Aging %K Area Under Curve %K Brain %K Brain Ischemia %K Cognition Disorders %K Constriction, Pathologic %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Logistic Models %K Male %K Middle Aged %K Prospective Studies %K Retrospective Studies %K Risk %K Severity of Illness Index %K Stroke %K White Matter %X

BACKGROUND: Post stroke cognitive impairment (PSCI), an important complication of strokes, has numerous risk factors. A scale adequately classifying risk of cognitive impairment 3-6 months after mild stroke will be useful for clinicians.

OBJECTIVE: To develop a risk score based on clinical and neuroimaging variables that will be useful in identifying mild ischemic stroke patients at high risk for PSCI.

METHODS: The risk score development cohort comprised of a retrospective dataset of 209 mild stroke patients with MRI confirmed infarcts, without pre-stroke cognitive impairment, and evaluated within 6 months post-stroke for PSCI. Logistic regression identified factors predictive of PSCI and a risk score was developed based on regression coefficients. The risk score was checked for stability using 10-fold cross-validation and validated in an independent prospective cohort of 185 ischemic mild stroke patients.

RESULTS: Within 6 months post-stroke, 37.32% developed PSCI in the retrospective dataset. A 15-point risk score based on age, education, acute cortical infarcts, white matter hyperintensity, chronic lacunes, global cortical atrophy, and intracranial large vessel stenosis was highly predictive of PSCI with an AUC of 0.829. 10.11% with low scores, 52.69% with moderate scores, and 74.07% with high scores developed PSCI. In the prospective validation cohort, the model had an AUC of 0.776, and exhibited similar accuracy and stability statistics at both 6 and 12 months.

CONCLUSION: The seven item risk score adequately identified mild stroke patients who are at an increased risk of developing PSCI.

%B J Alzheimers Dis %V 49 %P 1169-77 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599056?dopt=Abstract %R 10.3233/JAD-150736 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Profile and its Association with Neuroimaging Markers of Non-Demented Cerebral Amyloid Angiopathy Patients in a Stroke Unit. %A Xiong, Li %A Davidsdottir, Sigurros %A Reijmer, Yael D %A Shoamanesh, Ashkan %A Roongpiboonsopit, Duangnapa %A Thanprasertsuk, Sekh %A Martinez-Ramirez, Sergi %A Charidimou, Andreas %A Ayres, Alison M %A Fotiadis, Panagiotis %A Gurol, Edip %A Blacker, Deborah L %A Greenberg, Steven M %A Viswanathan, Anand %K Aged %K Atrophy %K Brain %K Cerebral Amyloid Angiopathy %K Cognition %K Cognition Disorders %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Stroke %X

BACKGROUND: Cerebral amyloid angiopathy (CAA) is increasingly recognized as a cause of cognitive impairment in the elderly, but the cognitive profile in patients with the disease has not been well characterized.

OBJECTIVE: To characterize the neuropsychological profile of CAA patients without dementia and to determine the association between cognitive performance in different domains and neuroimaging lesions characteristic of CAA.

METHODS: Fifty-eight non-demented CAA patients were compared to 138 cognitively normal subjects using a standard neuropsychological test battery. Total brain volume (TBV), white matter hyperintensities, number of lobar cerebral microbleeds, hippocampal volume, and cortical superficial siderosis in all CAA patients were assessed. The association between these neuroimaging markers and neuropsychological performance in different cognitive domains in the CAA group were analyzed.

RESULTS: Patients with CAA had significantly worse performance on all individual neuropsychological domains tested, when compared to the cognitive normal group. The cognitive decline of CAA patients was most noticeable in tests for processing speed with a Z score of -1.92±1.56 (mean±SD), then followed by executive function (-0.93±1.01), episodic memory (-0.87±1.29), semantic fluency (-0.73±1.06), and attention (-0.42±0.98). TBV of the CAA patients was correlated with processing speed (β= 0.335, p = 0.03) and executive function (β= 0.394, p = 0.01).

CONCLUSIONS: Non-demented patients with CAA had cognitive deficits in multiple areas. Lower TBV was related to slower processing speed and worse executive function.

%B J Alzheimers Dis %V 52 %P 171-8 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060947?dopt=Abstract %R 10.3233/JAD-150890 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Reserve in Alzheimer's Dementia: Diagnostic Accuracy of a Testing-the-Limits Paradigm. %A Küster, Olivia C %A Kösel, Jonas %A Spohn, Stephanie %A Schurig, Niklas %A Tumani, Hayrettin %A von Arnim, Christine A F %A Uttner, Ingo %X

Individuals with higher cognitive reserve are more able to cope with pathological brain alterations, potentially due to the application of more efficient cognitive strategies. The extent to which an individual's cognitive performance can be increased by advantageous conditions differs substantially between patients with Alzheimer's dementia (AD) and healthy older adults and can be assessed with the Testing-the-Limits (TtL) approach. Thus, TtL has been proposed as a tool for the early diagnosis of AD. Here, we report the diagnostic accuracy of a memory TtL paradigm to discriminate between AD patients and controls. The TtL paradigm was administered to 57 patients with clinically diagnosed AD and 94 controls. It consisted of a pre-test condition, representing baseline cognitive performance, the presentation of an encoding strategy, and two subsequent post-test conditions, representing learning potential. Receiver operating characteristic (ROC) curves were analyzed for each condition in order to receive optimal cutoff points along with their sensitivity and specificity and to compare the diagnostic accuracy of the conditions. Differentiation between AD patients and controls, indicated by the area under the ROC curve, increased significantly for the TtL post-test and total error scores compared to the pre-test score. The combined error score in the two post-tests could differentiate between AD patients and controls with a sensitivity of 0.93 and a specificity of 0.80. The presented approach can be carried out in 25 minutes and thus constitutes a time- and cost-effective way to diagnose AD with high accuracy.

%B J Alzheimers Dis %V 52 %P 519-28 %8 2016 Mar 29 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031485?dopt=Abstract %R 10.3233/JAD-151141 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Stimulation for People with Dementia in Long-Term Care Facilities: Baseline Cognitive Level Predicts Cognitive Gains, Moderated by Depression. %A Middelstädt, Jennifer %A Folkerts, Ann-Kristin %A Blawath, Sabrina %A Kalbe, Elke %X

BACKGROUND: Increasing evidence demonstrates the efficacy of cognitive stimulation (CS) in individuals with dementia. However, conducting studies in nursing homes engenders specific challenges that have limited the data gathered on this topic so far.

OBJECTIVE: The aim of this randomized controlled trial was to investigate the effects of CS on cognition, quality of life (QoL), behavioral symptoms, and activities of daily life in persons with dementia living in nursing homes. We further aimed to identify predictors of the intervention's benefits.

METHODS: Seventy-one persons with mild to moderate dementia were randomly allocated to the experimental group (EG; n = 36) that visited a CS program twice weekly for eight weeks or to the control group (CG; n = 35) that was receiving usual care. Neuropsychological tests were conducted before and after the intervention period and at six-week follow-up.

RESULTS: There were no significant interaction effects Time×Group for the outcome measures. However, regression analysis revealed that a low cognitive baseline level predicted cognitive improvements. Furthermore, a low baseline level of QoL predicted a QoL benefit. For both findings, depression was a significant moderator, meaning that persons with fewer depressive symptoms had a higher probability of showing improvements.

CONCLUSION: This study provides data on profiles of patients who are most likely to profit from CS intervention in nursing-home settings and demonstrates that treatment of depression is of the utmost relevance for a positive outcome of CS. Living conditions will have to be considered more thoroughly in future research.

%B J Alzheimers Dis %V 54 %P 253-68 %8 2016 Aug 04 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497474?dopt=Abstract %R 10.3233/JAD-160181 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Stimulation Modulates Platelet Total Phospholipases A2 Activity in Subjects with Mild Cognitive Impairment. %A Balietti, Marta %A Giuli, Cinzia %A Fattoretti, Patrizia %A Fabbietti, Paolo %A Postacchini, Demetrio %A Conti, Fiorenzo %K Blood Platelets %K Cognition %K Cognitive Dysfunction %K Cognitive Therapy %K Cohort Studies %K Humans %K Mental Status Schedule %K Neuropsychological Tests %K Phospholipases A2 %K Treatment Outcome %X

We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2 activity (tPLA2A) in patients with mild cognitive impairment (MCI_P). At baseline, tPLA2A negatively correlated with Mini-Mental State Examination score (MMSE_s): patients with MMSE_s <26 (Subgroup 1) had significantly higher activity than those with MMSE_s ≥26 (Subgroup 2), who had values similar to the healthy elderly. Regarding CS effect, Subgroup 1 had a significant tPLA2A reduction, whereas Subgroup 2 did not significantly changes after training. Our results showed for the first time that tPLA2A correlates with the cognitive conditions of MCI_P, and that CS acts selectively on subjects with a dysregulated tPLA2A.

%B J Alzheimers Dis %V 50 %P 957-62 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836161?dopt=Abstract %R 10.3233/JAD-150714 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cohort Effects in the Prevalence and Survival of People with Dementia in a Rural Area in Northern Sweden. %A Wimo, Anders %A Sjölund, Britt-Marie %A Sköldunger, Anders %A Qiu, Chengxuan %A Klarin, Inga %A Nordberg, Gunilla %A von Strauss, Eva %K Aged %K Aged, 80 and over %K Aging %K Cohort Effect %K Dementia %K Female %K Humans %K Male %K Prevalence %K Risk Factors %K Rural Population %K Sex Factors %K Survival Rate %K Sweden %X

BACKGROUND: Recent studies suggest that trends in cardiovascular risk may result in a decrease in age-specific prevalence of dementia. Studies in rural areas are rare.

OBJECTIVES: To study cohort effects in dementia prevalence and survival of people with dementia in a Swedish rural area.

METHODS: Participants were from the 1995-1998 Nordanstig Project (NP) (n = 303) and the 2001-2003 Swedish National study on Aging and Care in Nordanstig (SNAC-N) (n = 384). Overall 6-year dementia prevalence and mortality in NP and SNAC-N were compared for people 78 years and older. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for dementia occurrence using the NP study population as the reference group. Cox regression models were used to analyze time to death.

RESULTS: The crude prevalence of dementia was 21.8% in NP and 17.4% in SNAC-N. When the NP cohort was used as the reference group, the age- and gender-adjusted OR of dementia was 0.71 (95% CI 0.48-1.04) in SNAC-N; the OR was 0.47 (0.24-0.90) for men and 0.88 (0.54-1.44) for women. In the extended model, the OR of dementia was significantly lower in SNAC-N than in the NP cohort as a whole (0.63; 0.39-0.99) and in men (0.34; 0.15-0.79), but not in women (0.81; 0.46-1.44). The Cox regression models indicated that the hazard ratio of dying was lower in the SNAC-N than NP population.

CONCLUSIONS: Trends toward a lower prevalence of dementia in high-income countries seem to be evident in this Swedish rural area, at least in men.

%B J Alzheimers Dis %V 50 %P 387-96 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639970?dopt=Abstract %R 10.3233/JAD-150708 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cohort Study on Predictors of Need for Nursing Care in Alzheimer's Disease: An Analysis of Healthcare Data. %A Brüggenjürgen, Bernd %A Andersohn, Frank %A Burkowitz, Jörg %A Ezzat, Nadja %A Gaudig, Maren %A Willich, Stefan N %X

BACKGROUND: The individual and societal burden of Alzheimer's disease (AD) is substantial. Identifying relevant factors deteriorating AD and inducing need for nursing care would be of high relevance for healthcare planning.

OBJECTIVE: The main objective of this study was the identification of predictors of first assignment of a level of long-term care in AD, used as an approximation for disease progression.

METHODS: In a retrospective cohort study using data from a large German statutory health and long-term care insurance (SHI) company, co-morbidities and drug exposure were evaluated with respect to their predictive value for disease progression (first day the amount of daily nursing care exceeded 1.5 hours). Time to disease progression was modeled using COX-proportional hazard regression with stepwise selection of predictor variables.

RESULTS: The risk of nursing care need increased substantially with increasing age. Number of hospitalizations and number of different drugs used were significant indicators for progression, whereas outpatient visits were associated with a reduced need for care. Gender did not indicate significant influence on progression. Malignant neoplasms of ill-defined, secondary, and unspecified sites, malnutrition, renal failure, and injuries increased the risk of need for nursing care most significantly. Among prescribed drugs, significant increased risks were associated with drugs used in diabetes, preparations for treatment of wounds and ulcers, antiseptics and disinfectants, and analgesics.

CONCLUSIONS: Physical comorbidities are relevant contributors to an increase in need for nursing care. Some medical predicting conditions may be linked to cognition, while others may be directly linked to demand for care. AD patients with these comorbidities should be monitored with special attention, as they may be under an increased risk of care dependency.

%B J Alzheimers Dis %V 54 %P 1365-1372 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662286?dopt=Abstract %R 10.3233/JAD-160137 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Collapsin Response Mediator Protein-2 (CRMP2) is a Plausible Etiological Factor and Potential Therapeutic Target in Alzheimer's Disease: Comparison and Contrast with Microtubule-Associated Protein Tau. %A Hensley, Kenneth %A Kursula, Petri %K Alzheimer Disease %K Animals %K Humans %K Intercellular Signaling Peptides and Proteins %K Nerve Tissue Proteins %K tau Proteins %X

Alzheimer's disease (AD) has long been viewed as a pathology that must be caused either by aberrant amyloid-β protein precursor (AβPP) processing, dysfunctional tau protein processing, or a combination of these two factors. This is a reasonable assumption because amyloid-β peptide (Aβ) accumulation and tau hyperphosphorylation are the defining histological features in AD, and because AβPP and tau mutations can cause AD in humans or AD-like features in animal models. Nonetheless, other protein players are emerging that one can argue are significant etiological players in subsets of AD and potentially novel, druggable targets. In particular, the microtubule-associated protein CRMP2 (collapsin response mediator protein-2) bears striking analogies to tau and is similarly relevant to AD. Like tau, CRMP2 dynamically regulates microtubule stability; it is acted upon by the same kinases; collects similarly in neurofibrillary tangles (NFTs); and when sequestered in NFTs, complexes with critical synapse-stabilizing factors. Additionally, CRMP2 is becoming recognized as an important adaptor protein involved in vesicle trafficking, amyloidogenesis and autophagy, in ways that tau is not. This review systematically compares the biology of CRMP2 to that of tau in the context of AD and explores the hypothesis that CRMP2 is an etiologically significant protein in AD and participates in pathways that can be rationally engaged for therapeutic benefit.

%B J Alzheimers Dis %V 53 %P 1-14 %8 2016 04 15 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079722?dopt=Abstract %R 10.3233/JAD-160076 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Combination of Structural MRI and FDG-PET of the Brain Improves Diagnostic Accuracy in Newly Manifested Cognitive Impairment in Geriatric Inpatients. %A Ritter, Kerstin %A Lange, Catharina %A Weygandt, Martin %A Mäurer, Anja %A Roberts, Anna %A Estrella, Melanie %A Suppa, Per %A Spies, Lothar %A Prasad, Vikas %A Steffen, Ingo %A Apostolova, Ivayla %A Bittner, Daniel %A Gövercin, Mehmet %A Brenner, Winfried %A Mende, Christine %A Peters, Oliver %A Seybold, Joachim %A Fiebach, Jochen B %A Steinhagen-Thiessen, Elisabeth %A Hampel, Harald %A Haynes, John-Dylan %A Buchert, Ralph %X

BACKGROUND: The cause of cognitive impairment in acutely hospitalized geriatric patients is often unclear. The diagnostic process is challenging but important in order to treat potentially life-threatening etiologies or identify underlying neurodegenerative disease.

OBJECTIVE: To evaluate the add-on diagnostic value of structural and metabolic neuroimaging in newly manifested cognitive impairment in elderly geriatric inpatients.

METHODS: Eighty-one inpatients (55 females, 81.6±5.5 y) without history of cognitive complaints prior to hospitalization were recruited in 10 acute geriatrics clinics. Primary inclusion criterion was a clinical hypothesis of Alzheimer's disease (AD), cerebrovascular disease (CVD), or mixed AD+CVD etiology (MD), which remained uncertain after standard diagnostic workup. Additional procedures performed after enrollment included detailed neuropsychological testing and structural MRI and FDG-PET of the brain. An interdisciplinary expert team established the most probable etiologic diagnosis (non-neurodegenerative, AD, CVD, or MD) integrating all available data. Automatic multimodal classification based on Random Undersampling Boosting was used for rater-independent assessment of the complementary contribution of the additional diagnostic procedures to the etiologic diagnosis.

RESULTS: Automatic 4-class classification based on all diagnostic routine standard procedures combined reproduced the etiologic expert diagnosis in 31% of the patients (p = 0.100, chance level 25%). Highest accuracy by a single modality was achieved by MRI or FDG-PET (both 45%, p≤0.001). Integration of all modalities resulted in 76% accuracy (p≤0.001).

CONCLUSION: These results indicate substantial improvement of diagnostic accuracy in uncertain de novo cognitive impairment in acutely hospitalized geriatric patients with the integration of structural MRI and brain FDG-PET into the diagnostic process.

%B J Alzheimers Dis %V 54 %P 1319-1331 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567842?dopt=Abstract %R 10.3233/JAD-160380 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Combining Cerebrospinal Fluid Biomarkers and Neuropsychological Assessment: A Simple and Cost-Effective Algorithm to Predict the Progression from Mild Cognitive Impairment to Alzheimer's Disease Dementia. %A Mazzeo, Salvatore %A Santangelo, Roberto %A Bernasconi, Maria Paola %A Cecchetti, Giordano %A Fiorino, Agnese %A Pinto, Patrizia %A Passerini, Gabriella %A Falautano, Monica %A Comi, Giancarlo %A Magnani, Giuseppe %X

BACKGROUND: Correctly diagnosing Alzheimer's disease (AD) in prodromal phases would allow the adoption of experimental therapeutic strategies that could selectively interrupt the pathogenetic process before neuronal damage becomes irreversible. Therefore, great efforts have been aimed at finding early reliable disease markers.

OBJECTIVE: The aim of this study was to identify a simple, cost effective, and reliable diagnostic algorithm to predict conversion from mild cognitive impairment (MCI) to AD.

METHODS: 96 consecutive MCI patients admitted to the Neurology department of San Raffaele Hospital in Milan between January 2009 and January 2015 were included. All patients underwent neuropsychological assessment and lumbar puncture with CSF analysis of amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels. Each patient underwent clinical and neuropsychological follow-up, in order to identify a possible progression from MCI to AD. The mean follow up time was 36.73 months.

RESULTS: 37 out of 96 MCI converted to AD during follow up. CSF analysis and neuropsychological assessment reliably detected MCI patients who developed AD. In a subsample of 43 subjects, a Composite Cognitive Score (CCS) was calculated including episodic memory, executive function, and verbal fluency tests. Combining together CSF biomarkers and CCS increased the accuracy of the single predictors, correctly classifying 86% of patients with a specificity of 96% and a Positive Predictive Value of 93%.

DISCUSSION: Even if preliminary, our data seem to suggest that CSF analysis and neuropsychological assessment could detect MCI patients who will convert to AD with high confidence. Their relative low cost and availability could make them worldwide essential tools in future clinical trials.

%B J Alzheimers Dis %V 54 %P 1495-1508 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589522?dopt=Abstract %R 10.3233/JAD-160360 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Community-Dwelling People Screened Positive for Dementia in Primary Care: A Comprehensive, Multivariate Descriptive Analysis Using Data from the DelpHi-Study. %A Thyrian, Jochen René %A Eichler, Tilly %A Michalowsky, Bernhard %A Wucherer, Diana %A Reimann, Melanie %A Hertel, Johannes %A Richter, Steffen %A Dreier, Adina %A Hoffmann, Wolfgang %X

BACKGROUND: Efficient help and care for people with dementia (PWD) is dependent on knowledge about PWD in primary care.

OBJECTIVE: This analysis comprehensively describes community-dwelling PWD in primary care with respect to various dementia care specific variables.

METHODS: The analyses are based on baseline data of the ongoing general practitioner-based, randomized, controlled intervention trial DelpHi-MV (Dementia: life- and person-centered help). 6,838 patients were screened for dementia in 136 GP practices; 17.1% were screened positive, 54.4% of those agreed to participate and data could be assessed in n = 516 subjects. We assessed age, sex, living situation, cognitive status, functional status, level of impairment, comorbidities, formal diagnosis of dementia, depression, neuropsychiatric symptoms, quality of life, utilization of medical support, and pharmacological therapy.

RESULTS: Concerning clinical-, dementia-, and health-related variables, the sample under examination was on average mildly cognitively and functionally impaired (MMSE, m = 22.2; BADL, m = 3.7). A level of care was assigned in 38.0%. Depression was identified in 15.4% and other frequent comorbidities were high blood pressure (83.3%), coronary heart diseases (37.1%), cerebrovascular diseases (22.3%), among others. In 48.6%, neuropsychiatric symptoms were present in a clinically relevant severity. Pharmacological treatment with antidementia medication was received by 25.8% and antidepressant medication by 14.0%. Utilization of services was generally low.

CONCLUSION: The comprehensive description of people screened positive for dementia in primary care reveals a complex and unique population of patients. They are considerably underdiagnosed and in their majority mildly to moderately affected. More in-depth analyses are needed to study relations, associations and interactions between different variables.

%B J Alzheimers Dis %V 52 %P 609-17 %8 2016 Mar 30 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031481?dopt=Abstract %R 10.3233/JAD-151076 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Comorbid Mild Cognitive Impairment and Depressive Symptoms Predict Future Dementia in Community Older Adults: A 24-Month Follow-Up Longitudinal Study. %A Makizako, Hyuma %A Shimada, Hiroyuki %A Doi, Takehiko %A Tsutsumimoto, Kota %A Hotta, Ryo %A Nakakubo, Sho %A Makino, Keitaro %A Suzuki, Takao %X

BACKGROUND: Older adults with mild cognitive impairment (MCI) are non-demented, but demonstrate cognitive dysfunction, and have significantly higher risk of progressing to dementia. A better understanding of more sensitive risk factors, such as combination of cognitive and psychological status, for progression of MCI to dementia may be crucial for prevention of development of dementia.

OBJECTIVE: To examine MCI, depressive symptoms, and comorbid MCI and depressive symptoms as risk factors for development of dementia.

METHODS: A total of 3,663 community-dwelling older people were included in this prospective longitudinal study. MCI was determined by age- and education-adjusted objective cognitive impairment using computerized comprehensive cognitive measures including memory, attention/executive function, and processing speed. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS) and defined by a GDS score of 6 or more.

RESULTS: During the 24-month follow-up period, 72 participants (2.0%) developed dementia. Baseline MCI was significantly associated with an increased risk of incident dementia (hazard ratio [HR], 3.2; 95% confidence interval [CI], 1.8-5.5) but depressive symptoms were not (2.0; 1.0-4.2) after adjusting for age, sex, education, prescribed medications, and walking speed. Participants with comorbid MCI and depressive symptoms at baseline had a higher risk of developing dementia (HR, 4.8; 2.3-10.5).

CONCLUSION: Although MCI and depressive symptoms may be associated with increased risk for incident dementia independently, comorbid MCI and depressive symptoms have a significantly greater impact on dementia development among community-dwelling older adults.

%B J Alzheimers Dis %V 54 %P 1473-1482 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589518?dopt=Abstract %R 10.3233/JAD-160244 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Comparative Study Evaluating the Impact of Physical Exercise on Disease Progression in a Mouse Model of Alzheimer's Disease. %A Maliszewska-Cyna, Ewelina %A Xhima, Kristiana %A Aubert, Isabelle %X

Evidence suggests that physical exercise can serve as a preventive strategy against Alzheimer's disease (AD). In contrast, much less is known about the impact of exercise when it is introduced after cognitive deficits are established. Using the TgCRND8 mouse model of amyloidosis, we compared the effects of exercise as an intervention strategy aimed at altering disease progression. Voluntary running for 1 month or 2 months was introduced in 3-month-old TgCRND8 mice, which exhibit amyloid-beta (Aβ) plaque pathology and cognitive deficits at this age. Specifically, we examined Aβ plaque load, spatial memory, and neurogenesis in the dentate gyrus in the hippocampus. After 1 month of running, TgCRND8 mice spent more time in the novel arm of the Y-maze compared to the familiar arms, indicating improved memory. The levels of doublecortin (a marker of immature neurons) were increased in TgCRND8 mice running for 1 month, but with no significant difference in the number of new mature neurons or plaque burden. As the disease progressed, running prevented further deficits in the Y-maze performance and hippocampal neurogenesis and it reduced plaque load pathology in TgCRND8 mice running for 2 months, compared to non-running transgenics. Therefore, the impact of running on memory, neurogenesis, and amyloid pathology was of greater significance when sustained through later stages of the disease.

%B J Alzheimers Dis %V 53 %P 243-57 %8 2016 May 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163797?dopt=Abstract %R 10.3233/JAD-150660 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Comparing Longitudinal Behavior Changes in the Primary Progressive Aphasias. %A Van Langenhove, Tim %A Leyton, Cristian E %A Piguet, Olivier %A Hodges, John R %X

BACKGROUND: Differentiating between primary progressive aphasia (PPA) variants based on the profile of language deficits can be difficult in a proportion of patients. Further, little is presently know about the pattern of longitudinal changes in behavior in PPA variants.

OBJECTIVE: To determine the presence of behavioral changes in the main variants of PPA: semantic (sv-PPA), nonfluent/agrammatic (nfv-PPA), and logopenic (lv-PPA), and establish the course of these changes over time.

METHODS: We measured behavioral changes in 73 prospectively recruited PPA (30 sv-PPA, 22 nfv-PPA, and 21 lv-PPA), as well as 33 behavioral variant frontotemporal dementia (bv-FTD) and 31 Alzheimer's disease (AD) patients, at baseline and after 1 year, using the Cambridge Behavioural Inventory Revised. All included patients had mild dementia severity at baseline.

RESULTS: Both at baseline and follow-up, sv-PPA exhibited significantly more behavioral disturbances of the type characteristic of bv-FTD compared with other PPA variants. 74% of sv-PPA patients with mild dementia severity exhibited at least one behavior disturbance at baseline, which increased to 84% during follow-up. Behavioral symptoms did not differ between nfv-PPA and lv-PPA groups at baseline. At follow-up, however, empathy loss was significantly more pronounced in nfv-PPA. The prevalence and course of behavioral symptoms in lv-PPA was similar to that found in AD.

CONCLUSIONS: sv-PPA show more prominent FTD-like behavioral disturbances compared with other PPA variants which typically emerge already early in the disease course. Empathy loss may be an important factor that helps differentiating nfv-PPA from lv-PPA. Our results may allow improved prediction of likely progression in behavioral symptoms across the PPA variants.

%B J Alzheimers Dis %V 53 %P 1033-42 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340847?dopt=Abstract %R 10.3233/JAD-160010 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Comparing the Effects of Multisensory Stimulation and Individualized Music Sessions on Elderly People with Severe Dementia: A Randomized Controlled Trial. %A Sánchez, Alba %A Maseda, Ana %A Marante-Moar, M Pilar %A de Labra, Carmen %A Lorenzo-López, Laura %A Millán-Calenti, José Carlos %K Affect %K Aged %K Aged, 80 and over %K Anxiety %K Cognition %K Dementia %K Environment %K Female %K Follow-Up Studies %K Humans %K Male %K Mental Status Schedule %K Music Therapy %K Precision Medicine %K Sensory Art Therapies %K Severity of Illness Index %K Treatment Outcome %X

The objective of this study was to compare the effects of a multisensory stimulation environment (MSSE) and individualized music sessions on agitation, emotional and cognitive status, and dementia severity in a sample of institutionalized patients with severe dementia. Twenty-two participants with a diagnosis of severe or very severe dementia were randomly assigned to two groups: MSSE and individualized music sessions. Both groups participated in two 30-min weekly sessions over 16 weeks. Outcomes were agitation (Cohen-Mansfield Agitation Inventory, CMAI), mood (Cornell Scale for Depression in Dementia, CSDD), anxiety (Rating Anxiety in Dementia, RAID), cognitive function (Severe Mini-Mental State Examination, SMMSE), and the overall severity of dementia (Bedford Alzheimer Nursing Severity Scale, BANS-S). They were assessed at baseline (pre-trial), in the middle (mid-trial), at the end of the intervention (post-trial), and 8 weeks after the intervention (follow-up). Patients in the MSSE group showed significant improvement in their RAID and BANS-S scores compared with the individualized music group post- versus pre-trial. With regard to agitation, there was improvement during the intervention in both the MSSE and individualized music groups in the CMAI total score after 16 weeks of intervention, with no significant differences between the groups. The results suggest that MSSE could have better effects on anxiety symptoms and dementia severity in comparison with individualized music sessions in elderly patients with severe dementia.

%B J Alzheimers Dis %V 52 %P 303-15 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060958?dopt=Abstract %R 10.3233/JAD-151150 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics. %A Lelental, Natalia %A Brandner, Sebastian %A Kofanova, Olga %A Blennow, Kaj %A Zetterberg, Henrik %A Andreasson, Ulf %A Engelborghs, Sebastiaan %A Mroczko, Barbara %A Gabryelewicz, Tomasz %A Teunissen, Charlotte %A Mollenhauer, Brit %A Parnetti, Lucilla %A Chiasserini, Davide %A Molinuevo, José Luis %A Perret-Liaudet, Armand %A Verbeek, Marcel M %A Andreasen, Niels %A Brosseron, Frederic %A Bahl, Justyna M C %A Herukka, Sanna-Kaisa %A Hausner, Lucrezia %A Frölich, Lutz %A Labonte, Anne %A Poirier, Judes %A Miller, Anne-Marie %A Zilka, Norbert %A Kovacech, Branislav %A Urbani, Andrea %A Suardi, Silvia %A Oliveira, Catarina %A Baldeiras, Ines %A Dubois, Bruno %A Rot, Uros %A Lehmann, Sylvain %A Skinningsrud, Anders %A Betsou, Fay %A Wiltfang, Jens %A Gkatzima, Olymbia %A Winblad, Bengt %A Buchfelder, Michael %A Kornhuber, Johannes %A Lewczuk, Piotr %K Amyloid beta-Peptides %K Animals %K Anti-Bacterial Agents %K Biomarkers %K Cattle %K Clinical Chemistry Tests %K Dementia %K Humans %K Peptide Fragments %K Quality Control %K Reference Standards %K Serum Albumin, Bovine %K Sodium Azide %K tau Proteins %K Time Factors %K Tissue Preservation %X

BACKGROUND: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples.

OBJECTIVE: To prepare and test alternative matrices for QC samples that could facilitate intra- and inter-laboratory QC of the NDD biomarkers.

METHODS: Three matrices were validated in this study: (A) human pooled CSF, (B) Aβ peptides spiked into human prediluted plasma, and (C) Aβ peptides spiked into solution of bovine serum albumin in phosphate-buffered saline. All matrices were tested also after supplementation with an antibacterial agent (sodium azide). We analyzed short- and long-term stability of the biomarkers with ELISA and chemiluminescence (Fujirebio Europe, MSD, IBL International), and performed an inter-laboratory variability study.

RESULTS: NDD biomarkers turned out to be stable in almost all samples stored at the tested conditions for up to 14 days as well as in samples stored deep-frozen (at - 80°C) for up to one year. Sodium azide did not influence biomarker stability. Inter-center variability of the samples sent at room temperature (pooled CSF, freeze-dried CSF, and four artificial matrices) was comparable to the results obtained on deep-frozen samples in other large-scale projects.

CONCLUSION: Our results suggest that it is possible to replace self-made, CSF-based QC samples with large-scale volumes of QC materials prepared with artificial peptides and matrices. This would greatly facilitate intra- and inter-laboratory QC schedules for NDD measurements.

%B J Alzheimers Dis %V 52 %P 51-64 %8 2016 03 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967210?dopt=Abstract %R 10.3233/JAD-150883 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Comparison of Prefrontal Atrophy and Episodic Memory Performance in Dysexecutive Alzheimer's Disease and Behavioral-Variant Frontotemporal Dementia. %A Wong, Stephanie %A Bertoux, Maxime %A Savage, Greg %A Hodges, John R %A Piguet, Olivier %A Hornberger, Michael %K Aged %K Alzheimer Disease %K Atrophy %K Databases, Factual %K Diagnosis, Differential %K Executive Function %K Female %K Frontotemporal Dementia %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Memory, Episodic %K Middle Aged %K Neuropsychological Tests %K Prefrontal Cortex %X

Alzheimer's disease (AD) sometimes presents with prominent executive dysfunction and associated prefrontal cortex atrophy. The impact of such executive deficits on episodic memory performance as well as their neural correlates in AD, however, remains unclear. The aim of the current study was to investigate episodic memory and brain atrophy in AD patients with relatively spared executive functioning (SEF-AD; n = 12) and AD patients with relatively impaired executive functioning (IEF-AD; n = 23). We also compared the AD subgroups with a group of behavioral-variant frontotemporal dementia patients (bvFTD; n = 22), who typically exhibit significant executive deficits, and age-matched healthy controls (n = 38). On cognitive testing, the three patient groups showed comparable memory profiles on standard episodic memory tests, with significant impairment relative to controls. Voxel-based morphometry analyses revealed extensive prefrontal and medial temporal lobe atrophy in IEF-AD and bvFTD, whereas this was limited to the middle frontal gyrus and hippocampus in SEF-AD. Moreover, the additional prefrontal atrophy in IEF-AD and bvFTD correlated with memory performance, whereas this was not the case for SEF-AD. These findings indicate that IEF-AD patients show prefrontal atrophy in regions similar to bvFTD, and suggest that this contributes to episodic memory performance. This has implications for the differential diagnosis of bvFTD and subtypes of AD.

%B J Alzheimers Dis %V 51 %P 889-903 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923025?dopt=Abstract %R 10.3233/JAD-151016 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Complement Biomarkers as Predictors of Disease Progression in Alzheimer's Disease. %A Hakobyan, Svetlana %A Harding, Katharine %A Aiyaz, Mohammed %A Hye, Abdul %A Dobson, Richard %A Baird, Alison %A Liu, Benjamine %A Harris, Claire Louise %A Lovestone, Simon %A Morgan, Bryan Paul %X

There is a critical unmet need for reliable markers of disease and disease course in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). The growing appreciation of the importance of inflammation in early AD has focused attention on inflammatory biomarkers in cerebrospinal fluid or plasma; however, non-specific inflammation markers have disappointed to date. We have adopted a targeted approach, centered on an inflammatory pathway already implicated in the disease. Complement, a core system in innate immune defense and potent driver of inflammation, has been implicated in pathogenesis of AD based on a confluence of genetic, histochemical, and model data. Numerous studies have suggested that measurement of individual complement proteins or activation products in cerebrospinal fluid or plasma is useful in diagnosis, prediction, or stratification, but few have been replicated. Here we apply a novel multiplex assay to measure five complement proteins and four activation products in plasma from donors with MCI, AD, and controls. Only one complement analyte, clusterin, differed significantly between control and AD plasma (controls, 295 mg/l; AD, 388 mg/l: p < 10- 5). A model combining clusterin with relevant co-variables was highly predictive of disease. Three analytes (clusterin, factor I, terminal complement complex) were significantly different between MCI individuals who had converted to dementia one year later compared to non-converters; a model combining these three analytes with informative co-variables was highly predictive of conversion. The data confirm the relevance of complement biomarkers in MCI and AD and build the case for using multi-parameter models for disease prediction and stratification.

%B J Alzheimers Dis %V 54 %P 707-16 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567854?dopt=Abstract %R 10.3233/JAD-160420 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Complementary and Alternative Medicine in the Context of Earlier Diagnoses of Alzheimer's Disease: Opening the Conversation to Prepare Ethical Responses. %A Racine, Eric %A Forlini, Cynthia %A Aspler, John %A Chandler, Jennifer %K Alzheimer Disease %K Complementary Therapies %K Early Diagnosis %K Ethical Analysis %K Humans %X

Preclinical Alzheimer's disease (AD), a newly proposed, actively researched, and hotly debated research-only diagnostic category, raises the prospect of an ethical dilemma: whether, and possibly how, to treat a disorder with no target symptoms. This proposed category rests on the detection of a number of biomarkers thought to provide evidence of AD pathophysiology years before any behavioral symptoms manifest. Faced with limited treatment options, patients and their relatives may come to consider complementary and alternative medicine (CAM) a viable option, albeit one with minimal supporting evidence. Accordingly, the hopes and needs of some preclinical patients and their relatives could further fuel market-oriented entrepreneurship for CAM. In this ethics review, we provide background and reflect on some ethical questions related to the roles of key stakeholders arising from the potential for CAM use in the context of a possible preclinical AD diagnosis.

%B J Alzheimers Dis %V 51 %P 1-9 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836152?dopt=Abstract %R 10.3233/JAD-150534 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Concanavalin agglutinin levels are decreased in peripheral blood of Alzheimer's disease patients. %A Sun, Xuying %A Ma, Ronghong %A Yao, Xiuqing %A Shang, Xiaoling %A Wang, Qun %A Wang, Jian-Zhi %A Liu, Gongping %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Concanavalin A %K Female %K Humans %K Lectins %K Male %K Plant Lectins %X

Alzheimer's disease (AD) seriously threatens patients' lives and causes severe burden to the families. Early prevention and treatment can alleviate the development of the disease; therefore it is important to find new effective and non-traumatic biomarkers for early diagnosis. In this study, peripheral blood samples were collected from 24 AD patients and the same number of age- and gender-matched control subjects. Lectin reactive glycosylation levels including beta-D-galactosyl ricinus communis agglutinin 120 (RCA), peanut agglutinin (PNA), concanavalin agglutinin (Con A), alpha-L-fucosyl ulex europeus agglutinin (UEA), dolichos biflorus agglutinin (DBA), and galanthus nivalis (GNL), in the red blood cells of peripheral blood were examined by western blotting. We found that lectin levels were altered with aging and gender; some lectin levels were different between AD patients and the control subjects. Only Con A levels were significantly decreased in AD patients compared to age-matched control subjects. These results suggest that Con A levels in peripheral blood may be a potent diagnostic marker for AD.

%B J Alzheimers Dis %V 49 %P 63-72 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444791?dopt=Abstract %R 10.3233/JAD-150539 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Connected Language in Late Middle-Aged Adults at Risk for Alzheimer's Disease. %A Mueller, Kimberly Diggle %A Koscik, Rebecca L %A Turkstra, Lyn S %A Riedeman, Sarah K %A LaRue, Asenath %A Clark, Lindsay R %A Hermann, Bruce %A Sager, Mark A %A Johnson, Sterling C %X

Connected language is often impaired among people with Alzheimer's disease (AD), yet little is known about when language difficulties first emerge on the path to a clinical diagnosis. The objective of this study was to determine whether individuals with psychometric (preclinical) evidence of amnestic mild cognitive impairment (pMCI) showed deficits in connected language measures. Participants were 39 pMCI and 39 cognitively healthy (CH) adults drawn from the Wisconsin Registry for Alzheimer's Prevention, who were matched for age, literacy, and sex. Participants completed a connected language task in which they described the Cookie Theft picture from the Boston Diagnostic Aphasia Examination. Language samples were analyzed across three language domains: content, syntactic complexity, and speech fluency. Paired t-tests were used to compare CH and pMCI groups on all variables, and Cohen's d effect sizes were calculated for each comparison. The CH and pMCI groups differed significantly on measures of content (e.g., CH group produced more semantic units, more unique words and had larger idea density, on average, than the pMCI group). The picture description findings are consistent with previous retrospective studies showing semantic language differences in adults with autopsy-confirmed AD. Given that these comparisons are between cognitively healthy and pMCI individuals (before a clinical MCI diagnosis), these findings may represent subtle language difficulty in spontaneous speech, and may be predictive of larger language changes over time.

%B J Alzheimers Dis %V 54 %P 1539-1550 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636838?dopt=Abstract %R 10.3233/JAD-160252 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Consequences of Anosognosia on the Cost of Caregivers' Care in Alzheimer's Disease. %A Turró-Garriga, Oriol %A Garre-Olmo, Josep %A Reñé-Ramírez, Ramón %A Calvó-Perxas, Laia %A Gascón-Bayarri, Jordi %A Conde-Sala, Josep-Lluís %X

BACKGROUND: Anosognosia is common in patients with Alzheimer's disease (AD) and it is frequently related to an increase in time of care demand.

OBJECTIVE: The aim of the study was to examine the effect of anosognosia on the total costs of informal care in patients with AD.

METHODS: This was a prospective longitudinal study with community-dwelling AD patients. Anosognosia, time of informal care, and the use of support services (e.g., day care centers) were recorded at baseline and after 24 months. The cost of informal caregiving was calculated as 'market price'.

RESULTS: At baseline, the prevalence of anosognosia was 54.3% (n = 221), and 43.9% were classified as mild-AD. The average time of care was 5 h/day±2.4 (IADL: 1.3 h/day±1.4 and BADL: 3.6 h/day±1.5). Thirty percent of the patients used home care services, and 25.1% attended a day care center. Patients with anosognosia received more time of care and were more likely to use support services than did their no-anosognosia peers, including institutionalization. The mean cost of support services was 490.4€ /month (SD = 413.1€; range = 25-2,212.38€), while the overall cost of care (support services plus informal care) was 1,787€ /month (SD = 972.4€), ranging from 834.1€ in mild-AD without anosognosia patients, to 2,424.8€ in severe-AD with incident anosognosia patients.

CONCLUSIONS: Anosognosia was associated with an increased number of hours of informal care, and a greater use of support services, regardless of the severity of the dementia, which lead to an increase of the total family-care costs.

%B J Alzheimers Dis %V 54 %P 1551-1560 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636844?dopt=Abstract %R 10.3233/JAD-160419 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Contribution of the Cholinergic System to Verbal Memory Performance in Mild Cognitive Impairment. %A Peter, Jessica %A Lahr, Jacob %A Minkova, Lora %A Lauer, Eliza %A Grothe, Michel J %A Teipel, Stefan %A Köstering, Lena %A Kaller, Christoph P %A Heimbach, Bernhard %A Hüll, Michael %A Normann, Claus %A Nissen, Christoph %A Reis, Janine %A Klöppel, Stefan %X

Acetylcholine is critically involved in modulating learning and memory function, which both decline in neurodegeneration. It remains unclear to what extent structural and functional changes in the cholinergic system contribute to episodic memory dysfunction in mild cognitive impairment (MCI), in addition to hippocampal degeneration. A better understanding is critical, given that the cholinergic system is the main target of current symptomatic treatment in mild to moderate Alzheimer's disease. We simultaneously assessed the structural and functional integrity of the cholinergic system in 20 patients with MCI and 20 matched healthy controls and examined their effect on verbal episodic memory via multivariate regression analyses. Mediating effects of either cholinergic function or hippocampal volume on the relationship between cholinergic structure and episodic memory were computed. In MCI, a less intact structure and function of the cholinergic system was found. A smaller cholinergic structure was significantly correlated with a functionally more active cholinergic system in patients, but not in controls. This association was not modulated by age or disease severity, arguing against compensational processes. Further analyses indicated that neither functional nor structural changes in the cholinergic system influence verbal episodic memory at the MCI stage. In fact, those associations were fully mediated by hippocampal volume. Although the cholinergic system is structurally and functionally altered in MCI, episodic memory dysfunction results primarily from hippocampal neurodegeneration, which may explain the inefficiency of cholinergic treatment at this disease stage.

%B J Alzheimers Dis %V 53 %P 991-1001 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340852?dopt=Abstract %R 10.3233/JAD-160273 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Copeptin, a Marker of Vasopressin, Predicts Vascular Dementia but not Alzheimer's Disease. %A Nilsson, Erik D %A Melander, Olle %A Elmståhl, Sölve %A Lethagen, Eva %A Minthon, Lennart %A Pihlsgård, Mats %A Nägga, Katarina %X

BACKGROUND: Copeptin is a reliable surrogate marker for the neurohypophyseal hormone vasopressin. Elevated plasma level of copeptin has been associated with cardiovascular and metabolic disease risk.

OBJECTIVE: To investigate the association between copeptin and risk of dementia.

METHODS: In all, 18,240 individuals from Malmö, Sweden, were examined between 2002 and 2006 (mean age 69.3 years, 69.8% men). Incident cases of dementia until 31 December 2009 were identified by linkage with the Swedish National Patient Register. To validate the dementia diagnoses, medical records as well as laboratory and neuroimaging data were carefully reviewed. Baseline level of copeptin was measured in frozen plasma in: (1) all participants who were diagnosed with dementia during follow-up, (2) a random sample of 5100 individuals of the cohort.

RESULTS: During a median follow-up of 4.2 years, there were 374 incident dementia cases (age range 60-83 years at baseline): 120 were classified as Alzheimer's disease (AD), 84 as vascular dementia (VaD), and 102 as mixed dementia. In logistic regressions adjusted for cardiovascular risk factors, baseline level of copeptin predicted incident VaD (Odds ratio (OR) 1.30 per 1 SD increase in log copeptin, 95% CI 1.03-1.64). Copeptin did not predict incidence of all-cause dementia (OR 1.05, 95% CI 0.94-1.18), AD (OR 0.97, 95% CI 0.79-1.18), or mixed dementia (OR 0.85, 95% CI 0.68-1.05).

CONCLUSION: Elevated plasma level of copeptin is a risk marker for incident VaD, but not for incident AD. This suggests that the vasopressin hormonal system might be involved in the development of VaD.

%B J Alzheimers Dis %V 52 %P 1047-53 %8 2016 Apr 12 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079711?dopt=Abstract %R 10.3233/JAD-151118 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cortical Amyloid Burden Differences Across Empirically-Derived Mild Cognitive Impairment Subtypes and Interaction with APOE ɛ4 Genotype. %A Bangen, Katherine J %A Clark, Alexandra L %A Werhane, Madeline %A Edmonds, Emily C %A Nation, Daniel A %A Evangelista, Nicole %A Libon, David J %A Bondi, Mark W %A Delano-Wood, Lisa %X

We examined cortical amyloid-β (Aβ) levels and interactions with apolipoprotein (APOE) ɛ4 genotype status across empirically-derived mild cognitive impairment (MCI) subgroups and cognitively normal older adults. Participants were 583 ADNI participants (444 MCI, 139 normal controls [NC]) with baseline florbetapir positron emission tomography (PET) amyloid imaging and neuropsychological testing. Of those with ADNI-defined MCI, a previous cluster analysis [1] classified 51% (n = 227) of the current sample as amnestic MCI, 8% (n = 37) as dysexecutive/mixed MCI, and 41% (n = 180) as cluster-derived normal (cognitively normal). Results demonstrated that the dysexecutive/mixed and amnestic MCI groups showed significantly greater levels of amyloid relative to the cluster-derived normal and NC groups who did not differ from each other. Additionally, 78% of the dysexecutive/mixed, 63% of the amnestic MCI, 42% of the cluster-derived normal, and 34% of the NC group exceeded the amyloid positivity threshold. Finally, a group by APOE genotype interaction demonstrated that APOE ɛ4 carriers within the amnestic MCI, cluster-derived normal, and NC groups showed significantly greater amyloid accumulation compared to non-carriers of their respective group. Such an interaction was not revealed within the dysexecutive/mixed MCI group which was characterized by both greater cognitive impairment and amyloid accumulation compared to the other participant groups. Our results from the ADNI cohort show considerable heterogeneity in Aβ across all groups studied, even within a group of robust NC participants. Findings suggest that conventional criteria for MCI may be susceptible to false positive diagnostic errors, and that onset of Aβ accumulation may occur earlier in APOE ɛ4 carriers compared to non-carriers.

%B J Alzheimers Dis %V 52 %P 849-61 %8 2016 Mar 29 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031472?dopt=Abstract %R 10.3233/JAD-150900 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cost Related to Dementia in the Young and the Impact of Etiological Subtype on Cost. %A Kandiah, Nagaendran %A Wang, Vivian %A Lin, Xuling %A Nyu, Mei Mei %A Lim, Linda %A Ng, Adeline %A Hameed, Shahul %A Wee, Hwee Lin %K Age of Onset %K Aged %K Cohort Studies %K Costs and Cost Analysis %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Independent Living %K Male %K Mental Disorders %K Middle Aged %K Perceptual Disorders %K Prospective Studies %K Psychiatric Status Rating Scales %K Severity of Illness Index %K Surveys and Questionnaires %K Young Adult %X

BACKGROUND: Young onset dementia (YOD) presents in individuals who are economically productive and socially active. While the cost related to dementia in the elderly has been widely studied, the cost related to YOD is largely unknown.

OBJECTIVE: To study the economic burden of community dwelling YOD in relation to late onset dementia (LOD) and cost of YOD based on etiology.

METHODS: In this prospective cross-sectional study of 255 patients attending a tertiary neurology center, data on economic burden, clinical features, and caregiver burden were collected using structured financial questionnaire, standard cognitive and neuropsychiatric measures, and Zarit caregiver burden scale. Cost components were grouped into those relating to direct medical costs, direct non-medical costs, and those related to indirect costs. Cost was also categorized based on etiology of YOD.

RESULTS: The mean age at symptom onset in the YOD and LOD cohort was 57.0 (SD 5.1) and 75.0 (SD 5.9) years, respectively. The median annual cost for patients with YOD was almost twice that of LOD (USD 15,815 versus USD 8,396). Indirect cost contributed heavily to cost related to YOD. Even when grouped by dementia etiology, YOD patients with Alzheimer's disease, frontotemporal dementia (FTD), and vascular dementia had higher cost compared to their elderly counterparts. Young onset FTD had the highest cost. 43.2% of YOD reported loss of employment due to dementia, which was significantly higher than that in LOD (2.4%).

CONCLUSION: Patients with YOD have a high economic burden. Young patients with FTD have the highest cost followed by vascular dementia and Alzheimer's disease.

%B J Alzheimers Dis %V 49 %P 277-85 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444788?dopt=Abstract %R 10.3233/JAD-150471 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Course and Determinants of Anosognosia in Alzheimer's Disease: A 12-Month Follow-up. %A Turró-Garriga, Oriol %A Garre-Olmo, Josep %A Calvó-Perxas, Laia %A Reñé-Ramírez, Ramón %A Gascón-Bayarri, Jordi %A Conde-Sala, Josep Lluís %K Age Factors %K Aged %K Agnosia %K Alzheimer Disease %K Disability Evaluation %K Disease Progression %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Incidence %K Logistic Models %K Longitudinal Studies %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Prevalence %K Prospective Studies %K Risk Factors %K Severity of Illness Index %X

Anosognosia in Alzheimer's disease (AD) has been associated with greater cognitive impairment and more behavioural and psychological symptoms of dementia (BPSD). This study examines the incidence, persistence, and remission rates of anosognosia over a 12-month period, as well as the related risk factors. This was an observational 12-month prospective study. The longitudinal sample comprised 177 patients with mild or moderate AD, and their respective caregivers. Anosognosia was assessed using the Anosognosia Questionnaire in Dementia, and we also evaluated cognitive status (Mini-Mental State Examination), functional disability (Disability Assessment in Dementia), and the presence of BPSD (Neuropsychiatric Inventory). Multinomial logistic regression was used to determine the variables associated with the incidence, persistence and remission of anosognosia. The prevalence of anosognosia was 39.5% (95% CI = 32.1-47.1) at baseline. At 12 months, incidence was 38.3% (95% CI = 28.6-48.0), persistence was 80.0% (95% CI = 69.9-90.1) and remission was 20.0% (95% CI = 9.9-30.1). The regression model identified lower age, more education, and the presence of delusions as variables associated with incidence, and more education, lower instrumental DAD score, and disinhibition as variables associated with persistence. No variables were associated with remission (n = 14). The presence of anosognosia in AD patients is high. Education and certain neuropsychiatric symptoms may explain a greater and earlier incidence of anosognosia. However, anosognosia also increases with greater cognitive impairment and disease severity.

%B J Alzheimers Dis %V 51 %P 357-66 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890611?dopt=Abstract %R 10.3233/JAD-150706 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cycloheximide Treatment Causes a ZVAD-Sensitive Protease-Dependent Cleavage of Human Tau in Drosophila Cells. %A Geng, Junhua %A Xia, Lu %A Li, Wanjie %A Zhao, Changqi %A Dou, Fei %K Animals %K Apoptosis %K Caspase 3 %K Cell Line %K Cycloheximide %K Drosophila %K Drosophila Proteins %K Drug Evaluation, Preclinical %K Humans %K Oligopeptides %K Peptide Hydrolases %K Protease Inhibitors %K Protein Synthesis Inhibitors %K tau Proteins %K Time %X

Neurofibrillary tangles are the main pathological feature of Alzheimer's disease. Insoluble tau protein is the major component of neurofibrillary tangles. Defects in the tau protein degradation pathway in neurons can lead to the accumulation of tau and its subsequent aggregation. Currently, contradictory results on the tau degradation pathway have been reported by different groups. This discrepancy is most likely due to different cell lines and methods used in those studies. In this study, we found that cycloheximide treatment induced mild activation of a ZVAD-sensitive protease in Drosophila Kc cells, resulting in cleavage of tau at its C-terminus; this cleavage could generate misleading tau protein degradation pattern results depending on the antibodies used in the assay. Because cycloheximide is a broadly used chemical reagent for the study of protein degradation, the unexpected artificial effect we observed here indicates that cycloheximide is not suitable for the study of tau degradation. Other methods, such as inducible expression systems and pulse-chase assays, may be more appropriate for studying tau degradation under physiological conditions.

%B J Alzheimers Dis %V 49 %P 1161-8 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599052?dopt=Abstract %R 10.3233/JAD-150423 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Cytome Assay as a Tool to Investigate the Possible Association Between Exposure to Extremely Low Frequency Magnetic Fields and an Increased Risk for Alzheimer's Disease. %A Maes, Annemarie %A Anthonissen, Roel %A Wambacq, Sheleen %A Simons, Koen %A Verschaeve, Luc %K Apoptosis %K Carcinoma %K Cell Line, Tumor %K Chromosome Aberrations %K Cytokinesis %K Dose-Response Relationship, Radiation %K Humans %K Magnetic Fields %K Risk Factors %X

Exposure to extremely low frequency magnetic fields (ELF-MF) has been identified as one of the potential environmental risk factors for Alzheimer's disease (AD). However, this is far from being established. So far there is no experimental evidence supporting this alleged association. We have performed an in vitro cytogenetic laboratory investigation to explore the plausibility of such association. Our investigation was based on possible similarities found in cells from AD patients and in cells exposed to ELF-MF. We especially found that 50  Hz ELF-MF increase the frequency of cells with (large) micronuclei and nuclear buds indicating that fields above 50 μT may induce chromosome instabilities as those found in AD patients. It should be stressed yet that results from the few published experimental studies on ELF-MF and AD are rather reassuring. Thus, our findings certainly do not prove anything. They only suggest that further investigations might be necessary.

%B J Alzheimers Dis %V 50 %P 741-9 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757040?dopt=Abstract %R 10.3233/JAD-150669 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Daily Function as Predictor of Dementia in Cognitive Impairment, No Dementia (CIND) and Mild Cognitive Impairment (MCI): An 8-Year Follow-Up in the ILSA Study. %A Di Carlo, Antonio %A Baldereschi, Marzia %A Lamassa, Maria %A Bovis, Francesca %A Inzitari, Marco %A Solfrizzi, Vincenzo %A Panza, Francesco %A Galluzzo, Lucia %A Scafato, Emanuele %A Inzitari, Domenico %X

BACKGROUND: Preclinical cognitive changes may predict an increased risk of dementia, allowing selection of subgroups as possible targets for preventive or therapeutic interventions.

OBJECTIVE: To evaluate the predictive effect of daily functioning and motor performance (MP) on the progression to dementia in normal cognition, cognitive impairment, no dementia (CIND), and mild cognitive impairment (MCI).

METHODS: The Italian Longitudinal Study on Aging is a large population-based survey on age-related diseases of the cardiovascular and nervous systems. After the baseline assessment, to detect prevalent cases of cognitive impairment and dementia, participants were re-examined at 4-year and 8-year follow-ups. Functional independence was evaluated using the Index of Activities of Daily Living (ADL) and the Instrumental Activities of Daily Living (IADL) Scale. A six-test battery was used to assess MP.

RESULTS: Overall, 2,386 individuals were included, for a total of 16,545 person-years. Eight-year incidence of dementia (per 1,000 person-years) was 12.69 in total sample, 9.86 in subjects with normal cognition at baseline, 22.99 in CIND, and 21.43 in MCI. Progression to dementia was significantly higher with increasing baseline ADL and IADL impairment, and with a worse MP. In Cox regression analyses controlled for demographics and major age-related conditions, increased IADL impairment was the stronger predictor of progression to dementia (p < 0.001), with HR ranging from 2.16 (95% CI, 0.82-5.70) to 9.57 (95% CI, 3.40-26.91) in subjects with MCI at baseline.

CONCLUSIONS: Inclusion of IADL in the MCI construct significantly improves the prediction of dementia. Individuation of different transition rates is required to plan cost-effective interventions.

%B J Alzheimers Dis %V 53 %P 505-15 %8 2016 May 07 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163817?dopt=Abstract %R 10.3233/JAD-160087 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Death Preparation and Boredom Reduction as Functions of Reminiscence in Alzheimer's Disease. %A El Haj, Mohamad %A Antoine, Pascal %X

Reminiscence, or the process of thinking or telling about past experience, is thought to serve social, instrumental, and integrative functions. Our paper investigated these functions in Alzheimer's disease (AD). Twenty-six participants with a clinical diagnosis of probable mild AD and 28 control older adults filled in a French adaptation of the Reminiscence Functions Scale. Eight specific functions were assessed: death preparation, identity, problem-solving, teaching/informing, conversation, boredom reduction, bitterness revival, and intimacy maintenance. Both older adults and AD participants reported reminiscence about their past to prepare themselves for the idea of their own mortality. All participants also reported reminiscence "to reduce boredom" and "for something to do". However, reminiscence for death preparation and boredom reduction was reported more by AD participants than by older adults. In all participants, the death preparation function of reminiscence was significantly correlated with depression. Individuals with AD seem to reminiscence to cope with thoughts about their own mortality. This helps them to see that they have lived a full life and can therefore accept death more calmly. Individuals with AD also seem to cope with boredom by using reminiscence, probably as a tool to fill time or simply to create ease of conversation.

%B J Alzheimers Dis %V 54 %P 515-23 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567866?dopt=Abstract %R 10.3233/JAD-160497 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Decade of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in Belgium. %A Somers, Charisse %A Struyfs, Hanne %A Goossens, Joery %A Niemantsverdriet, Ellis %A Luyckx, Jill %A De Roeck, Naomi %A De Roeck, Ellen %A De Vil, Bart %A Cras, Patrick %A Martin, Jean-Jacques %A De Deyn, Peter-Paul %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

During the past ten years, over 5,000 cerebrospinal fluid (CSF) samples were analyzed at the Reference Center for Biological Markers of Dementia (BIODEM), UAntwerp, for core Alzheimer's disease (AD) CSF biomarkers: amyloid-β peptide of 42 amino acids (Aβ1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P). CSF biomarker analyses were performed using single-analyte ELISA kits. In-house validated cutoff values were applied: Aβ1-42 <638.5 pg/mL, T-tau >296.5 pg/mL, P-tau181P >56.5 pg/mL. A CSF biomarker profile was considered to be suggestive for AD if the CSF Aβ1-42 concentration was below the cutoff, in combination with T-tau and/or P-tau181P values above the cutoff (IWG2 criteria for AD). Biomarker analyses were requested for following clinical indications: 1) neurochemical confirmation of AD in case of clinical AD, 2) neurochemical confirmation of AD in case of doubt between AD and a non-AD dementia, 3) neurochemical diagnosis of prodromal AD in case of mild cognitive impairment, 4) neurochemical confirmation of AD in case of psychiatric symptoms (like depression, psychosis), or 5) other clinical indications. During these ten years, the number of yearly referred samples increased by 238% and clinical indications for referral showed a shift from neurochemical confirmation of AD in case of clinical AD to differential dementia diagnosis in case of doubt between AD and a non-AD dementia. Four percent of the patients also had a postmortem neuropathological examination. Together, these biomarker data were the basis for several research papers, and significantly contributed to the validation of these biomarkers in autopsy-confirmed subjects.

%B J Alzheimers Dis %V 54 %P 383-95 %8 2016 Aug 10 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567807?dopt=Abstract %R 10.3233/JAD-151097 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Decreased Inter-Hemispheric Functional Connectivity in Cognitively Intact Elderly APOE ɛ4 Carriers: A Preliminary Study. %A Luo, Xiao %A Qiu, Tiantian %A Xu, Xiaojun %A Huang, Peiyu %A Gu, Quanquan %A Shen, Zhujing %A Yu, Xinfeng %A Jia, YunLu %A Guan, Xiaojun %A Song, Ruirui %A Zhang, Minming %K Aged %K Aging %K Apolipoprotein E4 %K Brain %K Brain Mapping %K Female %K Functional Laterality %K Genotyping Techniques %K Heterozygote %K Humans %K Magnetic Resonance Imaging %K Male %K Memory %K Neuropsychological Tests %K Rest %X

The apolipoprotein E (APOE) ɛ4 allele is the best-known genetic risk factor for developing sporadic Alzheimer's disease (AD). According to neuroimaging studies, the APOE ɛ4 allele is associated with localized altered brain function. However, in long-range circuitry, APOE ɛ4 allele-related alterations in functional communication between hemispheres have rarely been directly investigated. We examined the alteration of resting-state functional connectivity (RSFC) between inter-hemispheric homotopic regions in cognitively intact, elderly APOE ɛ4 carriers. The voxel-mirrored homotopic connectivity method was used to assess the inter-hemispheric RSFC. The current study included 13 cognitively intact, elderly APOE ɛ4 carriers (with at least one copy of APOE ɛ4 allele) and 22 well-matched ɛ3 homozygotes. Comparisons between the two groups were conducted, and subsequently, the correlation between the differential inter-hemispheric RSFC and cognitive ability was analyzed. Compared with ɛ3 homozygotes, APOE ɛ4 carriers showed decreased inter-hemispheric RSFC in the bilateral medial temporal lobe (MTL) and orbital frontal cortex (OFC). Moreover, in APOE ɛ4 carriers, the inter-hemispheric RSFC of the MTL correlated with the Wechsler Memory Scale-Logical Memory (WMS-LM) (immediate and delayed performance, r = 0.64, p <  0.05; r = 0.65, p <  0.05, respectively), and the inter-hemispheric RSFC of the OFC correlated with the WMS-LM delayed performance (r = 0.71, p <  0.05). In our study, the presence of the APOE ɛ4 allele was linked with decreased inter-hemispheric RSFC, which was attributed to memory performance in carriers.

%B J Alzheimers Dis %V 50 %P 1137-48 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836191?dopt=Abstract %R 10.3233/JAD-150989 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia. %A Vallortigara, Julie %A Whitfield, David %A Quelch, William %A Alghamdi, Amani %A Howlett, David %A Hortobágyi, Tibor %A Johnson, Mary %A Attems, Johannes %A O'Brien, John T %A Thomas, Alan %A Ballard, Clive G %A Aarsland, Dag %A Francis, Paul T %K Aged %K Aged, 80 and over %K alpha-Synuclein %K Amyloid beta-Peptides %K Analysis of Variance %K Cognition Disorders %K Dementia %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Regression Analysis %K Synaptophysin %K tau Proteins %K Vesicle-Associated Membrane Protein 2 %X

Alpha-synuclein (α-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), but are also frequently present in Alzheimer's disease (AD). Much remains unknown about the role of α-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key 'SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor' (SNARE) proteins as a consequence of alterations in the aggregation state of α-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p <  0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric α-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α-syn.

%B J Alzheimers Dis %V 50 %P 101-10 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639969?dopt=Abstract %R 10.3233/JAD-150707 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model. %A Aso, Ester %A Andrés-Benito, Pol %A Ferrer, Isidro %X

Previous reports have demonstrated that the combination of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) botanical extracts, which are the components of an already approved cannabis-based medicine, reduce the Alzheimer-like phenotype of AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Here, we provide evidence that such natural cannabinoids are still effective in reducing memory impairment in AβPP/PS1 mice at advanced stages of the disease but are not effective in modifying the Aβ processing or in reducing the glial reactivity associated with aberrant Aβ deposition as occurs when administered at early stages of the disease. The present study also demonstrates that natural cannabinoids do not affect cognitive impairment associated with healthy aging in wild-type mice. The positive effects induced by Δ9-THC and CBD in aged AβPP/PS1 mice are associated with reduced GluR2/3 and increased levels of GABA-A Rα1 in cannabinoid-treated animals when compared with animals treated with vehicle alone.

%B J Alzheimers Dis %V 54 %P 903-912 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567873?dopt=Abstract %R 10.3233/JAD-160533 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Delusions in Patients with Alzheimer's Disease: A Multidimensional Approach. %A D'Onofrio, Grazia %A Panza, Francesco %A Sancarlo, Daniele %A Paris, Francesco F %A Cascavilla, Leandro %A Mangiacotti, Antonio %A Lauriola, Michele %A Paroni, Giulia H %A Seripa, Davide %A Greco, Antonio %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Delusions %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Prognosis %K Risk %K Severity of Illness Index %K Time Factors %X

In Alzheimer's disease (AD) patients with delusions, clinical outcomes and mortality result from a combination of psychological, biological, functional, and environmental factors. We determined the effect of delusions on mortality risk, clinical outcomes linked to comprehensive geriatric assessment (CGA), cognitive, depressive, and neuropsychiatric symptoms (NPS) in 380 consecutive AD patients with Mini-Mental State Examination, Clinical Dementia Rating scale, 15-item Geriatric Depression Scale, and Neuropsychiatric Inventory (NPI), assessing one-year mortality risk using the Multidimensional Prognostic Index (MPI). We included 121 AD patients with delusions (AD-D) and 259 AD patients without delusions (AD-noD). AD-D patients were significantly older, with higher age at onset and cognitive impairment, a more severe stage of dementia, and more depressive symptoms than AD-noD patients. Disease duration was slightly higher in AD-D patients than in those without delusions, although this difference was not statistically significant. At CGA, AD-D patients showed a higher grade of disability in basic and instrumental activities of daily living, and an increased risk of malnutrition and bedsores. The two groups of patients significantly differed in MPI score (AD-D: 0.65 versus AD-noD: 0.51, p <  0.0001) and MPI grade. AD-D patients showed also a significant higher score in NPI of the following NPS than AD-noD patients: hallucinations, agitation/aggression, depression mood, apathy, irritability/lability, aberrant motor activity, sleep disturbances, and eating disorders. Therefore, AD-D patients showed higher dementia severity, and higher impairment in cognitive and depressive symptoms, and several neuropsychiatric domains than AD-noD patients, and this appeared to be associated with higher multidimensional impairment and increased risk of mortality.

%B J Alzheimers Dis %V 51 %P 427-37 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890768?dopt=Abstract %R 10.3233/JAD-150944 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dementia and Rapid Mortality: Who is at Risk? %A Staekenborg, Salka S %A Pijnenburg, Yolande A L %A Lemstra, Afina W %A Scheltens, Philip %A Vd Flier, Wiesje M %X

BACKGROUND: Dementia is typically known for its insidious onset and slowly progressive course, but a subgroup deteriorates fast and dies within years or even months.

OBJECTIVE: The purpose of this study was to characterize dementia patients with a rapidly progressive course to death and evaluate their cause of death.

METHODS: We retrospectively included all patients from the Amsterdam Dementia Cohort who died within two years after diagnosis. We evaluated the characteristics of these rapid progressors and compared them to patients known to be alive two years after diagnosis ('non-rapid mortality').

RESULTS: We included 129 dementia patients (13% of our total cohort with known follow-up) with rapid mortality (age 72±10 y [29%  <65 y], 70[55%]M, MMSE 20±5). Mean(SD) survival was 12±7 months. Compared to non-rapid mortality patients (n = 892; age 68±9, 503(56%)M, MMSE 22±5), patients with rapid mortality were slightly older at time of diagnosis, had lower MMSE scores, more depressive symptoms and higher prevalence of a cardiovascular history (all p < 0.05). Alzheimer's disease (AD, 43%) was most frequent in patients with rapid mortality, but the occurrence was much lower compared to non-rapid mortality patients (71%), while all other dementia diagnoses, especially Creutzfeldt-Jakob disease (CJD), vascular dementia (VaD), and frontotemporal dementia (FTD), were more frequent (p < 0.001). There were no specific characteristics for AD patients with rapid versus non-rapid mortality, especially APOE genotypes and CSF-profiles were comparable (p > 0.70). Cause of death was highly variable without a clear relation to dementia diagnosis, with exception of dementia itself in CJD, intracerebral hematoma in VaD, and motor neuron disease in FTD.

CONCLUSIONS: Short survival is relatively common (∼13% in our cohort) and occurs in all different types of dementia, with overrepresentation of non-AD dementias like CJD, VaD, and FTD.

%B J Alzheimers Dis %V 53 %P 135-42 %8 2016 Apr 19 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104894?dopt=Abstract %R 10.3233/JAD-151063 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dementia Apraxia Test (DATE): A Brief Tool to Differentiate Behavioral Variant Frontotemporal Dementia from Alzheimer's Dementia Based on Apraxia Profiles. %A Johnen, Andreas %A Frommeyer, Jana %A Modes, Fenja %A Wiendl, Heinz %A Duning, Thomas %A Lohmann, Hubertus %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Apraxias %K Diagnosis, Differential %K Female %K Frontotemporal Dementia %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Psychometrics %K Reference Values %X

BACKGROUND: Standardized praxis assessments with modern, empirically validated screening tests have substantially improved clinical evaluation of apraxia in patients with stroke. Although apraxia may contribute to early differential diagnosis of Alzheimer's dementia (AD) and behavioral variant frontotemporal dementia (bvFTD), no comparable test is readily available to clinicians for this purpose to date.

OBJECTIVE: To design a clinically useful apraxia test for the differentiation of AD and bvFTD.

METHODS: 84 test items pertaining to twelve praxis subdomains were evaluated for their efficacy to discriminate between patients with bvFTD (n = 24), AD (n = 28), and elderly healthy controls (HC; n = 35). Items were then selected based on discriminative value and psychometric properties.

RESULTS: Items indicative of mild AD comprised spatially complex imitation of hand and finger postures and to a lesser degree, pantomime of common object-use. Buccofacial apraxia including imitation of face postures, emblematic face postures, and repetition of multisyllabic pseudowords differentiated bvFTD from HC and AD. The final test version consisting of 20 items proved highly efficient for the discrimination of biologically confirmed dementia patients from HC (sensitivity 91% , specificity 71%) but also for differential diagnosis of bvFTD and AD (sensitivity 74% , specificity 93%).

CONCLUSIONS: Assessment of praxis profiles effectively contributes to diagnosis and differential diagnosis of AD and bvFTD. The Dementia Apraxia Test (DATE) is a brief and easy to administer cognitive tool for dementia assessment, has a high inter-rater reliability (Cohen's κ= 0.885) and demonstrates content validity.

%B J Alzheimers Dis %V 49 %P 593-605 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484911?dopt=Abstract %R 10.3233/JAD-150447 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dementia Risk and Protective Factors Differ in the Context of Memory Trajectory Groups. %A Zahodne, Laura B %A Schupf, Nicole %A Brickman, Adam M %A Mayeux, Richard %A Wall, Melanie M %A Stern, Yaakov %A Manly, Jennifer J %X

BACKGROUND: Previous research has identified multiple risk and protective factors for late onset Alzheimer's disease (LOAD). However, it is not known whether these risk and protective factors differ for individuals who are cognitively stable versus those already experiencing declines.

OBJECTIVE: This study examined how dementia risk factors differ across subgroups of older adults defined by memory trajectory. This line of research may lead to more individualized risk profiles.

METHODS: Risk factors for incident LOAD were compared across previously-validated groups of older adults exhibiting different memory trajectories ("Stable-High," "Stable-Low," "Decliner," "Rapid Decliner") using stratified Cox regressions. Participants included 2,593 racially/ethnically diverse older adults (mean age of 76 at study entry) in the Washington Heights-Inwood Columbia Aging Project.

RESULTS: Predictors of incident dementia differed across trajectory groups: older age only incurred independent risk in stable groups, education did not incur independent protection in the rapidly declining group, depression only incurred independent risk in the stable-low group, stroke incurred independent risk in the two extreme groups, and APOE-ɛ4 only incurred independent risk in the rapidly declining group.

CONCLUSION: The finding that different risk factors for LOAD were associated with specific memory trajectories may reflect the existence of resilience or vulnerability factors that modify the individual influences of risk/protective factors. This study highlights the utility of considering interactions between dementia risk factors and a patient's unique cognitive history.

%B J Alzheimers Dis %V 52 %P 1013-20 %8 2016 Apr 12 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079709?dopt=Abstract %R 10.3233/JAD-151114 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Depressive Endophenotype for Predicting Cognitive Decline among Mexican American Adults and Elders. %A Johnson, Leigh A %A Gamboa, Adriana %A Vintimilla, Raul %A Edwards, Melissa %A Hall, James %A Weiser, Brent %A Yadav, Menaka %A Dickensheets, Tony %A O'Bryant, Sid E %X

BACKGROUND: Late life depression is a prodromal feature and a risk factor for Alzheimer's disease (AD) and mild cognitive impairment (MCI). We identified five items in the Geriatric Depression scale (DepE) that are important as a risk for MCI and AD: memory problems, feeling blue, crying, feeling worthless, and trouble concentrating.

OBJECTIVE: Our goal was to examine the relationship between DepE and cognition in a cohort of Mexican Americans.

METHODS: Data from 317 Mexican Americans from the HABLE study were analyzed. DepE scores were dichotomized into two groups: endorsement of 1 item or less, and endorsement of 2 or more items. Cognition was assessed via neuropsychological tests, and diagnosis was based on consensus review. We utilized linear regression to examine the association between DepE and cognitive performance, and logistic regression to examine the utility of DepE in predicting MCI. To examine the impact of DepE on memory over 12 months, we performed ANOVA analysis.

RESULTS: Elevated DepE scores were associated with poorer performance on various measures of memory and cognition, but not executive or visual spatial skills. Over 12 months, we found a decline in immediate memory among women but not men. Those with high scores were 4 times more likely to have MCI. ANOVA of total scores revealed differences between groups on immediate memory (p < 0.05) in women, with no significant differences on delay recall in either gender.

CONCLUSION: DepE can be utilized in Mexican Americans to identify those at risk of memory related cognitive decline.

%B J Alzheimers Dis %V 54 %P 201-6 %8 2016 Jul 25 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472872?dopt=Abstract %R 10.3233/JAD-150743 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Depressive Symptoms and Small Hippocampal Volume Accelerate the Progression to Dementia from Mild Cognitive Impairment. %A Chung, Jun Ku %A Plitman, Eric %A Nakajima, Shinichiro %A Chakravarty, M Mallar %A Caravaggio, Fernando %A Takeuchi, Hiroyoshi %A Gerretsen, Philip %A Iwata, Yusuke %A Patel, Raihaan %A Mulsant, Benoit H %A Graff-Guerrero, Ariel %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Dementia %K Depression %K Disease Progression %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Psychiatric Status Rating Scales %X

Previous studies have highlighted that decreased hippocampal volume, an early neural correlate of dementia, is commonly observed in patients with mild cognitive impairment (MCI). However, it is unclear whether neurodegenerative and resultant clinical trajectories are accelerated in MCI patients with concomitant depressive symptoms, leading to a faster conversion to dementia stages than those who are not depressed. No longitudinal study has investigated whether depressed amnestic MCI (DEP+aMCI) patients show an earlier onset of progression to dementia than non-depressed amnestic MCI (DEP-aMCI) patients and whether progressive hippocampal volume reductions are related in the conversion process. Using data from Alzheimer's Disease Neuroimaging Initiative, we examined 2-year follow-up data from 38 DEP+aMCI patients and 38 matched DEP-aMCI patients and compared their ages of conversion from aMCI to AD and trajectories of progressive hippocampal volume changes. DEP+ and DEP- patients were defined as having baseline Geriatric Depression Scale scores of 5 or above and 0, respectively. DEP+ converters showed earlier ages of conversion to dementia (p = 0.009) and greater left hippocampal volume loss than both DEP- converters and DEP+ non-converters over the 2-year period (p = 0.003, p = 0.001, respectively). These findings could not be explained by changes in total brain volume, differences in their clinical symptoms of dementia, daily functioning, or apolipoprotein E4 genotypes. No difference in conversion rate to dementia or progressive hippocampal volume change was found between DEP+ patients and DEP-patients, which suggested depressive symptoms themselves may not lead to progression of dementia from MCI. In conclusion, there is a synergistic effect of depressive symptoms and smaller left hippocampal volume in MCI patients that accelerates conversion to dementia.

%B J Alzheimers Dis %V 49 %P 743-54 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519442?dopt=Abstract %R 10.3233/JAD-150679 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Describing the Sequence of Cognitive Decline in Alzheimer's Disease Patients: Results from an Observational Study. %A Henneges, Carsten %A Reed, Catherine %A Chen, Yun-Fei %A Dell'Agnello, Grazia %A Lebrec, Jeremie %X

BACKGROUND: Improved understanding of the pattern of cognitive decline in Alzheimer's disease (AD) would be useful to assist primary care physicians in explaining AD progression to patients and caregivers.

OBJECTIVE: To identify the sequence in which cognitive abilities decline in community-dwelling patients with AD.

METHODS: Baseline data were analyzed from 1,495 patients diagnosed with probable AD and a Mini-Mental State Examination (MMSE) score ≤ 26 enrolled in the 18-month observational GERAS study. Proportional odds logistic regression models were applied to model MMSE subscores (orientation, registration, attention and concentration, recall, language, and drawing) and the corresponding subscores of the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), using MMSE total score as the index of disease progression. Probabilities of impairment start and full impairment were estimated at each MMSE total score level.

RESULTS: From the estimated probabilities for each MMSE subscore as a function of the MMSE total score, the first aspect of cognition to start being impaired was recall, followed by orientation in time, attention and concentration, orientation in place, language, drawing, and registration. For full impairment in subscores, the sequence was recall, drawing, attention and concentration, orientation in time, orientation in place, registration, and language. The sequence of cognitive decline for the corresponding ADAS-cog subscores was remarkably consistent with this pattern.

CONCLUSION: The sequence of cognitive decline in AD can be visualized in an animation using probability estimates for key aspects of cognition. This might be useful for clinicians to set expectations on disease progression for patients and caregivers.

%B J Alzheimers Dis %V 52 %P 1065-80 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079700?dopt=Abstract %R 10.3233/JAD-150852 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Detection of Alzheimer's Disease by Three-Dimensional Displacement Field Estimation in Structural Magnetic Resonance Imaging. %A Wang, Shuihua %A Zhang, Yudong %A Liu, Ge %A Phillips, Preetha %A Yuan, Ti-Fei %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Brain Mapping %K Datasets as Topic %K Female %K Humans %K Imaging, Three-Dimensional %K Machine Learning %K Magnetic Resonance Imaging %K Male %X

BACKGROUND: Within the past decade, computer scientists have developed many methods using computer vision and machine learning techniques to detect Alzheimer's disease (AD) in its early stages.

OBJECTIVE: However, some of these methods are unable to achieve excellent detection accuracy, and several other methods are unable to locate AD-related regions. Hence, our goal was to develop a novel AD brain detection method.

METHODS: In this study, our method was based on the three-dimensional (3D) displacement-field (DF) estimation between subjects in the healthy elder control group and AD group. The 3D-DF was treated with AD-related features. The three feature selection measures were used in the Bhattacharyya distance, Student's t-test, and Welch's t-test (WTT). Two non-parallel support vector machines, i.e., generalized eigenvalue proximal support vector machine and twin support vector machine (TSVM), were then used for classification. A 50 × 10-fold cross validation was implemented for statistical analysis.

RESULTS: The results showed that "3D-DF+WTT+TSVM" achieved the best performance, with an accuracy of 93.05 ± 2.18, a sensitivity of 92.57 ± 3.80, a specificity of 93.18 ± 3.35, and a precision of 79.51 ± 2.86. This method also exceled in 13 state-of-the-art approaches. Additionally, we were able to detect 17 regions related to AD by using the pure computer-vision technique. These regions include sub-gyral, inferior parietal lobule, precuneus, angular gyrus, lingual gyrus, supramarginal gyrus, postcentral gyrus, third ventricle, superior parietal lobule, thalamus, middle temporal gyrus, precentral gyrus, superior temporal gyrus, superior occipital gyrus, cingulate gyrus, culmen, and insula. These regions were reported in recent publications.

CONCLUSIONS: The 3D-DF is effective in AD subject and related region detection.

%B J Alzheimers Dis %V 50 %P 233-48 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682696?dopt=Abstract %R 10.3233/JAD-150848 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Detection of Striatal Amyloid Plaques with [18F]flutemetamol: Validation with Postmortem Histopathology. %A Beach, Thomas G %A Thal, Dietmar Rudolf %A Zanette, Michelle %A Smith, Adrian %A Buckley, Christopher %X

Amyloid imaging is limited by an inconsistent relationship between cerebral cortex amyloid- β (Aβ) plaques and dementia. Autopsy studies suggest that Aβ plaques first appear in the cerebral cortex while subcortical plaques are present only later in the disease course. The presence of abundant plaques in both cortex and striatum is more strongly correlated with the presence of dementia than cortical Aβ plaques alone. Additionally, detection of striatal plaques may allow, for the first time, pathology-based clinical staging of AD. Striatal plaques are reportedly identifiable by amyloid imaging but the accuracy and reliability of striatal amyloid imaging has never been tested against postmortem histopathology. To determine this, we correlated the presence of histopathologically-demonstrated striatal Aβ deposits with a visually positive panel consensus decision of a positive [18F]flutemetamol striatal PET signal in 68 subjects that later came to autopsy. The sensitivity of [18F]flutemetamol PET striatal amyloid imaging, for several defined density levels of histological striatal Aβ deposits, ranged between 69% and 87% while the specificity ranged between 96% and 100%. Sensitivity increased with higher histological density thresholds while the reverse was found for specificity. In general, as compared with PET alone, PET with CT had slightly higher sensitivities but slightly lower specificities. In conclusion, amyloid imaging of the striatum with [18F]flutemetamol PET has reasonable accuracy for the detection of histologically-demonstrated striatal Aβ plaques when present at moderate or frequent densities. Amyloid imaging of the cerebral cortex and striatum together may allow for a more accurate clinicopathological diagnosis of AD and enable pathology-based clinical staging of AD.

%B J Alzheimers Dis %V 52 %P 863-73 %8 2016 Mar 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031469?dopt=Abstract %R 10.3233/JAD-150732 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Developing Cognitive Markers of Alzheimer's Disease for Primary Care: Implications for Behavioral and Global Prevention. %A Levy, Boaz %A Tsoy, Elena %A Gable, Samuel %X

A comprehensive approach to the prevention of Alzheimer's disease (AD) warrants a synergy across multiple domains and procedures. Whereas the study of biological markers has mobilized major activity in the field, the development of cognitive markers is largely ignored, despite the unique advantages they may offer. Cognitive markers essentially assess the core clinical feature that biological markers intend to predict. In this respect, cognitive markers expand the foundation of preclinical diagnostics and disease staging in a manner that integrates both physiological and psychological factors. In addition, the cost-effective implementation of cognitive markers makes them remarkably conducive to community-wide screenings, and thereby a vital component of any global blueprint for prevention. Specifically, in the primary care setting, cognitive markers may provide effective gate keeping for more invasive, labor intensive, and expensive procedures. From this perspective, cognitive markers may provide the first step for identifying preclinical treatment recipients in general public. Moreover, the detection of preclinical decline via cognitive markers can increase awareness of AD risk and the motivation for making protective lifestyle changes. The behavioral approach might be expedient for prevention in light of the compelling evidence of lifestyle amelioration of AD risk. In an integrative view, incorporating cognitive markers to primary care may facilitate a synergetic development in preventive interventions that carries epidemiological significance. This paper addresses the theoretical, methodological, and pragmatic aspects of this prospect.

%B J Alzheimers Dis %V 54 %P 1259-1272 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567831?dopt=Abstract %R 10.3233/JAD-160309 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Development and Validation of the RxDx-Dementia Risk Index to Predict Dementia in Patients with Type 2 Diabetes and Hypertension. %A Mehta, Hemalkumar B %A Mehta, Vinay %A Tsai, Chu-Lin %A Chen, Hua %A Aparasu, Rajender R %A Johnson, Michael L %K Aged %K Aged, 80 and over %K Cohort Studies %K Dementia %K Diabetes Mellitus, Type 2 %K Female %K Humans %K Hypertension %K Male %K Middle Aged %K Predictive Value of Tests %K Prescription Drugs %K Proportional Hazards Models %K Reproducibility of Results %K Risk Assessment %K Risk Factors %X

BACKGROUND: Elderly patients with type 2 diabetes mellitus and hypertension are at high risk for developing dementia. In addition to comorbid disease conditions (Dx), prescription drugs (Rx) are important risk factors for dementia.

OBJECTIVE: Develop and validate the RxDx-Dementia risk index by combining diagnosis and prescription information in a single risk index to predict incident dementia, and compare its performance with diagnosis-based Charlson comorbidity score (CCS) and prescription-based chronic disease score (CDS).

METHODS: Elderly patients diagnosed with type 2 diabetes mellitus and hypertension, and without prior dementia were identified from the Clinical Practice Research Datalink (2003-2012). A Cox proportional hazard model was constructed to model the time to dementia by incorporating age, gender, and 31 RxDx disease conditions as independent variables. Points were assigned to risk factors to obtain summary risk score. Discrimination and calibration of the risk index were evaluated. Different risk indices were compared against RxDx-Dementia risk index using c-statistic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI).

RESULTS: Of 133,176 patients with type 2 diabetes mellitus and hypertension, 3.42% patients developed dementia.The c-statistics value for RxDx-Dementia risk index was 0.806 (95% CI, 0.799-0.812). Based on the c-statistics, NRI and IDI values, the RxDx-Dementia risk index performed better compared to CCS, CDS, and their combinations.

CONCLUSION: The RxDx-Dementia risk index can be a useful tool to identify hypertensive and diabetic patients who are at high risk of developing dementia. This has implications for clinical management of patients with multiple comorbid conditions as well as risk adjustment for database studies.

%B J Alzheimers Dis %V 49 %P 423-32 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519436?dopt=Abstract %R 10.3233/JAD-150466 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Development of a Proxy-Free Objective Assessment Tool of Instrumental Activities of Daily Living in Mild Cognitive Impairment Using Smart Home Technologies. %A Jekel, Katrin %A Damian, Marinella %A Storf, Holger %A Hausner, Lucrezia %A Frölich, Lutz %X

BACKGROUND: The assessment of activities of daily living (ADL) is essential for dementia diagnostics. Even in mild cognitive impairment (MCI), subtle deficits in instrumental ADL (IADL) may occur and signal a higher risk of conversion to dementia. Thus, sensitive and reliable ADL assessment tools are important. Smart homes equipped with sensor technology and video cameras may provide a proxy-free assessment tool for the detection of IADL deficits.

OBJECTIVE: The aim of this paper is to investigate the potential of a smart home environment for the assessment of IADL in MCI.

METHOD: The smart home consisted of a two-room flat equipped with activity sensors and video cameras. Participants with either MCI or healthy controls (HC) had to solve a standardized set of six tasks, e.g., meal preparation, telephone use, and finding objects in the flat.

RESULTS: MCI participants needed more time (1384 versus 938 seconds, p <  0.001) and scored less total points (48 versus 57 points, p <  0.001) while solving the tasks than HC. Analyzing the subtasks, intergroup differences were observed for making a phone call, operating the television, and retrieving objects. MCI participants showed more searching and task-irrelevant behavior than HC. Task performance was correlated with cognitive status and IADL questionnaires but not with participants' age.

CONCLUSION: This pilot study showed that smart home technologies offer the chance for an objective and ecologically valid assessment of IADL. It can be analyzed not only whether a task is successfully completed but also how it is completed. Future studies should concentrate on the development of automated detection of IADL deficits.

%B J Alzheimers Dis %V 52 %P 509-17 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031479?dopt=Abstract %R 10.3233/JAD-151054 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Development of a Standardized Approach to Disclosing Amyloid Imaging Research Results in Mild Cognitive Impairment. %A Lingler, Jennifer H %A Butters, Meryl A %A Gentry, Amanda L %A Hu, Lu %A Hunsaker, Amanda E %A Klunk, William E %A Mattos, Meghan K %A Parker, Lisa A %A Roberts, J Scott %A Schulz, Richard %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Brain %K Brain Chemistry %K Cognitive Dysfunction %K Disclosure %K Family %K Female %K Focus Groups %K Health Communication %K Humans %K Male %K Middle Aged %K Patient Satisfaction %K Pilot Projects %K Positron-Emission Tomography %X

The increased use of PET amyloid imaging in clinical research has sparked numerous concerns about whether and how to return such research test results to study participants. Chief among these is the question of how best to disclose amyloid imaging research results to individuals who have cognitive symptoms that could impede comprehension of the information conveyed. We systematically developed and evaluated informational materials for use in pre-test counseling and post-test disclosures of amyloid imaging research results in mild cognitive impairment (MCI). Using simulated sessions, persons with MCI and their family care partners (N = 10 dyads) received fictitious but realistic information regarding brain amyloid status, followed by an explanation of how results impact Alzheimer's disease risk. Satisfaction surveys, comprehension assessments, and focus group data were analyzed to evaluate the materials developed. The majority of persons with MCI and their care partners comprehended and were highly satisfied with the information presented. Focus group data reinforced findings of high satisfaction and included 6 recommendations for practice: 1) offer pre-test counseling, 2) use clear graphics, 3) review participants' own brain images during disclosures, 4) offer take-home materials, 5) call participants post-disclosure to address emerging questions, and 6) communicate seamlessly with primary care providers. Further analysis of focus group data revealed that participants understood the limitations of amyloid imaging, but nevertheless viewed the prospect of learning one's amyloid status as valuable and empowering.

%B J Alzheimers Dis %V 52 %P 17-24 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060950?dopt=Abstract %R 10.3233/JAD-150985 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnosing Dementia in the Clinical Setting: Can Amyloid PET Provide Additional Value Over Cerebrospinal Fluid? %A Weston, Philip S J %A Paterson, Ross W %A Dickson, John %A Barnes, Anna %A Bomanji, Jamshed B %A Kayani, Irfan %A Lunn, Michael P %A Mummery, Catherine J %A Warren, Jason D %A Rossor, Martin N %A Fox, Nick C %A Zetterberg, Henrik %A Schott, Jonathan M %X

Cerebrospinal fluid (CSF) measures of amyloid and tau are the first-line Alzheimer's disease biomarkers in many clinical centers. We assessed if and when the addition of amyloid PET following CSF measurements provides added diagnostic value. Twenty patients from a cognitive clinic, who had undergone detailed assessment including CSF measures, went on to have amyloid PET. The treating neurologist's working diagnosis, and degree of diagnostic certainty, was assessed both before and after the PET. Amyloid PET changed the diagnosis in 7/20 cases. Amyloid PET can provide added diagnostic value, particularly in young-onset, atypical dementias, where CSF results are borderline and diagnostic uncertainty remains.

%B J Alzheimers Dis %V 54 %P 1297-1302 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567830?dopt=Abstract %R 10.3233/JAD-160302 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnosis of Dementia in the Specialist Setting: A Comparison Between the Swedish Dementia Registry (SveDem) and the Registry of Dementias of Girona (ReDeGi). %A Garre-Olmo, Josep %A Garcia-Ptacek, Sara %A Calvó-Perxas, Laia %A Turró-Garriga, Oriol %A López-Pousa, Secundino %A Eriksdotter, Maria %X

The aim of this study was to compare the frequency of dementia diagnoses from two dementia registries in Europe. Patients registered between 2007 and 2013 in the Swedish Dementia Registry (SveDem; Sweden) and in the Registry of Dementias of Girona (ReDeGi; North-East of Spain) were selected. We compared sociodemographic data, Mini-Mental State Examination (MMSE) scores, dementia subtype, and medication consumption of 22,384 cases from SveDem and 5,032 cases from ReDeGi. The average age (78.1 years SveDem versus 79.7 years ReDeGi) and the gender (female 58.2% SveDem versus 61.5% ReDeGi) did not greatly differ. MMSE score at diagnosis was higher for SveDem cases (22.1 versus 17.8). Alzheimer's disease (AD) accounted for the main dementia subtype (36.6% SveDem versus 55.6% ReDeGi). The proportion of vascular dementia (VaD) and mixed dementia was higher in SveDem (18.8% versus 6.4% and 24.9 versus 13.4%), with an odds ratio (OR) and 95% confidence interval (CI) for SveDem relative to the ReDeGi of 3.41 (3.03-3.84) for VaD, and 2.15 (1.97-2.35) for mixed dementia. This was at the expense of a lower frequency of AD in SveDem (OR 0.41; 95% CI 0.39-0.44). Other dementia diagnoses such as frontotemporal dementia or dementia with Lewy bodies did not significantly differ between registries (2.3% versus 2.9%; 1.9 versus 3.1%). Large differences in medication consumption at the time of dementia diagnosis were detected (4.7 treatments SveDem versus 6.8 ReDeGi). Northern and southern European dementia cohorts differ in demographic characteristics, MMSE score at diagnosis, and drug treatment profile.

%B J Alzheimers Dis %V 53 %P 1341-51 %8 2016 Jul 01 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392854?dopt=Abstract %R 10.3233/JAD-160098 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnostic Accuracy of MRI and Additional [18F]FDG-PET for Behavioral Variant Frontotemporal Dementia in Patients with Late Onset Behavioral Changes. %A Vijverberg, Everard G B %A Wattjes, Mike P %A Dols, Annemiek %A Krudop, Welmoed A %A Möller, Christiane %A Peters, Anne %A Kerssens, Cora J %A Gossink, Flora %A Prins, Niels D %A Stek, Max L %A Scheltens, Philip %A van Berckel, Bart N M %A Barkhof, Frederik %A Pijnenburg, Yolande A L %X

BACKGROUND: Neuroimaging has a reasonable accuracy to differentiate behavioral variant frontotemporal dementia (bvFTD) from other neurodegenerative disorders, its value for the differentiation of bvFTD among subjects with acquired behavioral disturbances is unknown.

OBJECTIVE: To determine the diagnostic accuracy of MRI, additional [18F]FDG-PET, and their combination for bvFTD among subjects with late onset behavioral changes.

METHODS: Patients with late onset behavioral changes referred to a memory clinic or psychiatric services were included. At baseline, 111 patients had a brain MRI scan and 74 patients received an additional [18F]FDG-PET when the MRI was inconclusive. The consensus diagnosis after two-year-follow-up was used as the gold standard to calculate sensitivity and specificity for baseline neuroimaging.

RESULTS: 27 patients had probable/definite bvFTD and 84 patients had a non-bvFTD diagnosis (primary psychiatric diagnosis or other neurological disorders). MRI had a sensitivity of 70% (95% CI 52-85%) with a specificity of 93% (95% CI 86-97%). Additional [18F]FDG-PET had a sensitivity of 90% (95% CI 66-100%) with a specificity of 68% (95% CI 56-79%). The sensitivity of combined neuroimaging was 96% (95% CI 85-100%) with a specificity of 73% (95% CI 63-81%). In 66% of the genetic FTD cases, MRI lacked typical frontotemporal atrophy. 40% of cases with a false positive [18F]FDG-PET scan had a primary psychiatric diagnosis.

CONCLUSION: A good diagnostic accuracy was found for MRI and additional [18F]FDG-PET for bvFTD in patients with late onset behavioral changes. Caution with the interpretation of neuroimaging results should especially be taken in cases with a genetic background and in cases with a primary psychiatric differential diagnosis where [18F]FDG-PET is the only abnormal investigation.

%B J Alzheimers Dis %V 53 %P 1287-97 %8 2016 Jun 30 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372646?dopt=Abstract %R 10.3233/JAD-160285 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnostic Assessment and Management of Dysphagia in Patients with Alzheimer's Disease. %A Boccardi, Virginia %A Ruggiero, Carmelinda %A Patriti, Alberto %A Marano, Luigi %K Alzheimer Disease %K Deglutition Disorders %K Humans %X

A growing concern in patients affected by Alzheimer's disease (AD) is dysphagia, or swallowing impairment, which leads to malnutrition, dehydration, weight loss, functional decline and fear of eating and drinking, as well as a decrease in the quality of life. Thus the diagnostic assessment of dysphagia in patients with AD is imperative to ensure that they receive effective management, avoiding complications, and reducing comorbidity and mortality in such a growing population. Dysphagia management requires a multidisciplinary approach considering that no single strategy is appropriate for all patients. However, evidence for clinical diagnostic assessment, interventions, and medical management of dysphagia in these patients are still limited: few studies are reporting the evaluation and the management among this group of patients. Here we analyzed the most recent findings in diagnostic assessment and management of swallowing impairment in patients affected by AD.

%B J Alzheimers Dis %V 50 %P 947-55 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836016?dopt=Abstract %R 10.3233/JAD-150931 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnostic Distortions: A Case Report of Progressive Apraxia of Speech. %A Brodtmann, Amy %A Pemberton, Hugh %A Darby, David %A Vogel, Adam P %X

Apraxia of speech (AOS) can be the presenting symptom of neurodegenerative disease. The position of primary progressive AOS in the nosology of the dementias is still controversial. Despite seeing many specialists, patients are often misdiagnosed, in part due to a lack of quantitative measures of speech dysfunction. We present a single case report of a patient presenting with AOS, including acoustic analysis, language assessment, and brain imaging. A 52-year-old woman presenting with AOS had remained undiagnosed for 6 years despite seeing 8 specialists. Results of her MRI scans, genetic testing, and computerized speech analysis are provided. AOS is an underdiagnosed clinical syndrome causing great distress to patients and families. Using acoustic analysis of speech may lead to improved diagnostic accuracy. AOS is a complex entity with an expanding phenotype, and quantitative clinical measures will be critical for detection and to assess progression.

%B J Alzheimers Dis %V 53 %P 79-83 %8 2016 Apr 19 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104903?dopt=Abstract %R 10.3233/JAD-160069 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnostic Impact of Cerebrospinal Fluid Biomarker (Pre-)Analytical Variability in Alzheimer's Disease. %A Niemantsverdriet, Ellis %A Goossens, Joery %A Struyfs, Hanne %A Martin, Jean-Jacques %A Goeman, Johan %A De Deyn, Peter Paul %A Vanderstichele, Hugo %A Engelborghs, Sebastiaan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Autopsy %K Cognitive Dysfunction %K Enzyme-Linked Immunosorbent Assay %K Exercise %K Female %K Follow-Up Studies %K Humans %K Male %K Middle Aged %K Peptide Fragments %K Psychiatric Status Rating Scales %K Retrospective Studies %K Statistics, Nonparametric %K tau Proteins %X

Intra- and inter-laboratory variability of cerebrospinal fluid (CSF) biomarker analyses remains an important issue. We investigated the clinical-diagnostic impact of CSF biomarker concentration shifts in mild cognitive impairment (MCI) and autopsy-confirmed Alzheimer's disease (AD) dementia patients. MCI patients (n = 85), autopsy-confirmed AD dementia patients (n = 72), and cognitively healthy controls (n = 100) were included in this prospective, longitudinal study. AD dementia patients were followed up until death, and controls were included from 1992 until 2003. In-house validated cutoff values of biomarkers were applied: Aβ1-42 <638.5 pg/mL, T-tau>296.5 pg/mL, P-tau(181P) >56.5 pg/mL. Both increments and decrements (from ± 5% to ± 40% ) were added to the true (=observed) CSF biomarker values, imitating the anticipated differences in biomarker concentrations. Within certain limits, the clinical diagnostic performance of AD CSF biomarkers remains largely unchanged and clinical diagnostic accuracy deviated less than 8.2% from the reference when concentration shifts ranging between -20% and +20% were added to one of the three CSF biomarkers in MCI and autopsy-confirmed AD patients. Notwithstanding the fact that (pre- and post-)analytical parameters can affect the clinical classification, the present exploratory study provides evidence that for a specific context of use, the impact on clinical accuracy of biomarker concentration shifts might be lower than originally expected. In conclusion, induced shifts of ±20% in only one of the three biomarkers has limited impact on the clinical accuracy of AD CSF biomarkers in MCI and autopsy-confirmed AD patients when using the IWG-2 criteria.

%B J Alzheimers Dis %V 51 %P 97-106 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836187?dopt=Abstract %R 10.3233/JAD-150953 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnostic Value of Cerebrospinal Fluid Biomarkers (Phospho-Tau181, total-Tau, Aβ42, and Aβ40) in Prodromal Stage of Alzheimer's Disease and Dementia with Lewy Bodies. %A Bousiges, Olivier %A Cretin, Benjamin %A Lavaux, Thomas %A Philippi, Nathalie %A Jung, Barbara %A Hezard, Sylvie %A Heitz, Camille %A Demuynck, Catherine %A Gabel, Aurelia %A Martin-Hunyadi, Catherine %A Blanc, Frédéric %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Lewy Body Disease %K Male %K Middle Aged %K Peptide Fragments %K Prodromal Symptoms %K Psychiatric Status Rating Scales %K Retrospective Studies %K Statistics, Nonparametric %K tau Proteins %X

BACKGROUND: Dementia with Lewy bodies (DLB) symptoms are close to those of Alzheimer's disease (AD), and the differential diagnosis is difficult especially early in the disease. Unfortunately, AD biomarkers in cerebrospinal fluid (CSF), and more particularly Aβ1 - 42, appear to be altered in dementia with Lewy bodies (DLB). However, the level of these biomarkers has never been studied in the prodromal stage of the disease.

OBJECTIVE: To compare these biomarkers between DLB and AD, with a particular focus on the prodromal stage.

METHODS: A total of 166 CSF samples were collected at the memory clinic of Strasbourg. They were obtained from prodromal DLB (pro-DLB), DLB dementia, prodromal AD (pro-AD), and AD dementia patients, and elderly controls. Phospho-Tau181, total-Tau, Aβ42, and Aβ40 were measured in the CSF.

RESULTS: At the prodromal stage, contrary to AD patients, DLB patients' biomarker levels in the CSF were not altered. At the demented stage of DLB, Aβ42 levels were reduced as well as Aβ40 levels. Thus, the Aβ42/Aβ40 ratio remained unchanged between the prodromal and demented stages, contrary to what was observed in AD. Tau and Phospho-Tau181 levels were unaltered in DLB patients.

CONCLUSIONS: We have shown that at the prodromal stage the DLB patients had no pathological profile. Consequently, CSF AD biomarkers are extremely useful for differentiating AD from DLB patients particularly at this stage when the clinical diagnosis is difficult. Thus, these results open up new perspectives on the interpretation of AD biomarkers in DLB.

%B J Alzheimers Dis %V 51 %P 1069-83 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923009?dopt=Abstract %R 10.3233/JAD-150731 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diet and Inflammation in Alzheimer's Disease and Related Chronic Diseases: A Review. %A Gardener, Samantha L %A Rainey-Smith, Stephanie R %A Martins, Ralph N %K Alzheimer Disease %K Cardiovascular Diseases %K Chronic Disease %K Diet %K Humans %K Inflammation %K Neurodegenerative Diseases %X

Inflammation is one of the pathological features of the neurodegenerative disease, Alzheimer's disease (AD). A number of additional disorders are likewise associated with a state of chronic inflammation, including obesity, cardiovascular disease, and type-2 diabetes, which are themselves risk factors for AD. Dietary components have been shown to modify the inflammatory process at several steps of the inflammatory pathway. This review aims to evaluate the published literature on the effect of consumption of pro- or anti-inflammatory dietary constituents on the severity of both AD pathology and related chronic diseases, concentrating on the dietary constituents of flavonoids, spices, and fats. Diet-based anti-inflammatory components could lead to the development of potent novel anti-inflammatory compounds for a range of diseases. However, further work is required to fully characterize the therapeutic potential of such compounds, including gaining an understanding of dose-dependent relationships and limiting factors to effectiveness. Nutritional interventions utilizing anti-inflammatory foods may prove to be a valuable asset in not only delaying or preventing the development of age-related neurodegenerative diseases such as AD, but also treating pre-existing conditions including type-2 diabetes, cardiovascular disease, and obesity.

%B J Alzheimers Dis %V 50 %P 301-34 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682690?dopt=Abstract %R 10.3233/JAD-150765 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dietary high cholesterol and trace metals in the drinking water increase levels of ABCA1 in the rabbit hippocampus and temporal cortex. %A Schreurs, Bernard G %A Sparks, D Larry %K Aluminum %K Alzheimer Disease %K Animals %K ATP-Binding Cassette Transporters %K Brain Chemistry %K Cholesterol, Dietary %K Copper %K Drinking Water %K Hippocampus %K Male %K Neurons %K Rabbits %K Temporal Lobe %K Zinc %X

BACKGROUND: Cholesterol-fed rabbits have been documented to show increased amyloid-β (Aβ) deposits in the brain that can be exacerbated by the quality of drinking water especially if rabbits drink tap water or distilled water containing copper. One mechanism of cholesterol and Aβ clearance may be through the ATP-binding cassette transporter A1 (ABCA1).

OBJECTIVE AND METHODS: Using an ABCA1 antibody, we determined the number of ABCA1-immunopositive neurons in three areas of rabbit brain as a function of feeding 2% cholesterol and providing tap water, distilled water, or distilled water to which aluminum, copper, or zinc was added.

RESULTS: The number of neurons with ABCA1 immunoreactivity was increased significantly as a result of dietary cholesterol in the rabbit hippocampus and inferior and superior temporal cortex. The number of neurons with ABCA1 immunoreactivity was further increased in all three areas as a result of cholesterol-fed rabbits drinking tap water or distilled water with copper. Finally, cholesterol-fed rabbits that drank distilled water with aluminum also showed an increased number of ABCA1-immunopositive neurons in inferior and superior temporal cortex.

CONCLUSIONS: These data suggest that ABCA1 levels increase in parallel with previously documented increases in Aβ levels as a result of high dietary cholesterol and copper in the drinking water. Addition of aluminum to distilled water may have a similar effect in the temporal cortex. ABCA1 has been proposed as a means of clearing Aβ from the brain and manipulations that increase Aβ also result in an increase of clearance machinery.

%B J Alzheimers Dis %V 49 %P 201-9 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444796?dopt=Abstract %R 10.3233/JAD-150601 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differences in Depressive Patterns According to Disease Severityin Early-Onset Alzheimer's Disease. %A Yoon, Bora %A Yang, Dong Won %A Hong, Yun Jeong %A Choi, Seong Hye %A Park, Sun Ah %A Park, Hee Kyung %A Kim, Yong Duk %A Shim, Yong S %X

BACKGROUND & OBJECTIVE: Depression frequently combines with dementia, including early-onset Alzheimer's disease (EOAD). We investigated differences in prevalence and characteristics of depressive symptoms according to dementia severity in EOAD patients.

METHODS: The 15-item Korean version of the Geriatric Depression Scale (GDS-15) was administered to 412 EOAD patients. Factor analysis was used to assess GDS-15 factor structure. We subdivided participants into three groups by disease severity, then compared the frequencies and scores of individual GDS-15 items and performed logistic regression analysis to assess associations between depressive symptoms and EOAD stage.

RESULTS: Factor analysis yielded three factor categories: 1) "hopelessness and ominousness" (symptoms no. 6, 8, 12, 14, 15); 2) "unhappiness and dissatisfaction" (no. 1, 3, 5, 7, 11); and 3) "monotony and lack of energy" (no. 2, 4, 9, 10, 13). Factor 2 depressive symptoms (no. 1, 5, 11) were less common in moderate EOAD. The risk of Factor 1 symptoms: no. 12 (OR, 2.04; 95% CI, 1.19-3.50; p = 0.010) and 14 (OR, 1.84; 95% CI, 1.07-3.16; p = 0.028) was higher in mild than very mild EOAD. The risk of Factor 2 symptoms: no. 9 (OR, 2.69; 95% CI, 1.08-6.71; p = 0.033) and 13 (OR, 2.12; 95% CI, 1.02-4.40; p = 0.043) was higher in moderate than mild EOAD.

CONCLUSION: We confirmed that depressive symptoms differ according to EOAD severity. When assessing depressive symptoms related to dementia progression, we recommend focusing on "hopelessness and ominousness" in very mild EOAD and "unhappiness and dissatisfaction" in mild EOAD.

%B J Alzheimers Dis %V 52 %P 91-9 %8 2016 03 05 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060941?dopt=Abstract %R 10.3233/JAD-150703 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Different Clinical and Neuroimaging Characteristics in Early Stage Parkinson's Disease with Dementia and Dementia with Lewy Bodies. %A Takemoto, Mami %A Sato, Kota %A Hatanaka, Noriko %A Yamashita, Toru %A Ohta, Yasuyuki %A Hishikawa, Nozomi %A Abe, Koji %X

Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) both commonly exhibit brain Lewy body pathology and similar end-stage symptoms, but early symptoms differ. To clarify these differences, we compared the demographic characteristics, symptoms, cognitive and affective functioning, activities of daily life, and neuroimaging results between PDD (n = 52) and DLB (n = 46) patients. In measures of cognitive functioning, PDD patients had worse Hasegawa dementia scale-revised (HDS-R) scores (11.2±4.8) and better frontal assessment battery (FAB) scores (11.3±4.1) compared with DLB (17.0±6.4, p = 0.013 and 8.6±4.7, p = 0.039, respectively). DLB patients performed worse than PDD patients in "orientation to place" tasks. In affective functions, DLB patients had worse GDS (7.6±3.4) and ABS (9.9±5.3) scores than PDD patients (5.1±4.1 and 4.8±3.0, respectively). 99mTc-ECD images showed greater CBF in the whole cingulate gyrus and a lower CBF in the precuneus area in DLB than in PDD. These results suggest that PDD patients' lower average scores for "repetition" (MMSE), "recent memory" (HDS-R), and "lexical fluency" (FAB) were related to lower CBF in the cingulate gyrus than in DLB. Furthermore, DLB patients' poorer average subscale scores of "orientation to place" (MMSE) and "similarities", "conflicting instructions", and "go-no go" (FAB) tasks may be related to the lower CBF in the precuneus area in DLB than PDD.

%B J Alzheimers Dis %V 52 %P 205-11 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060948?dopt=Abstract %R 10.3233/JAD-150952 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Different Expression Patterns of Amyloid-β Protein Precursor Secretases in Human and Mouse Hippocampal Neurons: A Potential Contribution to Species Differences in Neuronal Susceptibility to Amyloid-β Pathogenesis. %A Xu, Zhi-Qiang %A Huang, Huang %A Chen, Ya-Li %A Gao, Yun-Ying %A Xu, Jun %A Marshall, Charles %A Cai, Zhi-You %A Xiao, Ming %K ADAM10 Protein %K Amyloid beta-Peptides %K Amyloid Precursor Protein Secretases %K Animals %K Antibodies %K Aspartic Acid Endopeptidases %K Cell Count %K Dose-Response Relationship, Drug %K Female %K Gene Expression Regulation %K Hippocampus %K Humans %K Low Density Lipoprotein Receptor-Related Protein-1 %K Male %K Mice %K Mice, Transgenic %K Middle Aged %K Mutation %K Neurons %K Peptide Fragments %K Presenilin-1 %K Species Specificity %K Time Factors %X

Extensive loss of hippocampal neurons serves a pathological basis for irreversible cognitive impairment in patients with Alzheimer's disease (AD). However, this characteristic cannot be replicated by transgenic mouse models, and its underlying mechanisms are unclear. Here, we present evidence that different expression patterns of amyloid-β protein precursor (AβPP) secretases in human and mouse hippocampal neurons are a decisive cause of species difference in the susceptibility to Aβ pathogenesis. Cell bodies of both pyramidal and granular neurons did not appear to undergo Aβ deposits in the 10-month-old transgenic mutant human AβPP/presenilin-1 (PS1) mice. They expressed high levels of non-amyloidogenic α-secretase, and its neuroprotective products soluble AβPPα, but low levels of amyloidogenic β-secretase and γ-secretase, and a neurotoxic product, Aβ42 peptide. Unlike those found in the mouse, human hippocampal neuronal cell bodies expressed β-secretase and γ-secretase, but not α-secretase, which could increase Aβ generation, thus undergoing death in response to various pathological conditions. Increased hippocampal neuronal apoptosis at 48 h following local microinjection of α-secretase antibody ADAM10 into the hippocampus of AβPP/PS1 mice further suggests that high α-secretase expression in mouse neuronal cell bodies is a factor in the paucity of neuronal loss in AD-like pathology. Therefore, selective down-regulation of brain α-secretase in transgenic AD models will better replicate the disease spectrum, including decreased brain soluble AβPPα levels and massive neuronal loss in AD patients, and be beneficial for preclinical therapeutic evaluation of AD.

%B J Alzheimers Dis %V 51 %P 179-95 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836155?dopt=Abstract %R 10.3233/JAD-150634 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Different Patterns of Correlation between Grey and White Matter Integrity Account for Behavioral and Psychological Symptoms in Alzheimer's Disease. %A Makovac, Elena %A Serra, Laura %A Spanò, Barbara %A Giulietti, Giovanni %A Torso, Mario %A Cercignani, Mara %A Caltagirone, Carlo %A Bozzali, Marco %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Atrophy %K Brain %K Depression %K Female %K Gray Matter %K Hallucinations %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K White Matter %X

Behavioral disorders and psychological symptoms (BPSD) in Alzheimer's disease (AD) are known to correlate with grey matter (GM) atrophy and, as shown recently, also with white matter (WM) damage. WM damage and its relationship with GM atrophy are reported in AD, reinforcing the interpretation of the AD pathology in light of a disconnection syndrome. It remains uncertain whether this disconnection might account also for different BPSD observable in AD. Here, we tested the hypothesis of different patterns of association between WM damage of the corpus callosum (CC) and GM atrophy in AD patients exhibiting one of the following BPSD clusters: Mood (i.e., anxiety and depression; ADmood), Frontal (i.e., dishinibition and elation; ADfrontal), and Psychotic (delusions and hallucinations; ADpsychotic) related symptoms, as well as AD patients without BPSD. Overall, this study brings to light the strict relationship between WM alterations in different parts of the CC and GM atrophy in AD patients exhibiting BPSD, supporting the hypothesis that such symptoms are likely to be caused by characteristic patterns of neurodegeneration of WM and GM, rather than being a reactive response to accumulation of cognitive disabilities, and should therefore be regarded as potential markers of diagnostic and prognostic value in AD.

%B J Alzheimers Dis %V 50 %P 591-604 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836635?dopt=Abstract %R 10.3233/JAD-150612 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Diagnosis of Dementia with High Levels of Cerebrospinal Fluid Tau Protein. %A Grangeon, Lou %A Paquet, Claire %A Bombois, Stephanie %A Quillard-Muraine, Muriel %A Martinaud, Olivier %A Bourre, Bertrand %A Lefaucheur, Romain %A Nicolas, Gaël %A Dumurgier, Julien %A Gerardin, Emmanuel %A Jan, Mary %A Laplanche, Jean-Louis %A Peoc'h, Katell %A Hugon, Jacques %A Pasquier, Florence %A Maltête, David %A Hannequin, Didier %A Wallon, David %K Adult %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Creutzfeldt-Jakob Syndrome %K Dementia, Vascular %K Diagnosis, Differential %K Female %K France %K Frontotemporal Dementia %K Humans %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %K Phosphorylation %K Retrospective Studies %K Sex Factors %K tau Proteins %X

BACKGROUND: Total Tau concentration in cerebrospinal fluid (CSF) is widely used as a biomarker in the diagnosis of neurodegenerative process primarily in Alzheimer's disease (AD). A particularly high Tau level may indicate AD but may also be associated with Creutzfeldt-Jakob disease (CJD). In such situations little is known about the distribution of differential diagnoses.

OBJECTIVE: Our study aimed to describe the different diagnoses encountered in clinical practice for patients with dementia and CSF Tau levels over 1000 pg/ml. We studied the p-Tau/Tau ratio to specify its ability to distinguish AD from CJD.

METHODS: Patients (n = 202) with CSF Tau levels over 1000 pg/ml were recruited in three memory clinics in France. All diagnoses were made using the same diagnostic procedure and criteria.

RESULTS: Patients were diagnosed with AD (n = 148, 73.2%), mixed dementia (n = 38, 18.8%), CJD, vascular dementia (n = 4, 2.0% for each), Lewy body dementia, and frontotemporal dementia (n = 3, 1.5% for each). Dispersion of CSF Tau levels clearly showed an overlap between all diagnoses. Using the p-Tau/Tau ratio suggestive of CJD (<0.075), all CJD patients were correctly categorized and only two AD patients were miscategorized. This ratio was highly associated with CJD compared to AD (p < 0.0001).

CONCLUSION: Our study showed that in clinical practice, extremely high CSF Tau levels are mainly related to diagnosis of AD. CJD patients represent a minority. Our results support a sequential interpretation algorithm for CSF biomarkers in dementia. High CSF Tau levels should alert clinicians to check the p-Tau/Tau ratio to consider a probable diagnosis of CJD.

%B J Alzheimers Dis %V 51 %P 905-13 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890785?dopt=Abstract %R 10.3233/JAD-151111 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Effects of APOE Genotypes on the Anterior and Posterior Subnetworks of Default Mode Network in Amnestic Mild Cognitive Impairment. %A Yuan, Baoyu %A Xie, Chunming %A Shu, Hao %A Liao, Wenxiang %A Wang, Zan %A Liu, Duan %A Zhang, Zhijun %X

BACKGROUND: The apolipoprotein E (APOE) ɛ4 carriers are at increased risk of developing Alzheimer's disease (AD) while the ɛ2 carriers appear to be protected against the disease. The default mode network (DMN), based in ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC), consists of functionally differentiable anterior and posterior subnetworks.

OBJECTIVE: This study was to investigate whether there are differential effects of APOE polymorphisms on DMN subnetworks in amnestic mild cognitive impairment (aMCI).

METHODS: Functional connectivity (FC) analyses were performed in DMN subnetworks in 74 aMCI (9 APOE ɛ2ɛ3, 44 ɛ3ɛ3, and 21 ɛ3ɛ4) and 105 healthy controls (HC; 32 APOE ɛ2ɛ3, 39 ɛ3ɛ3, and 34 ɛ3ɛ4). Logistic regression analysis was performed to obtain a model for classifying aMCI and HC.

RESULTS: Significant interactions of APOE by aMCI on FCs were found in right cerebellum posterior lobe, left lingual gyrus, and right middle cingulate cortex in the vmPFC subnetwork, and bilateral fusiform gyrus, left inferior frontal gyrus, and left precuneus in the PCC subnetwork. The impairment of episodic memory for ɛ4-carriers in aMCI negatively correlated with altered FC between vmPFC and right middle cingulate cortex, while positively correlated with altered FC between PCC and left fusiform gyrus. A model composed of episodic memory and FCs dexterity correctly classified 89.4% of aMCI and HC.

CONCLUSIONS: APOE ɛ4 and ɛ2 alleles differentially mediate anterior and posterior DMN subnetworks. Furthermore, it further suggests that the anterior and posterior DMN subnetworks in aMCI play an opposing role on the impairment of episodic memory.

%B J Alzheimers Dis %V 54 %P 1409-1423 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589521?dopt=Abstract %R 10.3233/JAD-160353 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Impairment of Cognitive and Affective Mentalizing Abilities in Neurodegenerative Dementias: Evidence from Behavioral Variant of Frontotemporal Dementia, Alzheimer's Disease, and Mild Cognitive Impairment. %A Dodich, Alessandra %A Cerami, Chiara %A Crespi, Chiara %A Canessa, Nicola %A Lettieri, Giada %A Iannaccone, Sandro %A Marcone, Alessandra %A Cappa, Stefano F %A Cacioppo, John T %K Aged %K Alzheimer Disease %K Cognition %K Cognitive Dysfunction %K Emotions %K Female %K Frontotemporal Dementia %K Humans %K Male %K Theory of Mind %X

Cognitive and affective theory of mind (ToM) can be impaired in the course of neurodegenerative dementias. Experimental tests based on different task conditions and/or complexity may fail to capture disease-specific patterns of impairments. In this study, we assessed with a single task both the affective and the cognitive facets of ToM ability in a sample of 47 patients (i.e., 12 AD, 20 bvFTD, and 15 aMCI fulfilling IWG criteria for AD in predementia phase) and 65 healthy controls. Subjects were administered the Story-based Empathy task (SET), a non-verbal task measuring the ability to infer others' intentions (IA) and emotions (EA) compared to a control condition (causal inferences, CI). Global and single sub-condition scores were evaluated with a vectorial method, analyzing the relationship between social abilities and basic cognitive functioning by means of two indices representing the basic ability to perform the task and the balance between basic functions and ToM skills.Dementia (AD and bvFTD) patients showed impaired performances on all SET sub-conditions, whereas aMCI subjects' performance was not different from healthy controls. Vectorial analysis revealed a specific change in the balance between EA and CI conditions only in the bvFTD group, supporting a disproportionate deficit in mental states attribution based on affective cues. The overall deficit in the task in AD appears to be more general and related to the severity of dementia. This latter finding is further supported by the normal performance of the prodromal AD group.

%B J Alzheimers Dis %V 50 %P 1011-22 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836153?dopt=Abstract %R 10.3233/JAD-150605 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Mass Spectrometry Profiles of Tau Protein in the Cerebrospinal Fluid of Patients with Alzheimer's Disease, Progressive Supranuclear Palsy, and Dementia with Lewy Bodies. %A Barthélemy, Nicolas R %A Gabelle, Audrey %A Hirtz, Christophe %A Fenaille, François %A Sergeant, Nicolas %A Schraen-Maschke, Susanna %A Vialaret, Jérôme %A Buée, Luc %A Junot, Christophe %A Becher, François %A Lehmann, Sylvain %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Analysis of Variance %K Chromatography, Liquid %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Peptide Fragments %K Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization %K Statistics as Topic %K Supranuclear Palsy, Progressive %K tau Proteins %X

Microtubule-associated Tau proteins are major actors in neurological disorders, the so-called tauopathies. In some of them, and specifically in Alzheimer's disease (AD), hyperphosphorylated forms of Tau aggregate into neurofibrillary tangles. Following and understanding the complexity of Tau's molecular profile with its multiple isoforms and post-translational modifications represent an important issue, and a major analytical challenge. Immunodetection methods are, in fact, limited by the number, specificity, sensitivity, and capturing property of the available antibodies. Mass spectrometry (MS) has recently allowed protein quantification in complex biological fluids using isotope-labeled recombinant standard for absolute quantification (PSAQ). To study Tau proteins, which are found at very low concentrations within the cerebrospinal fluid (CSF), we relied on an innovative two-step pre-fractionation strategy, which was not dependent on immuno-enrichment. We then developed a sensitive multiplex peptide detection capability using targeted high-resolution MS to quantify Tau-specific peptides covering its entire sequence. This approach was used on a clinical cohort of patients with AD, progressive supranuclear palsy (PSP), and dementia with Lewy body (DLB) and with control non-neurodegenerative disorders. We uncovered a common CSF Tau molecular profile characterized by a predominance of central core expression and 1N/3R isoform detection. While PSP and DLB tau profiles showed minimal changes, AD was characterized by a unique pattern with specific modifications of peptide distribution. Taken together these results provide important information on Tau biology for future therapeutic interventions, and improved molecular diagnosis of tauopathies.

%B J Alzheimers Dis %V 51 %P 1033-43 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923020?dopt=Abstract %R 10.3233/JAD-150962 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Membrane Toxicity of Amyloid-β Fragments by Pore Forming Mechanisms. %A Peters, Christian %A Bascuñán, Denisse %A Opazo, Carlos %A Aguayo, Luis G %K Amyloid beta-Peptides %K Animals %K Calcium %K Cell Membrane %K Cells, Cultured %K Fluorescent Antibody Technique %K HEK293 Cells %K Hippocampus %K Humans %K Microscopy, Electron, Transmission %K Neurons %K Patch-Clamp Techniques %K Peptide Fragments %K Porosity %K Rats, Sprague-Dawley %K Voltage-Sensitive Dye Imaging %X

A major characteristic of Alzheimer's disease (AD) is the presence of amyloid-β peptide (Aβ) oligomers and aggregates in the brain. It is known that Aβ oligomers interact with the neuronal membrane and induce perforations that cause an influx of calcium ions and enhance the release of synaptic vesicles leading to a delayed synaptic failure by vesicle depletion. To better understand the mechanism by which Aβ exerts its effect on the plasma membrane, we evaluated three Aβ fragments derived from different regions of Aβ(1-42); Aβ(1-28) from the N-terminal region, Aβ(25-35) from the central region, and Aβ(17-42) from the C-terminal region. The neuronal activities of these fragments were examined with patch clamp, immunofluorescence, transmission electron microscopy, aggregation assays, calcium imaging, and MTT reduction assays. The present results indicate that the fragment Aβ(1-28) contributes to aggregation, an increase in intracellular calcium and synaptotoxicity, but is not involved in membrane perforation; Aβ(25-35) is important for membrane perforation, calcium increase, and synaptotoxicity; and Aβ(17-42) induced mitochondrial toxicity similar to the full length Aβ(1-42), but was unable to induce membrane perforation and calcium increase, supporting the idea that it is less toxic in the non-amyloidogenic pathway.

%B J Alzheimers Dis %V 51 %P 689-99 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890761?dopt=Abstract %R 10.3233/JAD-150896 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Regulation of N-Methyl-D-Aspartate Receptor Subunits is an Early Event in the Actions of Soluble Amyloid-β(1-40) Oligomers on Hippocampal Neurons. %A Chang, Lirong %A Zhang, Yali %A Liu, Jinping %A Song, Yizhi %A Lv, Angchu %A Li, Yan %A Zhou, Wei %A Yan, Zhen %A Almeida, Osborne F X %A Wu, Yan %K Amyloid beta-Peptides %K Animals %K Animals, Newborn %K Cells, Cultured %K Dendrites %K Gene Expression Regulation %K Hippocampus %K Male %K Neurons %K Peptide Fragments %K Phosphorylation %K Rats %K Rats, Wistar %K Receptors, N-Methyl-D-Aspartate %X

Synaptic dysfunction during early stages of Alzheimer's disease (AD) is triggered by soluble amyloid-β (Aβ) oligomers that interact with NMDA receptors (NMDARs). We previously showed that Aβ induces synaptic protein loss through NMDARs, albeit through undefined mechanisms. Accordingly, we here examined the contribution of individual NMDAR subunits to synaptotoxicity and demonstrate that Aβ exerts differential effects on the levels and distribution of GluN2A and GluN2B subunits of NMDAR in dendrites. Treatment of cultured hippocampal neurons with Aβ1-40 (10 μM, 1 h) induced a significant increase of dendritic and synaptic GluN2B puncta densities with parallel decreases in the puncta densities of denritic and synaptic pTyr1472-GluN2B. Conversely, Aβ significantly decreased dendritic and synaptic GluN2A and dendritic pTyr1325-GluN2A puncta densities and increased synaptic pTyr1325-GluN2A puncta densities. Unexpectedly, Aβ treatment resulted in a significant reduction of GluN2B and pTyr1472-GluN2B protein levels but did not influence GluN2A and pTyr1325-GluN2A levels. These results show that Aβ exerts complex and distinct regulatory effects on the trafficking and phosphorylation of GluN2A and GluN2B, as well as on their localization within synaptic and non-synaptic sites. Increased understanding of these early events in Aβ-induced synaptic dysfunction is likely to be important for the development of timely preventive and therapeutic interventions.

%B J Alzheimers Dis %V 51 %P 197-212 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836185?dopt=Abstract %R 10.3233/JAD-150942 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Risk of Incident Alzheimer's Disease Dementia in Stable Versus Unstable Patterns of Subjective Cognitive Decline. %A Wolfsgruber, Steffen %A Kleineidam, Luca %A Wagner, Michael %A Mösch, Edelgard %A Bickel, Horst %A Lϋhmann, Dagmar %A Ernst, Annette %A Wiese, Birgitt %A Steinmann, Susanne %A König, Hans-Helmut %A Brettschneider, Christian %A Luck, Tobias %A Stein, Janine %A Weyerer, Siegfried %A Werle, Jochen %A Pentzek, Michael %A Fuchs, Angela %A Maier, Wolfgang %A Scherer, Martin %A Riedel-Heller, Steffi G %A Jessen, Frank %X

BACKGROUND: It is unknown whether longitudinal stability versus instability in subjective cognitive decline (SCD) is a modifying factor of the association between SCD and risk of incident Alzheimer's disease (AD) dementia.

OBJECTIVE: We tested the modifying role of temporal stability of the SCD report on AD dementia risk in cognitively normal elderly individuals.

METHODS: We analyzed data of 1,990 cognitively normal participants from the longitudinal AgeCoDe Study. We assessed SCD with/without associated worries both at baseline and first follow-up 18 months later. Participants were then classified either as (a) Controls (CO, with no SCD at both baseline and follow-up 1, n = 613), (b) inconsistent SCD (with SCD reported only at baseline or at follow-up 1, n = 637), (c) consistent SCD but without/or with inconsistent worries (n = 610) or (d) consistent SCD with worries (n = 130). We estimated incident AD dementia risk over up to 6 years for each group with Cox-Proportional Hazard Regression analyses adjusted for age, gender, education, ApoE4 status, and depression.

RESULTS: Compared to CO, inconsistent SCD was not associated with increased risk of incident AD dementia. In contrast, risk was doubled in the group of consistent SCD without/ with inconsistent worries, and almost 4-fold in the group of consistent SCD with worries. These results could be replicated when using follow-up 1 to follow-up 2 response patterns for group definition.

CONCLUSION: These findings suggest that longitudinal stability versus instability is an important modifying factor of the association between SCD and AD dementia risk. Worrisome SCD that is also consistently reported over time is associated with greatly increased risk of AD dementia.

%B J Alzheimers Dis %V 54 %P 1135-1146 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567852?dopt=Abstract %R 10.3233/JAD-160407 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dihydropyridine Derivatives Modulate Heat Shock Responses and have a Neuroprotective Effect in a Transgenic Mouse Model of Alzheimer's Disease. %A Kasza, Ágnes %A Hunya, Ákos %A Frank, Zsuzsa %A Fülöp, Ferenc %A Török, Zsolt %A Balogh, Gábor %A Sántha, Miklós %A Bálind, Árpád %A Bernáth, Sándor %A Blundell, Katie L I M %A Prodromou, Chrisostomos %A Horváth, Ibolya %A Zeiler, Hans-Joachim %A Hooper, Philip L %A Vigh, László %A Penke, Botond %X

Heat shock proteins (Hsps) have chaperone activity and play a pivotal role in the homeostasis of proteins by preventing misfolding, by clearing aggregated and damaged proteins from cells, and by maintaining proteins in an active state. Alzheimer's disease (AD) is thought to be caused by amyloid-β peptide that triggers tau hyperphosphorylation, which is neurotoxic. Although proteostasis capacity declines with age and facilitates the manifestation of neurodegenerative diseases such as AD, the upregulation of chaperones improves prognosis. Our research goal is to identify potent Hsp co-inducers that enhance protein homeostasis for the treatment of AD, especially 1,4-dihydropyridine derivatives optimized for their ability to modulate cellular stress responses. Based on favorable toxicological data and Hsp co-inducing activity, LA1011 was selected for the in vivo analysis of its neuroprotective effect in the APPxPS1 mouse model of AD. Here, we report that 6 months of LA1011 administration effectively improved the spatial learning and memory functions in wild type mice and eliminated neurodegeneration in double mutant mice. Furthermore, Hsp co-inducer therapy preserves the number of neurons, increases dendritic spine density, and reduces tau pathology and amyloid plaque formation in transgenic AD mice. In conclusion, the Hsp co-inducer LA1011 is neuroprotective and therefore is a potential pharmaceutical candidate for the therapy of neurodegenerative diseases, particularly AD.

%B J Alzheimers Dis %V 53 %P 557-71 %8 2016 May 07 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163800?dopt=Abstract %R 10.3233/JAD-150860 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diminished CRE-Induced Plasticity is Linked to Memory Deficits in Familial Alzheimer's Disease Mice. %A Bartolotti, Nancy %A Segura, Laura %A Lazarov, Orly %K Alzheimer Disease %K Animals %K Cyclic AMP Response Element-Binding Protein %K Disease Models, Animal %K Hippocampus %K Maze Learning %K Memory Disorders %K Mice %K Neuronal Plasticity %K Neurons %K Phosphorylation %X

The mechanism underlying impaired learning and memory in Alzheimer's disease is not fully elucidated. The phosphorylation of cyclic-AMP response element binding protein (pCREB) in the hippocampus is thought to be a critical initiating step in the formation of long-term memories. Here, we tested CRE-driven gene expression following learning in mice harboring the familial Alzheimer's disease-linked APPswe/PS1ΔE9 mutations using CRE-β galactosidase reporter. We show that young adult APPswe/PS1ΔE9 mice exhibit impaired recognition memory and reduced levels of pCREB, and its cofactors CREB binding protein (CBP) and p-300 following a learning task, compared to their wild type littermate counterparts. Impairments in learning-induced activation of CREB in these mice are manifested by reduced CRE-driven gene transcription. Importantly, expression of the CRE-driven immediate early gene, Egr-1 (Zif268) is decreased in the CA1 region of the hippocampus. These studies implicate defective CREB-dependent plasticity in the mechanism underlying learning and memory deficits in Alzheimer's disease.

%B J Alzheimers Dis %V 50 %P 477-89 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682682?dopt=Abstract %R 10.3233/JAD-150650 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Direct Evidence of Internalization of Tau by Microglia In Vitro and In Vivo. %A Bolós, Marta %A Llorens-Martín, María %A Jurado-Arjona, Jerónimo %A Hernández, Félix %A Rábano, Alberto %A Avila, Jesús %K Alzheimer Disease %K Analysis of Variance %K Animals %K Animals, Newborn %K Calcium-Binding Proteins %K Cells, Cultured %K Cerebral Cortex %K Glial Fibrillary Acidic Protein %K Hippocampus %K Humans %K Mice %K Mice, Inbred C57BL %K Microfilament Proteins %K Microglia %K Phosphorylation %K Protein Transport %K Rats %K tau Proteins %K Time Factors %X

The microtubule-associated protein (MAP) tau plays a critical role in the pathogenesis of tauopathies. Excess tau can be released into the extracellular medium in a physiological or pathological manner to be internalized by surrounding neurons-a process that contributes to the spread of this protein throughout the brain. Such spreading may correlate with the progression of the abovementioned diseases. In addition to neurons, tau can be internalized into other cells. Here we demonstrate that microglia take up tau in vitro and in vivo. In this regard, microglia from primary cultures internalized soluble (human recombinant tau42) and insoluble (homogenates derived from human AD brain) tau in vitro. Furthermore, using stereotaxic injection of tau in mice in vivo, we show that murine microglia internalize human tau. In addition, we demonstrate, for the first time, that microglia colocalize with various forms of tau in postmortem brain tissue of patients with Alzheimer's disease and non-demented control subjects. Our data reveal a potential role of microglia in the internalization of tau that might be relevant for the design of strategies to enhance the clearance of extracellular tau in neurodegenerative diseases characterized by the accumulation of this protein.

%B J Alzheimers Dis %V 50 %P 77-87 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26638867?dopt=Abstract %R 10.3233/JAD-150704 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Disconnection Hypothesis in Alzheimer's Disease Studied Through Multimodal Magnetic Resonance Imaging: Structural, Perfusion, and Diffusion Tensor Imaging. %A Lacalle-Aurioles, María %A Navas-Sánchez, Francisco Javier %A Alemán-Gómez, Yasser %A Olazarán, Javier %A Guzmán-De-Villoria, Juan Adán %A Cruz-Orduña, Isabel %A Mateos-Pérez, José María %A Desco, Manuel %K Aged %K Alzheimer Disease %K Brain %K Brain Mapping %K Cerebral Angiography %K Cerebrovascular Circulation %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Female %K Functional Laterality %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Models, Neurological %K Multimodal Imaging %K Organ Size %K Prospective Studies %X

According to the so-called disconnection hypothesis, the loss of synaptic inputs from the medial temporal lobes (MTL) in Alzheimer's disease (AD) may lead to reduced activity of target neurons in cortical areas and, consequently, to decreased cerebral blood flow (CBF) in those areas. The aim of this study was to assess whether hypoperfusion in parietotemporal and frontal cortices of patients with mild cognitive impairment who converted to AD (MCI-c) and patients with mild AD is associated with atrophy in the MTL and/or microstructural changes in the white matter (WM) tracts connecting these areas. We assessed these relationships by investigating correlations between CBF in hypoperfused areas, mean cortical thickness in atrophied regions of the MTL, and fractional anisotropy (FA) in WM tracts. In the MCI-c group, a strong correlation was observed between CBF of the superior parietal gyri and FA in the parahippocampal tracts (left: r = 0.90, p <  0.0001; right: r = 0.597, p = 0.024), and between FA in the right parahippocampal tract and the right precuneus (r = 0.551, p = 0.041). No significant correlations between CBF in hypoperfused regions and FA in the WM tract were observed in the AD group. These results suggest an association between perfusion deficits and altered WM tracts in prodromal AD, while microvasculature impairments may have a greater influence in more advanced stages. We did not find correlations between cortical thinning in the medial temporal lobes and decreased FA in the WM tracts of the limbic system in either group.

%B J Alzheimers Dis %V 50 %P 1051-64 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890735?dopt=Abstract %R 10.3233/JAD-150288 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Discovering New Genes in the Pathways of Common Sporadic Neurodegenerative Diseases: A Bioinformatics Approach. %A Kim, Yong Hwan %A Beak, Seung Han %A Charidimou, Andreas %A Song, Min %K Computational Biology %K Female %K Gene Regulatory Networks %K Genetic Predisposition to Disease %K Humans %K Male %K MEDLINE %K Neurodegenerative Diseases %X

Late onset Alzheimer's disease (AD) and Parkinson's disease (PD) are mostly "sporadic" age-related neurodegenerative disorders, but with a clear genetic component. However, their genetic architecture is complex and heterogeneous, largely remaining a conundrum, with only a handful of well-established genetic risk factors consistently associated with these diseases. It is possible that numerous, yet undiscovered, AD and PD related genes might exist. We focused on the 'gene' as a mediator to find new potential genes that might have a relationship with both disorders using bio-literature mining techniques. Based on Entrez Gene, we extracted the genes and directional gene-gene relation in the entire MEDLINE records and then constructed a directional gene-gene network. We identified common genes associated with two different but related diseases by performing shortest path analysis on the network. With our approach, we were able to identify and map already known genes that have a direct relationship with PD and AD. In addition, we identified 7 genes previously unknown to be a bridge between these two disorders. We confirmed 4 genes, ROS1, FMN1, ATP8A2, and SNORD12C, by biomedical literature and further checked 3 genes, ERVK-10, PRS, and C7orf49, that might have a high possibility to be related with both diseases. Additional experiments were performed to demonstrate the effectiveness of our proposed method. Comparing to the co-occurrence approach, our approach detected 25% more candidate genes and verified 10% more genes that have the relationship between both diseases than the co-occurrence approach did.

%B J Alzheimers Dis %V 51 %P 293-312 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836166?dopt=Abstract %R 10.3233/JAD-150769 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Discovery and Subsequent Confirmation of Novel Serum Biomarkers Diagnosing Alzheimer's Disease. %A Shah, Dipti Jigar %A Rohlfing, Frederick %A Anand, Swati %A Johnson, W Evan %A Alvarez, MeiHwa Tanielle Bench %A Cobell, Jesse %A King, Jackson %A Young, Sydney A %A Kauwe, John S K %A Graves, Steven W %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Chromatography, Liquid %K Female %K Humans %K Male %K Psychiatric Status Rating Scales %K Reproducibility of Results %K ROC Curve %K Tandem Mass Spectrometry %X

BACKGROUND: Alzheimer's disease (AD) remains challenging to diagnose, especially early disease. Having serum AD biomarkers would be of significant interest both in the clinical setting and in drug development efforts.

OBJECTIVE: We applied a novel serum proteomic approach to interrogate the low-molecular weight proteome for serum AD biomarkers.

METHODS: A discovery study used sera from 58 any-stage AD cases and 55 matched controls analyzed by capillary liquid chromatography-electrospray ionization-tandem mass spectrometry. Candidate biomarkers were statistically modeled and promising biomarkers were retested in a second, blinded confirmatory study (AD cases = 68, controls = 57). Biomarkers that replicated in the second study were modeled for the diagnosis of any-stage and very early stage AD. Further, they were chemically identified by tandem MS.

RESULTS: The initial discovery study found 59 novel potential AD biomarkers. Thirteen recurred in more than one multi-marker panel. In a second, blinded, confirmatory study, these same biomarkers were retested in separate specimens. In that study, four markers validated comparing controls to patients with any-stage AD and also with very early AD. The four biomarkers with replicable ability to diagnose AD were then chemically identified.

CONCLUSION: These results suggest novel serum AD diagnostic biomarkers can be found using this approach.

%B J Alzheimers Dis %V 49 %P 317-27 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484917?dopt=Abstract %R 10.3233/JAD-150498 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Discrepancy in Expression of β-Secretase and Amyloid-β Protein Precursor in Alzheimer-Related Genes in the Rat Medial Temporal Lobe Cortex Following Transient Global Brain Ischemia. %A Pluta, Ryszard %A Kocki, Janusz %A Ułamek-Kozioł, Marzena %A Petniak, Alicja %A Gil-Kulik, Paulina %A Januszewski, Sławomir %A Bogucki, Jacek %A Jabłoński, Mirosław %A Brzozowska, Judyta %A Furmaga-Jabłońska, Wanda %A Bogucka-Kocka, Anna %A Czuczwar, Stanisław J %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Brain Ischemia %K Disease Models, Animal %K Down-Regulation %K Female %K Rats %K Rats, Wistar %K Temporal Lobe %K Time Factors %X

Brain ischemia may be causally related with Alzheimer's disease. Presumably, β-secretase and amyloid-β protein precursor gene expression changes may be associated with Alzheimer's disease neuropathology. Consequently, we have examined quantitative changes in both β-secretase and amyloid-β protein precursor genes in the medial temporal lobe cortex with the use of quantitative rtPCR analysis following 10-min global brain ischemia in rats with survival of 2, 7, and 30 days. The greatest significant overexpression of β-secretase gene was noted on the 2nd day, while on days 7-30 the expression of this gene was only modestly downregulated. Amyloid-β protein precursor gene was downregulated on the 2nd day, but on days 7-30 postischemia, there was a significant reverse tendency. Thus, the demonstrated alterations indicate that the considerable changes of expression of β-secretase and amyloid-β protein precursor genes may be connected with a response of neurons in medial temporal lobe cortex to transient global brain ischemia. Finally, the ischemia-induced gene changes may play a key role in a late and slow onset of Alzheimer-type pathology.

%B J Alzheimers Dis %V 51 %P 1023-31 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890784?dopt=Abstract %R 10.3233/JAD-151102 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Disrupted Brain Network in Progressive Mild Cognitive Impairment Measured by Eigenvector Centrality Mapping is Linked to Cognition and Cerebrospinal Fluid Biomarkers. %A Qiu, Tiantian %A Luo, Xiao %A Shen, Zhujing %A Huang, Peiyu %A Xu, Xiaojun %A Zhou, Jiong %A Zhang, Minming %X

Mild cognitive impairment (MCI) is a heterogeneous condition associated with a high risk of progressing to Alzheimer's disease (AD). Although functional brain network alterations have been observed in progressive MCI (pMCI), the underlying pathological mechanisms of network alterations remain unclear. In the present study, we evaluated neuropsychological, imaging, and cerebrospinal fluid (CSF) data at baseline across a cohort of: 21 pMCI patients, 33 stable MCI (sMCI) patients, and 29 normal controls. Fast eigenvector centrality mapping (fECM) based on resting-state functional MRI (rsfMRI) was used to investigate brain network organization differences among these groups, and we further assessed its relation to cognition and AD-related pathology. Our results demonstrated that pMCI had decreased eigenvector centrality (EC) in left temporal pole and parahippocampal gyrus, and increased EC in left middle frontal gyrus compared to sMCI. In addition, compared to normal controls, patients with pMCI showed decreased EC in right hippocampus and bilateral parahippocampal gyrus, and sMCI had decreased EC in right middle frontal gyrus and superior parietal lobule. Correlation analysis showed that EC in the left temporal pole was related to Wechsler Memory Scale-Revised Logical Memory (WMS-LM) delay score (r = 0.467, p = 0.044) and total tau (t-tau) level in CSF (r = -0.509, p = 0.026) in pMCI. Our findings implicate EC changes of different brain network nodes in the prognosis of pMCI and sMCI. Importantly, the association between decreased EC of brain network node and pathological changes may provide a deeper understanding of the underlying pathophysiology of pMCI.

%B J Alzheimers Dis %V 54 %P 1483-1493 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589525?dopt=Abstract %R 10.3233/JAD-160403 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Disrupted White Matter Network and Cognitive Decline in Type 2 Diabetes Patients. %A Zhang, Junying %A Liu, Zhen %A Li, Zixiao %A Wang, Yunxia %A Chen, Yaojing %A Li, Xin %A Chen, Kewei %A Shu, Ni %A Zhang, Zhanjun %X

Type 2 diabetes mellitus is accompanied by cognitive impairment and is associated with an increased risk of dementia. Damage to brain structures such as white matter network disruption may underlie this cognitive disturbance. In the present study, 886 non-diabetic and 163 type 2 diabetic participants completed a battery of neuropsychological tests. Among them, 38 diabetic patients and 34 non-diabetic participants that matched the patients for age/sex/education received a magnetic resonance imaging-based diffusion tensor imaging. Then we calculated the topological properties of the white matter network using a graph theoretical method to investigate network efficiency differences between groups. We found that type 2 diabetic patients had inferior performances compared to the non-diabetic controls, in several cognitive domains involving executive function, spatial processing, memory, and attention. We also found that diabetic patients exhibited a disrupted topological organization of the white matter network (including the global network properties, i.e., network strength, global efficiency, local efficiency and shortest path length, and the nodal efficiency of the right rolandic operculum) in the brain. Moreover, those global network properties and the nodal efficiency of the right rolandic operculum both had positive correlations with executive function in the patient group. The results suggest that type 2 diabetes mellitus leads to an alteration in the topological organization of the cortical white matter network and this alteration may account for the observed cognitive decline.

%B J Alzheimers Dis %V 53 %P 185-95 %8 2016 May 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163818?dopt=Abstract %R 10.3233/JAD-160111 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Disruption of White Matter Integrity by Chronic Cerebral Hypoperfusion in Alzheimer's Disease Mouse Model. %A Zhai, Yun %A Yamashita, Toru %A Nakano, Yumiko %A Sun, Zhuoran %A Morihara, Ryuta %A Fukui, Yusuke %A Ohta, Yasuyuki %A Hishikawa, Nozomi %A Abe, Koji %X

A rapidly progressing aging society has raised attention to white matter lesions in Alzheimer's disease. In the present study, we applied an AD plus cerebral hypoperfusion (HP) mouse model and investigated the alternation of key protein molecules in the nodal, paranodal, and intermodal sites in the white matter as well as the efficacy of galantamine. Cerebral HP was induced in APP23 mice by bilateral common carotid arteries stenosis with ameroid constrictors. Compared with the wild type and simple APP23 mice, APP23 + HP mice showed a progressive loss of MAG and NF186 from 6 to 12 months, broken misdistribution of MBP, and extended relocation of Nav1.6 and AnkG beyond the primary nodal region in the corpus callosum. Such abnormal neuropathological processes were retrieved with galantamine treatment. The present study demonstrated that cerebral HP strongly disrupted white matter integrity (WMI) at intermodal, paranodal, and Ranvier's nodal sites which may be associated with cognitive decline. Galantamine treatment significantly protected such WMI probably by allosterically potentiating ligand action.

%B J Alzheimers Dis %V 52 %P 1311-9 %8 2016 Apr 12 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079724?dopt=Abstract %R 10.3233/JAD-160120 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Distinct Patterns of Cognitive Aging Modified by Education Level and Gender among Adults with Limited or No Formal Education: A Normative Study of the Mini-Mental State Examination. %A Xie, Haiqun %A Zhang, Chengguo %A Wang, Yukai %A Huang, Shuyun %A Cui, Wei %A Yang, Wenbin %A Koski, Lisa %A Xu, Xiping %A Li, Youbao %A Zheng, Meili %A He, Mingli %A Fu, Jia %A Shi, Xiuli %A Wang, Kai %A Tang, Genfu %A Wang, Binyan %A Huo, Yong %K Adult %K Aged %K Aged, 80 and over %K China %K Cognition Disorders %K Cognitive Aging %K Educational Status %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Reference Values %K Rural Population %K Sex Characteristics %X

BACKGROUND: Dementia is increasingly prevalent due to rapid aging of the population, but under-recognized among people with low education levels. This is partly due to a lack of appropriate and precise normative data, which underestimates cognitive aging in the use of screening tools for dementia.

OBJECTIVE: We aimed to improve the precision of screening for cognitive impairment, by characterizing the patterns of cognitive aging and derived normative data of the Mini-Mental State Examination (MMSE) for illiterate and low-educated populations.

METHODS: This community-based study included data from 2,280 individuals aged 40 years or older from two rural areas. Multiple linear modeling examined the effect of aging on cognition reflected by the MMSE, stratified by education level and gender. Threshold effect of age on cognition was performed using a smoothing function.

RESULTS: The majority of participants (60.4%) were illiterate or had attended only primary school (24.6%). The effect of aging on cognition varied by gender and education. Primary-school educated females and males remained cognitively stable up to 62 and 71 years of age, respectively, with MMSE score declining 0.4 and 0.8 points/year in females and males thereafter. Illiterates females scored 2.3 points lower than illiterate males, and scores for both declined 0.2 points/year. According to these results, normative data stratified by age, education and gender was generated.

CONCLUSION: This study suggests gender and educational differences exist in cognitive aging among adults with limited or no formal education. To improve screening precision for cognitive impairment with the use of MMSE in low-educated population, age, gender, and education level should be considered.

%B J Alzheimers Dis %V 49 %P 961-9 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26756324?dopt=Abstract %R 10.3233/JAD-143066 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Distinctive Resting State Network Disruptions Among Alzheimer's Disease, Subcortical Vascular Dementia, and Mixed Dementia Patients. %A Kim, Hee Jin %A Cha, Jungho %A Lee, Jong-Min %A Shin, Ji Soo %A Jung, Na-Yeon %A Kim, Yeo Jin %A Choe, Yearn Seong %A Lee, Kyung Han %A Kim, Sung Tae %A Kim, Jae Seung %A Lee, Jae Hong %A Na, Duk L %A Seo, Sang Won %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Aniline Compounds %K Cerebral Cortex %K Cross-Sectional Studies %K Dementia %K Dementia, Vascular %K Female %K Humans %K Image Processing, Computer-Assisted %K Male %K Middle Aged %K Models, Neurological %K Neural Pathways %K Neuropsychological Tests %K Oxygen %K Psychiatric Status Rating Scales %K Radionuclide Imaging %K Rest %K Thiazoles %X

BACKGROUND: Recent advances in resting-state functional MRI have revealed altered functional networks in Alzheimer's disease (AD), especially those of the default mode network (DMN) and central executive network (CEN). However, few studies have evaluated whether small vessel disease (SVD) or combined amyloid and SVD burdens affect the DMN or CEN.

OBJECTIVE: The aim of this study was to evaluate whether SVD or combined amyloid and SVD burdens affect the DMN or CEN.

METHODS: In this cross-sectional study, we investigated the resting-state functional connectivity within DMN and CEN in 37 Pittsburgh compound-B (PiB)(+) AD, 37 PiB(-) subcortical vascular dementia (SVaD), 13 mixed dementia patients, and 65 normal controls.

RESULTS: When the resting-state DMN of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(+) AD patients displayed lower functional connectivity in the inferior parietal lobule while the PiB(-) SVaD patients displayed lower functional connectivity in the medial frontal and superior frontal gyri. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the DMN in the posterior cingulate gyrus. When the resting-state CEN connectivity of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(-) SVaD patients displayed lower functional connectivity in the anterior insular region. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the CEN in the inferior frontal gyrus.

CONCLUSIONS: Our findings suggest that in PiB(+) AD and PiB(-) SVaD, there is divergent disruptions in resting-state DMN and CEN. Furthermore, patients with combined amyloid and SVD burdens exhibited more disrupted resting-state DMN and CEN than patients with only amyloid or SVD burden.

%B J Alzheimers Dis %V 50 %P 709-18 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757039?dopt=Abstract %R 10.3233/JAD-150637 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Divergent Longitudinal Propagation of White Matter Degradation in Logopenic and Semantic Variants of Primary Progressive Aphasia. %A Tu, Sicong %A Leyton, Cristian E %A Hodges, John R %A Piguet, Olivier %A Hornberger, Michael %K Aged %K Analysis of Variance %K Aphasia, Primary Progressive %K Brain %K Cohort Studies %K Cross-Sectional Studies %K Disease Progression %K Female %K Humans %K Image Processing, Computer-Assisted %K Leukoencephalopathies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Names %K Neuropsychological Tests %K Semantics %X

BACKGROUND: Clinico-pathological distinction of primary progressive aphasia (PPA) can be challenging at clinic presentation. In particular, cross-sectional neuroimaging signatures across the logopenic (lvPPA) and semantic (svPPA) variants are difficult to establish, with longitudinal profiles showing greater divergence.

OBJECTIVE: Assess longitudinal propagation of white matter degradation in lvPPA and svPPA to determine disease progression over time, and whether this reflects distinct underlying pathology.

METHOD: A cohort of 27 patients with dementia (12 lvPPA; 15 svPPA) and 12 healthy controls were assessed at baseline and 1-year follow-up on the Addenbrooke's Cognitive Examination-Revised and Sydney Language Battery. Diffusion weighted images were collected at both time-points and analyzed for longitudinal white matter change using DTI-TK and TBSS.

RESULTS: LvPPA patients showed a significant decline in naming and repetition, over 1 year, while svPPA patients declined in naming and comprehension. Longitudinal imaging revealed widespread bilateral degradation of white matter tracts in lvPPA over a 1-year period with early involvement of the left posterior inferior longitudinal fasciculus (ILF). SvPPA demonstrated focal left lateralized white matter degradation involving the uncinate fasciculus (UF) and anterior ILF, propagating to the right UF with disease progression.

CONCLUSIONS: LvPPA and svPPA cohorts showed distinct longitudinal cognitive and white matter profiles. We propose differences in multi-centric and focal white matter dysfunction in lvPPA and svPPA, respectively, reflect underlying pathological differences. The clinical relevance of white matter degradation and mechanisms underlying disease propagation are discussed.

%B J Alzheimers Dis %V 49 %P 853-61 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484929?dopt=Abstract %R 10.3233/JAD-150626 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diversity of Cognitive Phenotypes Associated with C9ORF72 Hexanucleotide Expansion. %A Gómez-Tortosa, Estrella %A Prieto-Jurczynska, Cristina %A Serrano, Soledad %A Franco-Macías, Emilio %A Olivié, Laura %A Gallego, Jesús %A Guerrero-López, Rosa %A Trujillo-Tiebas, María José %A Ayuso, Carmen %A García Ruiz, Pedro %A Pérez-Pérez, Julián %A Sainz, María José %K Adult %K Age of Onset %K Apolipoprotein E4 %K Cognition %K DNA Repeat Expansion %K Family %K Female %K Follow-Up Studies %K Frontotemporal Lobar Degeneration %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genotyping Techniques %K Humans %K Male %K Middle Aged %K Prevalence %K Proteins %K Spain %X

For diagnostic purposes, we screened for the C9ORF72 mutation in a) 162 FTLD cases, and b) 145 cases with other diagnoses but with some frontotemporal features or manifestations previously reported in C9 carriers. Ten cases (onset 50 to 75 years) harbored the expansion: seven had FTLD syndromes (4.3% of total, 11% of familial cases), and three (2%) had a different diagnosis. All positive cases had family history of dementia, psychiatric disease, or ALS, but only 20% of families with mixed FTLD/ALS phenotypes carried the expansion. Language impairment was the most common symptom, followed by behavioral changes, memory deficits, and parkinsonism. C9ORF72 mutation has a low frequency in our dementia series and very diverse clinical manifestations.

%B J Alzheimers Dis %V 52 %P 25-31 %8 2016 02 26 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967212?dopt=Abstract %R 10.3233/JAD-150922 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Do Chinese Researchers Conduct Ethical Research and Use Ethics Committee Review in Clinical Trials of Anti-Dementia Drugs? An Analysis of Biomedical Publications Originating from China. %A Zeng, Lingfeng %A Liang, Weixiong %A Pan, Jianke %A Cao, Ye %A Liu, Jun %A Wang, Qi %A Wang, Lu %A Zou, Yuanping %A Wang, Kezhu %A Kong, Lingshuo %A Xie, Hui %A Xu, Weihua %A Li, Weirong %A Zhao, Wei %A Mi, Suiqing %A Chen, Yunbo %A Cheng, Shuyi %A Li, Xiaoyan %A Cao, Qian %A Zeng, Xing %A Wang, Ningsheng %X

BACKGROUND: Medical research using human participants must conform to the basic ethical principles found in the Declaration of Helsinki (DoH) of the World Medical Association.

OBJECTIVE: The purpose of this review was to assess whether journals in China have improved in regard to the fulfillment of ethical disclosure procedures for clinical trials of anti-dementia drugs.

METHODS: Four medical databases were searched for articles reporting clinical trials of oral anti-dementia drugs published in China in 2003, 2009, and 2014. The frequencies of reporting of informed consent from participants (ICP), approval of a regional ethical committee (REC), reference to DoH, and study registration were estimated respectively. Statistical analyses were conducted with SPSS v21 software.

RESULTS: Among those randomized controlled trials published in 2003, 2009, and 2014, disclosure of REC approval was present for 2.67%, 1.15%, and 6.84%; statements of ICP were included in 9.33%, 7.76%, and 17.34%; reference to DoH was found for 4.00%, 1.44%, and 7.45%; and study registration reporting was included in 2.67%, 2.59%, and 9.28%, respectively. Improvements to reporting rates between 2009 and 2014 were seen, with more than twice as many trials reporting REC approval, ICP, reference to DoH, and study registration compared with 2009.

CONCLUSION: Compared with 2003 and 2009, reporting rates for REC approval, ICP, reference to DoH, and study registration for clinical trials of anti-dementia drugs were enhanced in 2014 in the major medical journals of China. However, biomedical publications without definite statements of ethical considerations remain common, and this continues to be seen in Chinese journals. It is imperative that measures are taken to reinforce the ethical protection in clinical trials in China.

%B J Alzheimers Dis %V 52 %P 813-23 %8 2016 Mar 25 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031471?dopt=Abstract %R 10.3233/JAD-150858 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Do Microglia Default on Network Maintenance in Alzheimer's Disease? %A Southam, Katherine A %A Vincent, Adele J %A Small, David H %K Alzheimer Disease %K Animals %K Humans %K Microglia %K Synapses %X

Although the cause of Alzheimer's disease (AD) remains unknown, a number of new findings suggest that the immune system may play a critical role in the early stages of the disease. Genome-wide association studies have identified a wide array of risk-associated genes for AD, many of which are associated with abnormal functioning of immune cells. Microglia are the brain's immune cells. They play an important role in maintaining the brain's extracellular environment, including clearance of aggregated proteins such as amyloid-β (Aβ). Recent studies suggest that microglia play a more active role in the brain than initially considered. Specifically, microglia provide trophic support to neurons and also regulate synapses. Microglial regulation of neuronal activity may have important consequences for AD. In this article we review the function of microglia in AD and examine the possible relationship between microglial dysfunction and network abnormalities, which occur very early in disease pathogenesis.

%B J Alzheimers Dis %V 51 %P 657-69 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890782?dopt=Abstract %R 10.3233/JAD-151075 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Does Microglial Activation Influence Hippocampal Volume and Neuronal Function in Alzheimer's Disease and Parkinson's Disease Dementia? %A Femminella, Grazia D %A Ninan, Siddharth %A Atkinson, Rebecca %A Fan, Zhen %A Brooks, David J %A Edison, Paul %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Antineoplastic Agents %K Brain Mapping %K Cognition %K Female %K Fluorodeoxyglucose F18 %K Hippocampus %K Humans %K Isoquinolines %K Magnetic Resonance Imaging %K Male %K Microglia %K Middle Aged %K Neurons %K Neuropsychological Tests %K Parkinson Disease %K Positron-Emission Tomography %K Psychiatric Status Rating Scales %K Supranuclear Palsy, Progressive %X

BACKGROUND: The influence of neuroinflammation on neuronal function and hippocampal atrophy in Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) is still unclear.

OBJECTIVES: Here we investigated whether microglial activation measured by [11C]PK11195 PET is associated with neuronal function measured by cerebral glucose metabolic rate (rCMRGlc) using FDG-PET and hippocampal volume measurements.

METHODS: We enrolled 25 subjects (9 PDD, 8 AD, and 8 controls) who underwent PET scans with [11C](R)PK11195, [18F]FDG, and volumetric MRI scanning.

RESULTS: SPM correlation analysis in AD and PDD showed a negative correlation between hippocampal volume and microglial activation within hippocampus or parahippocampus and with cortical and subcortical areas of projections from hippocampus, while there was a positive correlation between rCMRGlc in cortical and subcortical areas of projections from hippocampus and hippocampal volume. Hippocampal volume was significantly reduced in AD compared to controls but not in PDD.

CONCLUSIONS: These findings indicate that microglial activation inversely correlated with hippocampal volume and hippocampal rCMRGlc in neurodegenerative diseases with dementia, providing further evidence for the central role of microglial activation in neurodegenerative diseases.

%B J Alzheimers Dis %V 51 %P 1275-89 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060942?dopt=Abstract %R 10.3233/JAD-150827 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Does the Interplay Between Aging and Neuroinflammation Modulate Alzheimer's Disease Clinical Phenotypes? A Clinico-Pathological Perspective. %A Taipa, Ricardo %A Sousa, Ana Luísa %A Melo Pires, Manuel %A Sousa, Nuno %X

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and is the most common cause of dementia worldwide. Cumulative data suggests that neuroinflammation plays a prominent and early role in AD, and there is compelling data from different research groups of age-associated dysregulation of the neuroimmune system. From the clinical point of view, despite clinical resemblance and neuropathological findings, there are important differences between the group of patients with sporadic early-onset (<65 years old) and late-onset AD (>65 years old). Thus, it seems important to understand the age-dependent relationship between neuroinflammation and the underlying biology of AD in order to identify potential explanations for clinical heterogeneity, interpret biomarkers, and promote the best treatment to different clinical AD phenotypes. The study of the delicate balance between pro-inflammatory or anti-inflammatory sides of immune players in the different ages of onset of AD would be important to understand treatment efficacy in clinical trials and eventually, not only direct treatment to early disease stages, but also the possibility of establishing different treatment approaches depending on the age of the patient. In this review, we would like to summarize what is currently known about the interplay between "normal" age associated inflammatory changes and AD pathological mechanisms, and also the potential differences between early-onset and late-onset AD taking into account the age-related neuroimmune background at disease onset.

%B J Alzheimers Dis %V 53 %P 403-17 %8 2016 May 11 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27176075?dopt=Abstract %R 10.3233/JAD-160121 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dogs with Cognitive Dysfunction as a Spontaneous Model for Early Alzheimer's Disease: A Translational Study of Neuropathological and Inflammatory Markers. %A Schütt, Trine %A Helboe, Lone %A Pedersen, Lars Østergaard %A Waldemar, Gunhild %A Berendt, Mette %A Pedersen, Jan Torleif %K Aging %K Alzheimer Disease %K Animals %K Brain %K Cognitive Dysfunction %K Cytokines %K Denmark %K Disease Models, Animal %K Disease Progression %K Dog Diseases %K Dogs %K Female %K Humans %K Immunohistochemistry %K Longitudinal Studies %K Male %K Plaque, Amyloid %K Severity of Illness Index %K Species Specificity %K tau Proteins %K Translational Medical Research %X

Aged companion dogs with canine cognitive dysfunction (CCD) spontaneously develop varying degrees of progressive cognitive decline and particular neuropathological features correspondent to the changes associated with Alzheimer's disease (AD) in humans. The aim of the present study was to characterize certain aspects of neuropathology and inflammatory markers related to aging and CCD in dogs in comparison with human AD. Fifteen brains from aged dogs with normal cognitive function, mild cognitive impairment, or CCD were investigated and compared with two control brains from young dogs and brain sections from human AD subjects. The neuropathological investigations included evaluation of amyloid-β (Aβ) plaque deposition (N-terminally truncated and pyroglutamyl-modified Aβ included), tau pathology, and inflammatory markers in prefrontal cortex. Cortical Aβ deposition was found to be only of the diffuse subtype as no dense-core or neuritic plaques were found. The Aβ deposition followed a progressive pattern in four maturation stages. Accumulation of the Aβ peptide was also observed in the vessel walls. Both immunohistochemically and biochemically measured levels of Aβ pathology in prefrontal cortex showed a consistent positive correlation to age but not to cognitive deficit severity. No evidence of neurofibrillary tau pathology was found. The level of pro-inflammatory cytokines was generally low and showed no significant association to cognitive status. The findings of the present study support the senescent dog with spontaneous cognitive dysfunction as a valuable non-transgenic model for further investigations of the molecular events involved in the neurodegenerative processes associated with aging and early stage AD, especially the Aβ-related pathology.

%B J Alzheimers Dis %V 52 %P 433-49 %8 2016 03 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003213?dopt=Abstract %R 10.3233/JAD-151085 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dose-Dependent Neuroprotection and Neurotoxicity of Simvastatin through Reduction of Farnesyl Pyrophosphate in Mice Treated with Intracerebroventricular Injection of Aβ 1-42. %A Jin, Huafeng %A Chen, Tingting %A Li, Guoxi %A Wang, Conghui %A Zhang, Baofeng %A Cao, Xinyuan %A Sha, Sha %A Wan, Qi %A Chen, Ling %K Amyloid beta-Peptides %K Animals %K Dose-Response Relationship, Drug %K Hippocampus %K Injections, Intraventricular %K Male %K Maze Learning %K Mice %K Neuroprotective Agents %K Peptide Fragments %K Phosphorylation %K Polyisoprenyl Phosphates %K Receptors, N-Methyl-D-Aspartate %K Sesquiterpenes %K Simvastatin %K Spatial Memory %X

BACKGROUND: Simvastatin (SV) has been reported to improve dementia and slow progression of Alzheimer's disease (AD), however there are conflicting reports.

OBJECTIVE & METHODS: Intracerebroventricular injection of aggregated Aβ1-42 in mice (Aβ1-42-mice) caused spatial cognitive deficits, long-term potentiation (LTP) impairment, and death of hippocampal pyramidal cells. The present study focused on exploring the dose-dependent effects of SV (10-80 mg/kg) on Aβ1-42-impaired spatial memory and the underlying mechanisms.

RESULTS: The treatment of Aβ1-42-mice with SV for continuous 15 days could attenuate the spatial cognitive deficits and recover the LTP induction in a "U" type dose-dependent manner. The death of pyramidal cells in Aβ1-42-mice was significantly reduced by the SV-treatment at 20 mg/kg, but not at a dose of 10 or 40 mg/kg, even was aggravated at a dose of 80 mg/kg. Hippocampal NMDA receptor (NMDAr) NR2B phosphorylation (phospho-NR2B) was elevated in Aβ1-42-mice, which was further dose-dependently increased by SV-treatment. Replenishment of isoprenoid farnesyl pyrophosphate (FPP) by applying farnesol (FOH) could abolish the SV-increased phospho-NR2B in Aβ1-42-mice, but had no effect on the Aβ1-42-enhanced phospho-NR2B. NMDAr antagonist blocked the neurotoxicity of Aβ1-42 and SV (80 mg/kg) in Aβ1-42-mice, whereas FOH only inhibited SV (80 mg/kg)-neurotoxicity. The SV-treatment in Aβ1-42-mice corrected the decrease in hippocampal Akt phosphorylation. The PI3K inhibitor abolished the SV (20 mg/kg)-neuroprotection in Aβ1-42-mice.

CONCLUSION: SV-treatment in Aβ1-42-mice exerts dose-dependent neuroprotection and neurotoxicity by reducing FPP to enhance the phosphorylation of NR2B and Akt.

%B J Alzheimers Dis %V 50 %P 501-16 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757191?dopt=Abstract %R 10.3233/JAD-150782 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Drawing Disorders in Alzheimer's Disease and Other Forms of Dementia. %A Trojano, Luigi %A Gainotti, Guido %X

Drawing is a multicomponential process that can be impaired by many kinds of brain lesions. Drawing disorders are very common in Alzheimer's disease and other forms of dementia, and can provide clinical information for the distinction of the different dementing diseases. In our review we started from an overview of the neural and cognitive bases of drawing, and from a recollection of the drawing tasks more frequently used for assessing individuals with dementia. Then, we analyzed drawing disorders in dementia, paying special attention to those observed in Alzheimer's disease, from the prodromal stages of the amnesic mild cognitive impairment to the stages of full-blown dementia, both in the sporadic forms with late onset in the entorhino-hippocampal structures and in those with early onset in the posterior neocortical structures. We reviewed the drawing features that could differentiate Alzheimer's disease from vascular dementia and from the most frequent forms of degenerative dementia, namely frontotemporal dementia and Lewy body disease. Finally, we examined some peculiar aspects of drawing disorders in dementia, such as perseverations, rotations, and closing-in. We argue that a careful analysis of drawing errors helps to differentiate the different forms of dementia more than overall accuracy in drawing.

%B J Alzheimers Dis %V 53 %P 31-52 %8 2016 Apr 21 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104898?dopt=Abstract %R 10.3233/JAD-160009 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Drivers: A Biologically Contextualized, Cross-Inferential View of the Epidemiology of Neurodegenerative Disorders. %A de Pedro-Cuesta, Jesús %A Martínez-Martín, Pablo %A Rábano, Alberto %A Alcalde-Cabero, Enrique %A José García López, Fernando %A Almazán-Isla, Javier %A Ruiz-Tovar, María %A Medrano, Maria-José %A Avellanal, Fuencisla %A Calero, Olga %A Calero, Miguel %K Age Factors %K Aging %K Amyloid Precursor Protein Secretases %K Apolipoproteins E %K Aspartic Acid Endopeptidases %K Creutzfeldt-Jakob Syndrome %K Environment %K Female %K Humans %K Incidence %K Male %K Neurodegenerative Diseases %K Personality %K Risk Factors %K Vascular Diseases %X

BACKGROUND: Sutherland et al. (2011) suggested that, instead of risk factors for single neurodegenerative disorders (NDDs), there was a need to identify specific "drivers", i.e., risk factors with impact on specific deposits, such as amyloid-β, tau, or α-synuclein, acting across entities.

OBJECTIVES AND METHODS: Redefining drivers as "neither protein/gene- nor entity-specific features identifiable in the clinical and general epidemiology of conformational NDDs (CNDDs) as potential footprints of templating/spread/transfer mechanisms", we conducted an analysis of the epidemiology of ten CNDDs, searching for patterns.

RESULTS: We identified seven potential drivers, each of which was shared by at least two CNDDs: 1) an age-at-exposure-related susceptibility to Creutzfeldt-Jakob disease (CJD) and several late-life CNDDs; 2) a relationship between age at onset, survival, and incidence; 3) shared genetic risk factors for CJD and late-life CNNDs; 4) partly shared personal (diagnostic, educational, behavioral, and social risk factors) predating clinical onset of late-life CNDDs; 5) two environmental risk factors, namely, surgery for sporadic CJD and amyotrophic lateral sclerosis, and Bordetella pertussis infection for Parkinson's disease; 6) reticulo-endothelial system stressors or general drivers (andropause or premenopausal estrogen deficiency, APOEɛ4, and vascular risk factors) for late-life CNDDs such as dementia/Alzheimer's disease, type-2 diabetes mellitus, and some sporadic cardiac and vascular degenerative diseases; and 7) a high, invariant incidence ratio of sporadic to genetic forms of mid- and late-life CNDDs, and type-2 diabetes mellitus.

CONCLUSION: There might be a systematic epidemiologic pattern induced by specific proteins (PrP, TDP-43, SOD1, α-synuclein, amyloid-β, tau, Langerhans islet peptide, and transthyretin) or established combinations of these.

%B J Alzheimers Dis %V 51 %P 1003-22 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923014?dopt=Abstract %R 10.3233/JAD-150884 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dual Kinase Inhibition Affords Extended in vitro Neuroprotection in Amyloid-β Toxicity. %A Gourmaud, Sarah %A Mouton-Liger, François %A Abadie, Claire %A Meurs, Eliane F %A Paquet, Claire %A Hugon, Jacques %X

In Alzheimer's disease (AD), the amyloid cascade hypothesis proposes that amyloid-beta (Aβ) neurotoxicity leads to neuroinflammation, synaptic loss, and neuronal degeneration. In AD patients, anti-amyloid immunotherapies did not succeed because they were possibly administered late in AD progression. Modulating new targets associated with Aβ toxicity, such as PKR (double-stranded RNA dependent kinase), and JNK (c-Jun N-terminal kinase) is a major goal for neuroprotection. These two pro-apoptotic kinases are activated in AD brains and involved in Aβ production, tau phosphorylation, neuroinflammation, and neuronal death. In HEK cells transfected with siRNA directed against PKR, and in PKR knockout (PKR-/-) mice neurons, we showed that PKR triggers JNK activation. Aβ-induced neuronal apoptosis, measured by cleaved PARP (Poly ADP-ribose polymerase) and cleaved caspase 3 levels, was reduced in PKR-/- neurons. Two selective JNK inhibitory peptides also produced a striking reduction of Aβ toxicity. Finally, the dual inhibition of PKR and JNK nearly abolished Aβ toxicity in primary cultured neurons. These results reveal that dual kinase inhibition can afford neuroprotection and this approach is worth being tested in in vivo AD and oxidative stress models.

%B J Alzheimers Dis %V 54 %P 1659-1670 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636848?dopt=Abstract %R 10.3233/JAD-160509 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dysregulation and diagnostic potential of microRNA in Alzheimer's disease. %A Pan, Yaoqian %A Liu, Ruizhu %A Terpstra, Erin %A Wang, Yanqing %A Qiao, Fangfang %A Wang, Jin %A Tong, Yigang %A Pan, Bo %K Aged %K Alzheimer Disease %K Biomarkers %K Disease Progression %K Humans %K MicroRNAs %K Prognosis %X

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is considered to be the main cause of cognitive impairment in elderly people. The major symptom of AD is progressive dementia that eventually results in dysfunction of daily life. Due to the fact that AD has a long period of incubation before clinical symptoms emerge, the available therapeutic treatments can only improve the symptoms but not delay the progression of AD. Therefore, there is an urgent need to explore effective diagnostic approaches to catch and better treat the disease before clinical symptoms appear. Recent research revealed that abnormal expression of certain miRNA could have a crucial role in the pathological process of neurodegenerative disease including AD. Furthermore, given that AD patients show increased level of miRNAs in the blood and cerebrospinal fluid, miRNAs are considered promising non-invasive candidates for AD diagnosis and prognosis. Here, we reviewed the current research related to implications of miRNAs during the development of AD, summarized of actively used approaches to identifying potential miRNA biomarkers in body fluids, and discussed the diagnostic potential of microRNAs as biomarkers for AD.

%B J Alzheimers Dis %V 49 %P 1-12 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484912?dopt=Abstract %R 10.3233/JAD-150451 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dysregulation of Autophagy, Mitophagy, and Apoptotic Genes in the Medial Temporal Lobe Cortex in an Ischemic Model of Alzheimer's Disease. %A Ułamek-Kozioł, Marzena %A Kocki, Janusz %A Bogucka-Kocka, Anna %A Petniak, Alicja %A Gil-Kulik, Paulina %A Januszewski, Sławomir %A Bogucki, Jacek %A Jabłoński, Mirosław %A Furmaga-Jabłońska, Wanda %A Brzozowska, Judyta %A Czuczwar, Stanisław J %A Pluta, Ryszard %X

Ischemic brain damage is a pathological incident that is often linked with medial temporal lobe cortex injury and finally its atrophy. Post-ischemic brain injury associates with poor prognosis since neurons of selectively vulnerable ischemic brain areas are disappearing by apoptotic program of neuronal death. Autophagy has been considered, after brain ischemia, as a guardian against neurodegeneration. Consequently, we have examined changes in autophagy (BECN 1), mitophagy (BNIP 3), and apoptotic (caspase 3) genes in the medial temporal lobe cortex with the use of quantitative reverse-transcriptase PCR following transient 10-min global brain ischemia in rats with survival 2, 7, and 30 days. The intense significant overexpression of BECN 1 gene was noted on the 2nd day, while on days 7-30 the expression of this gene was still upregulated. BNIP 3 gene was downregulated on the 2nd day, but on days 7-30 post-ischemia, there was a significant reverse tendency. Caspase 3 gene, associated with apoptotic neuronal death, was induced in the same way as BNIP 3 gene after brain ischemia. Thus, the demonstrated changes indicate that the considerable dysregulation of expression of BECN 1, BNIP 3, and caspase 3 genes may be connected with a response of neuronal cells in medial temporal lobe cortex to transient complete brain ischemia.

%B J Alzheimers Dis %V 54 %P 113-21 %8 2016 Jul 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472881?dopt=Abstract %R 10.3233/JAD-160387 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dysregulation of Elongation Factor 1A Expression is Correlated with Synaptic Plasticity Impairments in Alzheimer's Disease. %A Beckelman, Brenna C %A Day, Stephen %A Zhou, Xueyan %A Donohue, Maggie %A Gouras, Gunnar K %A Klann, Eric %A Keene, C Dirk %A Ma, Tao %X

Synaptic dysfunction may represent an early and crucial pathophysiology in Alzheimer's disease (AD). Recent studies implicate a connection between synaptic plasticity deficits and compromised capacity of de novo protein synthesis in AD. The mRNA translational factor eukaryotic elongation factor 1A (eEF1A) is critically involved in several forms of long-lasting synaptic plasticity. By examining postmortem human brain samples, a transgenic mouse model, and application of synthetic human Aβ42 on mouse hippocampal slices, we demonstrated that eEF1A protein levels were significantly decreased in AD, particularly in the hippocampus. In contrast, brain levels of eukaryotic elongation factor 2 were unaltered in AD. Further, upregulation of eEF1A expression by the adenylyl cyclase activator forskolin, which induces long-lasting synaptic plasticity, was blunted in hippocampal slices derived from Tg2576 AD model mice. Finally, Aβ-induced hippocampal long-term potentiation defects were alleviated by upregulation of eEF1A signaling via brain-specific knockdown of the gene encoding tuberous sclerosis 2. In summary, our findings suggest a strong correlation between the dysregulation of eEF1A synthesis and AD-associated synaptic failure. These findings provide insights into the understanding of molecular mechanisms underlying AD etiology and may aid in identification of novel biomarkers and therapeutic targets.

%B J Alzheimers Dis %V 54 %P 669-78 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567813?dopt=Abstract %R 10.3233/JAD-160036 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Early Cognitive Deficits in Type 2 Diabetes: A Population-Based Study. %A Marseglia, Anna %A Fratiglioni, Laura %A Laukka, Erika J %A Santoni, Giola %A Pedersen, Nancy L %A Bäckman, Lars %A Xu, Weili %X

Evidence links type 2 diabetes to dementia risk. However, our knowledge on the initial cognitive deficits in diabetic individuals and the factors that might promote such deficits is still limited. This study aimed to identify the cognitive domains initially impaired by diabetes and the factors that play a role in this first stage. Within the population-based Swedish National Study on Aging and Care-Kungsholmen, 2305 cognitively intact participants aged ≥60 y were identified. Attention/working memory, perceptual speed, category fluency, letter fluency, semantic memory, and episodic memory were assessed. Diabetes (controlled and uncontrolled) and prediabetes were ascertained by clinicians, who also collected information on vascular disorders (hypertension, heart diseases, and stroke) and vascular risk factors (VRFs, including smoking and overweight/obesity). Data were analyzed with linear regression models. Overall, 196 participants (8.5%) had diabetes, of which 144 (73.5%) had elevated glycaemia (uncontrolled diabetes); 571 (24.8%) persons had prediabetes. In addition, diabetes, mainly uncontrolled, was related to lower performance in perceptual speed (β - 1.10 [95% CI - 1.98, - 0.23]), category fluency (β - 1.27 [95% CI - 2.52, - 0.03]), and digit span forward (β - 0.35 [95% CI - 0.54, - 0.17]). Critically, these associations were present only among APOEɛ4 non-carriers. The associations of diabetes with perceptual speed and category fluency were present only among participants with VRFs or vascular disorders. Diabetes, especially uncontrolled diabetes, is associated with poorer performance in perceptual speed, category fluency, and attention/primary memory. VRFs, vascular disorders, and APOE status play a role in these associations.

%B J Alzheimers Dis %V 53 %P 1069-78 %8 2016 Jun 15 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27314527?dopt=Abstract %R 10.3233/JAD-160266 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Early in vivo Effects of the Human Mutant Amyloid-β Protein Precursor (hAβPPSwInd) on the Mouse Olfactory Bulb. %A Rusznák, Zoltán %A Kim, Woojin Scott %A Hsiao, Jen-Hsiang T %A Halliday, Glenda M %A Paxinos, George %A Fu, YuHong %K Age Factors %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Cell Proliferation %K Disease Models, Animal %K Gene Expression Regulation %K Humans %K Ki-67 Antigen %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Nerve Tissue Proteins %K Neurogenesis %K Neurons %K Olfactory Bulb %K Piriform Cortex %X

The amyloid-β protein precursor (AβPP) has long been linked to Alzheimer's disease (AD). Using J20 mice, which express human AβPP with Swedish and Indiana mutations, we studied early pathological changes in the olfactory bulb. The presence of AβPP/amyloid-β (Aβ) was examined in mice aged 3 months (before the onset of hippocampal Aβ deposition) and over 5 months (when hippocampal Aβ deposits are present). The number of neurons, non-neurons, and proliferating cells was assessed using the isotropic fractionator method. Our results demonstrate that although AβPP is overexpressed in some of the mitral cells, widespread Aβ deposition and microglia aggregates are not prevalent in the olfactory bulb. The olfactory bulbs of the younger J20 group harbored significantly fewer neurons than those of the age-matched wild-type mice (5.57±0.13 million versus 6.59±0.36 million neurons; p = 0.011). In contrast, the number of proliferating cells was higher in the young J20 than in the wild-type group (i.e., 6617±425 versus 4455±623 cells; p = 0.011). A significant increase in neurogenic activity was also observed in the younger J20 olfactory bulb. In conclusion, our results indicate that (1) neurons participating in the mouse olfactory function overexpress AβPP; (2) the cellular composition of the young J20 olfactory bulb is different from that of wild-type littermates; (3) these differences may reflect altered neurogenic activity and/or delayed development of the J20 olfactory system; and (4) AβPP/Aβ-associated pathological changes that take place in the J20 hippocampus and olfactory bulb are not identical.

%B J Alzheimers Dis %V 49 %P 443-57 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484907?dopt=Abstract %R 10.3233/JAD-150368 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition. %A Kantarci, Kejal %A Lowe, Val J %A Lesnick, Timothy G %A Tosakulwong, Nirubol %A Bailey, Kent R %A Fields, Julie A %A Shuster, Lynne T %A Zuk, Samantha M %A Senjem, Matthew L %A Mielke, Michelle M %A Gleason, Carey %A Jack, Clifford R %A Rocca, Walter A %A Miller, Virginia M %X

BACKGROUND: It remains controversial whether hormone therapy in recently postmenopausal women modifies the risk of Alzheimer's disease (AD).

OBJECTIVE: To investigate the effects of hormone therapy on amyloid-β deposition in recently postmenopausal women.

METHODS: Participants within 5-36 months past menopause in the Kronos Early Estrogen Prevention Study, a randomized, double blinded placebo-controlled clinical trial, were randomized to: 1) 0.45 mg/day oral conjugated equine estrogens (CEE); 2) 50μg/day transdermal 17β-estradiol; or 3) placebo pills and patch for four years. Oral progesterone (200 mg/day) was given to active treatment groups for 12 days each month. 11C Pittsburgh compound B (PiB) PET imaging was performed in 68 of the 118 participants at Mayo Clinic approximately seven years post randomization and three years after stopping randomized treatment. PiB Standard unit value ratio (SUVR) was calculated.

RESULTS: Women (age = 52-65) randomized to transdermal 17β-estradiol (n = 21) had lower PiB SUVR compared to placebo (n = 30) after adjusting for age [odds ratio (95% CI) = 0.31(0.11-0.83)]. In the APOEɛ4 carriers, transdermal 17β-estradiol treated women (n = 10) had lower PiB SUVR compared to either placebo (n = 5) [odds ratio (95% CI) = 0.04(0.004-0.44)], or the oral CEE treated group (n = 3) [odds ratio (95% CI) = 0.01(0.0006-0.23)] after adjusting for age. Hormone therapy was not associated with PiB SUVR in the APOEɛ4 non-carriers.

CONCLUSION: In this pilot study, transdermal 17β-estradiol therapy in recently postmenopausal women was associated with a reduced amyloid-β deposition, particularly in APOEɛ4 carriers. This finding may have important implications for the prevention of AD in postmenopausal women, and needs to be confirmed in a larger sample.

%B J Alzheimers Dis %V 53 %P 547-56 %8 2016 May 07 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163830?dopt=Abstract %R 10.3233/JAD-160258 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Early-Life Exposure to Lead (Pb) Alters the Expression of microRNA that Target Proteins Associated with Alzheimer's Disease. %A Masoud, Anwar M %A Bihaqi, Syed W %A Machan, Jason T %A Zawia, Nasser H %A Renehan, William E %K Age Factors %K Amyloid beta-Protein Precursor %K Animals %K Animals, Newborn %K Disease Models, Animal %K Dose-Response Relationship, Drug %K Female %K Gene Expression Regulation, Developmental %K Lead %K Male %K Mice %K Mice, Inbred C57BL %K MicroRNAs %K Pregnancy %K RNA, Messenger %K Sp1 Transcription Factor %X

There is a growing recognition of the impact of environmental toxins on the epigenetic regulation of gene expression, including the genes that play a critical role in neural development, neural function, and neurodegeneration. We have shown previously that exposure to the heavy metal lead (Pb) in early life results in a latent over-expression of AD-related proteins in rodents and primates. The present study provides evidence that early postnatal exposure to Pb also alters the expression of select miRNA. Mice were exposed to 0.2% Pb acetate from Postnatal Day 1 (PND 1, first 24 h after birth) to PND 20 via their mother's milk. Brain tissue was harvested at PND 20, 180, or 700, and miRNA were isolated and quantified by qPCR. This exposure produced a transient increase (relative to control) in the expression of miR-106b (binds to AβPP mRNA), miR-29b (targets the mRNA for the transcription factor SP1) and two miRNAs (miR-29b and miR-132) that have the ability to inhibit translation of proteins involved in promoter methylation. The expression of miR-106b decreased over time in the Pb-exposed animals and was significantly less than the levels exhibited by the control animals at PND700. The level of miR-124, which binds to SP1 mRNA, was also reduced (relative to controls) at PND700. In summary, we show that exposure to the heavy metal Pb in early life has a significant impact on the short- and long-term expression of miRNA that target epigenetic mediators and neurotoxic proteins.

%B J Alzheimers Dis %V 51 %P 1257-64 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923026?dopt=Abstract %R 10.3233/JAD-151018 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Economic Analysis of Formal Care, Informal Care, and Productivity Losses in Primary Care Patients who Screened Positive for Dementia in Germany. %A Michalowsky, Bernhard %A Thyrian, Jochen René %A Eichler, Tilly %A Hertel, Johannes %A Wucherer, Diana %A Flessa, Steffen %A Hoffmann, Wolfgang %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Caregivers %K Cost of Illness %K Cross-Sectional Studies %K Dementia %K Female %K Germany %K Health Care Costs %K Home Care Services %K Humans %K Male %K Patient Care %K Sensitivity and Specificity %K Surveys and Questionnaires %X

BACKGROUND: The majority of people with dementia (PwD) live at home and require professional formal care and informal care that is generally provided by close relatives.

OBJECTIVE: To determine the utilization and costs of formal and informal care for PwD, indirect costs because of productivity losses of caregivers, and the associations between cost, socio-demographic and clinical variables.

METHODS: The analysis includes the data of 262 community-dwelling PwD and their caregivers. Socio-demographics, clinical variables, and the utilization of formal care were assessed within the baseline assessment. To evaluate informal care costs, the Resource Utilization in Dementia (RUD) questionnaire was used. Costs were calculated from a social perspective. Associations were evaluated using multiple linear and logistic regression models.

RESULTS: Formal care services were utilized less (26.3%) than informal care (85.1%), resulting in a cost ratio of one to ten(1,646 €; 16,473 €, respectively). In total, 29% of caregivers were employed, and every seventh (14.3%) experienced productivity losses, which corresponded to 1,258 € annually. Whereas increasing deficits in daily living activities were associated with higher formal and higher informal costs, living alone was significantly associated with higher formal care costs and the employment of a caregiver was associated with lower informal care costs.

CONCLUSION: Informal care contributes the most to total care costs. Living alone is a major cost driver for formal costs because of the lower availability of potential informal care. The availability of informal care is limited and productivity losses are increased when a caregiver is employed.

%B J Alzheimers Dis %V 50 %P 47-59 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639964?dopt=Abstract %R 10.3233/JAD-150600 %0 Journal Article %J J Alzheimers Dis %D 2016 %T EEG Markers of Dementia with Lewy Bodies: A Multicenter Cohort Study. %A Bonanni, Laura %A Franciotti, Raffaella %A Nobili, Flavio %A Kramberger, Milica G %A Taylor, John-Paul %A Garcia-Ptacek, Sara %A Falasca, N Walter %A Famá, Francesco %A Cromarty, Ruth %A Onofrj, Marco %A Aarsland, Dag %X

Quantitative EEG (QEEG) has demonstrated good discriminative capacity for dementia with Lewy bodies (DLB) diagnosis as compared to Alzheimer's disease (AD) with a predictive value of 100% in a single cohort study. EEG in DLB was characterized by a dominant frequency (DF) in pre-alpha (5.5-7.5 Hz), theta, or delta bands and DF variability (DFV) >1.2 Hz, frequency prevalence (FP) pre-alpha in >40% and FP alpha in <32% of the epochs. To validate the aforementioned QEEG findings in independent cohorts of clinically diagnosed DLB versus AD patients, we analyzed EEG traces of 79 DLB and 133 AD patients (MMSE >20) collected from four European Centers. EEG traces from 19 scalp derivations were acquired as at least 10 min continuous signals and epoched in off-setting as series of 2-second-long epochs, subsequently processed by Fast Fourier Transform (frequency resolution 0.5 Hz). DLB patients showed EEG specific abnormalities in posterior derivations characterized by DF <8 Hz FP pre-alpha >50%, FP alpha <25%. DFV was >0.5 Hz. AD patients displayed stable alpha DF, DFV <0.5 Hz, FP pre-alpha <30%, and FP alpha >55%. DLB and AD differed for DF (p < 10-6), DFV (p < 0.05), FP pre-alpha (p < 10-12) and FP alpha (p < 10-12). Discriminant analysis detected specific cut-offs for every EEG mathematical descriptor; DF = 8, DFV = 2.2 Hz, FP pre-alpha=33%, FP alpha = 41% for posterior derivations. If at least one of the cut-off values was met, the percentage of DLB and AD patients correctly classified was 90% and 64%, respectively. The findings in this multicenter study support the validity of QEEG analysis as a tool for diagnosis in DLB patients.

%B J Alzheimers Dis %V 54 %P 1649-1657 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589528?dopt=Abstract %R 10.3233/JAD-160435 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effect of Anserine/Carnosine Supplementation on Verbal Episodic Memory in Elderly People. %A Hisatsune, Tatsuhiro %A Kaneko, Jun %A Kurashige, Hiroki %A Cao, Yuan %A Satsu, Hideo %A Totsuka, Mamoru %A Katakura, Yoshinori %A Imabayashi, Etsuko %A Matsuda, Hiroshi %K Adult %K Aged %K Aging %K Anserine %K Brain %K Carnosine %K Cytokines %K Dietary Supplements %K Double-Blind Method %K Female %K Gene Expression Regulation %K Humans %K Image Processing, Computer-Assisted %K Male %K Memory, Episodic %K Middle Aged %K Neuropsychological Tests %K Oligonucleotide Array Sequence Analysis %K Verbal Learning %X

Our goal in this study was to determine whether or not anserine/carnosine supplementation (ACS) is capable of preserving cognitive function of elderly people. In a double-blind randomized controlled trial, volunteers were randomly assigned to an ACS or placebo group at a 1:1 ratio. The ACS group took 1.0 g of an anserine/carnosine (3:1) formula daily for 3 months. Participants were evaluated by psychological tests before and after the 3-month supplementation period. Thirty-nine healthy elderly volunteers (60-78 years old) completed the follow-up tests. Among the tests, delayed recall verbal memory assessed by the Wechsler Memory Scale-Logical Memory showed significant preservation in the ACS group, compared to the placebo group (p = 0.0128). Blood analysis revealed a decreased secretion of inflammatory cytokines, including CCL-2 and IL-8, in the ACS group. MRI analysis using arterial spin labeling showed a suppression in the age-related decline in brain blood flow in the posterior cingulate cortex area in the ACS group, compared to the placebo group (p = 0.0248). In another randomized controlled trial, delayed recall verbal memory showed significant preservation in the ACS group, compared to the placebo group (p = 0.0202). These results collectively suggest that ACS may preserve verbal episodic memory and brain perfusion in elderly people, although further study is needed.

%B J Alzheimers Dis %V 50 %P 149-59 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682691?dopt=Abstract %R 10.3233/JAD-150767 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effect of Continuous Propofol Infusion in Rat on Tau Phosphorylation with or without Temperature Control. %A Huang, Chunxia %A Ng, Olivia Tsz-Wa %A Ho, Yuen-Shan %A Irwin, Michael Garnet %A Chang, Raymond Chuen-Chung %A Wong, Gordon Tin-Chun %K Amyloid beta-Peptides %K Analysis of Variance %K Anesthetics, Intravenous %K Animals %K Body Temperature %K Brain %K Gene Expression Regulation %K Glycogen Synthase Kinase 3 beta %K Hypothermia, Induced %K Male %K Peptide Fragments %K Phosphorylation %K Propofol %K Rats %K Rats, Sprague-Dawley %K Signal Transduction %K tau Proteins %X

Several studies suggest a relationship between anesthesia-induced tau hyperphosphorylation and the development of postoperative cognitive dysfunction. This study further characterized the effects of continuous propofol infusion on tau protein phosphorylation in rats, with or without temperature control. Propofol was administered intravenously to 8-10-week-old male Sprague-Dawley rats and infused to the loss of the righting reflex for 2 h continuously. Proteins from cortex and hippocampus were examined by western blot and immunohistochemistry. Rectal temperature was significantly decreased during propofol infusion. Propofol with hypothermia significantly increased phosphorylation of tau at AT8, AT180, Thr205, and Ser199 in cortex and hippocampus except Ser396. With temperature maintenance, propofol still induced significant elevation of AT8, Thr205, and Ser199 in cortex and hippocampus; however, increase of AT180 and Ser396 was only found in hippocampus and cortex, respectively. Differential effects of propofol with or without hypothermia on multiple tau related kinases, such as Akt/GSK3β, MAPK pathways, or phosphatase (PP2A), were demonstrated in region-specific manner. These findings indicated that propofol increased tau phosphorylation under both normothermic and hypothermic conditions, and temperature control could partially attenuate the hyperphosphorylation of tau. Further studies are warranted to determine the long-term impact of propofol on the tau pathology and cognitive functions.

%B J Alzheimers Dis %V 51 %P 213-26 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836157?dopt=Abstract %R 10.3233/JAD-150645 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effect of Early Referral to Specialist in Dementia on Institutionalization and Functional Decline: Findings from a Population-Based Study. %A Pimouguet, Clément %A Le-Goff, Mélanie %A Rizzuto, Debora %A Berr, Claudine %A Leffondré, Karen %A Pérès, Karine %A Dartigues, Jean François %A Helmer, Catherine %K Activities of Daily Living %K Cognition Disorders %K Community Health Planning %K Dementia %K Disability Evaluation %K Female %K Finland %K Follow-Up Studies %K Humans %K Institutionalization %K Male %K Psychiatric Status Rating Scales %K Referral and Consultation %K Specialization %X

BACKGROUND: Although early diagnosis has been hypothesized to benefit both patients and caregivers, until now studies evaluating the effect of early dementia diagnosis are lacking.

OBJECTIVE: To investigate the influence of early specialist referral for dementia on the risk of institutionalization and functional decline in Activity of Daily Living (ADL).

METHODS: Incident dementia cases were screened in a prospective population-based cohort, the Three-City Study, and initial specialist consultation for cognitive complaint was assessed at dementia diagnosis. Proportional hazard regression and illness-death models were used to test the association between specialist referral and, respectively, institutionalization and functional decline.

RESULTS: Only one third of the incident individuals with dementia had consulted a specialist for cognitive problems early (36%). After adjustment on potential confounders (including cognitive and functional decline) and competing risk of death, participants who had consulted a specialist early in the disease course presented a higher rate of being institutionalized than those who did not (Hazard Ratio = 2.00, 95% Confidence Interval (CI): 1.09- 3.64). But early specialist referral was not associated with further functional decline (HR = 1.09, 95% CI: 0.71- 1.67).

CONCLUSIONS: Early specialist referral in dementia is associated with increased risk of institutionalization but not with functional decline in ADL. These findings suggest that early care referral in dementia may be a marker of concern for patients and/or caregivers; subsequent medical and social care could be suboptimal or inappropriate to allow patients to stay longer at home.

%B J Alzheimers Dis %V 49 %P 819-28 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484926?dopt=Abstract %R 10.3233/JAD-150574 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effect of Normal Aging and of Mild Cognitive Impairment on Event-Related Potentials to a Stroop Color-Word Task. %A Ramos-Goicoa, Marta %A Galdo-Álvarez, Santiago %A Díaz, Fernando %A Zurrón, Montserrat %X

Event-related potentials (ERPs) were recorded from 84 adults (51 to 87 years old) with the aim of exploring the effects of aging (middle-aged and older groups) and cognitive status (healthy or with amnestic mild cognitive impairment, aMCI) on the neural functioning associated with stimulus and response processing in a Stroop color-word task. An interference (or Stroop) effect was observed in the Reaction Time (RT), and the RT and number of errors results were consistent with the age-related decline in performance. Cognitive status did not affect the behavioral performance of the task, but age and cognitive status affected several ERP parameters. Aging was associated with a) slowing of the neural processing of the stimuli (P150, N2, and P3b latencies were longer), b) greater activation of the motor cortex for response preparation (LRP-R amplitude was larger), and c) use of more neural resources for cognitive control of stimuli (N2 amplitude was larger to the congruent and incongruent stimuli than to the colored X-strings, in the older group). Independent of age, aMCI dedicated more neural resources to processing the irrelevant dimension of the stimulus (they showed a greater difference than the control participants between the P3b amplitude to the colored X-strings and to the congruent/incongruent stimuli) and showed a deficit in the selection and preparation of the motor response (with smaller LRP-S and LRP-R amplitudes). Furthermore, the middle-aged aMCI participants evaluated and classified both congruent and incongruent stimuli more slowly (they showed longer P3b latencies) relative to middle-aged controls.

%B J Alzheimers Dis %V 52 %P 1487-501 %8 2016 Apr 08 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079705?dopt=Abstract %R 10.3233/JAD-151031 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial. %A Berger, Miles %A Nadler, Jacob W %A Friedman, Allan %A McDonagh, David L %A Bennett, Ellen R %A Cooter, Mary %A Qi, Wenjing %A Laskowitz, Daniel T %A Ponnusamy, Vikram %A Newman, Mark F %A Shaw, Leslie M %A Warner, David S %A Mathew, Joseph P %A James, Michael L %X

BACKGROUND: Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimer's disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-β (Aβ).

OBJECTIVE: We asked whether isoflurane and propofol have differential effects on the tau/Aβ ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers.

METHODS: Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n = 21) or propofol (n = 18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time.

RESULTS: The CSF tau/Aβ ratio did not differ between isoflurane- versus propofol-treated patients (p = 1.000). CSF tau/Aβ ratio and tau levels increased 10 and 24 h after drain placement (p = 2.002×10-6 and p = 1.985×10-6, respectively), mean CSF p-tau levels decreased (p = 0.005), and Aβ levels did not change (p = 0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4, were associated with tau increase (n = 9 polymorphisms, p > 0.05 for all associations).

CONCLUSION: Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aβ ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aβ ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.

%B J Alzheimers Dis %V 52 %P 1299-310 %8 2016 Apr 15 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079717?dopt=Abstract %R 10.3233/JAD-151190 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effect of Tween-20 on Core Biomarkers Measured in Cerebrospinal Fluid from Patients with Alzheimer's Disease, Mild Cognitive Impairment, or Healthy Control Individuals. %A Berge, Guro %A Lauridsen, Camilla %A Sando, Sigrid Botne %A Holder, Daniel Joseph %A Møller, Ina %A Aasly, Jan Olav %A Bråthen, Geir %A Savage, Mary Josephine %A White, Linda Rosemary %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Peptide Fragments %K Phosphorylation %K Polysorbates %K ROC Curve %K Surface-Active Agents %K tau Proteins %X

BACKGROUND: There is substantial variation caused by preanalytical procedures in the measurement of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) reported in the literature.

OBJECTIVE: Determine whether the detergent Tween-20 improves diagnostic accuracy.

METHODS: CSF proteins (Aβ42, Aβ40, total tau, and phosphorylated tau) were measured by standard ELISA, in uncentrifuged CSF with or without 0.05% Tween-20 from patients with AD or amnestic mild cognitive impairment, and healthy elderly controls. In the main study, collection tubes containing Tween-20 (Sarstedt 15 mL) were filled with 5 mL CSF to ensure consistent detergent concentration across subsequent aliquots into Corning 2 mL tubes. These latter were also the primary collection vessel for samples without Tween-20. The effect of centrifugation, and extra tube transfer of samples with Tween-20 were also examined.

RESULTS: 0.05% Tween-20 significantly increased mean measured CSF concentration of Aβ42 (30% ), Aβ40 (23% ), and total tau (4% ), but not phosphorylated tau. Generally, these increases were similar in all groups, although for Aβ42, the mean percentage increase with Tween-20 was slightly larger for AD. Areas under receiver-operator characteristic curves were similar whether Tween-20 was present or not. Centrifuged CSF without Tween-20 significantly reduced the measured concentration of Aβ42 versus non-centrifuged samples, a difference not seen when detergent was added. Similar CSF Aβ42 levels were found whether Tween-20 was added at collection in an extra tube or directly to the main collection tube.

CONCLUSION: Addition of Tween-20 to CSF did not improve differentiation of patients from controls.

%B J Alzheimers Dis %V 49 %P 493-502 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484901?dopt=Abstract %R 10.3233/JAD-150234 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effectiveness of Exercise- and Cognitive-Based Treatments on Salivary Cortisol Levels and Sundowning Syndrome Symptoms in Patients with Alzheimer's Disease. %A Venturelli, Massimo %A Sollima, Alessio %A Cè, Emiliano %A Limonta, Eloisa %A Bisconti, Angela V %A Brasioli, Anna %A Muti, Ettore %A Esposito, Fabio %X

Sundowning syndrome (SDS) in patients with Alzheimer's disease (AD) is characterized by the intensification of behavioral disorders at sunset. Despite SDS etiology being unclear, a strong relationship between high cortisol levels and SDS has been reported. Aerobic exercise (AE) and cognitive training (CT) can reduce cortisol levels. However, whether SDS would benefit from AE and CT is still unknown. Therefore, the aim of this study was to investigate whether AE and CT treatments are effective in reducing SDS via downregulation of cortisol levels. The possible additive effects of combined AE+CT were also assessed. Eighty AD patients were randomly assigned to AE (n = 20), CT (n = 20), AE+CT (n = 20), and standard therapy (no treatment, NT; n = 20). Treatments were administered for 3 months, 5 days/week, 1 hour before sunset. Before and after treatments, salivary cortisol levels were sampled at 7, 11, 15, at sunset, and 20 (time of day). Blind assessment of behavioral disorders (neuropsychiatric inventory, NPI) and agitation (agitated behavior scale, ABS) were also performed. After interventions, cortisol levels were reduced in AE and AE+CT by ∼26%. In the same groups, NPI and ABS decreased by ∼50%. By contrast, cortisol and behavioral disorders were similar to baseline in CT and NT. Changes in NPI and ABS were significantly correlated with the reduction in cortisol levels. AE or AE+CT effects on SDS and cortisol levels and the lack of effect of CT alone indicate the effectiveness of an exercise-based treatment on SDS, suggesting a possible hypothalamic-pituitary-adrenal axis dysregulation underpinning SDS.

%B J Alzheimers Dis %V 53 %P 1631-40 %8 2016 Jul 14 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27540967?dopt=Abstract %R 10.3233/JAD-160392 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effectiveness of Supporting Informal Caregivers of People with Dementia: A Systematic Review of Randomized and Non-Randomized Controlled Trials. %A Vandepitte, Sophie %A Van Den Noortgate, Nele %A Putman, Koen %A Verhaeghe, Sofie %A Faes, Kristof %A Annemans, Lieven %X

BACKGROUND: Dementia is known as a major public health problem affecting both patients and caregivers, and placing a high financial strain upon society. In community-dwelling patients, it is important to support informal caregivers in order to help them sustain their demanding role. Previous reviews about effectiveness of such supporting strategies often included a small number of studies, focused only on particular supportive types, particular outcomes, or solely on caregivers.

OBJECTIVE: A general systematic review was conducted investigating effectiveness of different supportive strategies on at least the well-being of the caregiver or the care-recipient.

METHODS: A systematic literature search was conducted in Web of Science and PubMed. An adapted version of the Downs and Black (1998) checklist was used to assess methodological quality. A new classification was developed to group different types of caregiver support.

RESULTS: Fifty-three papers met the inclusion criteria. Although 87% of the interventions were to some extent effective, methods and findings were rather inconsistent. Psychoeducational interventions generally lead to positive outcomes for caregivers, and delay permanent institutionalization of care-recipients. Cognitive behavioral therapy decreases dysfunctional thoughts among caregivers. Occupational therapy decreases behavioral problems among patients and improves self-efficacy of caregivers. In general, those interventions tailored on individual level generate better outcomes. Comparative research on respite care was very rare.

CONCLUSIONS: Despite methodological inconsistency, supporting caregivers appears to be an effective strategy often improving well-being of caregiver or care-recipient and resulting in additional benefits for society. However, there is a need for more research on the (cost)-effectiveness of respite care.

%B J Alzheimers Dis %V 52 %P 929-65 %8 2016 Apr 08 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079704?dopt=Abstract %R 10.3233/JAD-151011 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Effects of Amnestic Mild Cognitive Impairment on Go/NoGo Semantic Categorization Task Performance and Event-Related Potentials. %A Mudar, Raksha A %A Chiang, Hsueh-Sheng %A Eroh, Justin %A Nguyen, Lydia T %A Maguire, Mandy J %A Spence, Jeffrey S %A Kung, Fanting %A Kraut, Michael A %A Hart, John %K Aged %K Aged, 80 and over %K Amnesia %K Brain %K Brain Mapping %K Cognitive Dysfunction %K Electroencephalography %K Evoked Potentials %K Female %K Humans %K Inhibition (Psychology) %K Male %K Middle Aged %K Neuropsychological Tests %K Reaction Time %X

We examined the effects of amnestic mild cognitive impairment (aMCI) on behavioral (response times and error rates) and scalp-recorded event-related potential (ERP) measures of response execution and inhibition, using Go/NoGo tasks involving basic and superordinate semantic categorization. Twenty-five aMCI (16 F; 68.5±8 years) and 25 age- and gender-matched normal control subjects (16 F; 65.4±7.1 years) completed two visual Go/NoGo tasks. In the single car task, responses were made based on single exemplars of a car (Go) and a dog (NoGo) (basic). In the object animal task, responses were based on multiple exemplars of objects (Go) and animals (NoGo) (superordinate). The aMCI subjects had higher commission errors on the NoGo trials compared to the control subjects, whereas both groups had comparable omission errors and reaction times during the Go trials. The aMCI subjects had significantly prolonged N2 ERP latency during Go and NoGo trials across tasks compared to the controls. Both groups showed similar categorization effects and response type effects in N2/P3 ERP latencies and P3 amplitude. Our findings indicate that altered early neural processing indexed by N2 latency distinguishes subjects with aMCI from controls during the Go/NoGo task. Prolonged Go-N2 latency in aMCI appears to precede behavioral changes in response execution, whereas prolonged NoGo-N2 latency underlies behavioral deterioration in response inhibition.

%B J Alzheimers Dis %V 50 %P 577-90 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836634?dopt=Abstract %R 10.3233/JAD-150586 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effects of Hypertension and Anti-Hypertensive Treatment on Amyloid-β (Aβ) Plaque Load and Aβ-Synthesizing and Aβ-Degrading Enzymes in Frontal Cortex. %A Ashby, Emma L %A Miners, James S %A Kehoe, Patrick G %A Love, Seth %K Aged %K Aged, 80 and over %K Amyloid Precursor Protein Secretases %K Antihypertensive Agents %K Female %K Frontal Lobe %K Humans %K Hypertension %K Immunohistochemistry %K Insulysin %K Male %K Neprilysin %K Peptidyl-Dipeptidase A %K Plaque, Amyloid %K Retrospective Studies %X

Epidemiological data associate hypertension with a predisposition to Alzheimer's disease (AD), and a number of postmortem and in vivo studies also demonstrate that hypertension increases amyloid-β (Aβ) pathology. In contrast, anti-hypertensive medications reportedly improve cognition and decrease the risk of AD, while certain classes of anti-hypertensive drugs are associated with decreased AD-related pathology. We investigated the effects of hypertension and anti-hypertensive treatment on Aβ plaque load in postmortem frontal cortex in AD. Aβ load was significantly increased in hypertensive (n = 20) relative to normotensive cases (n = 62) and was also significantly higher in treated (n = 9) than untreated hypertensives (n = 11). We then looked into mechanisms by which hypertension and treatment might increase Aβ load, focusing on Aβ-synthesizing enzymes, β- and γ-secretase, and Aβ-degrading enzymes, angiotensin-converting enzyme (ACE), insulin-degrading enzyme (IDE) and neprilysin. ACE and IDE protein levels were significantly lower in hypertensive (n = 21) than normotensive cases (n = 64), perhaps translating to decreased Aβ catabolism in hypertensives. ACE level was significantly higher in treated (n = 9) than untreated hypertensives (n = 12), possibly reflecting feedback upregulation of the renin-angiotensin system. Prospective studies in larger cohorts stratified according to anti-hypertensive drug class are needed to confirm these initial findings and to elucidate the interactions between hypertension, anti-hypertensive treatments, and Aβ metabolism.

%B J Alzheimers Dis %V 50 %P 1191-203 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836178?dopt=Abstract %R 10.3233/JAD-150831 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Effects of Latrepirdine on Amyloid-β Aggregation and Toxicity. %A Porter, Tenielle %A Bharadwaj, Prashant %A Groth, David %A Paxman, Adrian %A Laws, Simon M %A Martins, Ralph N %A Verdile, Giuseppe %K Amyloid beta-Peptides %K Analysis of Variance %K Antipsychotic Agents %K Cell Line, Tumor %K Dose-Response Relationship, Drug %K Drug Interactions %K Humans %K Indoles %K L-Lactate Dehydrogenase %K Microscopy, Atomic Force %K Neuroblastoma %K Peptide Fragments %K Protein Aggregates %X

Latrepirdine (Dimebon) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer's disease (AD). The accumulation of amyloid-β (Aβ) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aβ:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aβ42 aggregates was assessed by thioflavin-T fluorescence, western immunoblotting and atomic force microscopy (AFM). Despite showing a reduction in thioflavin-T fluorescence with latrepirdine treatment, indicating a decrease in aggregation, immunoblotting and AFM showed a modest increase in both the formation and size of Aβ aggregates. The discrepancies between thioflavin-T and the other assays are consistent with previous evidence that cyclic molecules can interfere with thioflavin-T binding of amyloid protein preparations. The ability of latrepirdine to modulate Aβ aggregation appears to be independent of its neuroprotective effects, and is unlikely to be a mechanism by which latrepirdine offers protection. This study investigates the effect of latrepirdine on Aβ aggregation, and presents evidence suggesting that caution should be applied in the use of thioflavin-T fluorescence based assays as a method for screening compounds for protein aggregation altering properties.

%B J Alzheimers Dis %V 50 %P 895-905 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836170?dopt=Abstract %R 10.3233/JAD-150790 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Effects of LW-AFC on Intestinal Microbiome in Senescence-Accelerated Mouse Prone 8 Strain, a Mouse Model of Alzheimer's Disease. %A Wang, Jianhui %A Ye, Fuqiang %A Cheng, Xiaorui %A Zhang, Xiaorui %A Liu, Feng %A Liu, Gang %A Ni, Ming %A Qiao, Shanyi %A Zhou, Wenxia %A Zhang, Yongxiang %X

Microbes have deserved broader attention as causal factors in Alzheimer's disease (AD), a neurodegenerative disorder. The senescence-accelerated mouse prone 8 (SAMP8) strain, a spontaneous mice of accelerated aging, are considered a robust model for sporadic AD. LW-AFC, an herbal medicine, was prepared from LiuweiDihuang decoction, which is a classical traditional Chinese medicine prescription. Here, we showed that the treatment of LW-AFC improved cognitive impairments of SAMP8 mice, including spatial learning and memory ability, active avoidance response, and object recognition memory capability. Our data indicated that there were significantly 8 increased and 12 decreased operational taxonomic units (OTUs) in the gut microbiota of SAMP8 mice compared with senescence accelerated mouse resistant 1 (SAMR1) strains, the control of SAMP8 mice. The treatment of LW-AFC altered 22 (16 increased and 6 decreased) OTUs in SAMP8 mice and among them, 15 OTUs could be reversed by LW-AFC treatment resulting in a microbial composition similar to that of SAMR1 mice. We further showed that there were 7 (3 negative and 4 positive correlation) OTUs significantly correlated with all the three types of cognitive abilities, at the order level, including Bacteroidales, Clostridiales, Desulfovibrionales, CW040, and two unclassified orders. LW-AFC had influences on bacterial taxa correlated with the abilities of learning and memory in SAMP8 mice and restored them to SAMR1 mice. Our results indicate that the effects of LW-AFC on improving cognitive impairments of SAMP8 mice might be via modulating intestinal microbiome and LW-AFC could be used as a potential anti-AD agent.

%B J Alzheimers Dis %V 53 %P 907-19 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340848?dopt=Abstract %R 10.3233/JAD-160138 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effects of Meditation versus Music Listening on Perceived Stress, Mood, Sleep, and Quality of Life in Adults with Early Memory Loss: A Pilot Randomized Controlled Trial. %A Innes, Kim E %A Selfe, Terry Kit %A Khalsa, Dharma Singh %A Kandati, Sahiti %X

BACKGROUND: Older adults with subjective cognitive decline (SCD) are at increased risk not only for Alzheimer's disease, but for poor mental health, impaired sleep, and diminished quality of life (QOL), which in turn, contribute to further cognitive decline, highlighting the need for early intervention.

OBJECTIVE: In this randomized controlled trial, we assessed the effects of two 12-week relaxation programs, Kirtan Kriya Meditation (KK) and music listening (ML), on perceived stress, sleep, mood, and health-related QOL in older adults with SCD.

METHODS: Sixty community-dwelling older adults with SCD were randomized to a KK or ML program and asked to practice 12 minutes daily for 12 weeks, then at their discretion for the following 3 months. At baseline, 12 weeks, and 26 weeks, perceived stress, mood, psychological well-being, sleep quality, and health-related QOL were measured using well-validated instruments.

RESULTS: Fifty-three participants (88%) completed the 6-month study. Participants in both groups showed significant improvement at 12 weeks in psychological well-being and in multiple domains of mood and sleep quality (p's≤0.05). Relative to ML, those assigned to KK showed greater gains in perceived stress, mood, psychological well-being, and QOL-Mental Health (p's≤0.09). Observed gains were sustained or improved at 6 months, with both groups showing marked and significant improvement in all outcomes. Changes were unrelated to treatment expectancies.

CONCLUSIONS: Findings suggest that practice of a simple meditation or ML program may improve stress, mood, well-being, sleep, and QOL in adults with SCD, with benefits sustained at 6 months and gains that were particularly pronounced in the KK group.

%B J Alzheimers Dis %V 52 %P 1277-98 %8 2016 Apr 08 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079708?dopt=Abstract %R 10.3233/JAD-151106 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Efficacy and Safety of ABT-126 in Subjects with Mild-to-Moderate Alzheimer's Disease on Stable Doses of Acetylcholinesterase Inhibitors: A Randomized, Double-Blind, Placebo-Controlled Study. %A Florian, Hana %A Meier, Andreas %A Gauthier, Serge %A Lipschitz, Stanley %A Lin, Yunzhi %A Tang, Qi %A Othman, Ahmed A %A Robieson, Weining Z %A Gault, Laura M %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cholinesterase Inhibitors %K Disease Progression %K Dose-Response Relationship, Drug %K Double-Blind Method %K Female %K Humans %K Indans %K International Cooperation %K Male %K Medication Adherence %K Middle Aged %K Piperidines %K Psychiatric Status Rating Scales %K Treatment Outcome %X

BACKGROUND: ABT-126 is a potent, selective α7 nicotinic acetylcholine receptor agonist with putative procognitive effects as a monotherapy in treating Alzheimer's disease (AD).

OBJECTIVE: This randomized, double-blind, placebo-controlled multicenter study (NCT01549834) investigated the efficacy and safety of ABT-126 in subjects with mild-to-moderate AD who were taking stable doses of acetylcholinesterase inhibitors (AChEIs).

METHODS: Subjects received 25 mg ABT-126 (n = 143), 75 mg ABT-126 (n = 145), or placebo (n = 146) once daily for 24 weeks. Subjects who completed the 24-week double-blind study were eligible to enroll in a 28-week open-label extension study (NCT01690195) and received 75 mg ABT-126 daily. The primary efficacy endpoint was the change from baseline to week 24 in the 11-item total score of the Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog).

RESULTS: Neither dose of ABT-126 demonstrated significant improvement compared with placebo in the primary efficacy endpoint. However, 25 mg ABT-126 demonstrated significant improvement compared with placebo in ADAS-Cog scores at week 4 (least squares mean difference, -1.21; standard error, 0.51; p <  0.010, one-sided); 75 mg ABT-126 did not demonstrate significant improvements in ADAS-Cog scores compared with placebo at any time point. A treatment effect was not observed for any secondary efficacy measures of cognition, function, or global improvement. ABT-126 was generally well tolerated; the most common adverse events were agitation, constipation, diarrhea, fall, and headache.

CONCLUSIONS: Overall, the efficacy profile of ABT-126 did not warrant further development as add-on therapy to AChEIs to treat mild-to-moderate AD.

%B J Alzheimers Dis %V 51 %P 1237-47 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967214?dopt=Abstract %R 10.3233/JAD-150978 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Efficacy and Safety of Crocus sativus L. in Patients with Mild Cognitive Impairment: One Year Single-Blind Randomized, with Parallel Groups, Clinical Trial. %A Tsolaki, Magda %A Karathanasi, Elina %A Lazarou, Ioulietta %A Dovas, Kostas %A Verykouki, Eleni %A Karacostas, Anastasios %A Georgiadis, Kostas %A Tsolaki, Anthoula %A Adam, Katerina %A Kompatsiaris, Ioannis %A Sinakos, Zacharias %X

There is evidence to suggest the efficacy of Crocus (saffron) in the management of cognitive decline. This study examined the efficacy of Crocus in patients with amnesic and multi domain MCI (aMCImd). The participants included 17 patients on Crocus and 18 on a waiting list, who were examined with a short neuropsychological battery, MRI 3T, while some patients were examined via 256-channel electroencephalogram (HD-EEG) at baseline and after 12 months. The results showed that patients on Crocus had improved Mini-Mental State Examination scores (p = 0.015), while the control group deteriorated. Also, MRI, EEG, and ERP showed improvement in specific domains. This led us to conclude that Crocus is a good choice for management of aMCImd.

%B J Alzheimers Dis %V 54 %P 129-33 %8 2016 Jul 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472878?dopt=Abstract %R 10.3233/JAD-160304 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Efficacy and Safety of MMFS-01, a Synapse Density Enhancer, for Treating Cognitive Impairment in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial. %A Liu, Guosong %A Weinger, Jason G %A Lu, Zhong-Lin %A Xue, Feng %A Sadeghpour, Safa %K Aged %K Anxiety %K Butyrates %K Cognition %K Cognition Disorders %K Double-Blind Method %K Emotions %K Female %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Nootropic Agents %K Sleep %K Synapses %K Treatment Outcome %X

BACKGROUND: Cognitive impairment is a major problem in elderly, affecting quality of life. Pre-clinical studies show that MMFS-01, a synapse density enhancer, is effective at reversing cognitive decline in aging rodents.

OBJECTIVE: Since brain atrophy during aging is strongly associated with both cognitive decline and sleep disorder, we evaluated the efficacy of MMFS-01 in its ability to reverse cognitive impairment and improve sleep.

METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-designed trial in older adult subjects (age 50-70) with cognitive impairment. Subjects were treated with MMFS-01 (n = 23) or placebo (n = 21) for 12 weeks and cognitive ability, sleep quality, and emotion were evaluated. Overall cognitive ability was determined by a composite score of tests in four major cognitive domains.

RESULTS: With MMFS-01 treatment, overall cognitive ability improved significantly relative to placebo (p = 0.003; Cohen's d = 0.91). Cognitive fluctuation was also reduced. The study population had more severe executive function deficits than age-matched controls from normative data and MMFS-01 treatment nearly restored their impaired executive function, demonstrating that MMFS-01 may be clinically significant. Due to the strong placebo effects on sleep and anxiety, the effects of MMFS-01 on sleep and anxiety could not be determined.

CONCLUSIONS: The current study demonstrates the potential of MMFS-01 for treating cognitive impairment in older adults.

%B J Alzheimers Dis %V 49 %P 971-90 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519439?dopt=Abstract %R 10.3233/JAD-150538 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Efficacy and Safety of Sustained Release Donepezil High Dose versus Immediate Release Donepezil Standard Dose in Japanese Patients with Severe Alzheimer's Disease: A Randomized, Double-Blind Trial. %A Homma, Akira %A Atarashi, Hirotsugu %A Kubota, Naoki %A Nakai, Kenya %A Takase, Takao %K Aged %K Alzheimer Disease %K Cholinesterase Inhibitors %K Delayed-Action Preparations %K Double-Blind Method %K Female %K Humans %K Indans %K Japan %K Male %K Mental Status Schedule %K Nootropic Agents %K Outpatients %K Piperidines %K Psychiatric Status Rating Scales %K Severity of Illness Index %K Treatment Outcome %X

BACKGROUND: Donepezil is an established treatment for mild, moderate, and severe Alzheimer's disease (AD). An international study demonstrated superior efficacy of sustained release (SR) 23 mg/day donepezil over immediate release (IR) 10 mg/day donepezil for cognitive function, but not global function in moderate-to-severe AD.

OBJECTIVE: To demonstrate the superiority of SR 23 mg/day donepezil over IR 10 mg/day donepezil in Japanese patients with severe AD (SAD).

METHODS: In this multicenter, randomized, double-blind, parallel-group study, Japanese outpatients with SAD were randomly assigned to continue IR 10 mg/day or switch to SR 23 mg/day for 24 weeks. Endpoints included the Severe Impairment Battery (SIB), Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus), and safety.

RESULTS: Overall, 166 and 185 patients were randomized to receive IR 10 mg/day and SR 23 mg/day, respectively. SR 23 mg/day was not statistically superior to IR 10 mg/day by SIB (least squares mean difference [LSMD]: 0.0; 95% confidence interval [CI]: -1.7, 1.8; p = 0.981) or CIBIC-plus (LSMD: 0.2; 95% CI: 0.0, 0.4; p = 0.080). Common adverse events in the SR 23 mg group were decreased appetite, vomiting, diarrhea, and contusion. Safety findings were consistent with known safety profiles of donepezil.

CONCLUSION: SR 23 mg/day donepezil was not superior to IR 10 mg/day donepezil regarding the efficacy endpoints for Japanese SAD. Considering that a 10 mg/day dose is approved for SAD in Japan, the present findings suggest that IR 10 mg/day donepezil is the optimal dosage for Japanese patients with SAD.

%B J Alzheimers Dis %V 52 %P 345-57 %8 2016 03 11 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967222?dopt=Abstract %R 10.3233/JAD-151149 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Elevated mRNA Expression and Low Methylation of SNCA in Japanese Alzheimer's Disease Subjects. %A Yoshino, Yuta %A Mori, Takaaki %A Yoshida, Taku %A Yamazaki, Kiyohiro %A Ozaki, Yuki %A Sao, Tomoko %A Funahashi, Yu %A Iga, Jun-Ichi %A Ueno, Shu-Ichi %X

Despite the continuing debate about the amyloid hypothesis in Alzheimer's disease (AD), the precise pathogenesis is still unclear. Mixed pathology is common and multiple different protein aggregates are seen in human postmortem brains. Aggregates consisting of the alpha-synuclein protein encoded by the Synuclein Alpha gene (SCNA) are common in both dementia with Lewy bodies and AD. We examined SNCA mRNA expression and methylation rates of the CpG island at intron 1 of SNCA in peripheral leukocytes in 50 AD and age- and sex-matched control subjects to verify whether alpha-synuclein pathology affects the AD pathogenesis. SNCA mRNA expression in AD subjects was significantly higher than that in control subjects (1.62±0.73 versus 0.98±0.50, p < 0.001). We found significant differences between AD and control subjects at seven CpG sites (average rate; 8.8±2.7 versus 9.5±2.5, respectively: p = 0.027). The methylation rates tended to be lower in AD subjects at all CpG sites. We conclude that mRNA expression and methylation of SNCA intron 1 are altered in AD, which may be caused by Lewy body pathology in AD.

%B J Alzheimers Dis %V 54 %P 1349-1357 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567856?dopt=Abstract %R 10.3233/JAD-160430 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Empirically Defining Trajectories of Late-Life Cognitive and Functional Decline. %A Hochstetler, Helen %A Trzepacz, Paula T %A Wang, Shufang %A Yu, Peng %A Case, Michael %A Henley, David B %A Degenhardt, Elisabeth %A Leoutsakos, Jeannie-Marie %A Lyketsos, Constantine G %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Apolipoprotein E4 %K Cognition Disorders %K Databases, Factual %K Dementia %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Male %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Surveys and Questionnaires %X

BACKGROUND: Alzheimer's disease (AD) is associated with variable cognitive and functional decline, and it is difficult to predict who will develop the disease and how they will progress.

OBJECTIVE: This exploratory study aimed to define latent classes from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database who had similar growth patterns of both cognitive and functional change using Growth Mixture Modeling (GMM), identify characteristics associated with those trajectories, and develop a decision tree using clinical predictors to determine which trajectory, as determined by GMM, individuals will most likely follow.

METHODS: We used ADNI early mild cognitive impairment (EMCI), late MCI (LMCI), AD dementia, and healthy control (HC) participants with known amyloid-β status and follow-up assessments on the Alzheimer's Disease Assessment Scale - Cognitive Subscale or the Functional Activities Questionnaire (FAQ) up to 24 months postbaseline. GMM defined trajectories. Classification and Regression Tree (CART) used certain baseline variables to predict likely trajectory path.

RESULTS: GMM identified three trajectory classes (C): C1 (n = 162, 13.6%) highest baseline impairment and steepest pattern of cognitive/functional decline; C3 (n = 819, 68.7%) lowest baseline impairment and minimal change on both; C2 (n = 211, 17.7%) intermediate pattern, worsening on both, but less steep than C1. C3 had fewer amyloid- or apolipoprotein-E ɛ4 (APOE4) positive and more healthy controls (HC) or EMCI cases. CART analysis identified two decision nodes using the FAQ to predict likely class with 82.3% estimated accuracy.

CONCLUSIONS: Cognitive/functional change followed three trajectories with greater baseline impairment and amyloid and APOE4 positivity associated with greater progression. FAQ may predict trajectory class.

%B J Alzheimers Dis %V 50 %P 271-82 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639960?dopt=Abstract %R 10.3233/JAD-150563 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Enalapril Alone or Co-Administered with Losartan Rescues Cerebrovascular Dysfunction, but not Mnemonic Deficits or Amyloidosis in a Mouse Model of Alzheimer's Disease. %A Ongali, Brice %A Nicolakakis, Nektaria %A Tong, Xing-Kang %A Aboulkassim, Tahar %A Imboden, Hans %A Hamel, Edith %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloidosis %K Analysis of Variance %K Animals %K Antihypertensive Agents %K Cerebrovascular Disorders %K Cholinesterases %K Disease Models, Animal %K Drug Combinations %K Enalapril %K Female %K Glial Fibrillary Acidic Protein %K Humans %K Losartan %K Male %K Maze Learning %K Memory Disorders %K Mice %K Mice, Transgenic %K Mutation %X

The co-administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARB) that bind angiotensin type 1 receptors (AT1R) may protect from Alzheimer's disease (AD) better than each treatment taken alone. We tested the curative potential of the non brain-penetrant ACEi enalapril (3 mg/kg/day) administered for 3 months either alone or in combination with the brain penetrant ARB losartan (10 mg/kg/day) in aged (∼15 months) transgenic mice overexpressing a mutated form of the human amyloid-β protein precursor (AβPP, thereafter APP mice). We studied cerebrovascular function, protein levels of oxidative stress markers (superoxide dismutases SOD1, SOD2 and the NADPH oxidase subunit p67phox), amyloid-β (Aβ) pathology, astrogliosis, cholinergic innervation, AT1R and angiotensin IV receptor (AT4R) levels, together with cognitive performance. Both treatments normalized cerebrovascular reactivity and p67phox protein levels, but they did not reduce the cerebrovascular levels of SOD1. Combined treatment normalized cerebrovascular SOD2 levels, significantly attenuated astrogliosis, but did not reduce the increased levels of cerebrovascular AT1R. Yet, combined therapy enhanced thioflavin-S labeled Aβ plaque burden, a tendency not significant when Aβ1 - 42 plaque load was considered. None of the treatments rescued cognitive deficits, cortical AT4R or cholinergic innervation. We conclude that both treatments normalized cerebrovascular function by inhibiting the AngII-induced oxidative stress cascade, and that the positive effects of the combined therapy on astrogliosis were likely due to the ability of losartan to enter brain parenchyma. However, enalapril did not potentiate, and may even dampen, the reported cognitive benefits of losartan, raising caution when selecting the most appropriate antihypertensive therapy in AD patients.

%B J Alzheimers Dis %V 51 %P 1183-95 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923013?dopt=Abstract %R 10.3233/JAD-150868 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Epileptic Prodromal Alzheimer's Disease, a Retrospective Study of 13 New Cases: Expanding the Spectrum of Alzheimer's Disease to an Epileptic Variant? %A Cretin, Benjamin %A Sellal, François %A Philippi, Nathalie %A Bousiges, Olivier %A Di Bitonto, Laure %A Martin-Hunyadi, Catherine %A Blanc, Frédéric %X

BACKGROUND: Aside from rare case reports, only one study, with 12 patients, has addressed the phenotypic presentation of epilepsy in clinically defined amnestic mild cognitive impairment (aMCI, presumed to correspond to the AD prodromal stage): the authors highlighted a pharmacosensitive non-convulsive partial epileptic syndrome most probably related to the temporal or temporo-frontal cortices.

OBJECTIVE: The objective of this study was to verify the existence and the syndromic features of epileptic prodromal AD in a tertiary Memory Clinic.

METHODS: We conducted a retrospective, single-center study of the electro-radio-clinical features of 13 cases of epileptic prodromal AD patients (3.1% of a cohort of MCI, n = 430 subjects), selected on both clinical criteria and CSF biomarkers.

RESULTS: In our patients, a pharmacosensitive temporal lobe epilepsy syndrome, inaugurating prodromal AD, started at a mean age of 63 years (±12.8 years) and preceded MCI diagnosis by 4 to 7 years. At the stage of aMCI, median MMSE score was 26 and imaging showed mild hippocampal atrophy. After almost one year under treatment, cognitive complaints were not relieved but the MMSE score remained stable at 26 for 11 patients (2 patients were excluded from analysis because of the onset of aphasic or neurovisual symptoms altering MMSE scoring).

CONCLUSION: Our data, in conjunction with those of the 12 previously described subjects, suggest the existence of a currently unrecognized inaugural epilepsy syndrome of sporadic AD. Such a syndrome could be called the epileptic variant of AD because seizures are its sole feature for more than 2.5 years.

%B J Alzheimers Dis %V 52 %P 1125-33 %8 2016 Apr 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104892?dopt=Abstract %R 10.3233/JAD-150096 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. %A Chouraki, Vincent %A Reitz, Christiane %A Maury, Fleur %A Bis, Joshua C %A Bellenguez, Celine %A Yu, Lei %A Jakobsdottir, Johanna %A Mukherjee, Shubhabrata %A Adams, Hieab H %A Choi, Seung Hoan %A Larson, Eric B %A Fitzpatrick, Annette %A Uitterlinden, Andre G %A De Jager, Philip L %A Hofman, Albert %A Gudnason, Vilmundur %A Vardarajan, Badri %A Ibrahim-Verbaas, Carla %A van der Lee, Sven J %A Lopez, Oscar %A Dartigues, Jean-François %A Berr, Claudine %A Amouyel, Philippe %A Bennett, David A %A van Duijn, Cornelia %A DeStefano, Anita L %A Launer, Lenore J %A Ikram, M Arfan %A Crane, Paul K %A Lambert, Jean-Charles %A Mayeux, Richard %A Seshadri, Sudha %X

Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI =   [1.13-1.21] per standard deviation increase in GRS; p-value =  2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI =   [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI =   [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex =  0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

%B J Alzheimers Dis %V 53 %P 921-32 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340842?dopt=Abstract %R 10.3233/JAD-150749 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of Cerebrospinal Fluid Assay Variability in Alzheimer's Disease. %A White, Matthew T %A Shaw, Leslie M %A Xie, Sharon X %K Alzheimer Disease %K Amyloid beta-Peptides %K Area Under Curve %K Biomarkers %K Databases, Factual %K Female %K Humans %K Likelihood Functions %K Male %K Peptide Fragments %K Phosphorylation %K ROC Curve %K tau Proteins %X

Studies of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have indicated that much of the variability observed in the biomarkers may be due to measurement error. Biomarkers are often obtained with measurement error, which may make the diagnostic biomarker appear less effective than it truly is. In the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, technical replicates of CSF biomarkers are available; the National Alzheimer's Coordinating Center database contains longitudinal replicates of CSF biomarkers. We focus on the area under the receiver operating characteristic curve (AUC) as the measure of diagnostic effectiveness for differentiating AD from normal cognition using CSF biomarkers and compare AUC estimates obtained by a more standard, naïve method (which uses a single observation per subject and ignores measurement error) to a maximum likelihood (ML) based method (which uses all replicates per subject and adjusts for measurement error). The choice of analysis method depends upon the noise to signal ratio (i.e., the magnitude of the measurement error variability relative to the true biomarker variability); moderate to high ratios may significantly bias the naïve AUC estimate, and the ML-based method would be preferred. The noise to signal ratios were low for the ADNI biomarkers but high for the tTau and pTau biomarkers in NACC. Correspondingly, the naïve and ML-based AUC estimates were nearly identical in the ADNI data but dissimilar for the tTau and pTau biomarkers in the NACC data. Therefore, using the naïve method is adequate for analysis of CSF biomarkers in the ADNI study, but the ML method is recommended for the NACC data.

%B J Alzheimers Dis %V 51 %P 463-70 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890778?dopt=Abstract %R 10.3233/JAD-151045 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of Neuropathological Effects of a High-Fat Diet in a Presymptomatic Alzheimer's Disease Stage in APP/PS1 Mice. %A Ettcheto, Miren %A Petrov, Dmitry %A Pedrós, Ignacio %A Alva, Norma %A Carbonell, Teresa %A Beas-Zarate, Carlos %A Pallas, Merce %A Auladell, Carme %A Folch, Jaume %A Camins, Antoni %X

Alzheimer's disease (AD) is currently an incurable aging-related neurodegenerative disorder. Recent studies give support to the hypotheses that AD should be considered as a metabolic disease. The present study aimed to explore the relationship between hippocampal neuropathological amyloid-β (Aβ) plaque formation and obesity at an early presymptomatic disease stage (3 months of age). For this purpose, we used APPswe/PS1dE9 (APP/PS1) transgenic mice, fed with a high-fat diet (HFD) in order to investigate the potential molecular mechanisms involved in both disorders. The results showed that the hippocampus from APP/PS1 mice fed with a HFD had an early significant decrease in Aβ signaling pathway specifically in the insulin degrading enzyme protein levels, an enzyme involved in (Aβ) metabolism, and α-secretase. These changes were accompanied by a significant increase in the occurrence of plaques in the hippocampus of these mice. Furthermore, APP/PS1 mice showed a significant hippocampal decrease in PGC-1α levels, a cofactor involved in mitochondrial biogenesis. However, HFD does not provoke changes in neither insulin receptors gene expression nor enzymes involved in the signaling pathway. Moreover, there are no changes in any enzymes (kinases) involved in tau phosphorylation, such as CDK5, and neither in brain oxidative stress production. These results suggest that early changes in brains of APP/PS1 mice fed with a HFD are mediated by an increase in Aβ1 ‒ 42, which induces a decrease in PKA levels and alterations in the p-CREB/ NMDA2B /PGC1-α pathway, favoring early AD neuropathology in mice.

%B J Alzheimers Dis %V 54 %P 233-51 %8 2016 Jul 14 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567882?dopt=Abstract %R 10.3233/JAD-160150 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of Underlying Causes of Death in Patients with Dementia to Support Targeted Advance Care Planning. %A van de Vorst, Irene E %A Koek, Huiberdina L %A Bots, Michiel L %A Vaartjes, Ilonca %X

BACKGROUND: Insight in causes of death in demented patients may help physicians in end-of-life care.

OBJECTIVES: To investigate underlying causes of death (UCD) in demented patients stratified by age, sex, dementia subtype [Alzheimer's disease (AD), vascular dementia (VaD)] and to compare them with UCD in the general population (GP).

METHODS: A nationwide cohort of 59,201 patients with dementia (admitted to a hospital or visiting a day clinic) was constructed [38.7% men, 81.4 years (SD 7.0)] from 2000 through 2010. UCDs were reported and compared to the GP by calculating relative risks (RRs).

RESULTS: During follow up [median follow up time 1.3 years (IQR 0.3- 3.0)], 64.2% of women and 69.3% of men died. Leading UCDs were dementia (17.5% in men and 23.7% in women) and cardiovascular disease (CVD) (18.7% and 19.2%, respectively). When compared to the GP, dementia was a more common UCD (RR in men 4.65, 95% CI 4.43-4.88), while CVD (RR in men 0.67, 95% CI 0.65-0.68) and cancer (RR 0.40, 95% CI 0.39-0.41) were less common. These differences were more pronounced in patients aged between 60-69 as compared to those aged≥90 years. Patients with AD died less often of cerebrovascular diseases as compared to VaD (RR in men 0.53, 95% CI 0.47-0.59).

CONCLUSION: UCDs in patients with dementia differs from that of the GP, as dementia is more often and cancer less often an UCD. Although less frequent compared to the GP, CVD also is one of the leading UCDs in patients with dementia. This information is valuable for targeted advance care planning.

%B J Alzheimers Dis %V 53 %P 117-25 %8 2016 May 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163802?dopt=Abstract %R 10.3233/JAD-150925 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer's Disease. %A Jayne, Tanya %A Newman, Morgan %A Verdile, Giuseppe %A Sutherland, Greg %A Münch, Gerald %A Musgrave, Ian %A Moussavi Nik, Seyyed Hani %A Lardelli, Michael %X

The majority of mutations causing familial Alzheimer's disease (fAD) have been found in the gene PRESENILIN1 (PSEN1) with additional mutations in the related gene PRESENILIN2 (PSEN2). The best characterized function of PRESENILIN (PSEN) proteins is in γ-secretase enzyme activity. One substrate of γ-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (AβPP/APP) that is a fAD mutation locus. AβPP is the source of the amyloid-β (Aβ) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in a focus on γ-secretase activity and Aβ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on γ-secretase in AD. We then discuss the main ideas regarding the role of γ-secretase and the PSEN genes in this disease. We examine the significance of the "fAD mutation reading frame preservation rule" that applies to PSEN1 and PSEN2 (and AβPP) and look at alternative roles for AβPP and Aβ in fAD. We present a case for an alternative interpretation of published data on the role of γ-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a "PSEN holoprotein multimer hypothesis" where PSEN fAD mutations generate mutant PSEN holoproteins that multimerize with wild type holoprotein and dominantly interfere with an AD-critical function(s) such as autophagy or secretion of Aβ. Holoprotein multimerization may be required for the endoproteolysis that activates PSENs' γ-secretase activity.

%B J Alzheimers Dis %V 52 %P 781-99 %8 2016 Apr 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060961?dopt=Abstract %R 10.3233/JAD-151186 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Evolution of Caregiver Burden in Frontotemporal Dementia with and without Amyotrophic Lateral Sclerosis. %A Hsieh, Sharpley %A Leyton, Cristian E %A Caga, Jashelle %A Flanagan, Emma %A Kaizik, Cassandra %A O'Connor, Claire M %A Kiernan, Matthew C %A Hodges, John R %A Piguet, Olivier %A Mioshi, Eneida %K Adaptation, Psychological %K Aged %K Amyotrophic Lateral Sclerosis %K Analysis of Variance %K Caregivers %K Case-Control Studies %K Cost of Illness %K Disease Progression %K Female %K Frontotemporal Dementia %K Humans %K Interviews as Topic %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Surveys and Questionnaires %X

BACKGROUND AND AIMS: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) represent a disease spectrum. Caregiver burden in subtypes of FTD has not yet been directly compared with those patients who have co-existent FTD and ALS (ALSFTD).

METHOD: Perceived caregiver burden was evaluated using the short Zarit Burden Interview (ZBI) in patients with behavioral-variant FTD (bvFTD, n = 21), semantic dementia (SD, n = 18), and ALSFTD (n = 15) at the initial clinical presentation and follow-up assessments. The Mini-Addenbrooke's Cognitive Examination (M-ACE) and the Motor Neuron Disease Behaviour Scale (MiND-B) were also used. Linear mixed effects models examined longitudinal changes on the ZBI, M-ACE, and MiND-B across groups.

RESULTS: Burden at baseline was highest for the bvFTD group. Longitudinally, perceived burden increased for the SD and ALSFTD groups whereas in bvFTD, the level of burden which was high at baseline and remained high with disease progression. The severity of abnormal behaviors at baseline, as assessed by the MiND-B, correlated with baseline levels of caregiver burden and further accounted for 23% of the variance in caregiver burden at clinical follow-up.

CONCLUSIONS: The trajectory of perceived burden differs across the FTD-ALS spectrum, with SD and ALSFTD caregivers demonstrating an increased burden that develops over time, compared to a persistently high level for bvFTD caregivers, evident throughout the disease course. The evolution of burden in these three syndromes likely reflects the initial presentation and clinical characterization that develops with time. Psycho-education programs for caregivers, which provide better coping strategies for challenging behaviors, may reduce levels of burden experienced with disease progression.

%B J Alzheimers Dis %V 49 %P 875-85 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519438?dopt=Abstract %R 10.3233/JAD-150475 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evolution of the Antidepressant Prescribing in Alzheimer's Disease and Related Disorders Between 2010 and 2014: Results from the French National Database on Alzheimer's Disease (BNA). %A David, Renaud %A Manera, Valeria %A Fabre, Roxane %A Pradier, Christian %A Robert, Philippe %A Tifratene, Karim %X

BACKGROUND: Safety warnings from health authorities are currently intended to limit the use of psychotropic agents in dementia-related conditions. Evidence concerning the use of antidepressants in dementia is, however, scarce and contradictory.

OBJECTIVE: To evaluate antidepressant use among individuals with Alzheimer's disease (AD) and related disorders in the French population between 2010 and 2014.

METHOD: Antidepressant prescriptions in individuals with AD, mixed dementia (MD), and vascular dementia (VaD) in the French National Alzheimer Database between 2010 and 2014 were analyzed (N = 199,544).

RESULTS: Multivariate analysis showed an annual significant increase (p < 0.001) in the prescription rate of antidepressants from 26% (2010) to 31% (2014), and identified female gender, younger age, higher education, living in long-term facilities, more severe cognitive decline, and presence of vascular signs (VaD and MD) as associated factors for antidepressant prescribing.

CONCLUSION: The annual increase of antidepressant prescribing among individuals with AD, MD, and VaD in French specialized settings may be partially related to the lack of current valuable medications for dementia-related behavioral symptoms.

%B J Alzheimers Dis %V 53 %P 1365-73 %8 2016 Jul 02 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392860?dopt=Abstract %R 10.3233/JAD-160238 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Examining the Relationship Between Autobiographical Memory Impairment and Carer Burden in Dementia Syndromes. %A Kumfor, Fiona %A Teo, Drusilla %A Miller, Laurie %A Lah, Suncica %A Mioshi, Eneida %A Hodges, John R %A Piguet, Olivier %A Irish, Muireann %K Adaptation, Psychological %K Aged %K Alzheimer Disease %K Analysis of Variance %K Behavioral Symptoms %K Caregivers %K Female %K Frontotemporal Dementia %K Humans %K Male %K Memory Disorders %K Memory, Episodic %K Middle Aged %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Statistics as Topic %X

BACKGROUND: Autobiographical memory (ABM) refers to the capacity to remember one's own past, and is known to be central for supporting one's identity and sense of self. This capacity is commonly affected in Alzheimer's disease (AD), as well as semantic dementia (SD) and behavioral-variant frontotemporal dementia (bvFTD). Importantly, ABM plays a critical social function, facilitating relationship intimacy and empathy, and thus loss of ABM may also negatively affect families and carers.

OBJECTIVE: To explore the relationship between ABM disruption and carer burden in AD, SD, and bvFTD, and establish whether characteristic ABM profiles differentially relate to carer burden across dementia syndromes.

METHODS: We recruited 12 AD, 10 SD, and 13 bvFTD patients and their primary carer. All participants completed the Autobiographical Interview to assess memory for recent and remote events. Carers completed: the Zarit Burden Interview; Depression, Anxiety and Stress Scale (DASS-21); and the Intimate Bond Measure (IBM).

RESULTS: In AD, loss of recent ABM was associated with worse psychological wellbeing of carers on the DASS-21. In contrast in SD, remote ABM dysfunction was associated with SD patients showing greater controlling behavior within their intimate relationships. In bvFTD, surprisingly, despite pervasive ABM impairment, no relationship between extent of ABM loss and carer burden was observed.

CONCLUSION: These preliminary results reveal that ABM impairment impacts on patients' families and carers and suggest that these influences vary according to the pattern of ABM dysfunction. Disease-specific interventions focusing on preserved aspects of ABM may improve quality of life for both patients and carers.

%B J Alzheimers Dis %V 51 %P 237-48 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836163?dopt=Abstract %R 10.3233/JAD-150740 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Excess Costs Associated with Possible Misdiagnosis of Alzheimer's Disease Among Patients with Vascular Dementia in a UK CPRD Population. %A Happich, Michael %A Kirson, Noam Y %A Desai, Urvi %A King, Sarah %A Birnbaum, Howard G %A Reed, Catherine %A Belger, Mark %A Lenox-Smith, Alan %A Price, David %X

BACKGROUND: Prior diagnosis of Alzheimer's disease (AD) among patients later diagnosed with vascular dementia (VaD) has been associated with excess costs, suggesting potential benefits of earlier rule-out of AD diagnosis.

OBJECTIVE: To investigate whether prior diagnosis with AD among patients with VaD is associated with excess costs in the UK.

METHODS: Patients with a final VaD diagnosis, continuous data visibility for≥6 months prior to index date, and linkage to Hospital Episode Statistics data were retrospectively selected from de-identified Clinical Practice Research Datalink data. Patients with AD diagnosis before a final VaD diagnosis were matched to similar patients with no prior AD diagnosis using propensity score methods. Annual excess healthcare costs were calculated for 5 years post-index, stratified by time to final diagnosis.

RESULTS: Of 9,311 patients with VaD, 508 (6%) had prior AD diagnosis with a median time to VaD diagnosis exceeding 2 years from index date. Over the entire follow-up period, patients with prior AD diagnosis had accumulated healthcare costs that were approximately GBP2,000 higher than those for matched counterparts (mostly due to higher hospitalization costs). Cost differentials peaked particularly in the period including the final VaD diagnosis, with excess costs quickly declining thereafter.

CONCLUSION: Potential misdiagnosis of AD among UK patients with VaD resulted in substantial excess costs. The decline in excess costs following a final VaD diagnosis suggests potential benefits from earlier rule-out of AD.

%B J Alzheimers Dis %V 53 %P 171-83 %8 2016 May 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163798?dopt=Abstract %R 10.3233/JAD-150685 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Exercise Plus Cognitive Performance Over and Above Exercise Alone in Subjects with Mild Cognitive Impairment. %A Sacco, Guillaume %A Caillaud, Corinne %A Ben Sadoun, Gregory %A Robert, Philippe %A David, Renaud %A Brisswalter, Jeanick %K Aged %K Analysis of Variance %K Cognitive Dysfunction %K Cognitive Therapy %K Exercise %K Exercise Therapy %K Female %K Humans %K Inhibition (Psychology) %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Reaction Time %K Retrospective Studies %K Treatment Outcome %X

BACKGROUND: Epidemiological studies highlight the relevance of regular exercise interventions to enhance or maintain neurocognitive function in subjects with cognitive impairments.

OBJECTIVES: The aim of this study was to ascertain the effect of aerobic exercise associated with cognitive enrichment on cognitive performance in subjects with mild cognitive impairment (MCI).

METHOD: Eight participants with MCI (72 ± 2 years) were enrolled in a 9-month study that consisted of two 3-months experimental interventions separated by a training cessation period of 3 months. The interventions included either aerobic exercise alone or aerobic exercise combined with cognitive enrichment. The exercise program involved two 20-min cycling exercise bouts per week at an intensity corresponding to 60% of the heart rate reserve. Cognitive performance was assessed using a task of single reaction time (SRT) and an inhibition task (Go-no-Go) before, immediately after, and 1 month after each intervention.

RESULTS: The exercise intervention improved the speed of responses during the Go-no-Go task without any increase in errors. This improvement was enhanced by cognitive enrichment (6 ± 1% ; p >  0.05), when compared with exercise alone (4 ± 0.5% ,). Following exercise cessation, this positive effect disappeared. No effect was observed on SRT performance.

CONCLUSION: Regular aerobic exercise improved cognitive performance in MCI subjects and the addition of cognitive tasks during exercise potentiated this effect. However, the influence of aerobic exercise on cognitive performance did not persist after cessation of training. Studies involving a larger number of subjects are necessary to confirm these results.

%B J Alzheimers Dis %V 50 %P 19-25 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639954?dopt=Abstract %R 10.3233/JAD-150194 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Exercise Prevents Amyloid-β-Induced Hippocampal Network Disruption by Inhibiting GSK3β Activation. %A Isla, Arturo G %A Vázquez-Cuevas, Francisco Gabriel %A Peña-Ortega, Fernando %X

Exercise is becoming a promising therapeutic approach to prevent alterations both in Alzheimer's disease (AD) patients and in transgenic models of AD. This neuroprotection has been associated with changes in hippocampal structure and function, as well as with the reduction of amyloid-β (Aβ) production and accumulation. However, whether exercise produces lasting changes in hippocampal population activity and renders it resistant to Aβ-induced network dysfunction is still unknown. Thus, we tested whether voluntary exercise changes hippocampal population activity and prevents its alteration in the presence of Aβ, which has been associated to glycogen synthase kinase-3β (GSK3β) activation. We found that the hippocampal population activity recorded in slices obtained from mice that exercised voluntarily (with free access to a running wheel for 21 days) exhibits higher power and faster frequency composition than slices obtained from sedentary animals. Moreover, the hippocampal network of mice that exercised becomes insensitive to Aβ-induced inhibition of spontaneous population activity. This protective effect correlates with the inability of Aβ to activate GSK3β, is mimicked by GSK3β inhibition with SB126763 (in slices obtained from sedentary mice), and is abolished by the inhibition of PI3K with LY294002 (in slices obtained from mice that exercised). We conclude that voluntary exercise produces a lasting protective state in the hippocampus, maintained in hippocampal slices by a PI3K-dependent mechanism that precludes its functional disruption in the presence of Aβ by avoiding GSK3β activation.

%B J Alzheimers Dis %V 52 %P 333-43 %8 2016 03 16 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003207?dopt=Abstract %R 10.3233/JAD-150352 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Expression of Tau Produces Aberrant Plasma Membrane Blebbing in Glial Cells Through RhoA-ROCK-Dependent F-Actin Remodeling. %A Torres-Cruz, Francisco M %A Rodríguez-Cruz, Fanny %A Escobar-Herrera, Jaime %A Barragán-Andrade, Norma %A Basurto-Islas, Gustavo %A Ripova, Daniela %A Avila, Jesús %A Garcia-Sierra, Francisco %X

Abnormal aggregation of Tau in glial cells has been reported in Alzheimer's disease (AD) and other tauopathies; however, the pathological significance of these aggregates remains unsolved to date. In this study, we evaluated whether full-length Tau (Tau441) and its aspartic acid421-truncated Tau variant (Tau421) produce alterations in the normal organization of the cytoskeleton and plasma membrane (PM) when transiently expressed in cultured C6-glial cells. Forty-eight hours post-transfection, abnormal microtubule bundling was observed in the majority of the cells, which expressed either Tau441 or Tau421. Moreover, both variants of Tau produced extensive PM blebbing associated with cortical redistribution of filamentous actin (F-Actin). These effects were reverted when Tau-expressing cells were incubated with drugs that depolymerize F-Actin. In addition, when glial cells showing Tau-induced PM blebbing were incubated with inhibitors of the Rho-associated protein kinase (ROCK) signaling pathway, both formation of abnormal PM blebs and F-Actin remodeling were avoided. All of these effects were initiated upstream by abnormal Tau-induced microtubule bundling, which may release the microtubule-bound guanine nucleotide exchange factor-H1 (GEF-H1) into the cytoplasm in order to activate its major effector RhoA-GTPase. These results may represent a new mechanism of Tau toxicity in which Tau-induced microtubule bundling produces activation of the Rho-GTPase-ROCK pathway that in turn mediates the remodeling of cortical Actin and PM blebbing. In AD and other tauopathies, these Tau-induced abnormalities may occur and contribute to the impairment of glial activity.

%B J Alzheimers Dis %V 52 %P 463-82 %8 2016 03 21 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003208?dopt=Abstract %R 10.3233/JAD-150396 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Expression of the Alzheimer's Disease Mutations AβPP695sw and PSEN1M146I in Double-Transgenic Göttingen Minipigs. %A Jakobsen, Jannik E %A Johansen, Marianne G %A Schmidt, Mette %A Liu, Ying %A Li, Rong %A Callesen, Henrik %A Melnikova, Margarita %A Habekost, Mette %A Matrone, Carmela %A Bouter, Yvonne %A Bayer, Thomas A %A Nielsen, Anders Lade %A Duthie, Monika %A Fraser, Paul E %A Holm, Ida E %A Jørgensen, Arne Lund %X

Mutations in the amyloid-β protein precursor gene (AβPP), the presenilin 1 gene (PSEN1) or the presenilin 2 gene (PSEN2) that increase production of the AβPP-derived peptide Aβ42 cause early-onset Alzheimer's disease. Rodent models of the disease show that further increase in Aβ42 production and earlier brain pathology can be obtained by coexpressing AβPP and PSEN1 mutations. To generate such elevated Aβ42 level in a large animal model, we produced Göttingen minipigs carrying in their genome one copy of a human PSEN1 cDNA with the Met146Ile (PSEN1M146I) mutation and three copies of a human AβPP695 cDNA with the Lys670Asn/Met671Leu (AβPPsw) double-mutation. Both transgenes were expressed in fibroblasts and in the brain, and their respective proteins were processed normally. Immunohistochemical staining with Aβ42-specific antibodies detected intraneuronal accumulation of Aβ42 in brains from a 10- and an 18-month-old pig. Such accumulation may represent an early event in the pathogenesis of Alzheimer's disease.

%B J Alzheimers Dis %V 53 %P 1617-30 %8 2016 Jul 14 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27540966?dopt=Abstract %R 10.3233/JAD-160408 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Expression Pattern of Scavenger Receptors and Amyloid-β Phagocytosis of Astrocytes and Microglia in Culture are Modified by Acidosis: Implications for Alzheimer's Disease. %A Eugenín, Jaime %A Vecchiola, Andrea %A Murgas, Paola %A Arroyo, Pablo %A Cornejo, Francisca %A von Bernhardi, Rommy %X

The pathological hallmarks of Alzheimer's disease (AD) are amyloid-β (Aβ) plaques, neurofibrillary tangles, and glia activation. The pathology also includes vascular amyloidosis and cerebrovascular disease. Vascular compromise can result in hypoperfusion, local tissue hypoxia, and acidosis. Activated microglia and astrocytes can phagocytose Aβ through membrane receptors that include scavenger receptors. Changes in glial cells induced by extracellular acidosis could play a role in the development of AD. Here, we assess whether extracellular acidosis changes glial cell properties relevant for Aβ clearance capacity. Incubation of glial cells on acidified culture medium (pH 6.9 or 6.5) for 24-48 h resulted in decreased cell diameter, with thinner branches in astrocytes, slight reduction in cell body size in microglia, a transient decrease in astrocyte adhesion to substrates, and a persistent decrease in microglia adhesion compared with control media (pH 7.4). Astrocyte Aβ phagocytosis decreased at pH 6.9 and 6.5, whereas microglia phagocytosis only transiently decreased in acidified media. Scavenger receptors class B member I (SR-BI) increased and scavenger receptors-macrophage receptors with collagenous structures (SR-MARCO) decreased in astrocytes cultured at pH 6.5. In contrast, in microglia exposed to pH 6.5, expression of SR-BI and SR-MARCO increased and fatty acid translocase (CD-36) decreased. In conclusion, the acidic environment changed the adhesiveness and morphology of both microglia and astrocytes, but only astrocytes showed a persistent decrease in Aβ clearance activity. Expression of scavenger receptors was affected differentially in microglia and astrocytes by acidosis. These changes in scavenger receptor patterns can affect the activation of glia and their contribution to neurodegeneration.

%B J Alzheimers Dis %V 53 %P 857-73 %8 2016 May 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258416?dopt=Abstract %R 10.3233/JAD-160083 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Extracellular Tau Paired Helical Filaments Differentially Affect Tau Pathogenic Mechanisms in Mitotic and Post-Mitotic Cells: Implications for Mechanisms of Tau Propagation in the Brain. %A Varghese, Merina %A Santa-Maria, Ismael %A Ho, Lap %A Ward, Libby %A Yemul, Shrishailam %A Dubner, Lauren %A Księżak-Reding, Hanna %A Pasinetti, Giulio Maria %X

The release of paired helical filaments (PHFs) from neurons into the extracellular space may contribute to the propagation of tau pathology across brain regions in Alzheimer's disease (AD) and other tauopathies. The majority of available mechanistic studies exploring the pathologic role of extracellular PHFs are conducted in proliferating cell lines. Here, we compare how extracellular PHFs induce tauopathy in mitotic cells and in post-mitotic brain neurons. In a mitotic cell line (HEK 293T), extracellular exposure to AD PHFs leads to an intracellular "aggresomal" type deposition of tau, coincidental with redistribution of dynein, a retrograde motor protein. We also observed that PHFs impaired proteasome degradation, but not autophagy. Exposure of cells to proteasome inhibitors was sufficient to induce intracellular tau aggregate formation as well as reorganization of dynein and the intermediate filament protein, vimentin. Thus, in mitotic cells, extracellular PHFs promote cellular tau aggregation, in part, by interfering with cellular proteasome degradation processes. In contrast with our observations with proliferating cells, exposure of post-mitotic primary neuronal cultures to AD PHFs did not promote "aggresomal" tau deposition, but instead resulted in a widespread accumulation of phosphorylated tau-immunoreactive swellings in neuritic processes, characterized by disturbed cytoskeletal organization of dynein and vimentin. Collectively, our observations suggest that extracellular PHFs may contribute to the propagation of tau pathology by independent mechanisms in post-mitotic and mitotic brain cells. These outcomes indicate that in addition to post-mitotic brain neurons, mitotic brain cells should also be considered as targets for therapeutic interventions to attenuate propagation of tauopathy.

%B J Alzheimers Dis %V 54 %P 477-96 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567821?dopt=Abstract %R 10.3233/JAD-160166 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Extracellular Vesicles Containing P301L Mutant Tau Accelerate Pathological Tau Phosphorylation and Oligomer Formation but Do Not Seed Mature Neurofibrillary Tangles in ALZ17 Mice. %A Baker, Siân %A Polanco, Juan Carlos %A Götz, Jϋrgen %X

In Alzheimer's disease, the distribution of neurofibrillary tangles, a histological hallmark comprised of phosphorylated forms of the protein tau, follows a distinct pattern through anatomically connected brain regions. The well-documented correlation between the severity of tau pathology and disease progression implies a prion-like seeding and spreading mechanism for tau. Experimentally, this has been addressed in transgenic mice by the injection of protein lysates isolated from brains of transgenic mice or patients with tauopathies, including AD, that were shown to behave like seeds, accelerating tau pathology and tangle formation in predisposed mice. More specifically, in vivo data suggest that brain lysates from mice harboring the P301S mutation of tau can seed protein aggregation when injected into the hippocampi of human wild-type tau transgenic ALZ17 mice. Here, we compared the seeding potential of lysates and extracellular vesicles enriched for exosomes (EVs) from wild-type and human P301L tau transgenic rTg4510 mouse brains. We show that transgenic EVs cause increased tau phosphorylation and soluble oligomer formation in a manner comparable to that of freely available proteins in brain lysates, a prerequisite for the formation of mature protein aggregates.

%B J Alzheimers Dis %V 54 %P 1207-1217 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567840?dopt=Abstract %R 10.3233/JAD-160371 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Familial Presenilin Mutations and Sporadic Alzheimer's Disease Pathology: Is the Assumption of Biochemical Equivalence Justified? %A Roher, Alex E %A Maarouf, Chera L %A Kokjohn, Tyler A %K Alzheimer Disease %K Amyloid beta-Peptides %K Brain %K Humans %K Mutation %K Presenilins %X

Studies of presenilin (PSEN) gene mutations producing early onset Alzheimer's disease (AD) have helped elucidate the pathogenic mechanisms of dementia and guided clinical trials of potential therapeutic interventions. Although familial and sporadic forms of AD share features, it is unclear if the two are precisely equivalent. In addition, PSEN mutations do not all produce a single phenotype, but exhibit substantial variability in clinical manifestations, which are related to the position and chemical nature of their amino acid substitutions as well as ratios of critical molecules such as Aβ40 and Aβ42. These differences complicate the interpretation of critical clinical trial results and their desired extrapolation to sporadic AD treatment. In this perspective, we examine differences between familial AD and sporadic AD as well as attributes shared by these uniquely arising disturbances in brain biochemical homeostasis that culminate in dementia.

%B J Alzheimers Dis %V 50 %P 645-58 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757189?dopt=Abstract %R 10.3233/JAD-150757 %0 Journal Article %J J Alzheimers Dis %D 2016 %T FDG-PET and Neuropsychiatric Symptoms among Cognitively Normal Elderly Persons: The Mayo Clinic Study of Aging. %A Krell-Roesch, Janina %A Ruider, Hanna %A Lowe, Val J %A Stokin, Gorazd B %A Pink, Anna %A Roberts, Rosebud O %A Mielke, Michelle M %A Knopman, David S %A Christianson, Teresa J %A Machulda, Mary M %A Jack, Clifford R %A Petersen, Ronald C %A Geda, Yonas E %X

One of the key research agenda of the field of aging is investigation of presymptomatic Alzheimer's disease (AD). Furthermore, abnormalities in brain glucose metabolism (as measured by FDG-PET) have been reported among cognitively normal elderly persons. However, little is known about the association of FDG-PET abnormalities with neuropsychiatric symptoms (NPS) in a population-based setting. Thus, we conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging in order to examine the association between brain glucose metabolism and NPS among cognitively normal (CN) persons aged > 70 years. Participants underwent FDG-PET and completed the Neuropsychiatric Inventory Questionnaire (NPI-Q), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). Cognitive classification was made by an expert consensus panel. We conducted multivariable logistic regression analyses to compute odds ratios (OR) and 95% confidence intervals after adjusting for age, sex, and education. For continuous variables, we used linear regression and Spearman rank-order correlations. Of 668 CN participants (median 78.1 years, 55.4% males), 205 had an abnormal FDG-PET (i.e., standardized uptake value ratio < 1.32 in AD-related regions). Abnormal FDG-PET was associated with depression as measured by NPI-Q (OR = 2.12; 1.23-3.64); the point estimate was further elevated for APOE ɛ4 carriers (OR = 2.59; 1.00-6.69), though marginally significant. Additionally, we observed a significant association between abnormal FDG-PET and depressive and anxiety symptoms when treated as continuous measures. These findings indicate that NPS, even in community-based samples, can be an important additional tool to the biomarker-based investigation of presymptomatic AD.

%B J Alzheimers Dis %V 53 %P 1609-16 %8 2016 Jul 14 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27447426?dopt=Abstract %R 10.3233/JAD-160326 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Feasibility of a Memory Clinic-Based Physical Activity Prescription Program. %A Vidoni, Eric D %A Watts, Amber S %A Burns, Jeffrey M %A Greer, Colby S %A Graves, Rasinio S %A Van Sciver, Angela %A Black, Jessica R %A Cooper, Sarah K %A Nagely, Allison C %A Uphoff, Elaine %A Volmer, Jennifer M %A Bieberle, Natalie A %X

BACKGROUND: Effective programs for promoting physical activity are needed for those with cognitive impairment.

OBJECTIVE: To test the feasibility of mobile Health (mHealth) technology-supported physical activity prescription from a tertiary care memory clinic.

METHODS: This feasibility study was designed as a 16-week randomized, crossover trial of a physical activity prescription: 8 weeks of intervention, 8 weeks of baseline or maintenance phase data collection. We recruited 2 cohorts: 21 individuals with Alzheimer-related cognitive impairment (mean age 72.3 (5.2), 9 females), and 9 individuals with normal cognition (mean age 69.6 (5.8), 8 females). We gave each cohort an mHealth accelerometer-based physical activity prescription to double number of steps taken. Our primary outcomes were feasibility and safety. Our secondary outcomes were change in weekly steps taken, Dementia Quality of Life Scale, Self-efficacy Scale, 6-minute Walk, and mini-Physical Performance Test.

RESULTS: Set-up and use of the device was not a barrier to participation. However, only 62% of participants with cognitive impairment completed the intervention. The cohort with cognitive impairment did not change their weekly step count above Week 1. All participants in the cohort with normal cognition were able to set up and use their device and increased their weekly step count above Week 1. There were no differences between Week 1 and Week 8 for any secondary measures in either cohort.

CONCLUSIONS: Setup and daily use of mHealth technology appears to be feasible for a person with cognitive impairment with the help of a partner, but increasing daily step counts over 8 weeks was not achieved. Future work needs to assess alternative activity prescription goals or additional support for patients and their partners.

%B J Alzheimers Dis %V 53 %P 161-70 %8 2016 Apr 21 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104905?dopt=Abstract %R 10.3233/JAD-160158 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Fibrillar Amyloid-β Accumulation Triggers an Inflammatory Mechanism Leading to Hyperphosphorylation of the Carboxyl-Terminal End of Tau Polypeptide in the Hippocampal Formation of the 3×Tg-AD Transgenic Mouse. %A Ontiveros-Torres, Miguel Ángel %A Labra-Barrios, María Luisa %A Díaz-Cintra, Sofía %A Aguilar-Vázquez, Azucena Ruth %A Moreno-Campuzano, Samadhi %A Flores-Rodríguez, Paola %A Luna-Herrera, Claudia %A Mena, Raúl %A Perry, George %A Florán-Garduño, Benjamín %A Luna-Muñoz, José %A Luna-Arias, Juan Pedro %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Disease Models, Animal %K Female %K Hippocampus %K Humans %K Male %K Mice, Inbred C57BL %K Mice, Transgenic %K Neuroglia %K Phosphorylation %K Plaque, Amyloid %K Presenilin-1 %K Pyramidal Cells %K tau Proteins %X

Alzheimer's disease (AD) is a degenerative and irreversible disorder whose progressiveness is dependent on age. It is histopathologically characterized by the massive accumulation of insoluble forms of tau and amyloid-β (Aβ) asneurofibrillary tangles and neuritic plaques, respectively. Many studies have documented that these two polypeptides suffer several posttranslational modifications employing postmortem tissue sections from brains of patients with AD. In order to elucidate the molecular mechanisms underlying the posttranslational modifications of key players in this disease, including Aβ and tau, several transgenic mouse models have been developed. One of these models is the 3×Tg-AD transgenic mouse, carrying three transgenes encoding APPSWE, S1M146V, and TauP301L proteins. To further characterize this transgenicmouse, we determined the accumulation of fibrillar Aβ as a function of age in relation to the hyperphosphorylation patterns of TauP301L at both its N- and C-terminus in the hippocampal formation by immunofluorescence and confocal microscopy. Moreover, we searched for the expression of activated protein kinases and mediators of inflammation by western blot of wholeprotein extracts from hippocampal tissue sections since 3 to 28 months as well. Our results indicate that the presence of fibrillar Aβ deposits correlates with a significant activation of astrocytes and microglia in subiculum and CA1 regions of hippocampus. Accordingly, we also observed a significant increase in the expression of TNF-α associated to neuritic plaques and glial cells. Importantly, there is an overexpression of the stress activated protein kinases SAPK/JNK and Cdk-5 in pyramidal neurons, which might phosphorylate several residues at the C-terminus of TauP301L. Therefore, the accumulation of Aβ oligomers results in an inflammatory environment that upregulates kinases involved in hyperphosphorylation of TauP301L polypeptide.

%B J Alzheimers Dis %V 52 %P 243-69 %8 2016 03 22 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031470?dopt=Abstract %R 10.3233/JAD-150837 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Fine Particulate Matter, Residential Proximity to Major Roads, and Markers of Small Vessel Disease in a Memory Study Population. %A Wilker, Elissa H %A Martinez-Ramirez, Sergi %A Kloog, Itai %A Schwartz, Joel %A Mostofsky, Elizabeth %A Koutrakis, Petros %A Mittleman, Murray A %A Viswanathan, Anand %X

BACKGROUND: Long-term exposure to ambient air pollution has been associated with impaired cognitive function and vascular disease in older adults, but little is known about these associations among people with concerns about memory loss.

OBJECTIVE: To examine associations between exposures to fine particulate matter and residential proximity to major roads and markers of small vessel disease.

METHODS: From 2004-2010, 236 participants in the Massachusetts Alzheimer's Disease Research Center Longitudinal Cohort participated in neuroimaging studies. Residential proximity to major roads and estimated 2003 residential annual average of fine particulate air pollution (PM2.5) were linked to measures of brain parenchymal fraction (BPF), white matter hyperintensities (WMH), and cerebral microbleeds. Associations were modeled using linear and logistic regression and adjusted for clinical and lifestyle factors.

RESULTS: In this population (median age [interquartile range] = 74 [12], 57% female) living in a region with median 2003 PM2.5 annual average below the current Environmental Protection Agency (EPA) standard, there were no associations between living closer to a major roadway or for a 2μg/m3 increment in PM2.5 and smaller BPF, greater WMH volume, or a higher odds of microbleeds. However, a 2μg/m3 increment in PM2.5 was associated with -0.19 (95% Confidence Interval (CI): -0.37, -0.005) lower natural log-transformed WMH volume. Other associations had wide confidence intervals.

CONCLUSIONS: In this population, where median 2003 estimated PM2.5 levels were below the current EPA standard, we observed no pattern of association between residential proximity to major roads or 2003 average PM2.5 and greater burden of small vessel disease or neurodegeneration.

%B J Alzheimers Dis %V 53 %P 1315-23 %8 2016 Jun 30 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372639?dopt=Abstract %R 10.3233/JAD-151143 %0 Journal Article %J J Alzheimers Dis %D 2016 %T First Symptoms and Neurocognitive Correlates of Behavioral Variant Frontotemporal Dementia. %A Santamaría-García, Hernando %A Reyes, Pablo %A García, Adolfo %A Baez, Sandra %A Martinez, Angela %A Santacruz, José Manuel %A Slachevsky, Andrea %A Sigman, Mariano %A Matallana, Diana %A Ibáñez, Agustín %X

BACKGROUND: Previous works highlight the neurocognitive differences between apathetic and disinhibited clinical presentations of the behavioral variant frontotemporal dementia (bvFTD). However, little is known regarding how the early presentation (i.e., first symptom) is associated to the neurocognitive correlates of the disease's clinical presentation at future stages of disease.

OBJECTIVES: We analyzed the neurocognitive correlates of patients with bvFTD who debuted with apathy or disinhibition as first symptom of disease.

METHODS: We evaluated the neuropsychological, clinical, and neuroanatomical (3T structural images) correlates in a group of healthy controls (n = 30) and two groups of bvFTD patients (presented with apathy [AbvFTD, n = 18] or disinhibition [DbvFTD, n = 16]). To differentiate groups according to first symptoms, we used multivariate analyses.

RESULTS: The first symptom in patients described the evolution of the disease. AbvFTD and DbvFTD patients showed increased brain atrophy and increased levels of disinhibition and apathy, respectively. Whole brain analyzes in AbvFTD revealed atrophy in the frontal, insular, and temporal areas. DbvFTD, in turn, presented atrophy in the prefrontal regions, temporoparietal junction, insula, and temporoparietal region. Increased atrophy in DbvFTD patients (compared to AbvFTD) was observed in frontotemporal regions. Multivariate analyses confirmed that a set of brain areas including right orbitofrontal, right dorsolateral prefrontal, and left caudate were enough to distinguish the patients' subgroups.∥Conclusion: First symptom in bvFTD patients described the neurocognitive impairments after around three years of disease, playing an important role in the early detection, disease tracking, and neuroanatomical specification of bvFTD, as well as in future research on potential disease-modifying treatments.

%B J Alzheimers Dis %V 54 %P 957-970 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567867?dopt=Abstract %R 10.3233/JAD-160501 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Fluoxetine Treatment Induces Seizure Behavior and Premature Death in APPswe/PS1dE9 Mice. %A Sierksma, Annerieke S R %A de Nijs, Laurence %A Hoogland, Govert %A Vanmierlo, Tim %A van Leeuwen, Fred W %A Rutten, Bart P F %A Steinbusch, Harry W M %A Prickaerts, Jos %A van den Hove, Daniel L A %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Anticonvulsants %K Body Weight %K Disease Models, Animal %K Fluoxetine %K Humans %K Logistic Models %K Male %K Mice, Inbred C57BL %K Mice, Transgenic %K Neuroprotective Agents %K Presenilin-1 %K Seizures %X

Treatment of Alzheimer's disease (AD) patients with the antidepressant fluoxetine is known to improve memory and cognitive function. However, the mechanisms underlying these effects are largely unknown. To unravel these mechanisms, we aimed to treat APPswe/PS1dE9 mice with fluoxetine. Unexpectedly, with time, an increased number of animals displayed seizure behavior and died. Although spontaneous behavioral seizures have been reported previously in this mouse model, the observation of seizures and death consequential to fluoxetine treatment is new. Our results warrant further research on the underlying mechanisms as this may refine the treatment of AD patients.

%B J Alzheimers Dis %V 51 %P 677-82 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890781?dopt=Abstract %R 10.3233/JAD-151066 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Folate-Vitamin B12 Interaction, Low Hemoglobin, and the Mortality Risk from Alzheimer's Disease. %A Min, Jin-Young %A Min, Kyoung-Bok %X

Abnormal hemoglobin levels are a risk factor for Alzheimer's disease (AD). Although the mechanism underlying these associations is elusive, inadequate micronutrients, particularly folate and vitamin B12, may increase the risk for anemia, cognitive impairment, and AD. In this study, we investigated whether the nutritional status of folate and vitamin B12 is involved in the association between low hemoglobin levels and the risk of AD mortality. Data were obtained from the 1999-2006 National Health and Nutrition Examination Survey (NHANES) and the NHANES (1999-2006) Linked Mortality File. A total of 4,688 participants aged ≥60 years with available baseline data were included in this study. We categorized three groups based on the quartiles of folate and vitamin B12 as follows: Group I (low folate and vitamin B12); Group II (high folate and low vitamin B12 or low folate and high vitamin B12); and Group III (high folate and vitamin B12). Of 4,688 participants, 49 subjects died due to AD. After adjusting for age, sex, ethnicity, education, smoking history, body mass index, the presence of diabetes or hypertension, and dietary intake of iron, significant increases in the AD mortality were observed in Quartile1 for hemoglobin (HR: 8.4, 95% CI: 1.4-50.8), and the overall risk of AD mortality was significantly reduced with increases in the quartile of hemoglobin (p for trend = 0.0200), in subjects with low levels of both folate and vitamin B12 at baseline. This association did not exist in subjects with at least one high level of folate and vitamin B12. Our finding shows the relationship between folate and vitamin B12 levels with respect to the association between hemoglobin levels and AD mortality.

%B J Alzheimers Dis %V 52 %P 705-12 %8 2016 03 21 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003215?dopt=Abstract %R 10.3233/JAD-151095 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Formal Psychiatric Disorders are not Overrepresented in Behavioral Variant Frontotemporal Dementia. %A Gossink, Flora T %A Dols, Annemieke %A Krudop, Welmoed A %A Sikkes, Sietske A %A Kerssens, Cora J %A Prins, Niels D %A Scheltens, Philip %A Stek, Max L %A Pijnenburg, Yolande A L %K Aged %K Cohort Studies %K Diagnostic and Statistical Manual of Mental Disorders %K Female %K Frontotemporal Dementia %K Humans %K Male %K Mental Disorders %K Middle Aged %K Neuropsychological Tests %K Psychiatric Status Rating Scales %X

While psychiatric misdiagnosis is well-known in behavioral variant frontotemporal dementia (bvFTD), a systematic evaluation of standardized criteria for psychiatric disorders in bvFTD is still missing. Our aim was to define frequency and character of DSM-IV psychiatric disorders among patients with probable and definite bvFTD compared to possible bvFTD, other neurodegenerative diseases, and psychiatric diagnoses, using MINI-International Neuropsychiatric Interview. We additionally compared psychiatric prodromes between these groups. Subjects were participants of the late-onset frontal lobe (LOF) study, a longitudinal multicenter study. In each patient, after baseline diagnostic procedure, a neurologist and geriatric psychiatrist made a joint clinical diagnosis. Independently, a structured diagnostic interview according to DSM-IV and ICD-10 criteria (MINI-Plus) was performed by a trained professional blinded to clinical diagnosis. Out of 91 patients, 23 with probable and definite bvFTD, 3 with possible bvFTD, 25 with a non bvFTD neurodegenerative disease, and 40 with a clinical psychiatric diagnosis were included. Overall frequency of formal current and past psychiatric disorders in probable and definite bvFTD (21.7% current, 8.7% past) did not differ from other neurodegenerative diseases (12.0% current, 16.0% past) or possible bvFTD (66.7% current, 66.7% past), but was less than in patients with a clinical psychiatric diagnosis (57.5% current, 62.5% past; p <  0.01). In probable and definite bvFTD unipolar mood disorders were most common. Formally diagnosed psychiatric disorders are not overrepresented in probable bvFTD, suggesting that psychiatric misdiagnosis in bvFTD can be reduced by strictly applying diagnostic criteria. In suspected bvFTD close collaboration between neurologists and psychiatrists will advance diagnostics and subsequent treatment.

%B J Alzheimers Dis %V 51 %P 1249-56 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967225?dopt=Abstract %R 10.3233/JAD-151198 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Formulaic Language in People with Probable Alzheimer's Disease: A Frequency-Based Approach. %A Zimmerer, Vitor C %A Wibrow, Mark %A Varley, Rosemary A %X

BACKGROUND: Language change can be a valuable biological marker of overall cognitive change in Alzheimer's disease (AD) and other forms of dementia. Previous reports have described increased use of language formulas in AD, i.e., combinations likely processed in a holistic manner. Words that commonly occur together are more likely to become a formula.

OBJECTIVE: To determine if frequency of co-occurrence as one indicator for formulaic language can distinguish people with probable AD from controls and if variables are sensitive to time post-symptom onset.

METHODS: We developed the Frequency in Language Analysis Tool (FLAT), which indicates degrees of formulaicity in an individual language sample. The FLAT accomplishes this by comparing individual language samples to co-occurrence data from the British National Corpus (BNC). Our analysis also contained more conventional language variables in order to assess novel contributions of the FLAT. We analyzed data from the Pitt Corpus, which is part of DementiaBank.

RESULTS: Both conventional and co-occurrence variables were able to distinguish AD and control groups. According to co-occurrence data, people with probable AD produced more formulaic language than controls. Only co-occurrence variables correlated with disease progression.

DISCUSSION: Frequency of word co-occurrences is one indicator for formulaicity and a valuable contribution to characterizing language change in AD.

%B J Alzheimers Dis %V 53 %P 1145-60 %8 2016 Jun 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372642?dopt=Abstract %R 10.3233/JAD-160099 %0 Journal Article %J J Alzheimers Dis %D 2016 %T FOXP2 Expression in Frontotemporal Lobar Degeneration-Tau. %A López-González, Irene %A Palmeira, Andre %A Aso, Ester %A Carmona, Margarita %A Fernandez, Liana %A Ferrer, Isidro %X

FOXP2 is altered in a variety of language disorders. We found reduced mRNA and protein expression of FOXP2 in frontal cortex area 8 in Pick's disease, and frontotemporal lobar degeneration-tau linked to P301L mutation presenting with language impairment in comparison with age-matched controls and cases with parkinsonian variant progressive supranuclear palsy. Foxp2 mRNA and protein are also reduced with disease progression in the somatosensory cortex in transgenic mice bearing the P301S mutation in MAPT when compared with wild-type littermates. Our findings support the presence of FOXP2 expression abnormalities in sporadic and familial frontotemporal degeneration tauopathies.

%B J Alzheimers Dis %V 54 %P 471-5 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497476?dopt=Abstract %R 10.3233/JAD-160274 %0 Journal Article %J J Alzheimers Dis %D 2016 %T FTIR and Raman Spectroscopy Applied to Dementia Diagnosis Through Analysis of Biological Fluids. %A Lopes, Jéssica %A Correia, Marta %A Martins, Ilka %A Henriques, Ana Gabriela %A Delgadillo, Ivonne %A da Cruz E Silva, Odete %A Nunes, Alexandra %X

To date, it is still difficult to perform an early and accurate diagnosis of dementia, therefore significant research has focused on finding new dementia biomarkers that can aid in this respect. There is an urgent need for non-invasive, rapid, and relatively inexpensive procedures for early diagnostics. Studies have demonstrated that of spectroscopic techniques, such as Fourier Transform Infrared Spectroscopy (FTIR) and Raman Spectroscopy could be a useful and accurate procedure to diagnose dementia. Given that several biochemical mechanisms related to neurodegeneration and dementia can lead to changes in plasma components and others peripheral body fluids; blood-based samples coupled to spectroscopic analyses can be used as a simple and less invasive approach.

%B J Alzheimers Dis %V 52 %P 801-12 %8 2016 Apr 08 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079713?dopt=Abstract %R 10.3233/JAD-151163 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Functional Connectivity of Ventral and Dorsal Visual Streams in Posterior Cortical Atrophy. %A Migliaccio, Raffaella %A Gallea, Cécile %A Kas, Aurélie %A Perlbarg, Vincent %A Samri, Dalila %A Trotta, Laura %A Michon, Agnès %A Lacomblez, Lucette %A Dubois, Bruno %A Lehéricy, Stéphane %A Bartolomeo, Paolo %K Aged %K Alzheimer Disease %K Atrophy %K Case-Control Studies %K Cerebral Cortex %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Oxygen %K Visual Pathways %X

BACKGROUND: Posterior cortical atrophy (PCA) induces progressive dysfunction of ventral and dorsal visual networks. Little is known, however, about corresponding changes in functional connectivity (FC).

OBJECTIVES: To investigate FC changes in the visual networks, their relationship with cortical atrophy, and the association with Alzheimer's disease (AD) pathology.

METHODS: Ten PCA patients and 28 age-matched controls participated in the study. Using resting state fMRI, we measured FC in ventral and dorsal cortical visual networks, defined on the basis of a priori knowledge of long-range white matter connections. To assess the relationships with AD, we determined AD biomarkers in cerebrospinal fluid and FC in the default mode network (DMN), which is vulnerable to AD pathology. Voxel-based morphometry analysis assessed the pattern of grey matter (GM) atrophy.

RESULTS: PCA patients showed GM atrophy in bilateral occipital and inferior parietal regions. PCA patients had lower FC levels in a ventral network than controls, but higher FC in inferior components of the dorsal network. In particular, the increased connectivity correlated with greater GM atrophy in occipital regions. All PCA patients had positive cerebrospinal fluid biomarkers for AD; however, FC in global DMN did not differ from controls.

CONCLUSIONS: FC in PCA reflects brain structure in a non-univocal way. Hyperconnectivity of dorsal networks may indicate aberrant communication in response to posterior brain atrophy or processes of neural resilience during the initial stage of brain dysfunction. The lack of difference from controls in global DMN FC highlights the atypical nature of PCA with respect to typical AD.

%B J Alzheimers Dis %V 51 %P 1119-30 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923019?dopt=Abstract %R 10.3233/JAD-150934 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Future Dementia Severity is Almost Entirely Explained by the Latent Variable δ's Intercept and Slope. %A Palmer, Raymond F %A Royall, Donald R %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition %K Cognitive Dysfunction %K Factor Analysis, Statistical %K Female %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Psychiatric Status Rating Scales %X

BACKGROUND: Structural equation models (SEM) can explicitly distinguish dementia-relevant variance in cognitive task performance. The resulting latent construct "δ" (for dementia) provides a relatively "error free" continuously varying dementia-specific phenotype.

OBJECTIVE: To estimate δ's change over time (Δδ) and determine Δδ's predictive validity using future dementia status as an outcome.

METHODS: Data from n = 2,191 participants of the Texas Alzheimer's Research and Care Consortium (TARCC) were used to construct a latent growth curve model of longitudinal change over four years using five cognitive measures and one measure of Instrumental Activities of Daily Living. Four final latent factors, including baseline δ and Δδ, were simultaneously entered as predictors of wave 4 dementia severity, as estimated by the Clinical Dementia Rating Scale "sum of boxes" (CDR).

RESULTS: All observed measures exhibited significant change [χ2 = 1,152 (df = 229); CFI = 0.968; RMSEA = 0.043]. The final model demonstrated excellent fit to the data [χ2 = 543 (df = 245); CFI = 0.991; RMSEA = 0.023]. All latent indicator loadings were significant, yielding four distinct factors. After adjustment for demographic covariates and baseline CDR scores, d and Δd were significantly independently associated with CDR4, explaining 25% and 49% of its variance, respectively. The latent variable g' significantly explained 3% of CDR4 variance independently of d and Δd. Δg' was not significantly associated with CDR4. Baseline CDR explained 16% of CDR4 variance.

CONCLUSIONS: Future dementia severity is almost entirely explained by the latent construct δ's intercept and slope.

%B J Alzheimers Dis %V 49 %P 521-9 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444763?dopt=Abstract %R 10.3233/JAD-150254 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Gene Expression of Quaking in Sporadic Alzheimer's Disease Patients is Both Upregulated and Related to Expression Levels of Genes Involved in Amyloid Plaque and Neurofibrillary Tangle Formation. %A Farnsworth, Bryn %A Peuckert, Christiane %A Zimmermann, Bettina %A Jazin, Elena %A Kettunen, Petronella %A Emilsson, Lina Sors %X

Quaking (QKI) is a gene exclusively expressed within glial cells. QKI has previously been implicated in various neurological disorders and diseases, including Alzheimer's disease (AD), a condition for which increasing evidence suggests a central role of glia cells. The objective of the present study was to investigate the expression levels of QKI and three QKI isoforms (QKI5, QKI6, and QKI7) in AD. Genes that have previously been related to the ontogeny and progression of AD, specifically APP, PSEN1, PSEN2, and MAPT, were also investigated. A real-time PCR assay of 123 samples from human postmortem sporadic AD patients and control brains was performed. The expression values were analyzed with an analysis of covariance model and subsequent multiple regressions to explore the possibility of related expression values between QKI, QKI isoforms, and AD-related genes. Further, the sequences of AD-related genes were analyzed for the presence of QKI binding domains. QKI and all measured QKI isoforms were found to be significantly upregulated in AD samples, relative to control samples. However, APP, PSEN1, PSEN2, and MAPT were not found to be significantly different. QKI and QKI isoforms were found to be predictive for the variance of APP, PSEN1, PSEN2, and MAPT, and putative QKI binding sites suggests an interaction with QKI. Overall, these results implicate a possible role of QKI in AD, although the exact mechanism by which this occurs remains to be uncovered.

%B J Alzheimers Dis %V 53 %P 209-19 %8 2016 May 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163826?dopt=Abstract %R 10.3233/JAD-160160 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Gene Expression Profiling in the APP/PS1KI Mouse Model of Familial Alzheimer's Disease. %A Weissmann, Robert %A Hüttenrauch, Melanie %A Kacprowski, Tim %A Bouter, Yvonne %A Pradier, Laurent %A Bayer, Thomas A %A Kuss, Andreas W %A Wirths, Oliver %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Brain %K Disease Models, Animal %K Gene Expression Profiling %K Male %K Mice %K Mice, Transgenic %K Nerve Degeneration %K Presenilin-1 %K Transcriptome %X

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by early intraneuronal amyloid-β (Aβ) accumulation, extracellular deposition of Aβ peptides, and intracellular hyperphosphorylated tau aggregates. These lesions cause dendritic and synaptic alterations and induce an inflammatory response in the diseased brain. Although the neuropathological characteristics of AD have been known for decades, the molecular mechanisms causing the disease are still under investigation. Studying gene expression changes in postmortem AD brain tissue can yield new insights into the molecular disease mechanisms. To that end, one can employ transgenic AD mouse models and the next-generation sequencing technology. In this study, a whole-brain transcriptome analysis was carried out using the well-characterized APP/PS1KI mouse model for AD. These mice display a robust phenotype reflected by working memory deficits at 6 months of age, a significant neuron loss in a variety of brain areas including the CA1 region of the hippocampus and a severe amyloid pathology. Based on deep sequencing, differentially expressed genes (DEGs) between 6-month-old WT or PS1KI and APP/PS1KI were identified and verified by qRT-PCR. Compared to WT mice, 250 DEGs were found in APP/PS1KI mice, while 186 DEGs could be found compared to PS1KI control mice. Most of the DEGs were upregulated in APP/PS1KI mice and belong to either inflammation-associated pathways or lysosomal activation, which is likely due to the robust intraneuronal accumulation of Aβ in this mouse model. Our comprehensive brain transcriptome study further highlights APP/PS1KI mice as a valuable model for AD, covering molecular inflammatory and immune responses.

%B J Alzheimers Dis %V 50 %P 397-409 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639971?dopt=Abstract %R 10.3233/JAD-150745 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Genetic Counseling and Testing for Alzheimer's Disease and Frontotemporal Lobar Degeneration: An Italian Consensus Protocol. %A Bocchetta, Martina %A Mega, Anna %A Bernardi, Livia %A Di Maria, Emilio %A Benussi, Luisa %A Binetti, Giuliano %A Borroni, Barbara %A Colao, Rosanna %A Di Fede, Giuseppe %A Fostinelli, Silvia %A Galimberti, Daniela %A Gennarelli, Massimo %A Ghidoni, Roberta %A Piaceri, Irene %A Pievani, Michela %A Porteri, Corinna %A Redaelli, Veronica %A Rossi, Giacomina %A Suardi, Silvia %A Babiloni, Claudio %A Scarpini, Elio %A Tagliavini, Fabrizio %A Padovani, Alessandro %A Nacmias, Benedetta %A Sorbi, Sandro %A Frisoni, Giovanni B %A Bruni, Amalia C %K Alzheimer Disease %K Amyloid beta-Peptides %K Consensus %K Female %K Follow-Up Studies %K Frontotemporal Lobar Degeneration %K Genetic Counseling %K Genetic Testing %K Humans %K Italy %K Male %K Peptide Fragments %K Psychiatric Status Rating Scales %X

BACKGROUND: Genetic testing of familial Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) is attracting interest thanks to innovative primary prevention clinical trials and increased request for information by at-risk individuals. However, ethical, social, and psychological implications are paramount and genetic testing must be supported by structured genetic counseling. In Italy, practice parameters and guidelines for genetic counseling in dementia are not available.

OBJECTIVE: To develop a nationally harmonized protocol for genetic counseling and testing of familial AD and FTLD.

METHODS: Activities were carried out in the context of the Italian Dominantly Inherited Alzheimer's and Frontotemporal Network (IT-DIAfN) project, a national network of centers of excellence with expertise in managing patients with familial AD and FTLD. A survey of the literature on genetic counseling protocols and guidelines was conducted. Local protocols for genetic counseling were surveyed. Differences and commonalities among protocols were identified and discussed among project partners. Consensus was reached following implicit aggregation methods.

RESULTS: Consensus was reached on a protocol for patients with clinically diagnosed familial AD or FTLD and a distinct protocol for their at-risk relatives. Genetic counseling should be provided by a multidisciplinary team including a geneticist, a neurologist/geriatrician, and a psychologist/psychiatrist, according to the following schedule: (i) initial consultation with tailored information on the genetics of the dementias; (ii) clinical, psychological, and cognitive assessment; if deemed appropriate (iii) genetic testing following a structured decision tree for gene mutation search; (iv) genetic testing result disclosure; (v) psychological support follow-up.

CONCLUSION: This genetic counseling protocol provides Italian centers with a line of shared practice for dealing with the requests for genetic testing for familial AD and FTLD from patients and at-risk relatives, who may also be eligible participants for novel prevention clinical trials.

%B J Alzheimers Dis %V 51 %P 277-91 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26901402?dopt=Abstract %R 10.3233/JAD-150849 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians. %A Kim, Sungeun %A Nho, Kwangsik %A Ramanan, Vijay K %A Lai, Dongbing %A Foroud, Tatiana M %A Lane, Katie %A Murrell, Jill R %A Gao, Sujuan %A Hall, Kathleen S %A Unverzagt, Frederick W %A Baiyewu, Olusegun %A Ogunniyi, Adesola %A Gureje, Oye %A Kling, Mitchel A %A Doraiswamy, P Murali %A Kaddurah-Daouk, Rima %A Hendrie, Hugh C %A Saykin, Andrew J %K Adaptor Proteins, Signal Transducing %K African Americans %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Cohort Studies %K Cystathionine beta-Synthase %K Cytoskeletal Proteins %K Female %K Genetic Variation %K Genome-Wide Association Study %K Heterozygote %K Homocysteine %K Humans %K Indiana %K Longitudinal Studies %K Male %K Nigeria %K Prospective Studies %X

Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.

%B J Alzheimers Dis %V 49 %P 991-1003 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519441?dopt=Abstract %R 10.3233/JAD-150651 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Genetic Variability of UCP4 Affects the Individual Susceptibility to Late-Onset Alzheimer's Disease and Modifies the Disease's Risk in APOE-ɛ4 Carriers. %A Montesanto, Alberto %A Crocco, Paolina %A Anfossi, Maria %A Smirne, Nicoletta %A Puccio, Gianfranco %A Colao, Rosanna %A Maletta, Raffaele %A Passarino, Giuseppe %A Bruni, Amalia C %A Rose, Giuseppina %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Female %K Genetic Association Studies %K Genotype %K Humans %K Male %K Mental Status Schedule %K Mitochondrial Uncoupling Proteins %K Neuroimaging %K Polymorphism, Single Nucleotide %X

Uncoupling proteins (UCPs) are a group of five mitochondrial inner membrane transporters with a tissue specific expression that uncouple biofuel oxidation from ATP synthesis and function as regulators of energy homeostasis and antioxidants. Previous data suggested that neuronal UCPs (UCP2, UCP4, and UCP5) can directly influence synaptic plasticity, neurotransmission, and neurodegenerative processes, and have a crucial role in the function and protection of the central nervous system. In fact, it has been observed that the expression of neuronal UCPs significantly decreases in Alzheimer's disease (AD) patients. Here we analyzed the variability of UCP2, -3, -4, and 5 genes in sporadic and familial cases (n = 465) of late-onset AD (LOAD) with respect to healthy controls (n = 442). We showed that a genetic variant in the human UCP4, rs9472817, not only significantly affects the individual susceptibility to LOAD, but also modulates the effect of APOE-ɛ4 on AD risk. In fact, rs9472817-C allele was significantly more frequent in both groups of patients with respect to the control group (p = 6.934*10-4 for familial and p = 1.033*10-3 for sporadic cases). In addition, gene-gene interaction analysis revealed that the effect of APOE-ɛ4 allele on LOAD risk was doubled in homozygote CC subjects; conversely, the risk conferred by the APOE-ɛ4 allele was annulled in subjects with two copies of the G allele. Our findings are further evidence that the efficiency in mitochondrial energy metabolism and oxidative stress are important factors in AD pathogenesis.

%B J Alzheimers Dis %V 51 %P 1265-74 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923023?dopt=Abstract %R 10.3233/JAD-150993 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Genetic Variant of the Sortilin 1 Gene is Associated with Reduced Risk of Alzheimer's Disease. %A Andersson, Carl-Henrik %A Hansson, Oskar %A Minthon, Lennart %A Andreasen, Niels %A Blennow, Kaj %A Zetterberg, Henrik %A Skoog, Ingmar %A Wallin, Anders %A Nilsson, Staffan %A Kettunen, Petronella %X

Alzheimer's disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc = 0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD.

%B J Alzheimers Dis %V 53 %P 1353-63 %8 2016 Jul 01 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392867?dopt=Abstract %R 10.3233/JAD-160319 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Genetic Variations in ABCA7 Can Increase Secreted Levels of Amyloid-β40 and Amyloid-β42 Peptides and ABCA7 Transcription in Cell Culture Models. %A Bamji-Mirza, Michelle %A Li, Yan %A Najem, Dema %A Liu, Qing Yan %A Walker, Douglas %A Lue, Lih-Fen %A Stupak, Jacek %A Chan, Kenneth %A Li, Jianjun %A Ghani, Mahdi %A Yang, Ze %A Rogaeva, Ekaterina %A Zhang, Wandong %X

Alzheimer's disease (AD) is characterized by extracellular deposits of amyloid-β (Aβ) in the brain. ABCA7 is highly expressed in the brain and a susceptibility gene for late-onset AD (LOAD). The minor alleles at two ABCA7 single-nucleotide polymorphisms (SNPs), rs3764650 (T>G; intron13) and rs3752246 at a predicted myristoylation site (C>G; exon33; p.Gly1527Ala), are significantly associated with LOAD risk; however, the mechanism of this association is unknown. Functional consequences of both SNPs were examined in HEK293 and CHO cells stably expressing AβPPSwe. Luciferase reporter assays in HEK293 cells suggested that intron13 carrying rs3764650 major T-allele (int13-T) possessed promoter-enhancing capabilities. Co-transfection experiments with hABCA7 and int13-T resulted in significantly increased ABCA7 protein level relative to that with int13-G. Expression of hABCA7 carrying rs3752246 risk allele led to increases in secreted Aβ40 and Aβ42 and β-secretase activity in CHO- and HEK-AβPPSwe cells. Hydroxymyristic acid treatment of cells expressing hABCA7 carrying the rs3752246 major G allele resulted in increased β-secretase activity and levels of Aβ, suggesting that lack of myristoylation contributes to the observed cell-phenotypes. Molecular weight determination, by gel-electrophoresis and mass spectrometry, of hABCA7 peptides spanning position 1527 showed loss of post-translational modification in the risk-allele peptide. These results suggest that decreased expression, or impaired function, of ABCA7 may contribute to AD pathology.

%B J Alzheimers Dis %V 53 %P 875-92 %8 2016 Jun 13 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27314524?dopt=Abstract %R 10.3233/JAD-150965 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Genetics of Frontotemporal Lobar Degeneration: From the Bench to the Clinic. %A Tang, Shan-Shan %A Li, Jun %A Tan, Lan %A Yu, Jin-Tai %X

Frontotemporal lobar degeneration (FTLD) is a clinically heterogeneous neurodegenerative disease with a strong genetic component. In this review, we summarize most common mutations in MAPT, GRN, and C90RF72, as well as less common mutations in VCP, CHMP2B, TARDBP, FUS gene and so on. Several guidelines have been developed to help gene testing based on genotype-phenotype correlation, the underlying histopathological subtypes, and the neuroanatomic associations. Furthermore, we also summarize molecular pathways implicated by genes and novel targets for FTLD prevention and management in recent years.

%B J Alzheimers Dis %V 52 %P 1157-76 %8 2016 Apr 19 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104909?dopt=Abstract %R 10.3233/JAD-160236 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Geographical Variation in Antipsychotic Drug Use in Elderly Patients with Dementia: A Nationwide Study. %A Zakarias, Johanne Købstrup %A Jensen-Dahm, Christina %A Nørgaard, Ane %A Stevnsborg, Lea %A Gasse, Christiane %A Andersen, Bodil Gramkow %A Søren, Jakobsen %A Waldorff, Frans Boch %A Moos, Torben %A Waldemar, Gunhild %X

BACKGROUND: Use of antipsychotics in elderly patients with dementia has decreased in the past decade due to safety regulations; however use is still high. Geographical variation may indicate discrepancies in clinical practice and lack of adherence to evidence-based guidelines for the management of behavioral symptoms.

OBJECTIVE: To investigate potential geographical variances in use of antipsychotic drugs in dementia care.

METHODS: A registry-based cross-sectional study in the entire elderly population of Denmark (≥65 years) conducted in 2012. Data included place of residence, prescriptions filled, and hospital discharge diagnoses. Antipsychotic drug use among elderly with (n = 34,536) and without (n = 931,203) a dementia diagnosis was compared across the five regions and 98 municipalities in Denmark, adjusted for age and sex.

RESULTS: In 2012, the national prevalence of antipsychotic drug use was 20.7% for elderly patients with dementia, with a national incidence of 3.9%. The prevalence ranged from 17.0% to 23.3% in the five regions and from 7.5% to 33.1% in the 98 municipalities, demonstrating an over four-fold difference.

CONCLUSION: The observed geographical variation was more pronounced at municipal level as compared to regional level, suggesting that the variation may be related to variances in clinical practice in primary care. This study highlights an urgent need for further educating professional carers and physicians to guide non-pharmacological as well as pharmacological management of neuropsychiatric symptoms in elderly patients with dementia.

%B J Alzheimers Dis %V 54 %P 1183-1192 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567863?dopt=Abstract %R 10.3233/JAD-160485 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Gesture Imitation in Alzheimer's Disease Dementia and Amnestic Mild Cognitive Impairment. %A Li, Xudong %A Jia, Shuhong %A Zhou, Zhi %A Hou, Chunlei %A Zheng, Wenjing %A Rong, Pei %A Jiao, Jinsong %X

BACKGROUND: Alzheimer's disease dementia (ADD) has become an important health problem in the world. Visuospatial deficits are considered to be an early symptom besides memory disorder.

OBJECTIVES: The gesture imitation test was devised to detect ADD and amnestic mild cognitive impairment (aMCI).

METHODS: A total of 117 patients with ADD, 118 with aMCI, and 95 normal controls were included in this study. All participants were administered our gesture imitation test, the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Clock Drawing Test (CDT), and the Clinical Dementia Rating Scale (CDR).

RESULTS: Patients with ADD performed worse than normal controls on global scores and had a lower success rate on every item (p < 0.001). The area under the curve (AUC) for the global scores when comparing the ADD and control groups was 0.869 (p < 0.001). Item 4 was a better discriminator with a sensitivity of 84.62% and a specificity of 67.37%. The AUC for the global scores decreased to 0.621 when applied to the aMCI and control groups (p = 0.002). After controlling for age and education, the gesture imitation test scores were positively correlated with the MMSE (r = 0.637, p < 0.001), the MoCA (r = 0.572, p < 0.001), and the CDT (r = 0.514, p < 0.001) and were negatively correlated with the CDR scores (r = -0.558, p < 0.001).

CONCLUSIONS: The gesture imitation test is an easy, rapid tool for detecting ADD, and is suitable for the patients suspected of mild ADD and aMCI in outpatient clinics.

%B J Alzheimers Dis %V 53 %P 1577-84 %8 2016 Jul 14 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27540963?dopt=Abstract %R 10.3233/JAD-160218 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Glutamine and Glutamate Complex, as Measured by Functional Magnetic Resonance Spectroscopy, Alters During Face-Name Association Task in Patients with Mild Cognitive Impairment and Alzheimer's Disease. %A Jahng, Geon-Ho %A Oh, Janghoon %A Lee, Do-Wan %A Kim, Hyug-Gi %A Rhee, Hak Young %A Shin, Wonchul %A Paik, Jong-Woo %A Lee, Kyung Mi %A Park, Soonchan %A Choe, Bo-Young %A Ryu, Chang-Woo %X

BACKGROUND: The metabolite response during a memory task in Alzheimer's disease (AD) patients is unknown.

OBJECTIVE: To investigate the metabolite changes in subjects with AD, amnestic mild cognitive impairment (aMCI), and cognitively normal (CN) elderly during a memory task using functional magnetic resonance spectroscopy (fMRS).

METHODS: This study involved 23 young normal controls (YC), 24 CN elderly, 24 aMCI, and 24 mild and probable AD individuals. fMRS data were acquired at the precuneus and posterior cingulate brain regions during a face-name association task. Statistical analyses of quantified metabolites were performed to evaluate differences of the metabolite values between the stimulation conditions and among the four subject groups. Receiver operating curve analysis was performed to evaluate whether the metabolic changes after functional activations can differentiate the subject groups.

RESULT: Glutamine and glutamate complex (Glx) was statistically significantly different between the fixation and repeat conditions in aMCI (p = 0.0492) as well as between the fixation and the novel conditions in the AD (p = 0.0412) group. The total N-acetylaspartate (tNAA) was statistically significantly different among the four subject groups in the fixation condition (DF = 3, F = 7.673, p <  0.001), the novel condition (DF = 3, F = 6.945, p <  0.001), and the repeat condition (DF = 3, F = 7.127, p <  0.001). tNAA, tCr, and mIns could be used to differentiate CN from aMCI. Furthermore, tNAA, tCr, Glx, and Glu could also differentiate CN from AD, and aMCI from AD.

CONCLUSION: Glx was altered during a stimulation that may be used to evaluate neuronal dysfunction in a demented patient. tNAA and tCr were reduced in patients with AD.

%B J Alzheimers Dis %V 52 %P 145-59 %8 2016 03 05 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060946?dopt=Abstract %R 10.3233/JAD-150877 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Greater specificity for cerebrospinal fluid P-tau231 over P-tau181 in the differentiation of healthy controls from Alzheimer's disease. %A Spiegel, Jonathan %A Pirraglia, Elizabeth %A Osorio, Ricardo S %A Glodzik, Lidia %A Li, Yi %A Tsui, Wai %A Saint Louis, Leslie A %A Randall, Catherine %A Butler, Tracy %A Xu, Jinfeng %A Zinkowski, Raymond P %A Zetterberg, Henrik %A Fortea, Juan %A Fossati, Silvia %A Wisniewski, Thomas %A Davies, Peter %A Blennow, Kaj %A de Leon, Mony J %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Case-Control Studies %K Cross-Sectional Studies %K Female %K Humans %K Logistic Models %K Male %K Middle Aged %K Phosphorylation %K ROC Curve %K Sensitivity and Specificity %K tau Proteins %X

Cerebrospinal fluid (CSF) measures of phosphorylated-tau (P-tau) 231 and P-tau181 are two biomarkers for the identification of tau pathology as related to Alzheimer's disease (AD). While both are pathologically validated, their relative diagnostic performances are not well known. This cross-sectional diagnostic study of 87 normal (NL) subjects and 28 AD subjects compared CSF P-tau231 with CSF P-tau181. Logistic regression modeling demonstrated that the P-tau231 was superior to the P-tau181 in the diagnostic classifications. At a fixed 85% sensitivity cutoff, the ROC analysis shows that P-tau231 has greater overall specificity than P-tau181. While both P-tau analytes demonstrated equivalent negative predictive accuracies, P-tau231 yielded significantly fewer false positives. Moreover, P-tau231, but not P-tau181, demonstrated sensitivity to the E4 genotype. A postmortem validation with 9 AD subjects confirmed the superiority of the CSF P-tau231 specificity. This study suggests that P-tau231 has the potential to improve the CSF tau biomarker diagnosis of AD.

%B J Alzheimers Dis %V 49 %P 93-100 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444757?dopt=Abstract %R 10.3233/JAD-150167 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Greater than the Sum of Its Parts: δ can be Constructed from Item Level Data. %A Royall, Donald R %A Palmer, Raymond F %A Matsuoka, Teruyuki %A Kato, Yuka %A Taniguchi, Shogo %A Ogawa, Mayu %A Fujimoto, Hiroshi %A Okamura, Aiko %A Shibata, Keisuke %A Nakamura, Kaeko %A Nakaaki, Shutaro %A Koumi, Hiroyuki %A Mimura, Masaru %A Fukui, Kenji %A Narumoto, Jin %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Executive Function %K Female %K Humans %K Japan %K Male %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K ROC Curve %K United States %X

"δ", a latent variable constructed from cognitive performance and functional status measures, can accurately diagnose dementia. The minimal assessment needed is unknown. We have constructed a δ homolog, "dTEXAS", from Telephone Executive Assessment Scale (TEXAS) items, and validated it in a convenience sample of Japanese persons (n = 176). dTEXAS scores correlated strongly with both Instrumental Activities of Daily Living (IADL) (r = -0.86, p <  0.001) and Clinical Dementia Rating Scale (CDR) (r = 0.71, p <  0.001). Constructed independently of their diagnoses, dTEXAS scores accurately distinguished dementia versus controls (area under the receiver operating curve [(AUC; ROC) = 0.92], dementia versus mild cognitive impairment (MCI) (AUC = 0.80) and controls versus MCI (AUC = 0.74). These AUCs are higher than those of multiple observed executive measures, as reported recently by Matsuoka et al., 2014. A dTEXAS score of -0.58 best discriminated between dementia versus controls with 90.1% sensitivity and 80.0% specificity.

%B J Alzheimers Dis %V 49 %P 571-9 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444760?dopt=Abstract %R 10.3233/JAD-150250 %0 Journal Article %J J Alzheimers Dis %D 2016 %T GSK-3β is Dephosphorylated by PP2A in a Leu309 Methylation-Independent Manner. %A Chu, Dandan %A Tan, Jianxin %A Xie, Shutao %A Jin, Nana %A Yin, Xiaomin %A Gong, Cheng-Xin %A Iqbal, Khalid %A Liu, Fei %K Animals %K Brain %K Carboxylic Ester Hydrolases %K Cell Line, Transformed %K Dose-Response Relationship, Drug %K Enzyme Inhibitors %K Excitatory Amino Acid Agonists %K Glycogen Synthase Kinase 3 %K Glycogen Synthase Kinase 3 beta %K Humans %K Kainic Acid %K Leucine %K Luminescent Proteins %K Male %K Methylation %K Mice %K Phosphorylation %K Protein O-Methyltransferase %K Protein Phosphatase 2 %K RNA, Small Interfering %K Serine %K tau Proteins %X

Hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase-3β (GSK-3β) and protein phosphate 2A (PP2A) are crucial enzymes to regulate tau phosphorylation. GSK-3β activity is regulated by its inhibitory phosphorylation at Ser9. We previously reported the cross-talk between GSK-3β and PP2A signaling and showed that PP2A could dephosphorylate GSK-3β at Ser9. Here, we investigated the dephosphorylation of GSK-3β in brain extracts in the presence of phosphatase inhibitors and found that a PP2A-like phosphatase activity was required for dephosphorylation of GSK-3β at Ser9. PP2A interacted with GSK-3β and suppressed its Ser9 phosphorylation in vitro and in HEK-293FT cells. Activity of PP2A negatively correlated to the level of phosphorylated GSK-3β in kainic acid-induced excitotoxic mouse brain. Alteration of methylation of the catalytic subunit of PP2A (PP2Ac) at Leu309 did not affect GSK-3β phosphorylation. These findings suggest that Leu309 methylation is not required for PP2A to dephosphorylate GSK-3β at Ser9.

%B J Alzheimers Dis %V 49 %P 365-75 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484916?dopt=Abstract %R 10.3233/JAD-150497 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Gx-50 Inhibits Neuroinflammation via α7 nAChR Activation of the JAK2/STAT3 and PI3K/AKT Pathways. %A Shi, Shi %A Liang, Dongli %A Bao, Min %A Xie, Yilin %A Xu, Wangjie %A Wang, Lianyun %A Wang, Zhaoxia %A Qiao, Zhongdong %K Acrylamides %K alpha7 Nicotinic Acetylcholine Receptor %K Amyloid beta-Peptides %K Analysis of Variance %K Animals %K Anti-Inflammatory Agents %K Cell Line, Transformed %K Cytokines %K Enzyme Inhibitors %K Enzyme-Linked Immunosorbent Assay %K Gene Expression Regulation %K Janus Kinase 2 %K Mice %K Microglia %K Phosphatidylinositol 3-Kinases %K Protein Binding %K RNA, Messenger %K Signal Transduction %X

Recent studies have revealed that the α7 nicotinic acetylcholine receptor (α7 nAChR) is a critical link between inflammation and neurodegeneration, which is closely associated with Alzheimer's disease (AD). The JAK2/STAT3 and PI3K/AKT signaling pathways contribute to the neuroprotective and anti-inflammatory effects of α7nAChR. Our previous studies have shown that treatment with gx-50 improves cognitive function and is neuroprotective. Here, we investigated the effect of gx-50 on α7 nAChR and Aβ-induced inflammation in microglia. First, the binding affinity of gx-50 to α7 nAChR was examined using the fluorescence-based Octet RED system, and the expression of α7 nAChR was detected using real-time PCR and western blotting. We also investigated downstream events of α7 nAChR activity, including the translocation of p-STAT3 and the phosphorylation of JAK2, STAT3, PI3K, and AKT. Finally, the effect of gx-50 on Aβ-induced inflammation via α7 nAChR-mediated signaling pathways was investigated using cytokine assays. The results showed that gx-50 is able to act as a specific ligand to activate α7 nAChR, which then upregulates the JAK2/STAT3 and PI3K/AKT signaling pathways to inhibit the secretions of pro-inflammatory cytokines, such as IL-1β. In conclusion, the results suggest that gx-50 could inhibit the Aβ-induced inflammatory response in microglia via α7 nAChR activity, which might be a successful therapeutic target against AD.

%B J Alzheimers Dis %V 50 %P 859-71 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836188?dopt=Abstract %R 10.3233/JAD-150963 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Gypenoside XVII Enhances Lysosome Biogenesis and Autophagy Flux and Accelerates Autophagic Clearance of Amyloid-β through TFEB Activation. %A Meng, Xiangbao %A Luo, Yun %A Liang, Tian %A Wang, Mengxia %A Zhao, Jingyu %A Sun, Guibo %A Sun, Xiaobo %X

A strategy for activating transcription factor EB (TFEB) to restore autophagy flux may provide neuroprotection against Alzheimer's disease. Our previous study reported that gypenoside XVII (GP-17), which is a major saponin abundant in ginseng and Panax notoginseng, ameliorated amyloid-β (Aβ)25-35-induced apoptosis in PC12 cells by regulating autophagy. In the present study, we aimed to determine whether GP-17 has neuroprotective effects on PC12 cells expressing the Swedish mutant of APP695 (APP695swe) and APP/PS1 mice. We also investigated the underlying mechanism. We found that GP-17 could significantly increase Atg5 expression and the conversion of LC3-I to LC3-II in APP695 cells, which was associated with a reduction in p62 expression. GP-17 also elevated the number of LC3 puncta in APP695 cells transduced with pCMV-GFP-LC3. GP-17 promoted the autophagy-based elimination of AβPP, Aβ40, and Aβ42 in APP695swe cells and prevented the formation of Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Furthermore, spatial learning and memory deficits were cured. Atg5 knockdown could abrogate the GP-17-mediated removal of AβPP, Aβ40, and Aβ42 in APP695swe cells. GP-17 upregulated LAMP-1, increased LysoTracker staining, and augmented LAMP-1/LC3-II co-localization. GP-17 could release TFEB from TFEB/14-3-3 complexes, which led to TFEB nuclear translocation and the induction of autophagy and lysosome biogenesis and resulted in the amelioration of autophagy flux. The knockdown of TFEB could abolish these effects of GP-17. In summary, these results demonstrated that GP-17 conferred protective effects to the cellular and rodent models of Alzheimer's disease by activating TFEB.

%B J Alzheimers Dis %V 52 %P 1135-50 %8 2016 Apr 05 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060963?dopt=Abstract %R 10.3233/JAD-160096 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Halting of Caspase Activity Protects Tau from MC1-Conformational Change and Aggregation. %A Mead, Emma %A Kestoras, Dimitra %A Gibson, Yolanda %A Hamilton, Lucy %A Goodson, Ross %A Jones, Sophie %A Eversden, Sarah %A Davies, Peter %A O'Neill, Michael %A Hutton, Michael %A Szekeres, Philip %A Wolak, Joanna %X

Intracellular neurofibrillary tangles (NFTs) are the hallmark of Alzheimer's disease and other tauopathies in which tau, a microtubule-associated protein, loses its ability to stabilize microtubules. Several post-translational modifications including phosphorylation and truncation increase tau's propensity to aggregate thus forming NFTs; however, the mechanisms underlying tau conformational change and aggregation still remain to be defined. Caspase activation and subsequent proteolytic cleavage of tau is thought to be a potential trigger of this disease-related pathological conformation. The aim of this work was to investigate the link between caspase activation and a disease-related conformational change of tau in a neuroblastoma cell-based model of spontaneous tau aggregation. We demonstrated that caspase induction initiates proteolytic cleavage of tau and generation of conformationally altered and aggregated tau recognized by the MC1 conformational antibody. Most importantly, these events were shown to be attenuated with caspase inhibitors. This implies that therapeutics aimed at inhibiting caspase-mediated tau cleavage may prove beneficial in slowing cleavage and aggregation, thus potentially halting tau pathology and disease progression.

%B J Alzheimers Dis %V 54 %P 1521-1538 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589517?dopt=Abstract %R 10.3233/JAD-150960 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Health-Related Quality of Life in Patients with Alzheimer's Disease in Different German Health Care Settings. %A Heßmann, Philipp %A Seeberg, Greta %A Reese, Jens Peter %A Dams, Judith %A Baum, Erika %A Müller, Matthias J %A Dodel, Richard %A Balzer-Geldsetzer, Monika %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Caregivers %K Depression %K Female %K Germany %K Humans %K Inpatients %K Male %K Multivariate Analysis %K Neuropsychological Tests %K Outpatients %K Psychiatric Status Rating Scales %K Quality of Life %K Residential Facilities %K Self Report %K Severity of Illness Index %X

The purpose of this study is to evaluate the health-related quality of life (HrQoL) of patients with Alzheimer's disease (AD) in different care settings (institutionalized versus community-dwelling) across all severity stages of dementia. Patients were consecutively recruited with their primary caregivers (123 inpatients and 272 outpatients), and the impact of patient-related parameters such as behavioral and psychological symptoms of dementia (BPSD) (Geriatric Depression Scale [GDS] and Neuropsychiatric Inventory [NPI]) and functional capacity (Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]) on HrQoL was analyzed. Patients' HrQoL was assessed using self-reported and caregiver-rated generic (EuroQoL Instrument) and dementia-specific (Quality of Life-Alzheimer's Disease [Qol-AD]) scales. Patients reported a considerably higher HrQoL than their caregivers on the QoL-AD, EQ-5D, and EQ VAS (p <  0.001). Different dementia severity groups showed significantly worse results in HrQoL for patients with lower MMSE scores. The mean self-reported QoL-AD decreased from 32.3±5.7 in the group with the highest MMSE scores to 27.1±5.5 in patients with the lowest MMSE scores (p <  0.001). A considerably lower HrQoL was shown for institutionalized patients versus participants in outpatient settings (proxy-rated QoL-AD 19.7±4.6 versus 26.0±7.1, p <  0.001). Depressive symptoms (GDS), BPSD (NPI), and reduced functional capacity (ADCS-ADL) were evaluated for their impact on patients' HrQoL. Multivariate models explained between 22% and 54% of the variance in patients' HrQoL. To analyze the causative direction of the reported associations, further longitudinal studies should be conducted.

%B J Alzheimers Dis %V 51 %P 545-61 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890754?dopt=Abstract %R 10.3233/JAD-150835 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Heart Rate Spectra Confirm the Presence of Autonomic Dysfunction in Dementia Patients. %A Struhal, Walter %A Mahringer, Christoph %A Lahrmann, Heinz %A Mörtl, Christoph %A Buhl, Peter %A Huemer, Mario %A Ransmayr, Gerhard %X

Recent data suggest autonomic dysfunction in patients suffering dementia. This study evaluated autonomic modulation in dementia patients with and without autonomic involvement, employing ECG spectral analysis in the time-frequency domain (wavelet transform) in supine resting and head-up tilt (HUT) position. Thirty-six patients were prospectively evaluated at the Department of Neurology and Psychiatry, General Hospital of the City of Linz, between 2009 and 2014. A standard cardiovascular autonomic test series (Ewing battery) was performed to screen for autonomic dysfunction. The Ewing battery diagnoses were used as reference standard and compared to the diagnostic results obtained by spectral analysis (time-frequency domain) of ECG recordings. Based on the Ewing battery results, 14 patients suffered autonomic dysfunction, while 22 did not. Time frequency domain was accessed by using the continuous wavelet transformation (CWT) with an analytical Morlet mother wavelet in supine resting and HUT position. Within each cohort the modification of spectral components from supine resting to HUT was analyzed reflecting the autonomic modulation. For patients without autonomic dysfunction, a significant increase of autonomic modulation was detected by wavelet transformed ECG recordings (8%, p < 0.05; low frequency content) during HUT compared to supine resting. There was no significant modulation between HUT and supine resting in patients suffering autonomic dysfunction. In dementia patients suffering autonomic dysfunction, CWT identified blunted autonomic regulation only by analysis of ECG recordings without the need to assess other biosignals or tests depending on the patient's cooperation. Further studies are needed to evaluate whether CWT is a suitable method to support the standard Ewing battery in demented patients.

%B J Alzheimers Dis %V 54 %P 657-67 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567816?dopt=Abstract %R 10.3233/JAD-160084 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Hemisphere Asymmetry of Response to Pharmacologic Treatment in an Alzheimer's Disease Mouse Model. %A Manousopoulou, Antigoni %A Saito, Satoshi %A Yamamoto, Yumi %A Al-Daghri, Nasser M %A Ihara, Masafumi %A Carare, Roxana O %A Garbis, Spiros D %K Alzheimer Disease %K Animals %K Brain %K Disease Models, Animal %K Functional Laterality %K Male %K Mice, Transgenic %K Nootropic Agents %K Proteome %K Tetrazoles %X

The aim of this study was to examine hemisphere asymmetry of response to pharmacologic treatment in an Alzheimer's disease mouse model using cilostazol as a chemical stimulus. Eight-month-old mice were assigned to vehicle or cilostazol treatment for three months and hemispheres were analyzed using quantitative proteomics. Bioinformatics interpretation showed that following treatment, aggregation of blood platelets significantly decreased in the right hemisphere whereas neurodegeneration significantly decreased and synaptic transmission increased in the left hemisphere only. Our study provides novel evidence on cerebral laterality of pharmacologic activity, with important implications in deciphering regional pharmacodynamic effects of existing drugs thus uncovering novel hemisphere-specific therapeutic targets.

%B J Alzheimers Dis %V 51 %P 333-8 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836196?dopt=Abstract %R 10.3233/JAD-151078 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Herpes and Alzheimer's Disease: Subversion in the Central Nervous System and How It Might Be Halted. %A Itzhaki, Ruth F %X

The last 8 or so years have seen a large increase in the number of studies supporting the concept of a major role for herpes simplex virus type 1 (HSV1) in Alzheimer's disease (AD). The main advances have been made through studies in humans and in mice, investigating the likelihood of reactivation of the latent virus in brain. Others have aimed to explain the mechanisms in cells whereby the increase in amyloid-beta (Aβ) production on HSV1 infection of cells and mouse brains occurs, and the reason that infected cells make this increase. The possibility that other herpesviruses are involved in the development of AD has been explored, and human herpesvirus type 6, Epstein-Barr virus, and cytomegalovirus, in particular, have been implicated. Epidemiological studies have further supported the role specifically of HSV1 and its reactivation in the disease. Antiviral studies have continued, comparing those acting by different mechanisms, such as restricting viral replication, or blocking viral entry into cells, to treat HSV1-infected cell cultures, and then examining the extent to which the virus-induced increases in Aβ and AD-like tau are reduced. All the studies support the usage of antiviral treatment to slow or halt the progression of AD.

%B J Alzheimers Dis %V 54 %P 1273-1281 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497484?dopt=Abstract %R 10.3233/JAD-160607 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Heterogeneity of Cognitive Anosognosia and its Variation with the Severity of Dementia in Patients with Alzheimer's Disease. %A Avondino, Emilie %A Antoine, Pascal %K Agnosia %K Alzheimer Disease %K Attention %K Chi-Square Distribution %K Cognition Disorders %K Dementia %K Female %K Humans %K Male %K Memory %K Neuropsychological Tests %K Predictive Value of Tests %K Prospective Studies %K Psychiatric Status Rating Scales %K Severity of Illness Index %X

Currently, the lack of awareness of deficits, i.e., anosognosia, is a major obstacle in the healthcare circuit that delays the diagnosis of Alzheimer's disease (AD). However, a clear framework is lacking in the literature related to this phenomenon in terms of its definition, mechanisms, and objects. The aim of this study is to assess the different levels of cognitive anosognosia using a prediction-performance procedure and to identify the potential correlates of these levels. A sample of patients with probable AD was divided into three groups according to the severity of dementia (mild (MiD), moderate (MoD), and moderately severe (MSD) dementia), ranked according to the results of the Mini-Mental State Examination. We observed the following three scores: the real score, the prediction score, and the anosognosia score. These scores were calculated based on the prediction-performance task MISAwareness from the Dementia Rating Scale for cognitive processes (i.e., Attention, Initiation, Conceptualization, Construction, and Memory). We obtained a strong plateau effect between the MiD and MoD groups for anosognosia scores for actual performance or prediction for both the level of overall functioning and for specific processes. The sole exception was the result for memory processes. Moreover, the profiles of the patients' responses on the Memory subscale were substantially different and, indeed, opposite from those for the other processes. The main results confirm the multidimensionality of anosognosia and its variability with the stage of dementia and specifically implicate memory processes that indicate a cleavage between memory and other cognitive functions.

%B J Alzheimers Dis %V 50 %P 89-99 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26638866?dopt=Abstract %R 10.3233/JAD-150496 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Heterogeneous Language Profiles in Patients with Primary Progressive Aphasia due to Alzheimer's Disease. %A Louwersheimer, Eva %A Keulen, M Antoinette %A Steenwijk, Martijn D %A Wattjes, Mike P %A Jiskoot, Lize C %A Vrenken, Hugo %A Teunissen, Charlotte E %A van Berckel, Bart N M %A van der Flier, Wiesje M %A Scheltens, Philip %A van Swieten, John C %A Pijnenburg, Yolande A L %K Aged %K Alzheimer Disease %K Aphasia, Primary Progressive %K Atrophy %K Biomarkers %K Brain %K Female %K Humans %K Language %K Language Tests %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Organ Size %K Positron-Emission Tomography %K Retrospective Studies %X

BACKGROUND: The logopenic variant of Primary Progressive Aphasia (lvPPA) is associated with underlying Alzheimer's disease (AD) pathology and characterized by impaired single word retrieval and repetition of phrases and sentences.

OBJECTIVE: We set out to study whether logopenic aphasia is indeed the prototypic language profile in PPA patients with biomarker evidence of underlying AD pathology and to correlate language profiles with cortical atrophy patterns on MRI.

METHODS: Inclusion criteria: (I) clinical diagnosis of PPA; (II) CSF profile and/or PiB-PET scan indicative for amyloid pathology; (III) availability of expert language evaluation. Based on language evaluation, patients were classified as lvPPA (fulfilling lvPPA core criteria), lvPPA extended (fulfilling core criteria plus other language disturbances), or PPA unclassifiable (not fulfilling lvPPA core criteria). Cortical atrophy patterns on MRI were visually rated and quantitative measurements of cortical thickness were performed using FreeSurfer.

RESULTS: We included 22 patients (age 67±7 years, 50% female, MMSE 21±6). 41% were classified as lvPPA, 36% as lvPPA extended with additional deficits in language comprehension and/or confrontation naming, and 23% as PPA unclassifiable. By both qualitative and quantitative measurements, patients with lvPPA showed mild global cortical atrophy on MRI, whereas patients with lvPPA extended showed more focal cortical atrophy, predominantly at the left tempo-parietal side. For PPA unclassifiable, qualitative measurements revealed a heterogeneous atrophy pattern.

CONCLUSION: Although most patients fulfilled the lvPPA criteria, we found that their language profiles were heterogeneous. The clinical and radiological spectrum of PPA due to underlying AD pathology is broader than pure lvPPA.

%B J Alzheimers Dis %V 51 %P 581-90 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890751?dopt=Abstract %R 10.3233/JAD-150812 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Hierarchical Distribution of the Tau Cytoskeletal Pathology in the Thalamus of Alzheimer's Disease Patients. %A Rüb, Udo %A Stratmann, Katharina %A Heinsen, Helmut %A Del Turco, Domenico %A Ghebremedhin, Estifanos %A Seidel, Kay %A den Dunnen, Wilfred %A Korf, Horst-Werner %K Alzheimer Disease %K Cytoskeleton %K Humans %K tau Proteins %K Thalamus %X

In spite of considerable progress in neuropathological research on Alzheimer's disease (AD), knowledge regarding the exact pathoanatomical distribution of the tau cytoskeletal pathology in the thalamus of AD patients in the advanced Braak and Braak AD stages V or VI of the cortical cytoskeletal pathology is still fragmentary. Investigation of serial 100 μm-thick brain tissue sections through the thalamus of clinically diagnosed AD patients with Braak and Braak AD stage V or VI cytoskeletal pathologies immunostained with the anti-tau AT8 antibody, along with the affection of the extraterritorial reticular nucleus of the thalamus, reveals a consistent and severe tau immunoreactive cytoskeletal pathology in the limbic nuclei of the thalamus (e.g., paraventricular, anterodorsal and laterodorsal nuclei, limitans-suprageniculate complex). The thalamic nuclei integrated into the associative networks of the human brain (e.g., ventral anterior and mediodorsal nuclei) are only mildly affected, while its motor precerebellar (ventral lateral nucleus) and sensory nuclei (e.g., lateral and medial geniculate bodies, ventral posterior medial and lateral nuclei, parvocellular part of the ventral posterior medial nucleus) are more or less spared. The highly stereotypical and characteristic thalamic distribution pattern of the AD-related tau cytoskeletal pathology represents an anatomical mirror of the hierarchical topographic distribution of the cytoskeletal pathology in the interconnected regions of the cerebral cortex of AD patients. These pathoanatomical parallels support the pathophysiological concept of a transneuronal spread of the disease process of AD along anatomical pathways. The AD-related tau cytoskeletal pathology in the thalamus most likely contributes substantially to the neuropsychiatric disease symptoms (e.g., dementia), attention deficits, oculomotor dysfunctions, altered non-discriminative aspects of pain experience of AD patients, and the disruption of their waking and sleeping patterns.

%B J Alzheimers Dis %V 49 %P 905-15 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519431?dopt=Abstract %R 10.3233/JAD-150639 %0 Journal Article %J J Alzheimers Dis %D 2016 %T High Risk of Dementia in Ventricular Enlargement with Normal Pressure Hydrocephalus Related Symptoms1. %A Koivisto, Anne M %A Kurki, Mitja I %A Alafuzoff, Irina %A Sutela, Anna %A Rummukainen, Jaana %A Savolainen, Sakari %A Vanninen, Ritva %A Jääskeläinen, Juha E %A Soininen, Hilkka %A Leinonen, Ville %X

BACKGROUND: Differential diagnosis of ventricular enlargement with normal pressure hydrocephalus (NPH) related symptoms is challenging. Patients with enlarged ventricles often manifest cognitive deterioration but their long-term outcome is not well known.

OBJECTIVES: We aim to evaluate long-term cognitive outcome in patients with enlarged ventricles and clinically suspected NPH.

METHODS: A neurologist and a neurosurgeon clinically evaluated 468 patients with enlarged ventricles and suspected NPH using radiological methods, intraventricular pressure monitoring, and frontal cortical brain biopsy. The neurologist confirmed final diagnoses after a median follow-up interval of 4.8 years.

RESULTS: Altogether, 232 patients (50%) with enlarged ventricles did not fulfill the criteria for shunt surgery. The incidence of dementia among patients with enlarged ventricles, and at least one NPH-related symptom with adequate follow-up data (n = 446) was high, varying from 77 (iNPH, shunt responders) to 141/1000 person-years (non-shunted patients with enlarged ventricles). At the end of the follow-up, 59% of all these patients were demented. The demented population comprised 73% of non-shunted patients with enlarged ventricles, 63% of shunted iNPH patients that did not respond to treatment, and 46% of iNPH patients that were initially responsive to shunting. The most common cause of dementia was Alzheimer's disease (n = 94, 36%), followed by vascular dementia (n = 68, 26%).

CONCLUSIONS: One-half of patients with enlarged ventricles and clinically suspected NPH were not shunted after intraventricular pressure monitoring. Dementia caused by various neurodegenerative diseases was frequently seen in patients with ventricular enlargement. Thus, careful diagnostic evaluation in collaboration with neurologists and neurosurgeons is emphasized.

%B J Alzheimers Dis %V 52 %P 497-507 %8 2016 Mar 22 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031474?dopt=Abstract %R 10.3233/JAD-150909 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Higher Fasting Plasma Glucose Levels, within the Normal Range, are Associated with Decreased Processing Speed in High Functioning Young Elderly. %A Raizes, Meytal %A Elkana, Odelia %A Franko, Motty %A Ravona Springer, Ramit %A Segev, Shlomo %A Beeri, Michal Schnaider %K Aged %K Blood Glucose %K Cognition %K Diabetes Mellitus, Type 2 %K Fasting %K Female %K Humans %K Linear Models %K Male %K Middle Aged %K Neuropsychological Tests %K Psychomotor Performance %K Reaction Time %K Reference Values %X

We explored the association of plasma glucose levels within the normal range with processing speed in high functioning young elderly, free of type 2 diabetes mellitus (T2DM). A sample of 41 participants (mean age = 64.7, SD = 10; glucose 94.5 mg/dL, SD = 9.3), were examined with a computerized cognitive battery. Hierarchical linear regression analysis showed that higher plasma glucose levels, albeit within the normal range (<110 mg/dL), were associated with longer reaction times (p <  0.01). These findings suggest that even in the subclinical range and in the absence of T2DM, monitoring plasma glucose levels may have an impact on cognitive function.

%B J Alzheimers Dis %V 49 %P 589-92 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484908?dopt=Abstract %R 10.3233/JAD-150433 %0 Journal Article %J J Alzheimers Dis %D 2016 %T High-Sodium Diet Has Opposing Effects on Mean Arterial Blood Pressure and Cerebral Perfusion in a Transgenic Mouse Model of Alzheimer's Disease. %A Taheri, Saeid %A Yu, Jin %A Zhu, Hong %A Kindy, Mark S %X

BACKGROUND: Cerebral ionic homeostasis impairment, especially Ca2+, has been observed in Alzheimer's disease (AD) and also with hypertension. Hypertension and AD both have been implicated in impaired cerebral autoregulation. However, the relationship between the ionic homeostasis impairment in AD and hypertension and cerebral blood flow (CBF) autoregulation is not clear.

OBJECTIVE: To test the hypothesis that a high-salt diet regimen influences the accumulation of amyloid-β (Aβand CBF) and CBF, exacerbates cognitive decline, and increases the propensity to AD.

METHODS: Double transgenic mice harboring the amyloid-β protein precursor (APPswe), and presenilin-1 (PSEN1) along with control littermates, 2 months of age at initiation of special diet, were divided into 4 groups: Group A, APP/PS1 and Group B, controls fed a high-sodium (4.00%) chow diet for 3 months; Group C, APP/PS1 and Group D, controls fed a low-sodium (0.08%) regular chow diet for 3 months. Mean arterial blood pressure (MAP) and CBF were measured noninvasively using the tail MAP measurement device and magnetic resonance imaging, respectively. Aβ plaques numbers in the cortex and hippocampus of APP/PS1 were quantified.

RESULTS: In contrary to controls, APP/PS1 mice fed a high-salt diet did not show markedly elevated mean systolic and diastolic blood pressure (134±4.8 compared with 162±2.8 mmHg, and 114±5.0 compared with 137±20 mmHg, p< 0.0001). However, a high-salt diet increased CBF in both APP/PS1 and controls and did not alter the cerebral tissue integrity. Aβ plaques were significantly reduced in the cortex and hippocampus of mice fed a high-salt diet.

CONCLUSION: These data suggest that a high-salt diet differently affects MAP and CBF in APP/PS1 mice and controls.

%B J Alzheimers Dis %V 54 %P 1061-1072 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567835?dopt=Abstract %R 10.3233/JAD-160331 %0 Journal Article %J J Alzheimers Dis %D 2016 %T High-Throughput Screening for Identification of Blood-Brain Barrier Integrity Enhancers: A Drug Repurposing Opportunity to Rectify Vascular Amyloid Toxicity. %A Qosa, Hisham %A Mohamed, Loqman A %A Al Rihani, Sweilem B %A Batarseh, Yazan S %A Duong, Quoc-Viet %A Keller, Jeffrey N %A Kaddoumi, Amal %X

The blood-brain barrier (BBB) is a dynamic interface that maintains brain homeostasis and protects it from free entry of chemicals, toxins, and drugs. The barrier function of the BBB is maintained mainly by capillary endothelial cells that physically separate brain from blood. Several neurological diseases, such as Alzheimer's disease (AD), are known to disrupt BBB integrity. In this study, a high-throughput screening (HTS) was developed to identify drugs that rectify/protect BBB integrity from vascular amyloid toxicity associated with AD progression. Assessing Lucifer Yellow permeation across in-vitro BBB model composed from mouse brain endothelial cells (bEnd3) grown on 96-well plate inserts was used to screen 1280 compounds of Sigma LOPAC®1280 library for modulators of bEnd3 monolayer integrity. HTS identified 62 compounds as disruptors, and 50 compounds as enhancers of the endothelial barrier integrity. From these 50 enhancers, 7 FDA approved drugs were identified with EC50 values ranging from 0.76-4.56 μM. Of these 7 drugs, 5 were able to protect bEnd3-based BBB model integrity against amyloid toxicity. Furthermore, to test the translational potential to humans, the 7 drugs were tested for their ability to rectify the disruptive effect of Aβ in the human endothelial cell line hCMEC/D3. Only 3 (etodolac, granisetron, and beclomethasone) out of the 5 effective drugs in the bEnd3-based BBB model demonstrated a promising effect to protect the hCMEC/D3-based BBB model integrity. These drugs are compelling candidates for repurposing as therapeutic agents that could rectify dysfunctional BBB associated with AD.

%B J Alzheimers Dis %V 53 %P 1499-516 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392852?dopt=Abstract %R 10.3233/JAD-151179 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Hippocampal Lipid Homeostasis in APP/PS1 Mice is Modulated by a Complex Interplay Between Dietary DHA and Estrogens: Relevance for Alzheimer's Disease. %A Díaz, Mario %A Fabelo, Noemí %A Casañas-Sánchez, Verónica %A Marin, Raquel %A Gómez, Tomás %A Quinto-Alemany, David %A Pérez, José A %K Acyl Coenzyme A %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Analysis of Variance %K Animals %K Disease Models, Animal %K Docosahexaenoic Acids %K Dose-Response Relationship, Drug %K Estrogens %K Gene Expression Regulation %K Hippocampus %K Homeostasis %K Humans %K Lipid Metabolism %K Mice %K Mice, Transgenic %K Mutation %K Presenilin-1 %K RNA, Messenger %X

Current evidence suggests that lipid homeostasis in the hippocampus is affected by different genetic, dietary, and hormonal factors, and that its deregulation may be associated with the onset and progression of Alzheimer's disease (AD). However, the precise levels of influence of each of these factors and their potential interactions remain largely unknown, particularly during neurodegenerative processes. In the present study, we have performed multifactorial analyses of the combined effects of diets containing different doses of docosahexaenoic acid (DHA), estrogen status (ovariectomized animals receiving vehicle or 17β-estradiol), and genotype (wild-type or transgenic APP/PS1 mice) in hippocampal lipid profiles. We have observed that the three factors affect lipid classes and fatty acid composition to different extents, and that strong interactions between these factors exist. The most aberrant lipid profiles were observed in APP/PS1 animals receiving DHA-poor diets and deprived of estrogens. Conversely, wild-type animals under a high-DHA diet and receiving estradiol exhibited a lipid profile that closely resembled that of the hippocampus of control animals. Interestingly, though the lipid signatures of APP/PS1 hippocampi markedly differed from wild-type, administration of a high-DHA diet in the presence of estrogens gave rise to a lipid profile that approached that of control animals. Paralleling changes in lipid composition, patterns of gene expression of enzymes involved in lipid biosynthesis were also altered and affected by combination of experimental factors. Overall, these results indicate that hippocampal lipid homeostasis is strongly affected by hormonal and dietary conditions, and that manipulation of these factors might be incorporated in AD therapeutics.

%B J Alzheimers Dis %V 49 %P 459-81 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519437?dopt=Abstract %R 10.3233/JAD-150470 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Hippocampal Sclerosis of Aging, a Common Alzheimer's Disease 'Mimic': Risk Genotypes are Associated with Brain Atrophy Outside the Temporal Lobe. %A Nho, Kwangsik %A Saykin, Andrew J %A Nelson, Peter T %X

Hippocampal sclerosis of aging (HS-Aging) is a common brain disease in older adults with a clinical course that is similar to Alzheimer's disease. Four single-nucleotide polymorphisms (SNPs) have previously shown association with HS-Aging. The present study investigated structural brain changes associated with these SNPs using surface-based analysis. Participants from the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 1,239), with both MRI scans and genotype data, were used to assess the association between brain atrophy and previously identified HS-Aging risk SNPs in the following genes: GRN, TMEM106B, ABCC9, and KCNMB2 (minor allele frequency for each is >30%). A fifth SNP (near the ABCC9 gene) was evaluated in post-hoc analysis. The GRN risk SNP (rs5848_T) was associated with a pattern of atrophy in the dorsomedial frontal lobes bilaterally, remarkable since GRN is a risk factor for frontotemporal dementia. The ABCC9 risk SNP (rs704180_A) was associated with multifocal atrophy whereas a SNP (rs7488080_A) nearby (∼50 kb upstream) ABCC9 was associated with atrophy in the right entorhinal cortex. Neither TMEM106B (rs1990622_T), KCNMB2 (rs9637454_A), nor any of the non-risk alleles were associated with brain atrophy. When all four previously identified HS-Aging risk SNPs were summed into a polygenic risk score, there was a pattern of associated multifocal brain atrophy in a predominately frontal pattern. We conclude that common SNPs previously linked to HS-Aging pathology were associated with a distinct pattern of anterior cortical atrophy. Genetic variation associated with HS-Aging pathology may represent a non-Alzheimer's disease contribution to atrophy outside of the hippocampus in older adults.

%B J Alzheimers Dis %V 52 %P 373-83 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003218?dopt=Abstract %R 10.3233/JAD-160077 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A History of In Vivo Neutron Activation Analysis in Measurement of Aluminum in Human Subjects. %A Mohseni, Hedieh K %A Chettle, David R %K Aluminum %K Alzheimer Disease %K Humans %K Neutron Activation Analysis %X

Aluminum, as an abundant metal, has gained widespread use in human life, entering the body predominantly as an additive to various foods and drinking water. Other major sources of exposure to aluminum include medical, cosmetic, and occupational routes. As a common environmental toxin, with well-known roles in several medical conditions such as dialysis encephalopathy, aluminum is considered a potential candidate in the causality of Alzheimer's disease. Aluminum mostly accumulates in the bone, which makes bone an indicator of the body burden of aluminum and an ideal organ as a proxy for the brain. Most of the techniques developed for measuring aluminum include bone biopsy, which requires invasive measures, causing inconvenience for the patients. There has been a considerable effort in developing non-invasive approaches, which allow for monitoring aluminum levels for medical and occupational purposes in larger populations. In vivo neutron activation analysis, a method based on nuclear activation of isotopes of elements in the body and their subsequent detection, has proven to be an invaluable tool for this purpose. There are definite challenges in developing in vivo non-invasive techniques capable of detecting low levels of aluminum in healthy individuals and aluminum-exposed populations. The following review examines the method of in vivo neutron activation analysis in the context of aluminum measurement in humans focusing on different neutron sources, interference from other activation products, and the improvements made in minimum detectable limits and patient dose over the past few decades.

%B J Alzheimers Dis %V 50 %P 913-26 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890739?dopt=Abstract %R 10.3233/JAD-150595 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Homocysteine and Alzheimer's Disease: Evidence for a Causal Link from Mendelian Randomization. %A Hu, Qingting %A Teng, Wenhui %A Li, Jiajia %A Hao, Fangfang %A Wang, Naidong %X

BACKGROUND/OBJECTIVE: The relationship between plasma homocysteine (Hcy) levels and Alzheimer's disease (AD) has been studied for many years, but remains controversial. While a recent meta-analysis of epidemiological studies, which included observational studies, indicated that homocysteine may be a risk factor for AD, there remains a need to further demonstrate this link due to the large degree of heterogeneity between studies. Epidemiological studies have certain limitations, as their results can be affected by confounding factors and reverse causation. In this study, we evaluated the relationship between plasma homocysteine and AD by using a Mendelian randomization method to avoid problems of confounding bias and reverse causality.

METHODS: We searched the PubMed and EMBASE databases for reports regarding the MTHFR C677T polymorphism (rs1801133) from the time of their inception to September 2015. These reports were combined with related observational studies, and used to evaluate the effect of MTHFR C677T (rs1801133) on the risk for AD. A recent meta-analysis of genome-wide association studies had previously suggested a relationship between homocysteine and MTHFR C677T (rs 1801133).

RESULTS: Our met-analysis included 34 studies with 9397 subjects, and demonstrated a significant relationship between plasma total homocysteine levels and the risk for AD (OR = 3.37; 95% CI = 1.90-5.95; p = 2.9×10-5).

CONCLUSION: Our meta-analysis demonstrated a causal link between plasma total homocysteine and the risk for AD, and provides a new insight into the etiology and prevention of AD.

%B J Alzheimers Dis %V 52 %P 747-56 %8 2016 Mar 22 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031476?dopt=Abstract %R 10.3233/JAD-150977 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Homocysteine, Infections, Polyamines, Oxidative Metabolism, and the Pathogenesis of Dementia and Atherosclerosis. %A McCully, Kilmer S %X

Hyperhomocysteinemia is a risk factor for development of dementia and Alzheimer's disease (AD), and low blood levels of folate and cobalamin are associated with hyperhomocysteinemia and AD. In elderly subjects with cognitive decline, supplementation with folate, cobalamin, and pyridoxal demonstrated reduction of cerebral atrophy in gray matter regions vulnerable to the AD process. Multiple pathogenic microbes are implicated as pathogenic factors in AD and atherosclerosis, and the deposition of amyloid-β (Aβ), phosphorylation of tau protein, neuronal injury, and apoptosis in AD are secondary to microbial infection. Glucose utilization and blood flow are reduced in AD, and these changes are accompanied by downregulation of glucose transport, Na, K-ATPase, oxidative phosphorylation, and energy consumption. Thioretinaco ozonide, the complex formed from thioretinamide, cobalamin, ozone, and oxygen is proposed to constitute the active site of oxidative phosphorylation, catalyzing synthesis of adenosine triphosphate (ATP) from nicotinamide adenine dinucleotide (NAD+) and phosphate. Pathogenic microbes cause synthesis of polyamines in host cells by increasing the transfer of aminopropyl groups from adenosyl methionine to putrescine, resulting in depletion of intracellular adenosyl methionine concentrations in host cells. Depletion of adenosyl methionine causes dysregulation of methionine metabolism, hyperhomocysteinemia, reduced biosynthesis of thioretinamide and thioretinaco ozonide, decreased oxidative phosphorylation, decreased production of nitric oxide and peroxynitrite, and impaired host response to infectious microbes, contributing to the pathogenesis of dementia and atherosclerosis.

%B J Alzheimers Dis %V 54 %P 1283-1290 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567876?dopt=Abstract %R 10.3233/JAD-160549 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Homotaurine Effects on Hippocampal Volume Loss and Episodic Memory in Amnestic Mild Cognitive Impairment. %A Spalletta, Gianfranco %A Cravello, Luca %A Gianni, Walter %A Piras, Federica %A Iorio, Mariangela %A Cacciari, Claudia %A Casini, Anna Rosa %A Chiapponi, Chiara %A Sancesario, Giuseppe %A Fratangeli, Claudia %A Orfei, Maria Donata %A Caltagirone, Carlo %A Piras, Fabrizio %K Aged %K Aged, 80 and over %K Analysis of Variance %K Chi-Square Distribution %K Cognitive Dysfunction %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Memory, Episodic %K Mental Status Schedule %K Middle Aged %K Neuroprotective Agents %K Neuropsychological Tests %K Taurine %X

Homotaurine supplementation may have a positive effect on early Alzheimer's disease. Here, we investigated its potential neuroprotective effect on the hippocampus structure and episodic memory performances in amnestic mild cognitive impairment (aMCI). Neuropsychological, clinical, and neuroimaging assessment in 11 treated and 22 untreated patients were performed at baseline and after 1 year. Magnetic resonance data were analyzed using voxel-based morphometry to explore significant differences (Family Wise Error corrected) between the two groups over time. Patients treated with homotaurine showed decreased volume loss in the left and right hippocampal tail, left and right fusiform gyrus, and right inferior temporal cortex which was associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI has a positive effect on hippocampus atrophy and episodic memory loss. Future studies should further clarify the mechanisms of its effects on brain morphometry.

%B J Alzheimers Dis %V 50 %P 807-16 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757035?dopt=Abstract %R 10.3233/JAD-150484 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Human ApoE ɛ2 Promotes Regulatory Mechanisms of Bioenergetic and Synaptic Function in Female Brain: A Focus on V-type H+-ATPase. %A Woody, Sarah K %A Zhou, Helen %A Ibrahimi, Shaher %A Dong, Yafeng %A Zhao, Liqin %X

Humans possess three major isoforms of the apolipoprotein E (ApoE) gene encoded by three alleles: ApoE ɛ2 (ApoE2), ApoE ɛ3 (ApoE3), and ApoE ɛ4 (ApoE4). It is established that the three ApoE isoforms confer differential susceptibility to Alzheimer's disease (AD); however, an in-depth molecular understanding of the underlying mechanisms is currently unavailable. In this study, we examined the cortical proteome differences among the three ApoE isoforms using 6-month-old female, human ApoE2, ApoE3, and ApoE4 gene-targeted replacement mice and two-dimensional proteomic analyses. The results reveal that the three ApoE brains differ primarily in two areas: cellular bioenergetics and synaptic transmission. Of particular significance, we show for the first time that the three ApoE brains differentially express a key component of the catalytic domain of the V-type H+-ATPase (Atp6v), a proton pump that mediates the concentration of neurotransmitters into synaptic vesicles and thus is crucial in synaptic transmission. Specifically, our data demonstrate that ApoE2 brain exhibits significantly higher levels of the B subunit of Atp6v (Atp6v1B2) when compared to both ApoE3 and ApoE4 brains, with ApoE4 brain exhibiting the lowest expression. Our additional analyses show that Atp6v1B2 is significantly impacted by aging and AD pathology and the data suggest that Atp6v1B2 deficiency could be involved in the progressive loss of synaptic integrity during early development of AD. Collectively, our findings indicate that human ApoE isoforms differentially modulate regulatory mechanisms of bioenergetic and synaptic function in female brain. A more efficient and robust status in both areas-in which Atp6v may play a role-could serve as a potential mechanism contributing to the neuroprotective and cognition-favoring properties associated with the ApoE2 genotype.

%B J Alzheimers Dis %V 53 %P 1015-31 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340853?dopt=Abstract %R 10.3233/JAD-160307 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Human Truncated Tau Induces Mature Neurofibrillary Pathology in a Mouse Model of Human Tauopathy. %A Zimova, Ivana %A Brezovakova, Veronika %A Hromadka, Tomas %A Weisova, Petronela %A Cubinkova, Veronika %A Valachova, Bernadeta %A Filipcik, Peter %A Jadhav, Santosh %A Smolek, Tomas %A Novak, Michal %A Zilka, Norbert %X

Alzheimer's disease (AD) represents the most common neurodegenerative disorder. Several animal models have been developed in order to test pathophysiological mechanisms of the disease and to predict effects of pharmacological interventions. Here we examine the molecular and behavioral features of R3m/4 transgenic mice expressing human non-mutated truncated tau protein (3R tau, aa151-391) that were previously used for efficacy testing of passive tau vaccine. The mouse model reliably recapitulated crucial histopathological features of human AD, such as pre-tangles, neurofibrillary tangles, and neuropil threads. The pathology was predominantly located in the brain stem. Transgenic mice developed mature sarkosyl insoluble tau complexes consisting of mouse endogenous and human truncated and hyperphosphorylated forms of tau protein. The histopathological and biochemical features were accompanied by significant sensorimotor impairment and reduced lifespan. The sensorimotor impairment was monitored by a highly sensitive, fully-automated tool that allowed us to assess early deficit in gait and locomotion. We suggest that the novel transgenic mouse model can serve as a valuable tool for analysis of the therapeutic efficacy of tau vaccines for AD therapy.

%B J Alzheimers Dis %V 54 %P 831-43 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567836?dopt=Abstract %R 10.3233/JAD-160347 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Hyperactivity with Agitative-Like Behavior in a Mouse Tauopathy Model. %A Jul, Pia %A Volbracht, Christiane %A de Jong, Inge E M %A Helboe, Lone %A Elvang, Anders Brandt %A Pedersen, Jan Torleif %K Age Factors %K Analysis of Variance %K Animals %K Brain %K Cognition Disorders %K Disease Models, Animal %K Doxycycline %K Exploratory Behavior %K Humans %K Hyperkinesis %K Male %K Maze Learning %K Mice %K Mice, Transgenic %K Motor Activity %K Mutation %K Psychomotor Agitation %K tau Proteins %K Tauopathies %K Time Factors %X

Tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau. In addition to memory loss, patients experience behavioral symptoms such as agitation, aggression, depression, and insomnia. We explored the behavioral phenotype of a mouse model (rTg4510) carrying the human tau P301L mutation found in a familial form of FTD. We tested these mice in locomotor activity assays as well as in the Morris water maze to access spatial memory. In addition to cognitive impairments, rTg4510 mice exhibited a hyperactivity phenotype which correlated with progression of tau pathology and was dependent on P301L tau transgene expression. The hyperactive phenotype was characterized by significantly increased locomotor activity in a novel and in a simulated home cage environment together with a disturbed day/night cycle. The P301L-tau-dependent hyperactivity and agitative-like phenotype suggests that these mice may form a correlate to some of the behavioral disturbances observed in advanced AD and FTD.

%B J Alzheimers Dis %V 49 %P 783-95 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519432?dopt=Abstract %R 10.3233/JAD-150292 %0 Journal Article %J J Alzheimers Dis %D 2016 %T "I Don't Think Of It As An Illness": Illness Representations in Mild to Moderate Dementia. %A Clare, Linda %A Quinn, Catherine %A Jones, Ian Rees %A Woods, Robert T %K Adaptation, Psychological %K Aged %K Aged, 80 and over %K Aging %K Awareness %K Caregivers %K Dementia %K Female %K Follow-Up Studies %K Humans %K Male %K Middle Aged %K Psychiatric Status Rating Scales %K Residence Characteristics %K Self Concept %K Statistics, Nonparametric %K Surveys and Questionnaires %X

The self-regulatory model proposes that illness representations influence adjustment and coping in chronic conditions. Better understanding of the illness representations held by people with dementia could help with targeting information and support so as to optimize adjustment and coping. In this mixed-methods study of illness representations among people with mild to moderate Alzheimer's, vascular, or mixed dementia we aimed to clarify the nature of the representations held, to determine whether specific profiles can be identified based on perceptions of the identity and cause of the condition, and to examine associations between these profiles and other participant characteristics. Data were collected in the second wave of the Memory Impairment and Dementia Awareness Study (MIDAS). Sixty-four people with dementia, who had been told their diagnosis at a memory clinic, completed interviews and responded to questionnaires. In each case a carer was also interviewed. Cluster analysis based on responses about identity and cause identified three profiles. 'Illness' cluster participants saw themselves as living with an illness and used diagnostic labels, 'ageing' cluster participants did not use diagnostic labels and viewed their difficulties as related to ageing, and 'no problem' cluster participants considered that they did not have any difficulties. 'Illness' cluster participants had better cognition and better awareness, but lower mood, and perceived more practical consequences, than 'ageing' cluster participants. Holding an 'illness' model may not be advantageous. Rather than encouraging adoption of such a model, it may be preferable to target information and select interventions in line with the person's representation profile.

%B J Alzheimers Dis %V 51 %P 139-50 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836172?dopt=Abstract %R 10.3233/JAD-150794 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Identification of Aluminum in Human Brain Tissue Using Lumogallion and Fluorescence Microscopy. %A Mirza, Ambreen %A King, Andrew %A Troakes, Claire %A Exley, Christopher %X

Aluminum in human brain tissue is implicated in the etiologies of neurodegenerative diseases including Alzheimer's disease. While methods for the accurate and precise measurement of aluminum in human brain tissue are widely acknowledged, the same cannot be said for the visualization of aluminum. Herein we have used transversely-heated graphite furnace atomic absorption spectrometry to measure aluminum in the brain of a donor with Alzheimer's disease, and we have developed and validated fluorescence microscopy and the fluor lumogallion to show the presence of aluminum in the same tissue. Aluminum is observed as characteristic orange fluorescence that is neither reproduced by other metals nor explained by autofluorescence. This new and relatively simple method to visualize aluminum in human brain tissue should enable more rigorous testing of the aluminum hypothesis of Alzheimer's disease (and other neurological conditions) in the future.

%B J Alzheimers Dis %V 54 %P 1333-1338 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472886?dopt=Abstract %R 10.3233/JAD-160648 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Identification of Physician-Diagnosed Alzheimer's Disease and Related Dementias in Population-Based Administrative Data: A Validation Study Using Family Physicians' Electronic Medical Records. %A Jaakkimainen, R Liisa %A Bronskill, Susan E %A Tierney, Mary C %A Herrmann, Nathan %A Green, Diane %A Young, Jacqueline %A Ivers, Noah %A Butt, Debra %A Widdifield, Jessica %A Tu, Karen %X

BACKGROUND: Population-based surveillance of Alzheimer's and related dementias (AD-RD) incidence and prevalence is important for chronic disease management and health system capacity planning. Algorithms based on health administrative data have been successfully developed for many chronic conditions. The increasing use of electronic medical records (EMRs) by family physicians (FPs) provides a novel reference standard by which to evaluate these algorithms as FPs are the first point of contact and providers of ongoing medical care for persons with AD-RD.

OBJECTIVE: We used FP EMR data as the reference standard to evaluate the accuracy of population-based health administrative data in identifying older adults with AD-RD over time.

METHODS: This retrospective chart abstraction study used a random sample of EMRs for 3,404 adults over 65 years of age from 83 community-based FPs in Ontario, Canada. AD-RD patients identified in the EMR were used as the reference standard against which algorithms identifying cases of AD-RD in administrative databases were compared.

RESULTS: The highest performing algorithm was "one hospitalization code OR (three physician claims codes at least 30 days apart in a two year period) OR a prescription filled for an AD-RD specific medication" with sensitivity 79.3% (confidence interval (CI) 72.9-85.8%), specificity 99.1% (CI 98.8-99.4%), positive predictive value 80.4% (CI 74.0-86.8%), and negative predictive value 99.0% (CI 98.7-99.4%). This resulted in an age- and sex-adjusted incidence of 18.1 per 1,000 persons and adjusted prevalence of 72.0 per 1,000 persons in 2010/11.

CONCLUSION: Algorithms developed from health administrative data are sensitive and specific for identifying older adults with AD-RD.

%B J Alzheimers Dis %V 54 %P 337-49 %8 2016 Aug 10 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567819?dopt=Abstract %R 10.3233/JAD-160105 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Immunization Against Specific Fragments of Neurotrophin p75 Receptor Protects Forebrain Cholinergic Neurons in the Olfactory Bulbectomized Mice. %A Bobkova, Natalia %A Vorobyov, Vasily %A Medvinskaya, Natalia %A Nesterova, Inna %A Tatarnikova, Olga %A Nekrasov, Pavel %A Samokhin, Alexander %A Deev, Alexander %A Sengpiel, Frank %A Koroev, Dmitry %A Volpina, Olga %X

Alzheimer's disease (AD) is characterized by progressive cognitive impairment associated with marked cholinergic neuron loss and amyloid-β (Aβ) peptide accumulation in the brain. The cytotoxicity in AD is mediated, at least in part, by Aβ binding with the extracellular domain of the p75 neurotrophin receptor (p75NTR), localized predominantly in the membranes of acetylcholine-producing neurons in the basal forebrain. Hypothesizing that an open unstructured loop of p75NTR might be the effective site for Aβ binding, we have immunized both olfactory bulbectomized (OBX) and sham-operated (SO) mice (n = 82 and 49, respectively) with synthetic peptides, structurally similar to different parts of the loops, aiming to block them by specific antibodies. OBX-mice have been shown in previous studies, and confirmed in the present one, to be characterized by typical behavioral, morphological, and biochemical AD hallmarks, including cholinergic deficits in forebrain neurons. Immunization of OBX- or SO-mice with KLH conjugated fragments of p75NTR induced high titers of specific serum antibodies for each of nine chosen fragments. However, maximal protective effects on spatial memory, evaluated in a Morris water maze, and on activity of choline acetyltransferase in forebrain neurons, detected by immunoreactivity to specific antibodies, were revealed only for peptides with amino acid residue sequences of 155-164 and 167-176. We conclude that the approach based on immunological blockade of specific p75NTR sites, linked with the cytotoxicity, is a useful and effective tool for study of AD-associated mechanisms and for development of highly selective therapy of cholinergic malfunctioning in AD patients.

%B J Alzheimers Dis %V 53 %P 289-301 %8 2016 May 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163825?dopt=Abstract %R 10.3233/JAD-160146 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Immunization with Small Amyloid-β-derived Cyclopeptide Conjugates Diminishes Amyloid-β-Induced Neurodegeneration in Mice. %A Mulder, Cornelis K %A Dong, Yun %A Brugghe, Humphrey F %A Timmermans, Hans A M %A Tilstra, Wichard %A Westdijk, Janny %A van Riet, Elly %A van Steeg, Harry %A Hoogerhout, Peter %A Eisel, Ulrich L M %X

BACKGROUND: Soluble oligomeric (misfolded) species of amyloid-β (Aβ) are the main mediators of toxicity in Alzheimer's disease (AD). These oligomers subsequently form aggregates of insoluble fibrils that precipitate as extracellular and perivascular plaques in the brain. Active immunization against Aβ is a promising disease modifying strategy. However, eliciting an immune response against Aβ in general may interfere with its biological function and was shown to cause unwanted side-effects. Therefore, we have developed a novel experimental vaccine based on conformational neo-epitopes that are exposed in the misfolded oligomeric Aβ, inducing a specific antibody response.

OBJECTIVE: Here we investigate the protective effects of the experimental vaccine against oligomeric Aβ1-42-induced neuronal fiber loss in vivo.

METHODS: C57BL/6 mice were immunized or mock-immunized. Antibody responses were measured by enzyme-linked immunosorbent assay. Next, mice received a stereotactic injection of oligomeric Aβ1-42 into the nucleus basalis of Meynert (NBM) on one side of the brain (lesion side), and scrambled Aβ1-42 peptide in the contralateral NBM (control side). The densities of choline acetyltransferase-stained cholinergic fibers origination from the NBM were measured in the parietal neocortex postmortem. The percentage of fiber loss in the lesion side was determined relative to the control side of the brain.

RESULTS: Immunized responders (79%) showed 23% less cholinergic fiber loss (p = 0.01) relative to mock-immunized mice. Moreover, fiber loss in immunized responders correlated negatively with the measured antibody responses (R2 = 0.29, p = 0.02).

CONCLUSION: These results may provide a lead towards a (prophylactic) vaccine to prevent or at least attenuate (early onset) AD symptoms.

%B J Alzheimers Dis %V 52 %P 1111-23 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060957?dopt=Abstract %R 10.3233/JAD-151136 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impact of Depressive Symptoms on Conversion from Mild Cognitive Impairment Subtypes to Alzheimer's Disease: A Community-Based Longitudinal Study. %A Kida, Jiro %A Nemoto, Kiyotaka %A Ikejima, Chiaki %A Bun, Shogyoku %A Kakuma, Tatsuyuki %A Mizukami, Katsuyoshi %A Asada, Takashi %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Cognitive Dysfunction %K Depression %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Prodromal Symptoms %K Prognosis %K Risk %X

BACKGROUND: While longitudinal studies have investigated the relationships between mild cognitive impairment (MCI) subtypes and dementia subtypes, the results have been contradictory. In addition, some research shows that depression accompanied by MCI might increase the risk of Alzheimer's disease (AD).

OBJECTIVE: The aim of this study is to longitudinally investigate the relationships between MCI subtypes and dementia subtypes, with special attention to the effect of comorbid depressive symptoms in a Japanese rural community.

METHODS: Non-demented participants (n = 802) completed a baseline and follow-up study. Outcomes were conversion to dementia especially AD, MCI, or no conversion. A complementary log-log analysis was conducted to investigate the risk of dementia and AD in amnestic MCI (aMCI) compared to nonamnestic MCI (naMCI) groups. The impact of depressive symptoms on the transition from MCI to AD and from cognitively normal to MCI or AD was also analyzed.

RESULTS: The risk of developing dementia, in particular AD, for the aMCI group was significantly higher than that for the naMCI group. In the aMCI group, the presence of depressive symptoms increased the risk of developing AD, but depressive symptoms in the naMCI group did not. In the cognitively normal group, the presence of depressive symptoms increased the risk of aMCI but not naMCI or AD.

CONCLUSION: MCI subtyping could be useful in finding a prodrome for dementia and in particular for AD. The differing impacts of depressive symptoms on the development of AD suggest that the relationship between depressive symptoms and cognitive impairment could differ in aMCI and naMCI patients.

%B J Alzheimers Dis %V 51 %P 405-15 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890740?dopt=Abstract %R 10.3233/JAD-150603 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impact of Depressive Symptoms on Memory for Emotional Words in Mild Cognitive Impairment and Late-Life Depression. %A Callahan, Brandy L %A Simard, Martine %A Mouiha, Abderazzak %A Rousseau, François %A Laforce, Robert %A Hudon, Carol %X

BACKGROUND: Amnestic mild cognitive impairment (aMCI) and late-life depression (LLD) are associated with increased risk of Alzheimer's disease (AD). This is also true for aMCI with concomitant depressive symptoms (aMCI/D+), but few studies have investigated this syndrome.

OBJECTIVES: We aimed to clarify the association between cognitive and depressive symptoms in individuals at risk for AD by examining episodic memory for emotional stimuli in aMCI, aMCI/D+, and LLD.

METHODS: Participants were 34 patients with aMCI, 20 patients with aMCI/D+, 19 patients with LLD, and 28 healthy elderly adults. In an implicit encoding task, participants rated the emotional valence of 12 positive, 12 negative, and 12 neutral words. Immediately and 20 minutes later, participants recalled as many words as possible. They were also asked to identify previously presented words during a yes/no recognition trial.

RESULTS: At immediate recall, aMCI participants displayed better recall of emotional words, particularly positive words. aMCI/D+ and control participants displayed better recall of positive and negative words compared to neutral words. LLD participants recalled more negative than neutral words. At delayed recall, emotional words were generally better-remembered than neutral words by all groups. At recognition, all subjects responded more liberally to emotional than to neutral words.

CONCLUSION: We find that the type of emotional information remembered by aMCI patients at immediate recall depends on the presence or absence of depressive symptoms. These findings contribute to identifying sources of heterogeneity in individuals at risk for AD, and suggest that the cognitive profile of aMCI/D+ is different from that of aMCI and LLD. Future studies should systematically consider the presence of depressive symptoms in elderly at-risk individuals.

%B J Alzheimers Dis %V 52 %P 451-62 %8 2016 Mar 22 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031467?dopt=Abstract %R 10.3233/JAD-150585 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impact of Omega-3 Fatty Acid Supplementation on Memory Functions in Healthy Older Adults. %A Külzow, Nadine %A Witte, A Veronica %A Kerti, Lucia %A Grittner, Ulrike %A Schuchardt, Jan Philipp %A Hahn, Andreas %A Flöel, Agnes %K Aged %K Apolipoproteins E %K Auditory Perception %K Blood Chemical Analysis %K Cognitive Aging %K Dietary Supplements %K Double-Blind Method %K Fatty Acids, Omega-3 %K Feeding Behavior %K Female %K Humans %K Learning %K Male %K Memory %K Middle Aged %K Neuropsychological Tests %K Nootropic Agents %K Treatment Outcome %X

As the process of Alzheimer's disease (AD) begins years before disease onset, searching for prevention strategies is of major medical and economic importance. Nutritional supplementation with long-chain polyunsaturated omega-3 fatty acids (LC-n3-FA) may exert beneficial effects on brain structure and function. However, experimental evidence in older adults without clinical dementia is inconsistent, possibly due to low sensitivity of previously employed test batteries for detecting subtle improvements in cognition in healthy individuals. Here we used LOCATO, recently described as a robust and sensitive tool for assessing object-location memory (OLM) in older adults, to evaluate the impact of LC-n3-FA supplementation on learning and memory formation. In a double-blind placebo-controlled proof-of-concept study, 44 (20 female) cognitively healthy individuals aged 50-75 years received either LC-n3-FA (2,200 mg/day, n = 22) or placebo (n = 22) for 26 weeks. Before and after intervention, memory performance in the OLM-task (primary) was tested. As secondary outcome parameters, performance in Rey Auditory Verbal Learning Test (AVLT), dietary habits, omega-3-index, and other blood-derived parameters were assessed. Omega-3 index increased significantly in the LC-n3-FA group compared with the placebo group. Moreover, recall of object locations was significantly better after LC-n3-FA supplementation compared with placebo. Performance in the AVLT was not significantly affected by LC-n3-FA. This double-blind placebo-controlled proof-of-concept study provides further experimental evidence that LC-n3-FA exert positive effects on memory functions in healthy older adults. Our findings suggest novel strategies to maintain cognitive functions into old age.

%B J Alzheimers Dis %V 51 %P 713-25 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890759?dopt=Abstract %R 10.3233/JAD-150886 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impacts of High Serum Total Cholesterol Level on Brain Functional Connectivity in Non-Demented Elderly. %A Zhang, Ting %A Li, He %A Zhang, Junying %A Li, Xin %A Qi, Di %A Wang, Nuo %A Zhang, Zhanjun %K Aged %K Brain %K Brain Mapping %K Cholesterol %K Cognition %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Nerve Net %K Neuropsychological Tests %X

Epidemiological and clinical studies suggest that high serum cholesterol is a risk factor of dementia. However, the effects of cholesterol on cognition and brain remain largely unclear. This study aims to investigate the associations between serum total cholesterol (TC) and neuropsychological performance, and intrinsic functional networks in non-demented elderly. Among a cohort of 120 community-dwelling Beijing residents, 29 subjects in the high-TC group (1st quartile) and 31 in the low-TC group (4th quartile) were included in this study, and underwent a battery of neuropsychological tests and magnetic resonance imaging (MRI) scans, including T2- and T1-weighted imaging, and resting-state functional MRI. No significant group difference was found in any of the neuropsychological tests used. Stronger connectivity in the default mode network was observed in the high-TC group compared to that in the low-TC group (p <  0.001, uncorrected). While in the salience network (SN), the high-TC group showed lower connectivity in the anterior cingulate cortex and frontal regions, compared to the low-TC group (p <  0.05, FWE corrected). Our findings suggest that in non-demented elderly persons, high serum cholesterol is associated with disruption of functional connectivity in the SN. The results not only deepen our understanding of how cholesterol affects the brain, but are also significant for selecting sensitive indicators for monitoring the impairments of cholesterol on the neural system.

%B J Alzheimers Dis %V 50 %P 455-63 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682694?dopt=Abstract %R 10.3233/JAD-150810 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impacts of Illiteracy on the Risk of Dementia: A Global Health Perspective. %A Suh, Seung Wan %A Han, Ji Won %A Park, Jae Young %A Hong, Jong Woo %A Kim, Kayoung %A Kim, Taehyun %A Lee, Kyoung Hwan %A Han, Guehee %A Jeong, Hyeon %A Seo, Jiyeong %A Kim, Tae Hui %A Lee, Dong Young %A Lee, Dong Woo %A Ryu, Seung-Ho %A Kim, Shin-Gyeom %A Youn, Jong Chul %A Jhoo, Jin Hyeong %A Kim, Jeong Lan %A Lee, Seok Bum %A Lee, Jung Jae %A Kwak, Kyung Phil %A Kim, Bong-Jo %A Moon, Seok Woo %A Park, Joon Hyuk %A Kim, Ki Woong %X

Despite its significance as a contributing factor for late-life dementia risk, illiteracy is frequently underappreciated in the management of dementia. In this study, we estimated the proportion of dementia cases attributable to illiteracy using the population attributable fraction (PAF), and calculated to what extent the monetary cost of dementia could be saved in the future by reducing illiteracy from the South Korean, Latin American, South Asian/Middle Eastern, and African populations. We collected necessary data from the 2011 United Nations Human Development Report and prevalence studies conducted in these regions. Additional variables not included in the above sources were estimated using a logit model under a "trend scenario"-based assumption. Around 16% of the total number of dementia cases in South Korea in 2015 can be attributed to illiteracy, with this figure predicted to decline to around 2% by 2050. This translates to a saving in dementia care costs of approximately 52 billion USD, providing we are successful in theoretically eradicating illiteracy as of 2015, in the population aged 65 years or under. Likewise, reducing illiteracy to 50% in Latin America, South Asia/The Middle East, and Africa by 2050 could generate further cost savings of between 71 and 244 billion, 13 and 94 billion, and 17 and 78 billion USD, respectively. Even public policies aimed solely at reducing illiteracy in the childhood, adolescent, or middle-aged population could potentially have a role in the primary prevention of dementia. Moving forward, governments will need to address this issue in a purposeful and systematic manner.

%B J Alzheimers Dis %V 53 %P 731-41 %8 2016 May 23 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27232216?dopt=Abstract %R 10.3233/JAD-160108 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impaired Autophagy in APOE4 Astrocytes. %A Simonovitch, Shira %A Schmukler, Eran %A Bespalko, Alina %A Iram, Tal %A Frenkel, Dan %A Holtzman, David M %A Masliah, Eliezer %A Michaelson, Danny M %A Pinkas-Kramarski, Ronit %K Amyloid beta-Peptides %K Animals %K Apolipoprotein E3 %K Apolipoprotein E4 %K Astrocytes %K Autophagy %K Brain %K Cells, Cultured %K Central Nervous System Agents %K Chloroquine %K Disease Models, Animal %K Humans %K Mice, Transgenic %K Plaque, Amyloid %K Sirolimus %K Time Factors %X

Alzheimer's disease (AD) is the most prevalent form of dementia in elderly. Genetic studies revealed allelic segregation of the apolipoprotein E (ApoE) gene in sporadic AD and in families with higher risk of AD. The mechanisms underlying the pathological effects of ApoE4 are not yet entirely clear. Several studies indicate that autophagy, which plays an important role in degradation pathways of proteins, organelles and protein aggregates, may be impaired in AD. In the present study, we investigated the effects of ApoE4 versus the ApoE3 isoform on the process of autophagy in mouse-derived astrocytes. The results obtained reveal that under several autophagy-inducing conditions, astrocytes expressing ApoE4 exhibit lower autophagic flux compared to astrocytes expressing ApoE3. Using an in situ model, we examined the role of autophagy and the effects thereon of ApoE4 in the elimination of Aβ plaques from isolated brain sections of transgenic 5xFAD mice. This revealed that ApoE4 astrocytes eliminate Aβ plaques less effectively than the corresponding ApoE3 astrocytes. Additional experiments showed that the autophagy inducer, rapamycin, enhances Aβ plaque degradation by ApoE4 astrocytes whereas the autophagy inhibitor, chloroquine, blocks Aβ plaque degradation by ApoE3 astrocytes. Taken together, these findings show that ApoE4 impairs autophagy in astrocyte cultures and that this effect is associated with reduced capacity to clear Aβ plaques. This suggests that impaired autophagy may play a role in mediating the pathological effects of ApoE4 in AD.

%B J Alzheimers Dis %V 51 %P 915-27 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923027?dopt=Abstract %R 10.3233/JAD-151101 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impaired Parahippocampus Connectivity in Mild Cognitive Impairment and Alzheimer's Disease. %A Liu, Jieqiong %A Zhang, Xinqing %A Yu, Chunshui %A Duan, Yunyun %A Zhuo, Junjie %A Cui, Yue %A Liu, Bing %A Li, Kuncheng %A Jiang, Tianzi %A Liu, Yong %K Aged %K Alzheimer Disease %K Apolipoproteins E %K Brain Mapping %K Cognitive Dysfunction %K Female %K Hippocampus %K Humans %K Limbic System %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Neural Pathways %K Rest %K Severity of Illness Index %X

BACKGROUND: The parahippocampal gyrus (PHG) is an important region of the limbic system that plays an important role in episodic memory. Elucidation of the PHG connectivity pattern will aid in the understanding of memory deficits in neurodegenerative diseases.

OBJECTIVE: To investigate if disease severity associated altered PHG connectivity in Alzheimer's disease (AD) exists.

METHODS: We evaluated resting-state functional magnetic resonance imaging data from 18 patients with amnestic mild cognitive impairment (MCI), 35 patients with AD, and 21 controls. The PHG connectivity pattern was examined by calculating Pearson's correlation coefficients between the bilateral PHG and whole brain. Group comparisons were performed after controlling for the effects of age and gender. The functional connectivity strength in each identified region was correlated with the MMSE score to evaluate the relationship between connectivity and cognitive ability.

RESULTS: Several brain regions of the default mode network showed reduced PHG connectivity in the AD patients, and PHG connectivity was associated with disease severity in the MCI and AD subjects. More importantly, correlation analyses showed that there were positive correlations between the connectivity strengths of the left PHG-PCC/Pcu and left PHG-left MTG and the Mini-Mental State Examination, indicating that with disease progression from MCI to severe AD, damage to the functional connectivity of the PHG becomes increasingly severe.

CONCLUSIONS: These results indicate that disease severity is associated with altered PHG connectivity, contributing to knowledge about the reduction in cognitive ability and impaired brain activity that occur in AD/MCI. These early changes in the functional connectivity of the PHG might provide some potential clues for identification of imaging markers for the early detection of MCI and AD.

%B J Alzheimers Dis %V 49 %P 1051-64 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599055?dopt=Abstract %R 10.3233/JAD-150727 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Improved Neuroprotection Provided by Drug Combination in Neurons Exposed to Cell-Derived Soluble Amyloid-β Peptide. %A Colin, Julie %A Allouche, Ahmad %A Chauveau, Fabien %A Corbier, Catherine %A Pauron-Gregory, Lynn %A Lanhers, Marie-Claire %A Claudepierre, Thomas %A Yen, Frances T %A Oster, Thierry %A Malaplate-Armand, Catherine %X

Oligomeric amyloid-β (Aβ) peptide contributes to impaired synaptic connections and neurodegenerative processes, and as such, represents a primary therapeutic target for Alzheimer's disease (AD)-modifying approaches. However, the lack of efficacy of drugs that inhibit production of Aβ demonstrates the need for a better characterization of its toxic effects, both on synaptic and neuronal function. Here, we used conditioned medium obtained from recombinant HEK-AβPP cells expressing the human amyloid-β protein precursor (Aβ-CM), to investigate Aβ-induced neurotoxic and synaptotoxic effects. Characterization of Aβ-CM revealed that it contained picomolar amounts of cell-secreted Aβ in its soluble form. Incubation of primary cortical neurons with Aβ-CM led to significant decreases in synaptic protein levels as compared to controls. This effect was no longer observed in neurons incubated with conditioned medium obtained from HEK-AβPP cells grown in presence of the γ-secretase inhibitor, Semagacestat or LY450139 (LY-CM). However, neurotoxic and pro-apoptotic effects of Aβ-CM were only partially prevented using LY-CM, which could be explained by other deleterious compounds related to chronic oxidative stress that were released by HEK-AβPP cells. Indeed, full neuroprotection was observed in cells exposed to LY-CM by additional treatment with the antioxidant resveratrol, or with the pluripotent n-3 polyunsaturated fatty acid docosahexaenoic acid. Inhibition of Aβ production appeared necessary but insufficient to prevent neurodegenerative effects associated with AD due to other neurotoxic compounds that could exert additional deleterious effects on neuronal function and survival. Therefore, association of various types of protective agents needs to be considered when developing strategies for AD treatment.

%B J Alzheimers Dis %V 52 %P 975-87 %8 2016 May 07 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163806?dopt=Abstract %R 10.3233/JAD-151110 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Incidence and Duration of Cumulative Bisphosphonate Use among Community-Dwelling Persons with or without Alzheimer's Disease. %A Tiihonen, Miia %A Taipale, Heidi %A Tanskanen, Antti %A Tiihonen, Jari %A Hartikainen, Sirpa %X

We studied the incidence and duration of cumulative bisphosphonate use among older Finnish women and men with or without Alzheimer's disease (AD). The MEDALZ-2005 cohort is a nationwide sample of all persons with clinically diagnosed AD on 31 December 2005 and their age-, gender-, and region of residence-matched control persons without AD. Information on bisphosphonate use by persons with an AD diagnosis and their controls without AD during 2002-2009 was obtained from the prescription register database containing reimbursed medications. A total of 6,041 (11.8%) persons used bisphosphonates during the 8-year follow-up. Bisphosphonates were more commonly used among persons without AD (n = 3121, 12.3%) than among persons with AD (n = 2,920, 11.2%) (p = 0.001). The median duration of bisphosphonate use was 743 days (IQR). Among persons with AD, the median duration of use was 777 days (IQR) and among persons without AD, 701 days (IQR) (p = 0.011). People without AD more often used bisphosphonate combination preparations including vitamin D than did people with AD (p <  0.0001). Bisphosphonate use was more common among people without AD who had comorbidities, asthma/COPD, or rheumatoid arthritis compared with users with AD. Short-term users were more likely to be male, at least 80 years old, and not having AD. Although the incidence of bisphosphonate use was slightly higher among persons without AD, the cumulative duration of bisphosphonate use was longer in persons with AD. Short-term use was associated with male gender, older age, and not having AD.

%B J Alzheimers Dis %V 52 %P 127-32 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967224?dopt=Abstract %R 10.3233/JAD-151181 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Incidence of Benzodiazepine and Related Drug Use in Persons with and without Alzheimer's Disease. %A Saarelainen, Laura %A Taipale, Heidi %A Koponen, Marjaana %A Tanskanen, Antti %A Tolppanen, Anna-Maija %A Tiihonen, Jari %A Hartikainen, Sirpa %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Antipsychotic Agents %K Benzodiazepines %K Cohort Studies %K Female %K Finland %K Humans %K Incidence %K Male %K Middle Aged %K Substance-Related Disorders %X

BACKGROUND: Benzodiazepines and related drugs (BZDR) are occasionally used to treat certain symptoms of Alzheimer's disease (AD). However, the risks related to BZDR use are high in older persons. Although frequent BZDR use has been reported in persons with AD, no previous study has focused specifically on the incidence of BZDR use in this population.

OBJECTIVE: We investigated the incidence of BZDR use in persons with and without AD during a five-year follow-up.

METHODS: The Finnish nationwide, register-based MEDALZ cohort includes all AD cases who received a clinically verified AD diagnosis in 2005-2011 (n = 70,718) and their matched comparison persons. Incidence of BZDR, including benzodiazepines (lorazepam, oxazepam, temazepam, alprazolam, chlordiazepoxide, diazepam, and nitrazepam) and Z-drugs (zolpidem and zopiclone), use was investigated in the cohort from two years before to three years after the diagnosis of AD. Further, initial BZDRs were investigated.

RESULTS: The incidence of BZDR use was higher in persons with AD starting from 12 months before the diagnosis and peaked at six months after the diagnosis of AD (incidence rate ratio [IRR] = 2.6, 95% confidence interval [CI] = 2.5-2.8). Benzodiazepines were more frequently initiated by persons with AD, with the incidence peaking at six months after the diagnosis (IRR = 4.5, 95% CI = 4.1-4.9) and remaining over three times higher than in comparison persons until three years after the diagnosis.

CONCLUSION: Early symptomatic treatment with BZDRs is contrary to AD treatment guidelines. As BZDRs impair cognition, the observed early treatment with BZDRs may complicate the monitoring of AD treatment effectiveness.

%B J Alzheimers Dis %V 49 %P 809-18 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484930?dopt=Abstract %R 10.3233/JAD-150630 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Increase of α-Secretase ADAM10 in Platelets Along Cognitively Healthy Aging. %A Schuck, Florian %A Wolf, Dominik %A Fellgiebel, Andreas %A Endres, Kristina %K ADAM Proteins %K ADAM10 Protein %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Aging %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Analysis of Variance %K Apolipoprotein E4 %K Cognition %K Female %K Healthy Volunteers %K Humans %K Integrin beta3 %K Male %K Membrane Proteins %K Middle Aged %K Neuropsychological Tests %K Young Adult %X

ADAM10 is one of the key players in ectodomain-shedding of the amyloid-β protein precursor (AβPP). Previous research with postmortem tissue has shown reduced expression and activity of ADAM10 within the central nervous system (CNS) of Alzheimer's disease (AD) patients. Determination of cerebral ADAM10 in living humans is hampered by its transmembrane property; only the physiological AβPP cleavage product generated by ADAM10, sAβPPα, can be assessed in cerebrospinal fluid. Establishment of surrogate markers in easily accessible material therefore is crucial. It has been demonstrated that ADAM10 is expressed in platelets and that platelet amount is decreased in AD patients. Just recently it has been shown that platelet ADAM10 and cognitive performance of AD patients positively correlate. In contrast to AD patients, to our knowledge almost no information has been published regarding ADAM10 expression during normal aging. We investigated ADAM10 amount and activity in platelets of cognitively healthy individuals from three different age groups ranging from 22-85 years. Interestingly, we observed an age-dependent increase in ADAM10 levels and activity in platelets.

%B J Alzheimers Dis %V 50 %P 817-26 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757187?dopt=Abstract %R 10.3233/JAD-150737 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Increased Electron Paramagnetic Resonance Signal Correlates with Mitochondrial Dysfunction and Oxidative Stress in an Alzheimer's disease Mouse Brain. %A Fang, Du %A Zhang, Zhihua %A Li, Hang %A Yu, Qing %A Douglas, Justin T %A Bratasz, Anna %A Kuppusamy, Periannan %A Yan, Shirley ShiDu %K Adenosine Triphosphate %K Age of Onset %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Brain %K Cognition %K Disease Models, Animal %K Electron Spin Resonance Spectroscopy %K Electron Transport Complex IV %K Female %K Humans %K Male %K Maze Learning %K Mice, Transgenic %K Mitochondria %K Oxidative Stress %K Reactive Oxygen Species %K Spatial Memory %X

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized clinically by cognitive decline and memory loss. The pathological features are amyloid-β peptide (Aβ) plaques and intracellular neurofibrillary tangles. Many studies have suggested that oxidative damage induced by reactive oxygen species (ROS) is an important mechanism for AD progression. Our recent study demonstrated that oxidative stress could further impair mitochondrial function. In the present study, we adopted a transgenic mouse model of AD (mAPP, overexpressing AβPP/Aβ in neurons) and performed redox measurements using in vivo electron paramagnetic resonance (EPR) imaging with methoxycarbamyl-proxyl (MCP) as a redox-sensitive probe for studying oxidative stress in an early stage of pathology in a transgenic AD mouse model. Through assessing oxidative stress, mitochondrial function and cognitive behaviors of mAPP mice at the age of 8-9 months, we found that oxidative stress and mitochondrial dysfunction appeared in the early onset of AD. Increased ROS levels were associated with defects of mitochondrial and cognitive dysfunction. Notably, the in vivo EPR method offers a unique way of assessing tissue oxidative stress in living animals under noninvasive conditions, and thus holds a potential for early diagnosis and monitoring the progression of AD.

%B J Alzheimers Dis %V 51 %P 571-80 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890765?dopt=Abstract %R 10.3233/JAD-150917 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Increased Expression of Readthrough Acetylcholinesterase Variants in the Brains of Alzheimer's Disease Patients. %A Campanari, Maria-Letizia %A Navarrete, Francisco %A Ginsberg, Stephen D %A Manzanares, Jorge %A Sáez-Valero, Javier %A García-Ayllón, María-Salud %X

Alzheimer's disease (AD) is characterized by a decrease in the enzymatic activity of the enzyme acetylcholinesterase (AChE). AChE is expressed as multiple splice variants, which may serve both cholinergic degradative functions and non-cholinergic functions unrelated with their capacity to hydrolyze acetylcholine. We have recently demonstrated that a prominent pool of enzymatically inactive AChE protein exists in the AD brain. In this study, we analyzed protein and transcript levels of individual AChE variants in human frontal cortex from AD patients by western blot analysis using specific anti-AChE antibodies and by quantitative real-time PCR (qRT-PCR). We found similar protein and mRNA levels of the major cholinergic "tailed"-variant (AChE-T) and the anchoring subunit, proline-rich membrane anchor (PRiMA-1) in frontal cortex obtained from AD patients and non-demented controls. Interestingly, we found an increase in the protein and transcript levels of the non-cholinergic "readthrough" AChE (AChE-R) variants in AD patients compared to controls. Similar increases were detected by western blot using an antibody raised against the specific N-terminal domain, exclusive of alternative N-extended variants of AChE (N-AChE). In accordance with a subset of AChE-R monomers that display amphiphilic properties that are upregulated in the AD brain, we demonstrate that the increase of N-AChE species is due, at least in part, to N-AChE-R variants. In conclusion, we demonstrate selective alterations in specific AChE variants in AD cortex, with no correlation in enzymatic activity. Therefore, differential expression of AChE variants in AD may reflect changes in the pathophysiological role of AChE, independent of cholinergic impairment or its role in degrading acetylcholine.

%B J Alzheimers Dis %V 53 %P 831-41 %8 2016 May 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258420?dopt=Abstract %R 10.3233/JAD-160220 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Increased Intrinsic Activity of Medial-Temporal Lobe Subregions is Associated with Decreased Cortical Thickness of Medial-Parietal Areas in Patients with Alzheimer's Disease Dementia. %A Pasquini, Lorenzo %A Scherr, Martin %A Tahmasian, Masoud %A Myers, Nicholas E %A Ortner, Marion %A Kurz, Alexander %A Förstl, Hans %A Zimmer, Claus %A Grimmer, Timo %A Akhrif, Atae %A Wohlschläger, Afra M %A Riedl, Valentin %A Sorg, Christian %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Middle Aged %K Nerve Net %K Parietal Lobe %K Temporal Lobe %X

In Alzheimer's disease (AD), disrupted connectivity between medial-parietal cortices and medial-temporal lobes (MTL) is linked with increased MTL local functional connectivity, and parietal atrophy is associated with increased MTL memory activation. We hypothesized that intrinsic activity in MTL subregions is increased and associated with medial-parietal degeneration and impaired memory in AD. To test this hypothesis, resting-state-functional and structural-MRI was assessed in 22 healthy controls, 22 mild cognitive impairment patients, and 21 AD-dementia patients. Intrinsic activity was measured by power-spectrum density of blood-oxygenation-level-dependent signal, medial-parietal degeneration by cortical thinning. In AD-dementia patients, intrinsic activity was increased for several right MTL subregions. Raised intrinsic activity in dentate gyrus and cornu ammonis 1 was associated with cortical thinning in posterior cingulate cortices, and at-trend with impaired delayed recall. Critically, increased intrinsic activity in the right entorhinal cortex was associated with ipsilateral posterior cingulate degeneration. Our results provide evidence that in AD, intrinsic activity in MTL subregions is increased and associated with medial-parietal atrophy. Results fit a model in which medial-parietal degeneration contributes to MTL dysconnectivity from medial-parietal cortices, potentially underpinning disinhibition-like changes in MTL activity.

%B J Alzheimers Dis %V 51 %P 313-26 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836175?dopt=Abstract %R 10.3233/JAD-150823 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Increased Levels of Extracellular Microvesicle Markers and Decreased Levels of Endocytic/Exocytic Proteins in the Alzheimer's Disease Brain. %A Musunuri, Sravani %A Khoonsari, Payam Emami %A Mikus, Maria %A Wetterhall, Magnus %A Häggmark-Mänberg, Anna %A Lannfelt, Lars %A Erlandsson, Anna %A Bergquist, Jonas %A Ingelsson, Martin %A Shevchenko, Ganna %A Nilsson, Peter %A Kultima, Kim %X

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder accounting for more than 50% of all dementia cases. AD neuropathology is characterized by the formation of extracellular plaques and intracellular neurofibrillary tangles consisting of aggregated amyloid-β and tau, respectively. The disease mechanism has only been partially elucidated and is believed to also involve many other proteins.

OBJECTIVE: This study intended to perform a proteomic profiling of post mortem AD brains and compare it with control brains as well as brains from other neurological diseases to gain insight into the disease pathology.

METHODS: Here we used label-free shotgun mass spectrometry to analyze temporal neocortex samples from AD, other neurological disorders, and non-demented controls, in order to identify additional proteins that are altered in AD. The mass spectrometry results were verified by antibody suspension bead arrays.

RESULTS: We found 50 proteins with altered levels between AD and control brains. The majority of these proteins were found at lower levels in AD. Pathway analyses revealed that several of the decreased proteins play a role in exocytic and endocytic pathways, whereas several of the increased proteins are related to extracellular vesicles. Using antibody-based analysis, we verified the mass spectrometry results for five representative proteins from this group of proteins (CD9, HSP72, PI42A, TALDO, and VAMP2) and GFAP, a marker for neuroinflammation.

CONCLUSIONS: Several proteins involved in exo-endocytic pathways and extracellular vesicle functions display altered levels in the AD brain. We hypothesize that such changes may result in disturbed cellular clearance and a perturbed cell-to-cell communication that may contribute to neuronal dysfunction and cell death in AD.

%B J Alzheimers Dis %V 54 %P 1671-1686 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636840?dopt=Abstract %R 10.3233/JAD-160271 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Increased Total Homocysteine Levels Predict the Risk of Incident Dementia Independent of Cerebral Small-Vessel Diseases and Vascular Risk Factors. %A Miwa, Kaori %A Tanaka, Makiko %A Okazaki, Shuhei %A Yagita, Yoshiki %A Sakaguchi, Manabu %A Mochizuki, Hideki %A Kitagawa, Kazuo %K Aged %K Carotid Intima-Media Thickness %K Cerebral Small Vessel Diseases %K Dementia %K Female %K Homocysteine %K Humans %K Incidence %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Predictive Value of Tests %K Proportional Hazards Models %K Risk Factors %K Statistics, Nonparametric %X

BACKGROUND: Homocysteine has been identified as a potential risk factor for stroke, cerebral small-vessel diseases (SVD), and dementia.

OBJECTIVE: The present study aimed to investigate the predictive value of homocysteine levels on incident dementia while simultaneously controlling for MRI findings and vascular risk factors.

METHODS: Within a Japanese cohort of participants with vascular risk factors in an observational study, we evaluated the association between baseline total homocysteine (tHcy) levels (per 1 μmol/L and the tertile of tHcy), the prevalence of MRI-findings at baseline, and incident all-cause dementia. Baseline brain MRI was used to determine SVD (lacunas, white matter hyperintensities, and cerebral microbleeds [CMBs]) and atrophy (medial-temporal lobe atrophy and bicaudate ratio). Logistic regression analyses were used to estimate the cross-sectional association between tHcy and each of MRI findings. Cox proportional hazards analyses were performed to estimate the longitudinal association between tHcy and dementia.

RESULTS: In the 643 subjects (age: 67.2 ± 8.4 years, male: 59% ; education: 12.9 ± 2.6 years), multivariable analyses adjusted for several potential confounders, including estimated glomerular filtration rate (eGFR) and intima-media thickness, showed that highest tHcy tertile was associated with lacunas, CMBs, and strictly deep CMBs. During the mean 7.3-year follow-up (range: 2-13), 47 patients were diagnosed with dementia (Alzheimer's disease: 24; vascular dementia: 18; mixed-type: 3; other: 2). After adjusting for age, gender, APOE ɛ4, education, BMI, MMSE, hypertension, cerebrovascular events, eGFR, and MRI-findings, tHcy level (hazard ratios [HR]: 1.08, p = 0.043) and the highest tertile of tHcy (HR: 2.50, p = 0.047) for all-cause dementia remained significant.

CONCLUSIONS: Our results provide additional evidence of tHcy that contributes to increased susceptibility to dementia risk.

%B J Alzheimers Dis %V 49 %P 503-13 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484913?dopt=Abstract %R 10.3233/JAD-150458 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Inequalities in Access to Treatment and Care for Patients with Dementia and Immigrant Background: A Danish Nationwide Study. %A Stevnsborg, Lea %A Jensen-Dahm, Christina %A Nielsen, Thomas R %A Gasse, Christiane %A Waldemar, Gunhild %X

BACKGROUND: Previous studies demonstrated lower quality diagnostic assessment of dementia in immigrant populations, but knowledge about the quality of treatment and care for dementia is still lacking.

OBJECTIVE: To conduct a nationwide registry-based study to determine whether inequality exists regarding access to anti-dementia treatment and care between immigrant and Danish-born patients with dementia.

METHODS: A cross-sectional register-based study was conducted in the entire elderly (60≥years) population with dementia in Denmark in 2012 (n = 34,877). The use of anti-dementia drugs and residency in a nursing home were compared among Danish-born and Western and non-Western immigrants with dementia. Logistic regression analysis was done with adjustment for age, sex, comorbidity, marital status, basis of inclusion, and time since dementia diagnosis.

RESULTS: Immigrant background was associated with a significantly lower likelihood of receiving anti-dementia drug therapy (odds ratio (OR) [95% confidence interval (CI)]): non-Western = 0.70 [0.56-0.87]; Western = 0.74 [0.63-0.87]). No significant differences were found in type or amount of anti-dementia medication dispensed between the population groups (proxy measure for adherence). Non-Western immigrants were significantly less likely to live in a nursing home (0.52 [0.41-0.65]).

CONCLUSION: This nationwide registry-based study indicated a worrisome difference in access to anti-dementia treatment and care for dementia patients with an immigrant background, but similar levels of adherence compared with the Danish-born population. Further research is necessary to pinpoint barriers to access to suitable healthcare among elderly immigrants with dementia but also to identify and develop culturally sensitive methods for their treatment and care.

%B J Alzheimers Dis %V 54 %P 505-14 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567820?dopt=Abstract %R 10.3233/JAD-160124 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Inflammasome Involvement in Alzheimer's Disease. %A Olsen, Ingar %A Singhrao, Sim K %X

Inflammasomes are responsible for the maturation of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-18, and IL-33 and activation of inflammatory cell death, pyroptosis. They assemble in response to cellular infection and stress or to tissue damage, promote inflammatory reactions, and are important in regulating innate immunity particularly by acting as platforms for activation of caspase proteases. They appear to be involved in several pathological processes activated by microbes including Alzheimer's disease (AD). Best characterized in microbial pathogenesis is the nucleotide-binding domain and leucine-rich repeat (NLR)-protein 3 (NLRP3) inflammasome. AD is a neurodegenerative condition in which the neuropathological hallmarks are the deposition of amyloid-β (Aβ) and hyperphosphorylated tau protein coated neurofibrillary tangles. For decades, the role of the innate immune system in the etiology of AD was considered less important, but the recently discovered inflammatory genes by genome-wide association studies driving inflammation in this disease has changed this view. Innate immune inflammatory activity in the AD brain can result from the pathological hallmark protein Aβ as well as from specific bacterial infections that tend to possess weak immunostimulatory responses for peripheral blood myeloid cell recruitment to the brain. The weak immunostimulatory activity is a consequence of their immune evasion strategies and survival. In this review we discuss the possibility that inflammasomes, particularly via the NLR family of proteins NLRP3 are involved in the pathogenesis of AD. In addition, we discuss the plausible contribution of specific bacteria playing a role in influencing the activity of the NLRP3 inflammasome to AD progression.

%B J Alzheimers Dis %V 54 %P 45-53 %8 2016 Jun 15 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27314526?dopt=Abstract %R 10.3233/JAD-160197 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Inflammation, Antiinflammatory Agents, and Alzheimer's Disease: The Last 22 Years. %A McGeer, Patrick L %A Rogers, Joseph %A McGeer, Edith G %X

Two basic discoveries spurred research into inflammation as a driving force in the pathogenesis of Alzheimer's disease (AD). The first was the identification of activated microglia in association with the lesions. The second was the discovery that rheumatoid arthritics, who regularly consume anti-inflammatory agents, were relatively spared from the disease. These findings led to an exploration of the inflammatory pathways that were involved in AD pathogenesis. A pivotal advance was the discovery that amyloid-β protein (Aβ) activated the complement system. This focused attention on anti-inflammatories as blockers of complement activation. More than 15 epidemiological studies have since showed a sparing effect of non-steroidal anti-inflammatory drugs (NSAIDs) in AD. A consistent finding has been that the longer the NSAIDs were used prior to clinical diagnosis, the greater the sparing effect. The reason has since emerged from studies of biomarkers such as amyloid-β (Aβ) levels in the cerebrospinal fluid and Aβ deposits in brain. They have established that the onset of AD commences at least a decade before cognitive decline permits clinical diagnosis. Such biomarker studies have revealed that a huge window of opportunity exists when application of NSAIDs, other anti-inflammatory agents, or complement activation blockers, could arrest further progress of AD, thus eliminating its manifestation. It can be anticipated that this principle will apply to many other chronic neurodegenerative diseases. Neuroinflammation, discovered in AD more than 30 years ago, has now become a major field of brain research today. Inhibiting it may be the key to successful treatment of many chronic neurological disorders.

%B J Alzheimers Dis %V 54 %P 853-857 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716676?dopt=Abstract %R 10.3233/JAD-160488 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Influence of Incipient Dementia on Hospitalization for Primary Care Sensitive Conditions: A Population-Based Cohort Study. %A Pimouguet, Clément %A Rizzuto, Debora %A Fastbom, Johan %A Lagergren, Mårten %A Fratiglioni, Laura %A Xu, Weili %K Acute Disease %K Age Factors %K Aged %K Aged, 80 and over %K Chronic Disease %K Dementia %K Female %K Follow-Up Studies %K Hospitalization %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Primary Health Care %K Registries %K Risk %K Sensitivity and Specificity %K Socioeconomic Factors %K Sweden %X

BACKGROUND: Studies have reported that moderate/severe stages of dementia are linked to increased hospitalization rates, but little is known about the influence of incipient dementia on hospitalizations for primary care sensitive conditions (PCSCs).

OBJECTIVE: To examine the associations between incipient dementia and hospitalization outcomes, including all-cause and PCSC hospitalization.

METHODS: A total of 2,268 dementia-free participants in the Swedish National study on Aging and Care-Kungsholmen were interviewed and clinically examined at baseline. Participants aged ≥78 years were followed for 3 years, and those aged 60-72 years, for 6 years. Number of hospitalizations was retrieved from the National Patient Register. Dementia was diagnosed in accordance with Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Hospitalization outcomes were compared in participants who did and did not develop dementia. Zero-inflated Poisson regressions and logistic regressions were used in data analysis.

RESULTS: During the follow-up, 175 participants developed dementia. The unadjusted PCSC admission rate was 88.2 per 1000 person-years in those who developed dementia and 25.6 per 1000 person-years in those who did not. In the fully adjusted logistic regression model, incipient dementia was associated with an increased risk of hospitalization for PCSCs (OR = 2.3, 95% CI 1.3-3.9) but not with the number of hospitalizations or with all-cause hospitalization. Risks for hospitalization for diabetes, congestive heart failure, and pyelonephritis were higher in those who developed dementia than in those who did not. About 10% participants had a PCSC hospitalization attributable to incipient dementia.

CONCLUSION: People with incipient dementia are more prone to hospitalization for PCSCs but not to all-cause hospitalization.

%B J Alzheimers Dis %V 52 %P 213-22 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060943?dopt=Abstract %R 10.3233/JAD-150853 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Influence of Low-Dose Aspirin on Cerebral Amyloid Angiopathy in Mice. %A Hattori, Yorito %A Maki, Takakuni %A Saito, Satoshi %A Yamamoto, Yumi %A Nagatsuka, Kazuyuki %A Ihara, Masafumi %X

Accumulation of amyloid-β peptide (Aβ) in the brain is one of the most important features of Alzheimer's dementia (AD). Cerebral amyloid angiopathy (CAA) is characterized by Aβ accumulation in the walls of cerebral arteries and capillaries, and is present in over 90% of patients with AD. Several novel agents for AD/CAA developed around the amyloid hypothesis have shown positive signs in animal studies but have failed in clinical trials due to adverse events and/or lack of efficiency. As CAA is presumably caused by a failure in Aβ clearance, drugs that promote Aβ clearance may hold promise in the treatment of CAA and possibly AD. With this in mind, cilostazol, an anti-platelet drug with vasodilating action, has been found to promote Aβ clearance along perivascular drainage pathway, reduce Aβ accumulation in the brain, and restore memory impairment in Tg-SwDI mice, an animal model of CAA. We therefore tested whether the most common anti-platelet agent, aspirin, also reduced Aβ and rescued cognitive impairment in Tg-SwDI mice, and also whether aspirin affected hemorrhagic complications that can occur in Tg-SwDI mice. Mice aged 4 months were assigned into vehicle-treated and low-dose aspirin-treated groups. Low-dose aspirin for 8 months did not increase hemorrhagic lesions, nor increase resting cerebral blood flow or cerebral vascular reserve in response to hypercapnia or acetylcholine. Subsequently, aspirin did not restore cognitive dysfunction. These results suggest that low-dose aspirin does not have a direct influence on cerebrovascular Aβ metabolism nor aggravate hemorrhagic complications in CAA.

%B J Alzheimers Dis %V 52 %P 1037-45 %8 2016 Apr 12 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079719?dopt=Abstract %R 10.3233/JAD-160013 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Inhibition of Cholesterol Biosynthesis Reduces γ-Secretase Activity and Amyloid-β Generation. %A Kim, Yoonhee %A Kim, Chaeyoung %A Jang, Hye Young %A Mook-Jung, Inhee %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Analysis of Variance %K Animals %K Anticholesteremic Agents %K Cell Line %K Cholesterol %K Cricetinae %K Down-Regulation %K Humans %K In Situ Nick-End Labeling %K Luminescent Proteins %K Membrane Glycoproteins %K Membrane Microdomains %K Mutation %K Presenilin-1 %K Protein Transport %K trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride %K Transfection %X

Amyloid-β (Aβ) is one of major molecules contributing to the pathogenesis of Alzheimer's disease (AD). Aβ is derived from amyloid-β protein precursor (AβPP) through sequential cleavages by β- and γ-secretases. Regulation of these components is thought to be an important factor in Aβ generation during the pathogenesis of AD. AβPP, β-secretase, and γ-secretase reside in lipid rafts, where cholesterol regulates the integrity and flexibility of membrane proteins and Aβ is generated. However, the relationship between cholesterol and Aβ generation is controversial. In this study, we aimed to elucidate the direct effects of cholesterol depletion on AβPP processing using AY9944, which blocks the last step of cholesterol biosynthesis and thus minimizes the unknown side effects of upstream inhibitors, such as HMG-CoA reductase inhibitors. Treatment with AY9944 decreased γ-secretase activity and Aβ generation. These results suggested that changes in membrane composition by lowering cholesterol with AY9944 affected γ-secretase activity and Aβ generation, which is associated with AD pathogenesis.

%B J Alzheimers Dis %V 51 %P 1057-68 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923021?dopt=Abstract %R 10.3233/JAD-150982 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Inhibition of Histone Deacetylase 3 Restores Amyloid-β Oligomer-Induced Plasticity Deficit in Hippocampal CA1 Pyramidal Neurons. %A Krishna, Kumar %A Behnisch, Thomas %A Sajikumar, Sreedharan %K Acrylamides %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Excitatory Postsynaptic Potentials %K Hippocampus %K Histone Deacetylase Inhibitors %K Histone Deacetylases %K Long-Term Potentiation %K Male %K Patch-Clamp Techniques %K Peptide Fragments %K Phenylenediamines %K Pyramidal Cells %K Rats, Wistar %K Tissue Culture Techniques %X

Neurodegenerative diseases such as Alzheimer's disease (AD) are associated with alterations in epigenetic factors leading to cognitive decline. Histone deacetylase 3 (HDAC3) is a known critical epigenetic negative regulator of learning and memory. In this study, attenuation of long-term potentiation by amyloid-β oligomer, and its reversal by specific HDAC3 inhibitor RGFP966, was performed in rat CA1 pyramidal neurons using whole cell voltage-clamp and field recording techniques. Our findings provide the first evidence that amyloid-β oligomer-induced synaptic plasticity impairment can be prevented by inhibition of HDAC3 enzyme both at the single neuron as well as in a population of neurons, thus identifying HDAC3 as a potential target for ameliorating AD related plasticity impairments.

%B J Alzheimers Dis %V 51 %P 783-91 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890755?dopt=Abstract %R 10.3233/JAD-150838 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Insight into the Dissociation of Behavior from Histology in Synucleinopathies and in Related Neurodegenerative Diseases. %A Sekiyama, Kazunari %A Takamatsu, Yoshiki %A Koike, Wakako %A Waragai, Masaaki %A Takenouchi, Takato %A Sugama, Shuei %A Hashimoto, Makoto %X

Recent clinical trials using immunization approaches against Alzheimer's disease (AD) have failed to demonstrate improved cognitive functions in patients, despite potent suppression in the formation of both senile plaques and other amyloid-β deposits in postmortem brains. Similarly, we observed that treatment with ibuprofen, a non-steroidal anti-inflammatory drug, was effective in improving the histopathology, such as reducing both protein aggregation and glial activation, in the brains of transgenic mice expressing dementia with Lewy bodies-linked P123H β-synuclein. In contrast, only a small improvement in cognitive functions was observed in these mice. Collectively, it is predicted that histology does not correlate with behavior that is resilient and resistant to therapeutic stimuli. Notably, such a 'discrepancy between histology and behavior' is reminiscent of AD-like pathologies and incidental Lewy bodies, which are frequently encountered in postmortem brains of the elderly who had been asymptomatic for memory loss and Parkinsonism during their lives. We suggest that 'the discrepancy between histology and behavior' may be a universal feature that is associated with various aspects of neurodegenerative diseases. Furthermore, given that the cognitive reserve is specifically observed in human brains, human behavior may be evolutionally distinct from that in other animals, thus, contributing to the differential efficiency of therapy between human and lower animals, an important issue in the therapy of neurodegenerative diseases. Overall, it is important to better understand 'the discrepancy between histology and behavior' in the mechanism of neurodegeneration for the development of effective therapies against neurodegenerative diseases.

%B J Alzheimers Dis %V 52 %P 831-41 %8 2016 Mar 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031478?dopt=Abstract %R 10.3233/JAD-151015 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Instrumental Activity of Daily Living Profile in Aging: A Feasibility Study. %A Bier, Nathalie %A Belchior, Patricia da Cunha %A Paquette, Guillaume %A Beauchemin, Émilie %A Lacasse-Champagne, Ariane %A Messier, Chantal %A Pellerin, Marie-Line %A Petit, Marisol %A Mioshi, Eneida %A Bottari, Carolina %X

BACKGROUND: Dysfunctions in complex activities of daily living (ADLs) are a normal part of the aging process. However, differentiating functional decline associated with healthy aging from the subtle decline experienced by individuals with mild cognitive impairment and early dementia constitutes a challenge. Finding an appropriate tool that can capture these subtle but important functional changes represents a priority.

OBJECTIVES: The aims of this study were to evaluate the feasibility of using the Instrumental Activities of Daily Living Profile (IADL Profile) with elderly participants and to describe their level of difficulty encountered in each task.

METHODS: The tool was administered to a group of 40 elderly participants living in the community.

RESULTS: The IADL Profile was found to be feasible to use in older individuals; the tool also showed sensitivity to the difficulties experienced by this population in everyday functioning.

CONCLUSION: The IADL Profile is a promising ecological tool to evaluate independence in aging and may help to identify individuals with MCI. This tool may also contribute to the development of tailored interventions to enhance everyday functioning in the older population.

%B J Alzheimers Dis %V 52 %P 1361-71 %8 2016 Apr 12 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079703?dopt=Abstract %R 10.3233/JAD-150957 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults. %A Hoscheidt, Siobhan M %A Starks, Erika J %A Oh, Jennifer M %A Zetterberg, Henrik %A Blennow, Kaj %A Krause, Rachel A %A Gleason, Carey E %A Puglielli, Luigi %A Atwood, Craig S %A Carlsson, Cynthia M %A Asthana, Sanjay %A Johnson, Sterling C %A Bendlin, Barbara B %X

BACKGROUND: Type 2 diabetes is associated with an increased risk for Alzheimer's disease (AD). Regulation of normal insulin function may be important in reducing the prevalence of dementia due to AD, particularly in individuals who harbor genetic risk for or have a parental family history of AD. The relationship between insulin resistance (IR) and AD pathology remains poorly understood, particularly in midlife prior to the onset of clinical metabolic disease or cognitive decline.

OBJECTIVE: We examined associations between IR as indexed by HOMA-IR, cerebrospinal fluid (CSF) biomarkers of AD pathology, and memory in middle-aged adults enriched for AD. We postulated that higher HOMA-IR and APOEɛ4 carriage would be associated with greater CSF AD pathology and poor memory performance.

METHODS: Cognitively asymptomatic middle-aged adults (N = 70, mean age = 57.7 years) from the Wisconsin Alzheimer's Disease Research Center with a parental family history of dementia due to AD underwent lumbar puncture, blood draw, and neuropsychological testing. CSF AD biomarkers including soluble amyloid-β protein precursor β (sAβPPβ), amyloid-β42 (Aβ42), and phosphorylated tau (P-tau181) were examined with respect to HOMA-IR and APOEɛ4 status. Delayed memory performance was examined with respect to HOMA-IR, CSF AD biomarkers, and APOEɛ4 status.

RESULTS: Higher HOMA-IR was associated with higher sAβPPβ and Aβ42 . APOEɛ4 carriers had significantly higher levels of sAβPPα, sAβPPβ, and P-tau181/Aβ42 compared to noncarriers. The concurrent presence of higher HOMA-IR and CSF AD pathology predicted worse delayed memory performance.

CONCLUSION: Overall, the findings suggest that IR and APOEɛ4 are contributing factors to the development of AD pathology in midlife, and provide support for targeting insulin function as a potentially modifiable risk factor for AD.

%B J Alzheimers Dis %V 52 %P 1373-83 %8 2016 Apr 12 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079723?dopt=Abstract %R 10.3233/JAD-160110 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Integrated Analysis of Alzheimer's Disease and Schizophrenia Dataset Revealed Different Expression Pattern in Learning and Memory. %A Li, Wen-Xing %A Dai, Shao-Xing %A Liu, Jia-Qian %A Wang, Qian %A Li, Gong-Hua %A Huang, Jing-Fei %K Adult %K Aged %K Aged, 80 and over %K Algorithms %K Alzheimer Disease %K Bayes Theorem %K Brain %K Datasets as Topic %K Gene Expression Profiling %K Humans %K Learning %K Memory %K Microarray Analysis %K Middle Aged %K Schizophrenia %K Schizophrenic Psychology %K Young Adult %X

Alzheimer's disease (AD) and schizophrenia (SZ) are both accompanied by impaired learning and memory functions. This study aims to explore the expression profiles of learning or memory genes between AD and SZ. We downloaded 10 AD and 10 SZ datasets from GEO-NCBI for integrated analysis. These datasets were processed using RMA algorithm and a global renormalization for all studies. Then Empirical Bayes algorithm was used to find the differentially expressed genes between patients and controls. The results showed that most of the differentially expressed genes were related to AD whereas the gene expression profile was little affected in the SZ. Furthermore, in the aspects of the number of differentially expressed genes, the fold change and the brain region, there was a great difference in the expression of learning or memory related genes between AD and SZ. In AD, the CALB1, GABRA5, and TAC1 were significantly downregulated in whole brain, frontal lobe, temporal lobe, and hippocampus. However, in SZ, only two genes CRHBP and CX3CR1 were downregulated in hippocampus, and other brain regions were not affected. The effect of these genes on learning or memory impairment has been widely studied. It was suggested that these genes may play a crucial role in AD or SZ pathogenesis. The different gene expression patterns between AD and SZ on learning and memory functions in different brain regions revealed in our study may help to understand the different mechanism between two diseases.

%B J Alzheimers Dis %V 51 %P 417-25 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890750?dopt=Abstract %R 10.3233/JAD-150807 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Integrating Biomarkers for Underlying Alzheimer's Disease in Mild Cognitive Impairment in Daily Practice: Comparison of a Clinical Decision Support System with Individual Biomarkers. %A Rhodius-Meester, Hanneke F M %A Koikkalainen, Juha %A Mattila, Jussi %A Teunissen, Charlotte E %A Barkhof, Frederik %A Lemstra, Afina W %A Scheltens, Philip %A Lötjönen, Jyrki %A van der Flier, Wiesje M %K Aged %K Aged, 80 and over %K Algorithms %K Alzheimer Disease %K Area Under Curve %K Biomarkers %K Cognitive Dysfunction %K Cohort Studies %K Decision Support Systems, Clinical %K Disease Progression %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Outcome Assessment (Health Care) %K Predictive Value of Tests %X

BACKGROUND: Recent criteria allow biomarkers to provide evidence of Alzheimer's disease (AD) pathophysiology. How they should be implemented in daily practice remains unclear, especially in mild cognitive impairment (MCI) patients.

OBJECTIVE: We evaluated how a clinical decision support system such as the PredictAD tool can aid clinicians to integrate biomarker evidence to support AD diagnosis.

METHODS: With available data on demographics, cerebrospinal fluid (CSF), and MRI, we trained the PredictAD tool on a reference population of 246 controls and 491 AD patients. We then applied the identified algorithm to 211 MCI patients. For comparison, we also classified patients based on individual biomarkers (MRI; CSF) and the NIA-AA criteria. Progression to dementia was used as outcome measure.

RESULTS: After a median follow up of 3 years, 72 (34%) MCI patients remained stable and 139 (66%) progressed to AD. The PredictAD tool assigned a likelihood of underlying AD to each patient (AUC 0.82). Excluding patients with missing data resulted in an AUC of 0.87. According to the NIA-AA criteria, half of the MCI patients had uninformative biomarkers, precluding an assignment of AD likelihood. A minority (41%) was assigned to high or low AD likelihood with good predictive value. The individual biomarkers showed best value for CSF total tau (AUC 0.86).

CONCLUSION: The ability of the PredictAD tool to identify AD pathophysiology was comparable to individual biomarkers. The PredictAD tool has the advantage that it assigns likelihood to all patients, regardless of missing or conflicting data, allowing clinicians to integrate biomarker data in daily practice.

%B J Alzheimers Dis %V 50 %P 261-70 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26577521?dopt=Abstract %R 10.3233/JAD-150548 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Interaction Between Midlife Blood Glucose and APOE Genotype Predicts Later Alzheimer's Disease Pathology. %A Bangen, Katherine J %A Himali, Jayandra J %A Beiser, Alexa S %A Nation, Daniel A %A Libon, David J %A Fox, Caroline S %A Seshadri, Sudha %A Wolf, Philip A %A McKee, Ann C %A Au, Rhoda %A Delano-Wood, Lisa %X

Elevated blood glucose and the apolipoprotein (APOE) ɛ4 allele have both been associated with increased dementia risk; however, the neuropathological mechanisms underlying these associations remain unclear. We examined the impact of APOE genotype and midlife blood glucose on post-mortem vascular and Alzheimer's disease (AD) neuropathology. Ninety-four participants from the Framingham Heart Study without diagnosed diabetes underwent health examination at midlife and brain autopsy at death. Histopathological measures of vascular and AD neuropathology were obtained and analyzed. Results demonstrated that, among APOE ɛ4 carriers, elevated blood glucose was associated with more severe AD pathology. There was no such relationship with vascular pathology. In a relatively healthy sample with low vascular risk burden, midlife elevated blood glucose was associated with greater AD pathology among APOE ɛ4 carriers. A better understanding of interactive effects of APOE genotype and vascular risk on neuropathology has implications for identification of individuals at risk for decline and long-term preventive treatment.

%B J Alzheimers Dis %V 53 %P 1553-62 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392855?dopt=Abstract %R 10.3233/JAD-160163 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Intracerebroventricular Infusion of Angiotensin-(1-7) Ameliorates Cognitive Impairment and Memory Dysfunction in a Mouse Model of Alzheimer's Disease. %A Uekawa, Ken %A Hasegawa, Yu %A Senju, Satoru %A Nakagata, Naomi %A Ma, Mingjie %A Nakagawa, Takashi %A Koibuchi, Nobutaka %A Kim-Mitsuyama, Shokei %X

This work was performed to test our hypothesis that angiotensin-(1-7) can ameliorate cognitive impairment and cerebrovascular reactivity in 5XFAD mice, a useful model of Alzheimer's disease. 5XFAD mice received intracerebroventricular infusion of (1) vehicle, (2) angiotensin-(1-7), or (3) angiotensin-(1-7)+A779, a specific Mas receptor antagonist, for 4 weeks. Angiotensin-(1-7), through Mas receptor, significantly ameliorated cognitive impairment in 5XFAD mice. As estimated by acetazolamide-induced increase in cerebral blood flow, angiotensin-(1-7), through Mas receptor, enhanced cerebrovascular reactivity in 5XFAD mice. In conclusion, angiotensin-(1-7)/Mas receptor axis improves cognitive function and cerebrovascular function in a mouse model of Alzheimer's disease.

%B J Alzheimers Dis %V 53 %P 127-33 %8 2016 Apr 23 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128367?dopt=Abstract %R 10.3233/JAD-150642 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Intranasal Administration of a Polyethylenimine-Conjugated Scavenger Peptide Reduces Amyloid-β Accumulation in a Mouse Model of Alzheimer's Disease. %A Lin, Chih-Yun %A Cheng, Yu-Sung %A Liao, Tai-Yan %A Lin, Chen %A Chen, Zih-Ten %A Twu, Woan-Ing %A Chang, Chi-Wei %A Tan, David Tat-Wei %A Liu, Ren-Shyan %A Tu, Pang-Hsien %A Chen, Rita P-Y %X

Amyloid-β (Aβ) aggregation in the brain plays a central and initiatory role in pathogenesis and/or progression of Alzheimer's disease (AD). Inhibiting Aβ aggregation is a potential strategy in the prevention of AD. A scavenger peptide, V24P(10-40), designed to decrease Aβ accumulation in the brain, was conjugated to polyethylenimine (PEI) and tested as a preventive/therapeutic strategy for AD in this study. This PEI-conjugated V24P(10-40) peptide was delivered intranasally, as nasal drops, to four-month-old APP/PS1 double transgenic mice for four or eight months. Compared with control values, peptide treatment for four months significantly reduced the amount of GdnHCl-extracted Aβ40 and Aβ42 in the mice's hippocampus and cortex. After treatment for eight months, amyloid load, as quantified by Pittsburgh compound B microPET imaging, was significantly decreased in the mice's hippocampus, cortex, amygdala, and olfactory bulb. Our data suggest that this intranasally delivered scavenger peptide is effective in decreasing Aβ accumulation in the brain of AD transgenic mice. Nasal application of peptide drops is easy to use and could be further developed to prevent and treat AD.

%B J Alzheimers Dis %V 53 %P 1053-67 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340844?dopt=Abstract %R 10.3233/JAD-151024 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Intranasal TAT-haFGF Improves Cognition and Amyloid-β Pathology in an AβPP/PS1 Mouse Model of Alzheimer's Disease. %A Lou, Guofeng %A Zhang, Qihao %A Xiao, Fei %A Xiang, Qi %A Su, Zhijian %A Huang, Yadong %K Administration, Intranasal %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Brain %K Cognition Disorders %K Disease Models, Animal %K Fibroblast Growth Factors %K Gene Products, tat %K Humans %K Injections, Intraventricular %K Maze Learning %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Movement %K Mutation %K Peptide Fragments %K Plaque, Amyloid %K Presenilin-1 %X

Neurotoxic amyloid-β (Aβ) peptide causing cognitive function disabilities is one of the most characteristic pathological features in Alzheimer's disease (AD). A novel fusion protein, TAT-haFGF, was administrated to AβPP/PS1 transgenic mice by intravenous (IV) injection and intranasal (IN) delivery, respectively, for 5 weeks to compare the pharmacodynamics between the two routes of administration. Our results showed that IN administration of TAT-haFGF improved cognition and reduced Aβ plaques more significantly in AβPP/PS1 mice, when compared with IV injection. Our new findings suggest that TAT-haFGF might be a promising new therapy to attenuate AD pathological process.

%B J Alzheimers Dis %V 51 %P 985-90 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890786?dopt=Abstract %R 10.3233/JAD-151121 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Intraneuronal Amylin Deposition, Peroxidative Membrane Injury and Increased IL-1β Synthesis in Brains of Alzheimer's Disease Patients with Type-2 Diabetes and in Diabetic HIP Rats. %A Verma, Nirmal %A Ly, Han %A Liu, Miao %A Chen, Jing %A Zhu, Haining %A Chow, Martin %A Hersh, Louis B %A Despa, Florin %X

Amylin is a hormone synthesized and co-secreted with insulin by pancreatic β-cells that crosses the blood-brain barrier and regulates satiety. Amylin from humans (but not rodents) has an increased propensity to aggregate into pancreatic islet amyloid deposits that contribute to β-cell mass depletion and development of type-2 diabetes by inducing oxidative stress and inflammation. Recent studies demonstrated that aggregated amylin also accumulates in brains of Alzheimer's disease (AD) patients, preponderantly those with type-2 diabetes. Here, we report that, in addition to amylin plaques and mixed amylin-Aβ deposits, brains of diabetic patients with AD show amylin immunoreactive deposits inside the neurons. Neuronal amylin formed adducts with 4-hydroxynonenal (4-HNE), a marker of peroxidative membrane injury, and increased synthesis of the proinflammatory cytokine interleukin (IL)-1β. These pathological changes were mirrored in rats expressing human amylin in pancreatic islets (HIP rats) and mice intravenously injected with aggregated human amylin, but not in hyperglycemic rats secreting wild-type non-amyloidogenic rat amylin. In cultured primary hippocampal rat neurons, aggregated amylin increased IL-1β synthesis via membrane destabilization and subsequent generation of 4-HNE. These effects were blocked by membrane stabilizers and lipid peroxidation inhibitors. Thus, elevated circulating levels of aggregated amylin negatively affect the neurons causing peroxidative membrane injury and aberrant inflammatory responses independent of other confounding factors of diabetes. The present results are consistent with the pathological role of aggregated amylin in the pancreas, demonstrate a novel contributing mechanism to neurodegeneration, and suggest a direct, potentially treatable link of type-2 diabetes with AD.

%B J Alzheimers Dis %V 53 %P 259-72 %8 2016 May 05 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163815?dopt=Abstract %R 10.3233/JAD-160047 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Iron Regulates Apolipoprotein E Expression and Secretion in Neurons and Astrocytes. %A Xu, He %A Perreau, Victoria M %A Dent, Krista A %A Bush, Ashley I %A Finkelstein, David I %A Adlard, Paul A %K Amyloid beta-Peptides %K Animals %K Apolipoproteins E %K Astrocytes %K Blotting, Western %K Cell Survival %K Cells, Cultured %K Cerebral Cortex %K Copper %K Ferritins %K Immunohistochemistry %K Iron %K Mice, Inbred C57BL %K Neurons %K Polymerase Chain Reaction %K Reactive Oxygen Species %K Receptors, LDL %K RNA, Messenger %K Tumor Suppressor Proteins %K Zinc %X

BACKGROUND: There is strong evidence that iron homeostasis is impaired in the aging and Alzheimer's disease (AD) brain and that this contributes to neurodegeneration. Apolipoprotein E (APOE) has been identified as the strongest genetic risk factor for AD. However, the interaction between the two has yet to be fully explored.

OBJECTIVE: This study aimed to investigate the relationship between exogenous iron levels and ApoE in neurons and astrocytes.

METHODS: Our study used primary cultured cortical neurons and astrocytes to investigate the changes in ApoE caused by iron. Western blot and RT-PCR were used to measure ApoE.

RESULTS: We observed that iron upregulated intracellular ApoE levels in both neurons and astrocytes at the post-transcriptional and transcriptional level, respectively. However, there was less full-length ApoE secreted by neurons and astrocytes after iron treatment. We speculate that this might impair brain lipid metabolism and amyloid-β clearance. In terms of ApoE receptors, we observed that neuronal LRP-1 levels were increased by the addition of exogenous iron, which could contribute to AβPP endocytosis in neurons. However, there were no significant changes in neuronal LDLR, astrocyte LDLR, or astrocyte LRP-1.

CONCLUSION: Our study reveals that iron may contribute to the pathogenesis of AD by affecting ApoE and its receptors and supports the notion that iron chelation should be investigated as a therapeutic strategy for AD.

%B J Alzheimers Dis %V 51 %P 471-87 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890748?dopt=Abstract %R 10.3233/JAD-150797 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Japanese Care Location and Medical Procedures for People with Dementia in the Last Month of Life. %A Nakanishi, Miharu %A Nakashima, Taeko %A Shindo, Yumi %A Niimura, Junko %A Nishida, Atsushi %K Aged, 80 and over %K Cross-Sectional Studies %K Dementia %K Female %K Hospitals %K Housing %K Humans %K Japan %K Male %K Nursing Homes %K Pain Management %K Retrospective Studies %K Terminal Care %K Time Factors %X

BACKGROUND: Dementia-related societies worldwide have called for palliative end-of-life care for those suffering dementia; meanwhile, the Japanese dementia plan was revised on January 2015 to introduce into its objectives the support for end-of-life care via increased social and health care collaboration.

OBJECTIVE: The study focus was the use of medical procedures in the last month of life among dementia patients in different care locations in Japan.

METHODS: This study was conducted using a retrospective study design. Data from the Survey of Institutions and Establishments for Long-Term Care, which is a nationally representative cross-sectional survey of the public long-term care insurance services, were used. The 6,148 patients who received end-of-life care in their own home, nursing homes, or hospitals in September 2007, 2010, and 2013 were included for analysis. The primary disease of each patient was based on the ICD-10 code; a diagnosis of dementia included F00 (Alzheimer's), F01 (vascular), F02 (other), and F03 (unspecified).

RESULTS: Of 6,148 patients, 886 (14.4%) had dementia as a primary disease; most received care in the last month of life in nursing homes (48.0%) or hospitals (44.8%) rather than in their own home (7.2%). Patients were less likely to undergo pain management when their primary disease was dementia (adjusted odds ratio, 0.44; 95% confidence interval, 0.21-0.91).

CONCLUSION: Education and policy efforts are required to provide palliative end-of-life care to people with dementia at home. The national dementia plan should also explore possible approaches regarding pain management for dying people who have dementia.

%B J Alzheimers Dis %V 51 %P 747-55 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890762?dopt=Abstract %R 10.3233/JAD-150898 %0 Journal Article %J J Alzheimers Dis %D 2016 %T JNK: A Putative Link Between Insulin Signaling and VGLUT1 in Alzheimer's Disease. %A Rodriguez-Perdigon, Manuel %A Solas, Maite %A Ramirez, Maria Javier %K Aged %K Alzheimer Disease %K Animals %K Brain %K Corticosterone %K Disease Models, Animal %K Female %K Humans %K Insulin %K Insulin Resistance %K Male %K MAP Kinase Kinase 4 %K Mice, Inbred C57BL %K Mitogen-Activated Protein Kinase 1 %K Neuroprotective Agents %K RNA, Messenger %K Vesicular Glutamate Transport Protein 1 %X

In the present work, the involvement of JNK in insulin signaling alterations and its role in glutamatergic deficits in Alzheimer's disease (AD) has been studied. In postmortem cortical tissues, pJNK levels were increased, while insulin signaling and the expression of VGLUT1 were decreased. A significant correlation was found between reduced expression of insulin receptor and VGLUT1. The administration of a JNK inhibitor reversed the decrease in VGLUT1 expression found in a mice model of insulin resistance. It is suggested that activation of JNK in AD inhibits insulin signaling which could lead to a decreased expression of VGLUT1, therefore contributing to the glutamatergic deficit in AD.

%B J Alzheimers Dis %V 50 %P 963-7 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836159?dopt=Abstract %R 10.3233/JAD-150659 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Korean Size/Weight Attribute Test: A Semantic Knowledge Test for Korean Older Adults and Brain-Imaging Evidence. %A Yoo, Yongjoon %A Shin, Seong A %A Park, Soowon %A Lee, Ji-Hye %A Youn, Jung-Hae %A Kim, Yu Kyeong %A Lee, Jun-Young %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Analysis of Variance %K Brain %K Dementia %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Republic of Korea %K ROC Curve %K Semantics %X

BACKGROUND: A standardized tool for evaluating semantic knowledge of the Korean population is needed.

OBJECTIVE: The purpose of this study was to develop a neuropsychological test for the evaluation of semantic knowledge in the Korean elderly population.

METHODS: The Korean version of the Size/Weight Attribute Test (SWAT-K) was developed in reference to the original version. The diagnostic validity of SWAT-K was evaluated with 95 elderly outpatients [67 normal controls; 18 with Alzheimer's disease (AD); 10 with semantic-variant progressive aphasia (SV-PPA)]. Voxel-based morphometry (VBM) was employed to examine associations between SWAT-K scores and morphological changes of the brain.

RESULTS: SWAT-K could discriminate the three subject groups (normal >AD, p <  0.001; AD >SV-PPA, p = 0.040), whereas Boston Naming Test could not distinguish SV-PPA from AD. ROC curve analysis confirmed high levels of sensitivity (0.90) and specificity (0.93) for SWAT-K. The test's inter-rater reliability (ICC = 0.827) and test-retest reliability (ICC = 0.666) were assessed as well. VBM found a significant positive correlation (uncorrected p <  0.005, k >  100) between SWAT-K scores and gray matter volume in right inferior frontal cortex (T = 4.08, k = 191) and bilateral temporal cortices (left, T = 4.42, k = 135; right, T = 3.55, k = 253), the areas the most affected in SV-PPA.

CONCLUSIONS: SWAT-K is a sensitive and reliable test for evaluating semantic knowledge in the Korean elderly population. Strong positive correlations between SWAT-K scores and the brain areas responsible for semantic processing further corroborate the validity of SWAT-K.

%B J Alzheimers Dis %V 49 %P 377-86 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484915?dopt=Abstract %R 10.3233/JAD-150492 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Lack of evidence for a role of HHV-6 in the pathogenesis of Alzheimer's disease. %A Agostini, Simone %A Mancuso, Roberta %A Baglio, Francesca %A Cabinio, Monia %A Hernis, Ambra %A Guerini, Franca Rosa %A Calabrese, Elena %A Nemni, Raffaello %A Clerici, Mario %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Antibodies %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Herpesvirus 1, Human %K Herpesvirus 6, Human %K Humans %K Immunity, Humoral %K Magnetic Resonance Imaging %K Male %K Seroepidemiologic Studies %K Temporal Lobe %X

BACKGROUND: Alzheimer's disease (AD), the most common form of dementia worldwide, is associated with impairment in the mechanisms of the clearing of amyloid-β within a scenario of neuroinflammation. The etiopathogenesis of the AD is unclear, but a role for viral infection is suspected to play a role in initiating the disease. We recently described a positive correlation between high titers of HSV-1-specific antibodies (Ab) and the volumes of brain regions typically affected in disease.

OBJECTIVE: The exploration of a possible role for Herpesviridae in AD was extended by analyzing HHV-6-specific humoral immunity in individuals with AD or a diagnosis of amnestic mild cognitive impairment (aMCI), a condition that is often prodromic of the development of AD.

METHODS: 59 AD, 60 aMCI, and 61 age-matched healthy controls were enrolled in the study. Serum HHV-6 IgG antibody titers and avidity index were tested by ELISA. Two randomly selected subgroups of AD and aMCI in whom HHV-6 serum antibodies were detected underwent brain magnetic resonance imaging (MRI) by 1.5 T scanner.

RESULTS: HHV-6 seroprevalence, antibody titers, and avidity were similar in the three groups. No correlation was found between Ab titers or avidity and brain volumes, either overall or in the regions typically affected by disease.

CONCLUSIONS: The lack of any relation between humoral immune response against HHV-6 and AD and aMCI seems to rule out a role for this virus in the pathogenesis of AD.

%B J Alzheimers Dis %V 49 %P 229-35 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444787?dopt=Abstract %R 10.3233/JAD-150464 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Language Profile of Behavioral Variant Frontotemporal Dementia. %A Hardy, Chris J D %A Buckley, Aisling H %A Downey, Laura E %A Lehmann, Manja %A Zimmerer, Vitor C %A Varley, Rosemary A %A Crutch, Sebastian J %A Rohrer, Jonathan D %A Warrington, Elizabeth K %A Warren, Jason D %K Aged %K Aphasia, Primary Progressive %K Atrophy %K Brain %K Cognition %K Comprehension %K Female %K Frontotemporal Dementia %K Humans %K Language %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Primary Progressive Nonfluent Aphasia %X

BACKGROUND: The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined.

OBJECTIVE: We aimed to quantify the extent of language deficits in this patient group.

METHODS: We assessed a cohort of patients with bvFTD (n = 24) in relation to patients with semantic variant primary progressive aphasia (svPPA; n = 14), nonfluent variant primary progressive aphasia (nfvPPA; n = 18), and healthy age-matched individuals (n = 24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients' brain magnetic resonance images.

RESULTS: Relative to healthy controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech, and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network.

CONCLUSIONS: bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker.

%B J Alzheimers Dis %V 50 %P 359-71 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682693?dopt=Abstract %R 10.3233/JAD-150806 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Late Life Risk Index for Severe Cognitive Impairment in Mexico. %A Downer, Brian %A Veeranki, Sreenivas P %A Wong, Rebeca %K Age Factors %K Aged %K Cognitive Dysfunction %K Female %K Humans %K Life Style %K Logistic Models %K Longitudinal Studies %K Male %K Mexico %K Middle Aged %K Multivariate Analysis %K Risk Factors %K Social Behavior %K Socioeconomic Factors %X

BACKGROUND: Several dementia risk indices have been developed for older adults in high-income countries. However, no index has been developed for populations in low- or middle-income countries.

OBJECTIVE: To create a risk index for predicting severe cognitive impairment among adults aged ≥60 in Mexico and to compare the accuracy of this index to the Dementia Screening Indicator (DSI).

METHODS: This study included 3,002 participants from the Mexican Health and Aging Study (MHAS) interviewed in 2001 and 2012. The MHAS risk index included sociodemographic, health, and functional characteristics collected in 2001. A point value based on the beta coefficients from a multivariable logistic regression model was assigned to each risk factor and the total score was calculated.

RESULTS: The MHAS risk index (AUC = 0.74 95% CI = 0.70-0.77) and DSI (AUC = 0.72 95% CI = 0.69-0.77) had similar accuracy for discriminating between participants who developed severe cognitive impairment from those who did not. A score of ≥16 on the MHAS risk index had a sensitivity of 0.69 (95% CI = 0.64-0.70) and specificity of 0.67 (95% CI = 0.66-0.69). A score of ≥23 on the DSI had a sensitivity of 0.56 (95% CI = 0.50-0.63) and specificity of 0.78 (95% CI = 0.76-0.79).

DISCUSSION: The MHAS risk index and DSI have moderate accuracy for predicting severe cognitive impairment among older adults in Mexico. This provides evidence that existing dementia risk indices may be applicable in low- and middle-income countries such as Mexico. Future research should seek to identify additional risk factors that can improve the accuracy of the MHAS risk index.

%B J Alzheimers Dis %V 52 %P 191-203 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060940?dopt=Abstract %R 10.3233/JAD-150702 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Late-Life Depressive Symptoms and Lifetime History of Major Depression: Cognitive Deficits are Largely Due to Incipient Dementia rather than Depression. %A Heser, Kathrin %A Bleckwenn, Markus %A Wiese, Birgitt %A Mamone, Silke %A Riedel-Heller, Steffi G %A Stein, Janine %A Lühmann, Dagmar %A Posselt, Tina %A Fuchs, Angela %A Pentzek, Michael %A Weyerer, Siegfried %A Werle, Jochen %A Weeg, Dagmar %A Bickel, Horst %A Brettschneider, Christian %A König, Hans-Helmut %A Maier, Wolfgang %A Scherer, Martin %A Wagner, Michael %X

BACKGROUND: Late-life depression is frequently accompanied by cognitive impairments.

OBJECTIVE: Whether these impairments indicate a prodromal state of dementia, or are a symptomatic expression of depression per se is not well-studied.

METHODS: In a cohort of very old initially non-demented primary care patients (n = 2,709, mean age = 81.1 y), cognitive performance was compared between groups of participants with or without elevated depressive symptoms and with or without subsequent dementia using ANCOVA (adjusted for age, sex, and education). Logistic regression analyses were computed to predict subsequent dementia over up to six years of follow-up. The same analytical approach was performed for lifetime major depression.

RESULTS: Participants with elevated depressive symptoms without subsequent dementia showed only small to medium cognitive deficits. In contrast, participants with depressive symptoms with subsequent dementia showed medium to very large cognitive deficits. In adjusted logistic regression models, learning and memory deficits predicted the risk for subsequent dementia in participants with depressive symptoms. Participants with a lifetime history of major depression without subsequent dementia showed no cognitive deficits. However, in adjusted logistic regression models, learning and orientation deficits predicted the risk for subsequent dementia also in participants with lifetime major depression.

CONCLUSION: Marked cognitive impairments in old age depression should not be dismissed as "depressive pseudodementia", but require clinical attention as a possible sign of incipient dementia. Non-depressed elderly with a lifetime history of major depression, who remained free of dementia during follow-up, had largely normal cognitive performance.

%B J Alzheimers Dis %V 54 %P 185-99 %8 2016 Aug 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497475?dopt=Abstract %R 10.3233/JAD-160209 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment. %A Koppara, Alexander %A Wolfsgruber, Steffen %A Kleineidam, Luca %A Schmidtke, Klaus %A Frölich, Lutz %A Kurz, Alexander %A Schulz, Stefanie %A Hampel, Harald %A Heuser, Isabella %A Peters, Oliver %A Reischies, Friedel M %A Jahn, Holger %A Luckhaus, Christian %A Hüll, Michael %A Gertz, Hermann-Josef %A Schröder, Johannes %A Pantel, Johannes %A Rienhoff, Otto %A Rüther, Eckart %A Henn, Fritz %A Wiltfang, Jens %A Maier, Wolfgang %A Jessen, Frank %A Kornhuber, Johannes %A Wagner, Michael %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Dementia %K Disease Progression %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Phenotype %K Predictive Value of Tests %K Retrospective Studies %K tau Proteins %X

BACKGROUND: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials.

OBJECTIVE: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI).

METHODS: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences.

RESULTS: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aβ42/tau ratio indicative of AD (n = 340, AUC = 0.78, p <  0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC = 0.84, p <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects.

CONCLUSION: These findings support the interpretation of δ as a construct capturing the disease-related "essence" of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.

%B J Alzheimers Dis %V 49 %P 547-60 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484902?dopt=Abstract %R 10.3233/JAD-150257 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Late-Onset Metachromatic Leukodystrophy with Early Onset Dementia Associated with a Novel Missense Mutation in the Arylsulfatase A Gene. %A Stoeck, Katharina %A Psychogios, Marios Nikos %A Ohlenbusch, Andreas %A Steinfeld, Robert %A Schmidt, Jens %K Age of Onset %K Brain %K Cerebroside-Sulfatase %K Dementia %K Diagnosis, Differential %K DNA Mutational Analysis %K Exons %K Humans %K Leukodystrophy, Metachromatic %K Male %K Middle Aged %K Mutation, Missense %K Neuropsychological Tests %X

A 48-year-old male patient presented with personality changes and progressive memory loss over 2 years with initially suspected Hashimoto's encephalopathy. Strategy of diagnostic workup of early onset dementia included dementia from neurodegenerative, neuroinflammatory, metabolic/toxic, and psychiatric origin. The patient's neurological exam was normal. MRI revealed a leukencephalopathy, predominantly in the frontal periventricular white matter, without notable changes over 2 years. On neurophysiological examination, prolonged central conduction times and a sensorimotor polyneuropathy were noted. Neuropsychological impairment included disorientation in place and a reduced short time memory. Behavioral alterations were predominated by sudden mood changes and disinhibition. Cerebrospinal fluid was normal. Despite presence of thyroid autoantibodies, glucocorticosteroid treatment did not improve the dementia. A metachromatic leukodystrophy was diagnosed by decreased arylsulfatase-A activity in leucocytes/fibroblasts and identification of a compound heterozygous mutation in the ARSA gene: c.542T>G (exon 3) and the novel mutation c.1013T>C (exon 6). Pathogenic function was suggested by bioinformatic mutation search. In a patient with early onset dementia, strategic diagnostic workup including genetic assessment revealed an adult-onset metachromatic leukodystrophy with a novel mutation in the arylsulfatase A gene.

%B J Alzheimers Dis %V 51 %P 683-7 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890752?dopt=Abstract %R 10.3233/JAD-150819 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Less Daily Computer Use is Related to Smaller Hippocampal Volumes in Cognitively Intact Elderly. %A Silbert, Lisa C %A Dodge, Hiroko H %A Lahna, David %A Promjunyakul, Nutta-On %A Austin, Daniel %A Mattek, Nora %A Erten-Lyons, Deniz %A Kaye, Jeffrey A %X

BACKGROUND: Computer use is becoming a common activity in the daily life of older individuals and declines over time in those with mild cognitive impairment (MCI). The relationship between daily computer use (DCU) and imaging markers of neurodegeneration is unknown.

OBJECTIVE: The objective of this study was to examine the relationship between average DCU and volumetric markers of neurodegeneration on brain MRI.

METHODS: Cognitively intact volunteers enrolled in the Intelligent Systems for Assessing Aging Change study underwent MRI. Total in-home computer use per day was calculated using mouse movement detection and averaged over a one-month period surrounding the MRI. Spearman's rank order correlation (univariate analysis) and linear regression models (multivariate analysis) examined hippocampal, gray matter (GM), white matter hyperintensity (WMH), and ventricular cerebral spinal fluid (vCSF) volumes in relation to DCU. A voxel-based morphometry analysis identified relationships between regional GM density and DCU.

RESULTS: Twenty-seven cognitively intact participants used their computer for 51.3 minutes per day on average. Less DCU was associated with smaller hippocampal volumes (r = 0.48, p = 0.01), but not total GM, WMH, or vCSF volumes. After adjusting for age, education, and gender, less DCU remained associated with smaller hippocampal volume (p = 0.01). Voxel-wise analysis demonstrated that less daily computer use was associated with decreased GM density in the bilateral hippocampi and temporal lobes.

CONCLUSIONS: Less daily computer use is associated with smaller brain volume in regions that are integral to memory function and known to be involved early with Alzheimer's pathology and conversion to dementia. Continuous monitoring of daily computer use may detect signs of preclinical neurodegeneration in older individuals at risk for dementia.

%B J Alzheimers Dis %V 52 %P 713-7 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967228?dopt=Abstract %R 10.3233/JAD-160079 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation. %A Peters, Christian %A Sepúlveda, Fernando J %A Fernández-Pérez, Eduardo J %A Peoples, Robert W %A Aguayo, Luis G %X

Alzheimer's disease is a neurodegenerative disorder that affects mostly the elderly. The main histopathological markers are the senile plaques formed by amyloid-β peptide (Aβ) aggregates that can perforate the plasma membrane of cells, increasing the intracellular calcium levels and releasing synaptic vesicles that finally lead to a delayed synaptic failure. Several membrane proteins and lipids interact with Aβ affecting its toxicity in neurons. Here, we focus on NMDA receptors (NMDARs) as proteins that could be modulating the association and neurotoxic perforation induced by Aβ on the plasma membrane. In fact, our results showed that decreasing NMDARs, using enzymatic or siRNA approaches, increased the association of Aβ to the neurons. Furthermore, overexpression of NMDARs also resulted in an enhanced association between NMDA and Aβ. Functionally, the reduction in membrane NMDARs augmented the process of membrane perforation. On the other hand, overexpressing NMDARs had a protective effect because Aβ was now unable to cause membrane perforation, suggesting a complex relationship between Aβ and NMDARs. Because previous studies have recognized that Aβ oligomers are able to increase membrane permeability and produce amyloid pores, the present study supports the conclusion that NMDARs play a critical protective role on Aβ actions in hippocampal neurons. These results could explain the lack of correlation between brain Aβ burden and clinically observed dementia.

%B J Alzheimers Dis %V 53 %P 197-207 %8 2016 May 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163827?dopt=Abstract %R 10.3233/JAD-160170 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Lewy Bodies, Vascular Risk Factors, and Subcortical Arteriosclerotic Leukoencephalopathy, but not Alzheimer Pathology, are Associated with Development of Psychosis in Alzheimer's Disease. %A Fischer, Corinne E %A Qian, Winnie %A Schweizer, Tom A %A Millikin, Colleen P %A Ismail, Zahinoor %A Smith, Eric E %A Lix, Lisa M %A Shelton, Paul %A Munoz, David G %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition Disorders %K Databases, Factual %K Dementia, Vascular %K Female %K Hemorrhage %K Humans %K Lewy Bodies %K Male %K Middle Aged %K Psychiatric Status Rating Scales %K Psychotic Disorders %K Retrospective Studies %K Risk Factors %K Severity of Illness Index %K Surveys and Questionnaires %X

BACKGROUND: The neuropathological correlates of psychosis in Alzheimer's disease (AD) is unclear, with some studies reporting a correlation between psychosis and increased AD pathology while others have found no association.

OBJECTIVE: To determine the demographic, clinical, and neuropathological features associated with psychotic symptoms in clinically attributed and neuropathologically proven AD.

METHOD: We separately reviewed two overlapping groups of clinically diagnosed (cAD) AD patients with neuropathology data and neuropathologically definite (npAD) cases (regardless of clinical diagnosis) from the NACC database, and explored the relationships between psychosis and clinical variables, neuropathologic correlates, and vascular risk factors. Delusions and hallucinations, defined according to the NPI-Q, were analyzed separately.

RESULTS: 1,073 subjects in the database fulfilled our criteria (890 cAD and 728 npAD patients). 34% of cAD and 37% of npAD had psychotic symptoms during their illness. Hallucinations were associated with greater cognitive and functional impairments on the MMSE and CDR, while delusional patients showed less impairment on CDR, consistent across cAD and npAD groups. Burden of AD pathology appears to relate to presence of psychotic symptoms in the clinical AD group, but this result is not confirmed in the neuropathologically confirmed group suggesting the findings in the clinical group were due to misdiagnosis of AD. Lewy body pathology, subcortical arteriosclerotic leukoencephalopathy, and vascular risk factors, including a history of hypertension and diabetes, were associated with the development of psychosis.

METHOD: Vascular and Lewy body pathologies and vascular risk factors are important modifiers of the risk of psychosis in AD.

%B J Alzheimers Dis %V 50 %P 283-95 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682680?dopt=Abstract %R 10.3233/JAD-150606 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Lifelong Reading Disorder and Mild Cognitive Impairment: Implications for Diagnosis. %A Lebowitz, Brian K %A Weinstein, Cheryl %A Beiser, Alexa %A Seshadri, Sudha %A Wolf, Philip A %A Auerbach, Sandford %A Au, Rhoda %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Dyslexia %K Female %K Humans %K Independent Living %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Psychometrics %K Retrospective Studies %X

Although neuropsychological tests are commonly used in the evaluation of possible mild cognitive impairment (MCI), poor test scores may be indicative of factors other than neurological compromise. The current study assessed the role of lifelong reading disorder on MCI classification. Community dwelling older adults with a suspected developmental reading disorder were identified by inference based on reading test performance. Individuals with a suspected reading disorder were significantly more likely to perform at a level consistent with MCI on several commonly used neuropsychological tests. The findings suggest a relationship between a history of reading disorder and MCI classification.

%B J Alzheimers Dis %V 50 %P 41-5 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639959?dopt=Abstract %R 10.3233/JAD-150543 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Life's Simple 7's Cardiovascular Health Metrics are Associated with Hispanic/Latino Neurocognitive Function: HCHS/SOL Results. %A González, Hector M %A Tarraf, Wassim %A Gouskova, Natalia %A Rodríguez, Carlos J %A Rundek, Tatjana %A Grober, Ellen %A Pirzada, Amber %A González, Patricia %A Lutsey, Pamela L %A Camacho, Alvaro %A Daviglus, Martha L %A Wright, Clinton %A Mosley, Thomas H %X

BACKGROUND: Hispanics/Latinos are purportedly at increased risk for neurocognitive decline and dementias. Without dementia cures, low-cost, well-tolerated public health means for mitigating neurocognitive decline are needed.

OBJECTIVE: We examined associations between neurocognition and cardiovascular health (CVH) metrics (Life's Simple 7; LS7) among diverse Hispanics/Latinos. We hypothesized that higher LS7 would be associated with healthier brain function (neurocognitive performance).

METHODS: We used baseline (2008-2011) Hispanic Community Health Study/Study of Latinos (HCHS/SOL; N = 9,623; ages 45-74 years) to examine neurocognition in relation to CVH LS7 scores.

RESULTS: In age and sex adjusted models, a one unit LS7 score increase (range = 0-14) was associated with higher neurocognitive function on the B-SEVLT sum (0.23 [p < 0.01]; range = 3-42), B-SEVLT recall (0.12 [p < 0.01]; range = 0-15), Word Fluency (phonemic; 0.46 (p < 0.01); range = 0-49), and Digit Symbol Substitution (0.49 (p < 0.01); range = 0-83) tests, respectively. Stated differently, a change from the minimum LS7 (0) to maximum LS7 (14) score corresponded to higher scores on verbal learning (4.62) and memory (2.24), verbal fluency (7.0), and psychomotor processing speed (12). In fully adjusted models the associations were attenuated, but remained statistically significant. Incremental adjustments indicated that Latino background and, to a lesser extent, education were primary contributors to the evinced attenuations.

CONCLUSIONS: We found that higher neurocognitive function was associated with better LS7 CVH metrics among middle-aged and older Hispanics/Latinos. Associations between neurocognitive function and LS7 were strongest among two at-risk groups for neurocognitive decline and dementia, women and Hispanics/Latinos with lower education. Public health efforts to reduce cardiovascular disease morbidity and mortality may have additional neurocognitive benefits among at-risk Hispanics/Latinos.

%B J Alzheimers Dis %V 53 %P 955-65 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340845?dopt=Abstract %R 10.3233/JAD-151125 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Limiting Factors of Brain Donation in Neurodegenerative Diseases: The Example of French Memory Clinics. %A Le Bouc, Raphael %A Marelli, Cecilia %A Beaufils, Emilie %A Berr, Claudine %A Hommet, Caroline %A Touchon, Jacques %A Pasquier, Florence %A Deramecourt, Vincent %K Autopsy %K Brain %K France %K Health Knowledge, Attitudes, Practice %K Humans %K Neurodegenerative Diseases %K Physicians %K Retrospective Studies %X

Postmortem neuropathological examination of the brain is essential in neurodegenerative diseases, to ensure accurate diagnosis, to obtain an a posteriori critical assessment of the adequacy of clinical care, and to validate new biomarkers, but is only rarely performed. The purpose of this study was to assess factors limiting brain donation, such as reluctance of physicians to seek donation consent, opposition from patients and families, and organizational constraints. We conducted a survey across French memory clinics and major neuropathological centers. Few postmortem examinations were performed annually, as less than one third of the centers had performed at least five autopsies, and 41% had performed none. The main limiting factor was the lack of donation requests made by physicians, as half of them never approach patients for brain donation. Reasons for not seeking donation consent often include discomfort broaching the subject and lack of awareness of the medical and scientific benefit of postmortems (77%), organizational constraints (61%), and overestimation of families' negative reaction (51%). Family refusals represented a second major obstacle, and were often caused by misconceptions. Identifying and addressing these biases early could help improve physicians' rate of making requests and the public's awareness about the importance of brain donation.

%B J Alzheimers Dis %V 49 %P 1075-83 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26756326?dopt=Abstract %R 10.3233/JAD-150825 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Linguistic Features Identify Alzheimer's Disease in Narrative Speech. %A Fraser, Kathleen C %A Meltzer, Jed A %A Rudzicz, Frank %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Diagnosis, Computer-Assisted %K Factor Analysis, Statistical %K Female %K Humans %K Language Disorders %K Linguistics %K Logistic Models %K Machine Learning %K Male %K Mental Status Schedule %K Middle Aged %K Narration %K Photic Stimulation %K Speech %K Verbal Behavior %X

BACKGROUND: Although memory impairment is the main symptom of Alzheimer's disease (AD), language impairment can be an important marker. Relatively few studies of language in AD quantify the impairments in connected speech using computational techniques.

OBJECTIVE: We aim to demonstrate state-of-the-art accuracy in automatically identifying Alzheimer's disease from short narrative samples elicited with a picture description task, and to uncover the salient linguistic factors with a statistical factor analysis.

METHODS: Data are derived from the DementiaBank corpus, from which 167 patients diagnosed with "possible" or "probable" AD provide 240 narrative samples, and 97 controls provide an additional 233. We compute a number of linguistic variables from the transcripts, and acoustic variables from the associated audio files, and use these variables to train a machine learning classifier to distinguish between participants with AD and healthy controls. To examine the degree of heterogeneity of linguistic impairments in AD, we follow an exploratory factor analysis on these measures of speech and language with an oblique promax rotation, and provide interpretation for the resulting factors.

RESULTS: We obtain state-of-the-art classification accuracies of over 81% in distinguishing individuals with AD from those without based on short samples of their language on a picture description task. Four clear factors emerge: semantic impairment, acoustic abnormality, syntactic impairment, and information impairment.

CONCLUSION: Modern machine learning and linguistic analysis will be increasingly useful in assessment and clustering of suspected AD.

%B J Alzheimers Dis %V 49 %P 407-22 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484921?dopt=Abstract %R 10.3233/JAD-150520 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Living Alone with Dementia: Prevalence, Correlates and the Utilization of Health and Nursing Care Services. %A Eichler, Tilly %A Hoffmann, Wolfgang %A Hertel, Johannes %A Richter, Steffen %A Wucherer, Diana %A Michalowsky, Bernhard %A Dreier, Adina %A Thyrian, Jochen René %X

BACKGROUND: Little is known about the proportion and the characteristics of community-dwelling people with dementia (PWD) living alone in Germany.

OBJECTIVES: To analyze the prevalence of PWD living alone (with and without the support of an informal caregiver) and socio-demographical and clinical characteristics as well as health and nursing care utilization associated with living alone.

METHODS: DelpHi-MV (Dementia: Life- and person-centered help in Mecklenburg-Western Pomerania) is a general practitioner-based, randomized controlled intervention trial. The present analyses are based on baseline data of 511 patients (≥70 years, community-dwelling) who had screened positive for dementia (DemTect <9).

RESULTS: N = 251 (51%) of the patients lived alone. PWD living alone were statistically significantly more often female, older, and more often widowed than those not living alone. About 9% of the patients (n = 24) were not supported by any informal caregiver. Regarding the clinical variables (cognitive and functional impairment, depression, falls, number of drug-related problems, malnutrition, quality of life), there were no statistically significant group differences. Patients living alone utilized professional services such as home care, help with medication, home-delivered meals, or housekeeping assistance significantly more often. Multivariate analyses confirmed these findings.

CONCLUSION: Our results reveal the high proportion of PWD living alone in Germany. PWD living alone did not seem to be at an increased health risk. Our findings indicate that living alone with dementia is possible. In order to ensure the sufficient provision of health and nursing care services for PWD living alone, providers should consider the present results for future planning.

%B J Alzheimers Dis %V 52 %P 619-29 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031480?dopt=Abstract %R 10.3233/JAD-151058 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Alteration of Intrinsic Brain Activity in the Striatum in Mild Cognitive Impairment. %A Ren, Ping %A Lo, Raymond Y %A Chapman, Benjamin P %A Mapstone, Mark %A Porsteinsson, Anton %A Lin, Feng %X

The striatum is a critical functional hub in understanding neurological disorders. However, the Alzheimer's disease (AD)-associated striatal change is unclear, as is the relationship between striatal change and AD pathology. Three-year resting-state fMRI data from 15 healthy control (HC) and 20 mild cognitive impairment (MCI) participants were obtained. We analyzed the amplitude of low-frequency fluctuations (ALFF) (0.01-0.08 Hz) and two subdivided bands (slow-4:0.027-0.073 Hz; slow-5:0.01-0.027 Hz). We calculated Aβ/pTau ratio using baseline cerebrospinal fluid pTau and Aβ1-42 to represent AD pathology. Compared to HC, MCI participants showed greater decline in right putaminal ALFF, including the slow-4 band. Greater decline of ALFF in the right putamen was significantly related to the memory decline over time and lower baseline Aβ/pTau ratio regardless of age or group. The slow-4 band, relative to slow-5 band, showed a stronger correlation between Aβ/pTau ratio and decline of ALFF in the right putamen. The results suggest that the putaminal function declines early in the AD-associated neurodegeneration. The continuous decline in putaminal ALFF, especially slow-4 band, may be a sensitive marker of AD pathology such as Aβ/pTau ratio regardless of clinical diagnosis.

%B J Alzheimers Dis %V 54 %P 69-78 %8 2016 Jul 25 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472880?dopt=Abstract %R 10.3233/JAD-160368 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Longitudinal Association Between a Discrepancy Measure of Anosognosia in Patients with Dementia, Caregiver Burden and Depression. %A Perales, Jaime %A Turró-Garriga, Oriol %A Gascón-Bayarri, Jordi %A Reñé-Ramírez, Ramón %A Conde-Sala, Josep Lluís %X

BACKGROUND: According to cross-sectional studies, there is an association between anosognosia in people with dementia and caregiver's burden and depression. Anosognosia in patients may be a cause of caregiver burden and depression. However, variability in caregiver anosognosia ratings may exist as caregivers with burden and depression may have a more pessimistic view of the patients' health.

OBJECTIVE: To assess the variability of caregiver anosognosia ratings of patients with dementia using a widely used anosognosia scale and its longitudinal relationship with caregiver burden and depression.

METHODS: A convenience cohort of 221 consecutive dementia outpatient and caregiver dyads was followed up at 12 and 24 months. The main instruments used were the Anosognosia Questionnaire-Dementia (AQ-D), Caregiver Burden Interview, and Geriatric Depression Scale. Linear mixed models were used including time as a factor in every model. Multivariate analyses controlled for caregiver's socio-demographic and possible confounding factors.

RESULTS: Attrition at 12 and 24 months was 24.9% and 42.5% respectively. Patients at baseline were on average 77.8 years of age, 63.3% were women, and 63.3% had < 5 years of education. In the bivariate analyses, caregiver burden, depression, and gender were associated with caregiver ratings of total, cognitive, and personality AQ-D of the patient at different time points. Multivariate analyses revealed burden as the caregiver variable most consistently associated with total, cognitive, and personality caregiver AQ-D ratings of the patient.

CONCLUSION: Some caregiver characteristics, especially burden, are associated with caregiver ratings of AQ-D with regard to the patient.

%B J Alzheimers Dis %V 53 %P 1133-43 %8 2016 May 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258415?dopt=Abstract %R 10.3233/JAD-160065 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Changes in Functional Brain Connectivity Predicts Conversion to Alzheimer's Disease. %A Serra, Laura %A Cercignani, Mara %A Mastropasqua, Chiara %A Torso, Mario %A Spanò, Barbara %A Makovac, Elena %A Viola, Vanda %A Giulietti, Giovanni %A Marra, Camillo %A Caltagirone, Carlo %A Bozzali, Marco %K Aged %K Alzheimer Disease %K Atrophy %K Brain %K Brain Mapping %K Cognitive Dysfunction %K Cross-Sectional Studies %K Discriminant Analysis %K Disease Progression %K Female %K Follow-Up Studies %K Gray Matter %K Humans %K Image Processing, Computer-Assisted %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Neural Pathways %K Neuropsychological Tests %K Prognosis %K Rest %X

This longitudinal study investigates the modifications in structure and function occurring to typical Alzheimer's disease (AD) brains over a 2-year follow-up, from pre-dementia stages of disease, with the aim of identifying biomarkers of prognostic value. Thirty-one patients with amnestic mild cognitive impairment were recruited and followed-up with clinical, neuropsychological, and MRI assessments. Patients were retrospectively classified as AD Converters or Non-Converters, and the data compared between groups. Cross-sectional MRI data at baseline, assessing volume and functional connectivity abnormalities, confirmed previous findings, showing a more severe pattern of regional grey matter atrophy and default-mode network disconnection in Converters than in Non-Converters. Longitudinally, Converters showed more grey matter atrophy in the frontotemporal areas, accompanied by increased connectivity in the precuneus. Discriminant analysis revealed that functional connectivity of the precuneus within the default mode network at baseline is the parameter able to correctly classify patients in Converters and Non-Converters with high sensitivity, specificity, and accuracy.

%B J Alzheimers Dis %V 51 %P 377-89 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890769?dopt=Abstract %R 10.3233/JAD-150961 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Memory Profiles in Behavioral-Variant Frontotemporal Dementia and Alzheimer's Disease. %A Schubert, Samantha %A Leyton, Cristian E %A Hodges, John R %A Piguet, Olivier %K Alzheimer Disease %K Aniline Compounds %K Brain %K Diagnosis, Differential %K Disease Progression %K Executive Function %K Female %K Follow-Up Studies %K Frontotemporal Dementia %K Humans %K Longitudinal Studies %K Male %K Memory %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %K Radiopharmaceuticals %K Thiazoles %X

BACKGROUND: Alzheimer's disease (AD) and behavioral-variant of frontotemporal dementia (bvFTD) can present with an overlapping neuropsychological profile, which often hinders their clinical differentiation.

OBJECTIVE: To compare changes over time in memory, general cognition tasks, and functional scales between bvFTD and AD.

METHODS: Consecutive cases diagnosed with probable bvFTD (n = 22) and typical AD (n = 31) with at least two clinical visits were selected. Of these, 13 (9 AD, 4 bvFTD) underwent Pittsburgh compound B PET scan, which supported the clinical diagnosis in all cases. Mixed-model regressions were used to estimate the differential rate of decline on selected tasks between cohorts.

RESULTS: Analyses demonstrated that, despite equivalent baseline performance, bvFTD patients experienced a more rapid functional deterioration and a steeper decline in global cognition than AD patients. At baseline, both groups were impaired on executive function and memory tasks compared to controls, but these deficits were more marked in the bvFTD group. In addition, performance on these domains continued to decline more rapidly in this group.

CONCLUSIONS: Neither the initial neuropsychological assessment nor projected performances can reliably distinguish the totality of bvFTD and AD individuals. Nevertheless, annual rates of progression on cognitive tasks provide valuable information and will potentially help establish the impact of future therapeutic treatments in these dementia syndromes.

%B J Alzheimers Dis %V 51 %P 775-82 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890749?dopt=Abstract %R 10.3233/JAD-150802 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Protein Changes in Blood Plasma Associated with the Rate of Cognitive Decline in Alzheimer's Disease. %A Sattlecker, Martina %A Khondoker, Mizanur %A Proitsi, Petroula %A Williams, Stephen %A Soininen, Hilkka %A Kłoszewska, Iwona %A Mecocci, Patrizia %A Tsolaki, Magda %A Vellas, Bruno %A Lovestone, Simon %A Dobson, Richard Jb %K Aged %K Alzheimer Disease %K Biomarkers %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Mental Status Schedule %K Neuropsychological Tests %X

Biomarkers of Alzheimer's disease (AD) progression are needed to support the development of urgently needed disease modifying drugs. We employed a SOMAscan assay for quantifying 1,001 proteins in blood samples from 90 AD subjects, 37 stable mild cognitive impaired (MCI) subjects, 39 MCI subjects converting to AD within a year and 69 controls at baseline and one year follow up. We used linear mixed effects models to identify proteins changing significantly over one year with the rate of cognitive decline, which was quantified as the reduction in Mini Mental State Examination (MMSE) scores. Additionally, we investigated proteins changing differently across disease groups and during the conversion from MCI to AD. We found that levels of proteins belonging to the complement cascade increase significantly in fast declining AD patients. Longitudinal changes in the complement cascade might be a surrogate biomarker for disease progression. We also found that members of the cytokine-cytokine receptor interaction pathway change during AD when compared to healthy aging subjects.

%B J Alzheimers Dis %V 49 %P 1105-14 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599049?dopt=Abstract %R 10.3233/JAD-140669 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Relationships between Caloric Expenditure and Gray Matter in the Cardiovascular Health Study. %A Raji, Cyrus A %A Merrill, David A %A Eyre, Harris %A Mallam, Sravya %A Torosyan, Nare %A Erickson, Kirk I %A Lopez, Oscar L %A Becker, James T %A Carmichael, Owen T %A Gach, H Michael %A Thompson, Paul M %A Longstreth, W T %A Kuller, Lewis H %X

BACKGROUND: Physical activity (PA) can be neuroprotective and reduce the risk for Alzheimer's disease (AD). In assessing physical activity, caloric expenditure is a proxy marker reflecting the sum total of multiple physical activity types conducted by an individual.

OBJECTIVE: To assess caloric expenditure, as a proxy marker of PA, as a predictive measure of gray matter (GM) volumes in the normal and cognitively impaired elderly persons.

METHODS: All subjects in this study were recruited from the Institutional Review Board approved Cardiovascular Health Study (CHS), a multisite population-based longitudinal study in persons aged 65 and older. We analyzed a sub-sample of CHS participants 876 subjects (mean age 78.3, 57.5% F, 42.5% M) who had i) energy output assessed as kilocalories (kcal) per week using the standardized Minnesota Leisure-Time Activities questionnaire, ii) cognitive assessments for clinical classification of normal cognition, mild cognitive impairment (MCI), and AD, and iii) volumetric MR imaging of the brain. Voxel-based morphometry modeled the relationship between kcal/week and GM volumes while accounting for standard covariates including head size, age, sex, white matter hyperintensity lesions, MCI or AD status, and site. Multiple comparisons were controlled using a False Discovery Rate of 5 percent.

RESULTS: Higher energy output, from a variety of physical activity types, was associated with larger GM volumes in frontal, temporal, and parietal lobes, as well as hippocampus, thalamus, and basal ganglia. High levels of caloric expenditure moderated neurodegeneration-associated volume loss in the precuneus, posterior cingulate, and cerebellar vermis.

CONCLUSION: Increasing energy output from a variety of physical activities is related to larger gray matter volumes in the elderly, regardless of cognitive status.

%B J Alzheimers Dis %V 52 %P 719-29 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967227?dopt=Abstract %R 10.3233/JAD-160057 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Study of Impaired Intra- and Inter-Network Brain Connectivity in Subjects at High Risk for Alzheimer's Disease. %A Zhan, Yafeng %A Ma, Jianhua %A Alexander-Bloch, Aaron F %A Xu, Kaibin %A Cui, Yue %A Feng, Qianjin %A Jiang, Tianzi %A Liu, Yong %X

Alzheimer's disease (AD) is associated with abnormal resting-state network (RSN) architecture of the default mode network (DMN), the dorsal attention network (DAN), the executive control network (CON), the salience network (SAL), and the sensory-motor network (SMN). However, little is known about the disrupted intra- and inter-network architecture in mild cognitive impairment (MCI). Here, we employed a priori defined regions of interest to investigate the intra- and inter-network functional connectivity profiles of these RSNs in longitudinal participants, including normal controls (n = 23), participants with early MCI (n = 26), and participants with late MCI (n = 19). We found longitudinal alterations of functional connectivity within the DMN, where they were correlated with variation in cognitive ability. The SAL as well as the interaction between the DMN and the SAL were disrupted in MCI. Furthermore, our results demonstrate that longitudinal alterations of functional connectivity are more profound in earlier stages as opposed to later stages of the disease. The increased severity of cognitive impairment is associated with increasingly altered RSN connectivity patterns, suggesting that disruptions in functional connectivity may contribute to cognitive dysfunction and may represent a potential biomarker of impaired cognitive ability in MCI. Earlier prevention and treatment may help to delay disease progression to AD.

%B J Alzheimers Dis %V 52 %P 913-27 %8 2016 Apr 05 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060962?dopt=Abstract %R 10.3233/JAD-160008 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Looking for Measures of Disease Severity in the Frontotemporal Dementia Continuum. %A Premi, Enrico %A Gualeni, Vera %A Costa, Paolo %A Cosseddu, Maura %A Gasparotti, Roberto %A Padovani, Alessandro %A Borroni, Barbara %X

Frontotemporal dementia (FTD) is characterized by executive dysfunctions, behavioral disturbances, language deficits and extrapyramidal symptoms. Frontotemporal lobar degeneration-modified Clinical Dementia Rating Scale (FTLD modified-CDR) has been proposed to measure disease severity in behavioral variant FTD (bvFTD). No tools of global disease severity are available in the other FTLD phenotypes [primary progressive aphasias (PPAs), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS)]. This would be strategic as outcome measures in clinical trials. To this aim, we evaluated the association between brain volume (voxel based morphometry) and available clinical scales in FTD. In 176 FTD patients (64 bvFTD, 40 PPAs, 32 PSP, 40 CBS), instrumental activities of daily living (ADLs), FTLD-modified CDR, Mini-Mental State Examination (MMSE), Frontal Behavioral Inventory (FBI), and Neuropsychiatry Inventory (NPI) were administered and MRI performed. Whole-brain linear correlation between each clinical rating scale and brain volume was performed. In bvFTD and PPAs, FTLD-modified CDR was associated with regional brain volume, thereby providing evidence for validity of the FTLD-modified CDR. In PSP, none of the clinical indicators were associated with regional brain volume. In CBS, ADLs and MMSE correlated with frontotemporal lower volume. Considering monogenic disease, FTLD-modified CDR was the best measure. In FTD continuum, different measures able to correlate with brain damage should be considered for the different clinical phenotypes or genetic traits.

%B J Alzheimers Dis %V 52 %P 1227-35 %8 2016 Apr 16 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104906?dopt=Abstract %R 10.3233/JAD-160178 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Looking for Neuroimaging Markers in Frontotemporal Lobar Degeneration Clinical Trials: A Multi-Voxel Pattern Analysis Study in Granulin Disease. %A Premi, Enrico %A Cauda, Franco %A Costa, Tommaso %A Diano, Matteo %A Gazzina, Stefano %A Gualeni, Vera %A Alberici, Antonella %A Archetti, Silvana %A Magoni, Mauro %A Gasparotti, Roberto %A Padovani, Alessandro %A Borroni, Barbara %K Adult %K Aged %K Brain %K Brain Mapping %K Cohort Studies %K Female %K Frontotemporal Lobar Degeneration %K Humans %K Image Processing, Computer-Assisted %K Intercellular Signaling Peptides and Proteins %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Mutation %K Neural Pathways %K Oxygen %K Phenylalanine %K Threonine %X

In light of future pharmacological interventions, neuroimaging markers able to assess the response to treatment would be crucial. In Granulin (GRN) disease, preclinical data will prompt pharmacological trials in the future. Two main points need to be assessed: (1) to identify target regions in different disease stages and (2) to determine the most accurate functional and structural neuroimaging index to be used. To this aim, we have taken advantage of the multivariate approach of multi-voxel pattern analysis (MVPA) to explore the information of brain activity patterns in a cohort of GRN Thr272fs carriers at different disease stages (14 frontotemporal dementia (FTD) patients and 17 asymptomatic carriers) and a group of 33 healthy controls. We studied structural changes by voxel-based morphometry (VBM), functional connectivity by assessing salience, default mode, fronto-parietal, dorsal attentional, executive networks, and local connectivity by regional homogeneity, amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), degree centrality, and voxel-mirrored homotopic connectivity. In FTD patients with GRN mutation, the most predictive measure was VBM structural analysis, while in asymptomatic carriers the best predictor marker was the local connectivity measure (fALFF). Altogether, all indexes demonstrated fronto-temporo-parietal damage in GRN pathology, with widespread structural damage of fronto-parietal and temporal regions when disease is overt. MVPA could be of aid in identifying the most accurate neuroimaging marker for clinical trials. This approach was able to identify both the target region and the best neuroimaging approach, which would be specific in the different disease stages. Further studies are needed to simultaneously integrate multimodal indexes in a classifier able to trace the disease progression moving from preclinical to clinical stage of the disease.

%B J Alzheimers Dis %V 51 %P 249-62 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836150?dopt=Abstract %R 10.3233/JAD-150340 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Low Plasma Cholinesterase Activities are Associated with Deficits in Spatial Orientation, Reduced Ability to Perform Basic Activities of Daily Living, and Low Body Mass Index in Patients with Progressed Alzheimer's Disease. %A Dingova, Dominika %A Fazekas, Tomas %A Okuliarova, Petra %A Strbova, Jaroslava %A Kucera, Matej %A Hrabovska, Anna %K Acetylcholinesterase %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Blood Chemical Analysis %K Body Mass Index %K Butyrylcholinesterase %K Female %K Hospitalization %K Humans %K Male %K Middle Aged %K Orientation, Spatial %X

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by a central cholinergic deficit. Non-neuronal cholinergic changes are, however, described as well. Here we focused on possible changes in the activity of the plasma cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), in hospitalized AD patients. We analyzed plasma AChE and BChE activities with regards to age, gender, body mass index (BMI), cognitive functions, and ability to perform activities of daily living in AD patients in comparison to healthy subjects. We observed lower AChE activity and trend toward lower BChE activity in AD patients, which both correlated with low BMI. AD patients unable to perform basic activities of daily living (feeding, bathing, dressing, and grooming) showed reduced plasma AChE activities, while worse spatial orientation was linked to lower BChE activities. Three out of four AD patients with the lowest BChE activities died within one year. In conclusion, progressed AD was accompanied by lower plasma AChE activity and trend toward lower BChE activity, which correlated with BMI and deficits in different components of the AD.

%B J Alzheimers Dis %V 51 %P 801-13 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890780?dopt=Abstract %R 10.3233/JAD-151060 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Low Prevalence of Mixed Dementia in a Cohort of 2,000 Elderly Patients in a Memory Clinic Setting. %A Claus, Jules J %A Staekenborg, Salka S %A Roorda, Jelmen J %A Stevens, Martijn %A Herderschee, Dirk %A van Maarschalkerweerd, Willy %A Schuurmans, Lilly %A Tielkes, Caroline E M %A Koster, Pieter %A Bavinck, Chris %A Scheltens, Philip %K Age Factors %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cognitive Dysfunction %K Cohort Studies %K Dementia %K Female %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Prevalence %K Regression Analysis %K Risk Factors %K Tomography Scanners, X-Ray Computed %X

BACKGROUND: It is generally assumed that with increasing age, pathology in clinically diagnosed Alzheimer's disease (AD) becomes more mixed, i.e., co-existence of amyloid plaques and cerebrovascular pathology.

OBJECTIVE: To test the hypothesis of increasing prevalence of mixed dementia in late-onset clinically diagnosed Alzheimer's disease (AD) in a single-center memory clinic population.

METHODS: Patients included had diagnoses of AD (n = 832), subjective cognitive impairment (SCI, n = 333), mild cognitive impairment (MCI, n = 492), vascular dementia (VaD, n = 57), other dementia (n = 53), or other diagnosis (n = 233). Prevalence of severe white matter lesions (WML) was defined as a score of 2 or higher on the Fazekas-scale on brain computed tomography to classify AD patients as having mixed dementia. We examined the effect of age on WML using multiple linear regression analysis, and AD patients were compared to SCI to determine the effect of disease on WML.

RESULTS: Prevalence of severe WML was 33.6% in AD patients (mixed dementia), 11.4% in SCI, 22.7% in MCI, 75.4% in VaD, 3.8% in other dementia, and 15.5% in other diagnosis. With increasing age there was a significant and similar increase of WML scores in SCI, MCI, AD, other dementia, and other diagnosis, indicating no effect modification by AD. The difference between AD patients and SCI averaged 0.16 on the WML score and difference in percentage severe WML between AD and SCI patients was 15% across all ages.

CONCLUSION: We found a low prevalence of mixed dementia. Furthermore, severe WML in AD was largely explained by age rather than effect of disease.

%B J Alzheimers Dis %V 50 %P 797-806 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757192?dopt=Abstract %R 10.3233/JAD-150796 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Low Serum Insulin-Like Growth Factor-I Predicts Cognitive Decline in Alzheimer's Disease. %A Vidal, Jean-Sébastien %A Hanon, Olivier %A Funalot, Benoît %A Brunel, Nadège %A Viollet, Cécile %A Rigaud, Anne-Sophie %A Seux, Marie-Laure %A le-Bouc, Yves %A Epelbaum, Jacques %A Duron, Emmanuelle %X

BACKGROUND: The relationship between the insulin-like growth factor-I (IGF-I) system and Alzheimer's disease (AD) is mostly based on transversal studies. It remains, however, to demonstrate whether IGF-I is associated with cognitive decline over time in AD.

OBJECTIVE: The objective of the study was to analyze the course of cognitive decline of AD subjects over a 24-month period in relation to serum IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) measured at baseline.

METHODS: Data are from the SIGAL follow-up study. IGF-I and IGFBP-3 were measured in AD subjects who performed a Mini-Mental State Examination (MMSE) every 6 months for 2 years. MMSE course was analyzed using a mixed model with random intercept and slope function.

RESULTS: Among the 200 AD participants, 146 (mean age = 81.1 (standard deviation (SD) = 5.9) years, 62.6% of women) had at least one follow-up visit. Mean IGF-I at baseline was 147.8 (74.2) ng/mL. Hundred forty-six participants (62.6%) had at least one follow-up visit. Mean MMSE was 21.7 (4.7)/30 and dropped on average by 2.28 points per year. MMSE decline was steeper among participants with lower IGF-I. For each decrease of 1 SD of IGF-I, subjects lost an additional 0.63 points per year in MMSE, e.g., participants with IGF-I level of 74 ng/mL lost 2.91 MMSE points per year whereas participants with IGF-I of 222 ng/mL lost 1.65 MMSE points per year. There was no association between IGFBP-3 and cognitive decline.

CONCLUSION: Lower baseline serum IGF-I was associated with faster cognitive decline in AD over a 2-year period.

%B J Alzheimers Dis %V 52 %P 641-9 %8 2016 Mar 29 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031487?dopt=Abstract %R 10.3233/JAD-151162 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Lower Late-Life Body-Mass Index is Associated with Higher Cortical Amyloid Burden in Clinically Normal Elderly. %A Hsu, David C %A Mormino, Elizabeth C %A Schultz, Aaron P %A Amariglio, Rebecca E %A Donovan, Nancy J %A Rentz, Dorene M %A Johnson, Keith A %A Sperling, Reisa A %A Marshall, Gad A %X

BACKGROUND: Lower body-mass index (BMI) in late life has been associated with an increased risk of dementia, and weight loss has been associated with more rapid decline in Alzheimer's disease (AD) dementia.

OBJECTIVE: To explore the association between BMI and cortical amyloid burden in clinically normal (CN) elderly at risk for AD dementia.

METHODS: Cross-sectional analyses were completed using baseline data from the Harvard Aging Brain Study, consisting of 280 community-dwelling CN older adults aged 62-90. Assessments included medical histories and physical exam, Pittsburgh compound B (PiB) positron emission tomography (PET) amyloid imaging, and apolipoprotein E ɛ4 (APOE4) genotyping. For the primary analysis, a general linear regression model was used to evaluate the association of BMI with PiB retention. Covariates included age, sex, years of education, and APOE4 carrier status. Secondary analyses were performed for BMI subdivisions (normal, overweight, obese), APOE4 carriers, and BMI×APOE4 interaction.

RESULTS: In the primary analysis, greater PiB retention was associated with lower BMI (β  =  -0.14, p = 0.02). In the secondary analyses, APOE4 carrier status (β= -0.27, p = 0.02) and normal BMI (β= -0.25, p = 0.01), as opposed to overweight or obese BMI, were associated with greater PiB retention. The BMI×APOE4 interaction was also significant (β= -0.14, p = 0.04).

CONCLUSIONS: This finding offers new insight into the role of BMI at the preclinical stage of AD, wherein lower BMI late in life is associated with greater cortical amyloid burden. Future studies are needed to elucidate the mechanism behind this association, especially in those with lower BMI who are APOE4 carriers.

%B J Alzheimers Dis %V 53 %P 1097-105 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340843?dopt=Abstract %R 10.3233/JAD-150987 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Lower Prevalence of Alzheimer's Disease among Tibetans: Association with Religious and Genetic Factors. %A Huang, Fukai %A Shang, Ying %A Luo, Yuandai %A Wu, Peng %A Huang, Xue %A Tan, Xiaohui %A Lu, Xingyi %A Zhen, Lifang %A Hu, Xianda %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Clusterin %K Cognition Disorders %K Cross-Sectional Studies %K Female %K Genetic Association Studies %K Genetic Predisposition to Disease %K Humans %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Polymorphism, Single Nucleotide %K Psychiatric Status Rating Scales %K Religion %K Risk Factors %K Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization %K Tibet %X

BACKGROUND: The prevalence of dementia differs among racial groups, the highest prevalence being in Latin America (8.5%) compared to sub-Saharan African regions (2-4%). The most common type of dementia is Alzheimer's disease (AD).

OBJECTIVE: To estimate the prevalence of AD in the Qinghai-Tibet plateau and to investigate the related factors.

METHODS: This was a cross-sectional, multistage cluster sampling design survey. Data was collected from May 2014 to September 2014 from 4,060 Tibetan aged >60 years. Participants underwent clinical examinations and neuropsychological evaluations. MALDI-TOF was used to test the genotypes of CLU, TFAM, TP53INP1, IGHV1-67, CR1, ApoE, and BIN1. Logistic regression models were used to ascertain the associations with AD.

RESULTS: The prevalence of AD among Tibetan individuals aged >60 years was 1.33% (95% CI: 0.98-1.69). The CLU haplotypes AA+GA (odds ratio (OR) = 4.483; 95% CI: 1.069-18.792) of rs2279590 was correlated with AD. The CLU haplotypes GG+GC (OR = 0.184; 95% CI: 0.038-0.888) of rs9331888 and kowtow (OR = 0.203; 95% CI 0.046-0.896) were negatively correlated with AD.

CONCLUSION: A low prevalence of AD was found in Tibetans from the Qinghai-Tibet plateau. Multivariate analysis might suggest that regular "mind-body" religious meditative activities may be negatively associated with AD in this population, as well as the CLU genotype at rs9331888.

%B J Alzheimers Dis %V 50 %P 659-67 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757186?dopt=Abstract %R 10.3233/JAD-150697 %0 Journal Article %J J Alzheimers Dis %D 2016 %T LRP/LR Antibody Mediated Rescuing of Amyloid-β-Induced Cytotoxicity is Dependent on PrPc in Alzheimer's Disease. %A Pinnock, Emma C %A Jovanovic, Katarina %A Pinto, Maxine G %A Ferreira, Eloise %A Dias, Bianca Da Costa %A Penny, Clement %A Knackmuss, Stefan %A Reusch, Uwe %A Little, Melvyn %A Schatzl, Hermann M %A Weiss, Stefan F T %K Amyloid beta-Peptides %K Animals %K Antibodies %K Cell Line, Transformed %K Cell Survival %K Flow Cytometry %K Gene Expression Regulation %K Humans %K Mice %K Peptide Fragments %K Prions %K Receptors, Laminin %K Transfection %X

The neuronal perturbations in Alzheimer's disease are attributed to the formation of extracellular amyloid-β (Aβ) neuritic plaques, composed predominantly of the neurotoxic Aβ42 isoform. Although the plaques have demonstrated a role in synaptic dysfunction, neuronal cytotoxicity has been attributed to soluble Aβ42 oligomers. The 37kDa/67kDa laminin receptor has been implicated in Aβ42 shedding and Aβ42-induced neuronal cytotoxicity, as well as internalization of this neurotoxic peptide. As the cellular prion protein binds to both LRP/LR and Aβ42, the mechanism underlying this cytotoxicity may be indirectly due to the PrPc-Aβ42 interaction with LRP/LR. The effects of this interaction were investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assays. PrPc overexpression significantly enhanced Aβ42 cytotoxicity in vitro, while PrP-/-  cells were more resistant to the cytotoxic effects of Aβ42 and exhibited significantly less cell death than PrPc expressing N2a cells. Although anti-LRP/LR specific antibody IgG1-iS18 significantly enhanced cell viability in both pSFV1-huPrP1-253 transfected and non-transfected cells treated with exogenous Aβ42, it failed to have any cell rescuing effect in PrP-/-  HpL3-4 cells. These results suggest that LRP/LR plays a significant role in Aβ42-PrPc mediated cytotoxicity and that anti-LRP/LR specific antibodies may serve as potential therapeutic tools for Alzheimer's disease.

%B J Alzheimers Dis %V 49 %P 645-57 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484914?dopt=Abstract %R 10.3233/JAD-150482 %0 Journal Article %J J Alzheimers Dis %D 2016 %T M2 Macrophage Transplantation Ameliorates Cognitive Dysfunction in Amyloid-β-Treated Rats Through Regulation of Microglial Polarization. %A Zhu, Dan %A Yang, Nan %A Liu, Yan-Yong %A Zheng, Ji %A Ji, Chao %A Zuo, Ping-Ping %X

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly population. Neuroinflammation induced by amyloid-β (Aβ) aggregation is considered to be the critical factor underlying AD pathological mechanisms. Alternatively activated (M2) macrophages/microglia have been reported to have neuroprotective effects in neurodegenerative disease. In this study, we characterized the neuroprotective effects of M2 macrophage transplantation in AD model rats and investigated the underlying mechanisms. Intracerebroventricular injection of Aβ1 - 42 to rats was used to model AD and resulted in cognitive impairment, neuronal damage, and inflammatory changes in the brain microenvironment. We observed an increased interferon regulatory factor (IRF) 5/IRF4 ratio, resulting in greater production of classically activated (M1) versus M2 microglia. M2 macrophage transplantation attenuated inflammation in the brain, reversed Aβ1 - 42-induced changes in the IRF4-IRF5 ratio, drove endogenous microglial polarization toward the M2 phenotype, and ameliorated cognitive impairment. Nerve growth factor (NGF) treatment reduced the IRF5/IRF4 ratio and induced primary microglial polarization to the M2 phenotype in vitro; these effects were prevented by tyrosine Kinase Receptor A (TrkA) inhibition. M2 macrophage transplantation restored the balance of IRF4-IRF5 by affecting the expression of NGF and inflammatory cytokines in the brains of AD model rats. This drove microglial polarization to the M2 phenotype, promoted termination of neuroinflammation, and resulted in improved cognitive abilities.

%B J Alzheimers Dis %V 52 %P 483-95 %8 2016 03 16 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003214?dopt=Abstract %R 10.3233/JAD-151090 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Maintenance of Cognitive Performance and Mood for Individuals with Alzheimer's Disease Following Consumption of a Nutraceutical Formulation: A One-Year, Open-Label Study. %A Remington, Ruth %A Bechtel, Cynthia %A Larsen, David %A Samar, Annemarie %A Page, Robert %A Morrell, Christopher %A Shea, Thomas B %K Aged %K Aged, 80 and over %K alpha-Tocopherol %K Alzheimer Disease %K Cognition Disorders %K Dietary Supplements %K Disease Progression %K Female %K Folic Acid %K Follow-Up Studies %K Humans %K Male %K Mood Disorders %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Time Factors %K Vitamin B 12 %X

Nutritional interventions have shown varied efficacy on cognitive performance during Alzheimer's disease (AD). Twenty-four individuals diagnosed with AD received a nutraceutical formulation (NF: folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) under open-label conditions (ClinicalTrials.gov NCT01320527). Primary outcome was cognitive performance. Secondary outcomes were behavioral and psychological symptoms of dementia (BPSD) and activities of daily living. Participants maintained their baseline cognitive performance and BPSD over 12 months. These findings are consistent with improvement in cognitive performance and BPSD in prior placebo-controlled studies with NF, and contrast with the routine decline for participants receiving placebo.

%B J Alzheimers Dis %V 51 %P 991-5 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967219?dopt=Abstract %R 10.3233/JAD-151098 %0 Journal Article %J J Alzheimers Dis %D 2016 %T MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium. %A Pastor, Pau %A Moreno, Fermín %A Clarimón, Jordi %A Ruiz, Agustin %A Combarros, Onofre %A Calero, Miguel %A López de Munain, Adolfo %A Bullido, Maria J %A de Pancorbo, Marian M %A Carro, Eva %A Antonell, Anna %A Coto, Eliecer %A Ortega-Cubero, Sara %A Hernandez, Isabel %A Tárraga, Lluís %A Boada, Merce %A Lleo, Alberto %A Dols-Icardo, Oriol %A Kulisevsky, Jaime %A Vázquez-Higuera, José Luis %A Infante, Jon %A Rábano, Alberto %A Fernández-Blázquez, Miguel Ángel %A Valentí, Meritxell %A Indakoetxea, Begoña %A Barandiarán, Myriam %A Gorostidi, Ana %A Frank-García, Ana %A Sastre, Isabel %A Lorenzo, Elena %A Pastor, María A %A Elcoroaristizabal, Xabier %A Lennarz, Martina %A Maier, Wolfang %A Rámirez, Alfredo %A Serrano-Ríos, Manuel %A Lee, Suzee E %A Sánchez-Juan, Pascual %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Female %K Frontotemporal Dementia %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Logistic Models %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Spain %K tau Proteins %X

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.

%B J Alzheimers Dis %V 49 %P 343-52 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444794?dopt=Abstract %R 10.3233/JAD-150555 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Matrix Metalloproteinase in Blood-Brain Barrier Breakdown in Dementia. %A Weekman, Erica M %A Wilcock, Donna M %K Animals %K Blood-Brain Barrier %K Dementia %K Humans %K Matrix Metalloproteinase 2 %K Matrix Metalloproteinase 9 %X

The neurovascular unit, which consists of astrocytic end-feet, neurons, pericytes, and endothelial cells, plays a key role in maintaining brain homeostasis by forming the blood-brain barrier and carefully controlling local cerebral blood flow. When the blood-brain barrier is disrupted, blood components can leak into the brain, damage the surrounding tissue and lead to cognitive impairment. This disruption in the blood-brain barrier and subsequent impairment in cognition are common after stroke and during cerebral amyloid angiopathy and Alzheimer's disease. Matrix metalloproteinases are proteases that degrade the extracellular matrix as well as tight junctions between endothelial cells and have been implicated in blood-brain barrier breakdown in neurodegenerative diseases. This review will focus on the roles of MMP2 and MMP9 in dementia, primarily post-stroke events that lead to dementia, cerebral amyloid angiopathy, and Alzheimer's disease.

%B J Alzheimers Dis %V 49 %P 893-903 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599057?dopt=Abstract %R 10.3233/JAD-150759 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Measurement Error, Reliability, and Minimum Detectable Change in the Mini-Mental State Examination, Montreal Cognitive Assessment, and Color Trails Test among Community Living Middle-Aged and Older Adults. %A Feeney, Joanne %A Savva, George M %A O'Regan, Claire %A King-Kallimanis, Bellinda %A Cronin, Hilary %A Kenny, Rose Anne %X

BACKGROUND: Knowing the reliability of cognitive tests, particularly those commonly used in clinical practice, is important in order to interpret the clinical significance of a change in performance or a low score on a single test.

OBJECTIVE: To report the intra-class correlation (ICC), standard error of measurement (SEM) and minimum detectable change (MDC) for the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Color Trails Test (CTT) among community dwelling older adults.

METHODS: 130 participants aged 55 and older without severe cognitive impairment underwent two cognitive assessments between two and four months apart. Half the group changed rater between assessments and half changed time of day.

RESULTS: Mean (standard deviation) MMSE was 28.1 (2.1) at baseline and 28.4 (2.1) at repeat. Mean (SD) MoCA increased from 24.8 (3.6) to 25.2 (3.6). There was a rater effect on CTT, but not on the MMSE or MoCA. The SEM of the MMSE was 1.0, leading to an MDC (based on a 95% confidence interval) of 3 points. The SEM of the MoCA was 1.5, implying an MDC95 of 4 points. MoCA (ICC = 0.81) was more reliable than MMSE (ICC = 0.75), but all tests examined showed substantial within-patient variation.

CONCLUSION: An individual's score would have to change by greater than or equal to 3 points on the MMSE and 4 points on the MoCA for the rater to be confident that the change was not due to measurement error. This has important implications for epidemiologists and clinicians in dementia screening and diagnosis.

%B J Alzheimers Dis %V 53 %P 1107-14 %8 2016 May 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258421?dopt=Abstract %R 10.3233/JAD-160248 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Measuring Information Processing Speed in Mild Cognitive Impairment: Clinical Versus Research Dichotomy. %A Haworth, Judy %A Phillips, Michelle %A Newson, Margaret %A Rogers, Peter J %A Torrens-Burton, Anna %A Tales, Andrea %K Aged %K Aged, 80 and over %K Attention %K Cognitive Dysfunction %K Electroencephalography %K Female %K Humans %K Male %K Mental Processes %K Mental Status Schedule %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Photic Stimulation %K Reaction Time %K Residence Characteristics %X

A substantial body of research evidence is indicative of disproportionately slowed information processing speed in a wide range of multi-trial, computer-based, neuroimaging- and electroencephalography-based reaction time (RT) tests in Alzheimer's disease and mild cognitive impairment (MCI). However, in what is arguably a dichotomy between research evidence and clinical practice, RT associated with different brain functions is rarely assessed as part of their diagnosis. Indeed, often only the time taken to perform a single, specific task, commonly the Trail making test (TMT), is measured. In clinical practice therefore, there can be a failure to assess adequately the integrity of the rapid, serial information processing and response, necessary for efficient, appropriate, and safe interaction with the environment. We examined whether a typical research-based RT task could at least match the TMT in differentiating amnestic MCI (aMCI) from cognitively healthy aging at group level. As aMCI is a heterogeneous group, typically containing only a proportion of individuals for whom aMCI represents the early stages of dementia, we examined the ability of each test to provide intra-group performance variation. The results indicate that as well as significant slowing in performance of the operations involved in TMT part B (but not part A), individuals with aMCI also experience significant slowing in RT compared to controls. The results also suggest that research-typical RT tests may be superior to the TMT in differentiating between cognitively healthy aging and aMCI at group level and in revealing the performance variability one would expect from an etiologically heterogeneous disorder such as aMCI.

%B J Alzheimers Dis %V 51 %P 263-75 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836171?dopt=Abstract %R 10.3233/JAD-150791 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Mechanism Underlying Amyloid Polymorphism is Opened for Alzheimer's Disease Amyloid-β Peptide. %A Selivanova, Olga M %A Surin, Alexey K %A Marchenkov, Victor V %A Dzhus, Ulyana F %A Grigorashvili, Elizaveta I %A Suvorina, Mariya Yu %A Glyakina, Anna V %A Dovidchenko, Nikita V %A Galzitskaya, Oxana V %X

It has been demonstrated using Aβ40 and Aβ42 recombinant and synthetic peptides that their fibrils are formed of complete oligomer ring structures. Such ring structures have a diameter of about 8-9 nm, an oligomer height of about 2- 4 nm, and an internal diameter of the ring of about 3-4 nm. Oligomers associate in a fibril in such a way that they interact with each other, overlapping slightly. There are differences in the packing of oligomers in fibrils of recombinant and synthetic Aβ peptides. The principal difference is in the degree of orderliness of ring-like oligomers that leads to generation of morphologically different fibrils. Most ordered association of ring-like structured oligomers is observed for a recombinant Aβ40 peptide. Less ordered fibrils are observed with the synthetic Aβ42 peptide. Fragments of fibrils the most protected from the action of proteases have been determined by tandem mass spectrometry. It was shown that unlike Aβ40, fibrils of Aβ42 are more protected, showing less ordered organization compared to that of Aβ40 fibrils. Thus, the mass spectrometry data agree with the electron microscopy data and structural models presented here.

%B J Alzheimers Dis %V 54 %P 821-30 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567850?dopt=Abstract %R 10.3233/JAD-160405 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Memory Binding Test: Development of Two Alternate Forms into Spanish and Catalan. %A Gramunt, Nina %A Sánchez-Benavides, Gonzalo %A Buschke, Herman %A Diéguez-Vide, Faustino %A Peña-Casanova, Jordi %A Masramon, Xavier %A Fauria, Karine %A Gispert, Juan D %A Molinuevo, José L %X

BACKGROUND: The Memory Binding Test (MBT) is emerging as a promising tool for the detection of subtle memory impairment suggestive of Alzheimer's disease (AD). For such a test to be widely accessed and used, the availability of both alternate forms and language adaptations is required.

OBJECTIVES: To develop a thorough methodology for obtaining alternate forms (A and B) of the MBT in Spanish and Catalan and to assess their equivalence.

METHOD: According to the original development of the test, frequency was taken as the lexical variable of reference for the Spanish and Catalan adaptations. A crossed design protocol by form and language was used to compare the MBT results in a sample of 290 cognitively normal middle-aged participants. Pairwise Intraclass Correlation Coefficients (ICCs) were calculated among the six possible combinations.

RESULTS: The Spanish and Catalan lists of words for the MBT A and B resulting from the adaptation process as well as the original lists in English are presented. ICC indices for the comparisons between forms and languages ranged from 0.56 to 0.82.

CONCLUSION: The MBT A and B in Spanish and Catalan showed similar outcomes and can be considered equivalent. Moreover, the thorough methodology presented here for the transcultural adaptation and equivalence study, could serve as a model for future adaptations of the MBT and other verbal tests.

%B J Alzheimers Dis %V 52 %P 283-93 %8 2016 03 05 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060959?dopt=Abstract %R 10.3233/JAD-151175 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Memory Binding Test Predicts Incident Amnestic Mild Cognitive Impairment. %A Mowrey, Wenzhu B %A Lipton, Richard B %A Katz, Mindy J %A Ramratan, Wendy S %A Loewenstein, David A %A Zimmerman, Molly E %A Buschke, Herman %X

BACKGROUND: The Memory Binding Test (MBT), previously known as Memory Capacity Test, has demonstrated discriminative validity for distinguishing persons with amnestic mild cognitive impairment (aMCI) and dementia from cognitively normal elderly.

OBJECTIVE: We aimed to assess the predictive validity of the MBT for incident aMCI.

METHODS: In a longitudinal, community-based study of adults aged 70+, we administered the MBT to 246 cognitively normal elderly adults at baseline and followed them annually. Based on previous work, a subtle reduction in memory binding at baseline was defined by a Total Items in the Paired (TIP) condition score of ≤22 on the MBT. Cox proportional hazards models were used to assess the predictive validity of the MBT for incident aMCI accounting for the effects of covariates. The hazard ratio of incident aMCI was also assessed for different prediction time windows ranging from 4 to 7 years of follow-up, separately.

RESULTS: Among 246 controls who were cognitively normal at baseline, 48 developed incident aMCI during follow-up. A baseline MBT reduction was associated with an increased risk for developing incident aMCI (hazard ratio (HR) = 2.44, 95% confidence interval: 1.30-4.56, p = 0.005). When varying the prediction window from 4-7 years, the MBT reduction remained significant for predicting incident aMCI (HR range: 2.33-3.12, p: 0.0007-0.04).

CONCLUSION: Persons with poor performance on the MBT are at significantly greater risk for developing incident aMCI. High hazard ratios up to seven years of follow-up suggest that the MBT is sensitive to early disease.

%B J Alzheimers Dis %V 53 %P 1585-95 %8 2016 Jul 14 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27540964?dopt=Abstract %R 10.3233/JAD-160291 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Memory for Public Events in Mild Cognitive Impairment and Alzheimer's Disease: The Importance of Rehearsal. %A Langlois, Roxane %A Joubert, Sven %A Benoit, Sophie %A Dostie, Valérie %A Rouleau, Isabelle %K Aged %K Alzheimer Disease %K Cognitive Dysfunction %K Female %K Humans %K Learning %K Male %K Memory %K Psychological Tests %K Semantics %X

Ribot's law refers to the better preservation of remote memories compared with recent ones that presumably characterizes retrograde amnesia. Even if Ribot-type temporal gradient has been extensively studied in retrograde amnesia, particularly in Alzheimer's disease (AD), this pattern has not been consistently found. One explanation for these results may be that rehearsal frequency rather than remoteness accounts for the better preservation of these memories. Thus, the aim of present study was to address this question by studying retrograde semantic memory in subjects with amnestic mild cognitive impairment (aMCI) (n = 20), mild AD (n = 20) and in healthy older controls (HC; n = 19). In order to evaluate the impact of repetition as well as the impact of remoteness, we used a test assessing memory for enduring and transient public events that occurred in the recent and remote past. Results show no clear temporal gradient across time periods (1960-1975; 1976-1990; 1991-2005; 2006-2011), but a better performance was observed in all three groups for enduring compared with transient events. Moreover, although deficits were globally found in both patients groups compared with HC, more specific analyses revealed that aMCI patients were only impaired on transient events while AD patients were impaired on both transient and enduring events. Exploratory analyses also revealed a tendency suggesting preservation of remote transient events in aMCI. These findings are discussed with regards to memory consolidation models.

%B J Alzheimers Dis %V 50 %P 1023-33 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836162?dopt=Abstract %R 10.3233/JAD-150722 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Memory Impairment at Initial Clinical Presentation in Posterior Cortical Atrophy. %A Ahmed, Samrah %A Baker, Ian %A Husain, Masud %A Thompson, Sian %A Kipps, Christopher %A Hornberger, Michael %A Hodges, John R %A Butler, Christopher R %X

Posterior cortical atrophy (PCA) is characterized by core visuospatial and visuoperceptual deficits, and predominant atrophy in the parieto-occipital cortex. The most common underlying pathology is Alzheimer's disease (AD). Existing diagnostic criteria suggest that episodic memory is relatively preserved. The aim of this study was to examine memory performance at initial clinical presentation in PCA, compared to early-onset AD patients (EOAD). 15 PCA patients and 32 EOAD patients, and 34 healthy controls were entered into the study. Patients were tested on the Addenbrooke's Cognitive Examination (ACE-R), consisting of subscales in memory and visuospatial skills. PCA and EOAD patients were significantly impaired compared to controls on the ACE total score (p < 0.001), visuospatial skills (p < 0.001), and memory (p < 0.001). Consistent with the salient diagnostic deficits, PCA patients were significantly more impaired on visuospatial skills compared to EOAD patients (p < 0.001). However, there was no significant difference between patient groups in memory. Further analysis of learning, recall, and recognition components of the memory subscale showed that EOAD and PCA patients were significantly impaired compared to controls on all three components (p < 0.001), however, there was no significant difference between EOAD and PCA patients. The results of this study show that memory is impaired in the majority of PCA patients at clinical presentation. The findings suggest that memory impairment must be considered in assessment and management of PCA. Further study into memory in PCA is warranted, since the ACE-R is a brief screening tool and is likely to underestimate the presence of memory impairment.

%B J Alzheimers Dis %V 52 %P 1245-50 %8 2016 Apr 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128371?dopt=Abstract %R 10.3233/JAD-160018 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Mercaptoacetamide-Based Class II Histone Deacetylase Inhibitor Increases Dendritic Spine Density via RasGRF1/ERK Pathway. %A Song, Jung Min %A Sung, You Me %A Nam, Jin Han %A Yoon, Hyejin %A Chung, Andrew %A Moffat, Emily %A Jung, Mira %A Pak, Daniel T S %A Kim, Jungsu %A Hoe, Hyang-Sook %K Acetamides %K Animals %K Blotting, Western %K Cells, Cultured %K Cerebral Cortex %K Dendritic Spines %K Gene Knockdown Techniques %K Green Fluorescent Proteins %K Hippocampus %K Histone Deacetylase Inhibitors %K Immunohistochemistry %K MAP Kinase Signaling System %K Mice, Inbred C57BL %K ras-GRF1 %K Rats, Sprague-Dawley %K Real-Time Polymerase Chain Reaction %K Receptors, AMPA %K Receptors, N-Methyl-D-Aspartate %K RNA, Messenger %K Thioglycolates %K Transfection %X

BACKGROUND: The accumulation of amyloid-β (Aβ) leads to the loss of dendritic spines and synapses, which is hypothesized to cause cognitive impairments in Alzheimer's disease (AD) patients. In our previous study, we demonstrated that a novel mercaptoacetamide-based class II histone deacetylase inhibitor (HDACI), known as W2, decreased Aβ levels and improved learning and memory in mice. However, the underlying mechanism of this effect is unknown.

OBJECTIVE: Because dendritic spine formation is associated with cognitive performance, here we investigated whether HDACI W2 regulates dendritic spine density and its molecular mechanism of action.

METHODS: To examine the effect of HDACI W2 on dendritic spine density, we conducted morphological analysis of dendritic spines using GFP transfection and Golgi staining. In addition, to determine the molecular mechanism of W2 effects on spines, we measured the levels of mRNAs and proteins involved in the Ras signaling pathway using quantitative real-time PCR, immunocytochemistry, and western analysis.

RESULTS: We found that HDACI W2 altered dendritic spine density and morphology in vitro and in vivo. Additionally, W2 increased the mRNA or protein levels of Ras GRF1 and phospho-ERK. Moreover, knockdown of RasGRF1 and inhibition of ERK activity prevented the W2-mediated spinogenesis in primary hippocampal neurons.

CONCLUSION: Our Class II-selective HDACI W2 promotes the formation and growth of dendritic spines in a RasGRF1 and ERK dependent manner in primary hippocampal neurons.

%B J Alzheimers Dis %V 51 %P 591-604 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890742?dopt=Abstract %R 10.3233/JAD-150717 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Meta-Analysis of Alzheimer's Disease Incidence and Prevalence Comparing African-Americans and Caucasians. %A Steenland, Kyle %A Goldstein, Felicia C %A Levey, Allan %A Wharton, Whitney %K African Americans %K Alzheimer Disease %K Community Health Planning %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Prevalence %X

BACKGROUND: Several studies have shown higher Alzheimer's disease (AD) incidence rates are in African-Americans (AAs) than Caucasians (CCs). If this finding is consistent across studies, it raises important etiologic questions regarding factors responsible for this discrepancy. It also affects the likely public health burden of AD in the US in the future, as the non-Caucasian population becomes the majority.

OBJECTIVE: Estimate the AA/CC rate ratio for AD incidence across all available studies.

METHODS: We conducted a meta-analysis of population-based studies for the rate ratio (RR) of AD incidence for AAs versus CCs, after identifying six relevant studies from the literature. We calculated an AA/CC rate ratio across all studies using inverse-variance weighting, and assessed inter-study heterogeneity. Using these incidence data, as well as data on survival after diagnosis, and on all-cause mortality, we also estimated the US prevalence of AD among AAs and CCs.

RESULTS: There were six population-based studies with data comparing AD incidence between AAs and CCs, with an estimated 370 AA and 640 CC incident cases. The meta-analysis RR showed that the AD rate for AAs was 64% higher than for CCs (RR = 1.64 (95% CI 1.35-2.00)) 1.35-2.00)), with no evidence of heterogeneity. We estimated the current US AD prevalence for ages 65-90 to be 5.5% for CCs, and 8.6% for AAs (prevalence ratio 1.56).

CONCLUSION: AAs have an increased risk of incident and prevalent AD compared to CCs for reasons which are unknown, but are hypothesized to reflect biological, psychological, and socioeconomic factors.

%B J Alzheimers Dis %V 50 %P 71-6 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639973?dopt=Abstract %R 10.3233/JAD-150778 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Meta-Analysis of Transcriptome Data Related to Hippocampus Biopsies and iPSC-Derived Neuronal Cells from Alzheimer's Disease Patients Reveals an Association with FOXA1 and FOXA2 Gene Regulatory Networks. %A Wruck, Wasco %A Schröter, Friederike %A Adjaye, James %K Alzheimer Disease %K Biopsy %K Cells, Cultured %K Gene Regulatory Networks %K Hepatocyte Nuclear Factor 3-alpha %K Hepatocyte Nuclear Factor 3-beta %K Hippocampus %K Humans %K Induced Pluripotent Stem Cells %K Transcriptome %X

Although the incidence of Alzheimer's disease (AD) is continuously increasing in the aging population worldwide, effective therapies are not available. The interplay between causative genetic and environmental factors is partially understood. Meta-analyses have been performed on aspects such as polymorphisms, cytokines, and cognitive training. Here, we propose a meta-analysis approach based on hierarchical clustering analysis of a reliable training set of hippocampus biopsies, which is condensed to a gene expression signature. This gene expression signature was applied to various test sets of brain biopsies and iPSC-derived neuronal cell models to demonstrate its ability to distinguish AD samples from control. Thus, our identified AD-gene signature may form the basis for determination of biomarkers that are urgently needed to overcome current diagnostic shortfalls. Intriguingly, the well-described AD-related genes APP and APOE are not within the signature because their gene expression profiles show a lower correlation to the disease phenotype than genes from the signature. This is in line with the differing characteristics of the disease as early-/late-onset or with/without genetic predisposition. To investigate the gene signature's systemic role(s), signaling pathways, gene ontologies, and transcription factors were analyzed which revealed over-representation of response to stress, regulation of cellular metabolic processes, and reactive oxygen species. Additionally, our results clearly point to an important role of FOXA1 and FOXA2 gene regulatory networks in the etiology of AD. This finding is in corroboration with the recently reported major role of the dopaminergic system in the development of AD and its regulation by FOXA1 and FOXA2.

%B J Alzheimers Dis %V 50 %P 1065-82 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890743?dopt=Abstract %R 10.3233/JAD-150733 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Metabolic Syndrome and Mild Cognitive Impairment: A Case-Control Study among Elderly in a Shanghai Suburb. %A Yao, Qian %A Jiang, Guo-Xin %A Zhou, Zhi-Ming %A Chen, Jin-Mei %A Cheng, Qi %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Aging %K Case-Control Studies %K Chi-Square Distribution %K China %K Cities %K Cognition Disorders %K Community Health Planning %K Female %K Humans %K Male %K Mental Status Schedule %K Metabolic Diseases %K Risk Factors %X

BACKGROUND: Metabolic syndrome (MetS) maybe associated with mild cognitive impairment (MCI).

OBJECTIVE: To investigate the relationship between MetS, with its individual or combined components, and MCI among elderly.

METHODS: A case-control study was conducted among the elderly aged 65 years and over in a community located in the southwestern suburb of Shanghai, China. The Chinese version of the Mini-Mental Status Examination (C-MMSE) was used to screen subjects with MCI. Associations of MetS with its individual or combined components and MCI were analyzed using conditional regression analyses with or without adjustment for gender, education, current smoking, current drinking, and physical activities.

RESULTS: There were 379 subjects with MCI and 379 gender- and age-matched healthy controls in the study. Compared with healthy controls in univariate analyses, subjects with MCI were more likely to have less time spent on physical activity, lower C-MMSE score, heavier weight, larger waistline and hipline, higher diastolic blood pressure, higher body mass index, higher abdominal obesity index, higher serum glycated hemoglobin, higher serum triglycerides, higher serum cholesterol, higher serum uric acid, and higher serum alanine aminotransferase. After multivariable adjustment, MetS was significantly associated with an increased risk of MCI (OR = 2.277; 95% CI: 1.086-4.773). Among MetS components, abdominal obesity (OR = 2.101; 95% CI: 1.224-3.608) and hypertension (OR = 2.075; 95% CI: 1.170-3.678) showed a significant association with MCI, respectively; while these two components were combined, the association was stronger (OR = 2.459; 95% CI: 1.360-4.447).

CONCLUSION: MetS and its components, particularly abdominal obesity and hypertension, were found to be significantly associated with the risk of MCI.

%B J Alzheimers Dis %V 51 %P 1175-82 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923017?dopt=Abstract %R 10.3233/JAD-150920 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Metallothioneins in Prion- and Amyloid-Related Diseases. %A Adam, Pavlína %A Křížková, Soňa %A Heger, Zbyněk %A Babula, Petr %A Pekařík, Vladimír %A Vaculovičoá, Markéta %A Gomes, Cláudio M %A Kizek, René %A Adam, Vojtěch %K Amyloidosis %K Animals %K Brain Diseases %K Humans %K Metallothionein %K Prion Diseases %X

Prion and other amyloid-forming diseases represent a group of neurodegenerative disorders that affect both animals and humans. The role of metal ions, especially copper and zinc is studied intensively in connection with these diseases. Their involvement in protein misfolding and aggregation and their role in creation of reactive oxygen species have been shown. Recent data also show that metal ions not only bind the proteins with high affinity, but also modify their biochemical properties, making them important players in prion-related diseases. In particular, the level of zinc ions is tightly regulated by several mechanisms, including transporter proteins and the low molecular mass thiol-rich metallothioneins. From four metallothionein isoforms, metallothionein-3, a unique brain-specific metalloprotein, plays a crucial role only in this regulation. This review critically evaluates the involvement of metallothioneins in prion- and amyloid-related diseases in connection with the relationship between metallothionein isoforms and metal ion regulation of their homeostasis.

%B J Alzheimers Dis %V 51 %P 637-56 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923022?dopt=Abstract %R 10.3233/JAD-150984 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Metformin Facilitates Amyloid-β Generation by β- and γ-Secretases via Autophagy Activation. %A Son, Sung Min %A Shin, Hong-Joon %A Byun, Jayoung %A Kook, Sun Young %A Moon, Minho %A Chang, Yu Jin %A Mook-Jung, Inhee %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Autophagy %K Cell Line, Tumor %K Disease Models, Animal %K Female %K Humans %K Hypoglycemic Agents %K Lysosomes %K Metformin %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microscopy, Electron %K Mutation %K Neuroblastoma %K Signal Transduction %X

The evidence of strong pathological associations between type 2 diabetes and Alzheimer's disease (AD) has increased in recent years. Contrary to suggestions that anti-diabetes drugs may have potential for treating AD, we demonstrate here that the insulin sensitizing anti-diabetes drug metformin (Glucophage®) increased the generation of amyloid-β (Aβ), one of the major pathological hallmarks of AD, by promoting β- and γ-secretase-mediated cleavage of amyloid-β protein precursor (AβPP) in SH-SY5Y cells. In addition, we show that metformin caused autophagosome accumulation in Tg6799 AD model mice. Extremely high γ-secretase activity was also detected in autophagic vacuoles, apparently a novel site of Aβ peptide generation. Together, these data suggest that metformin-induced accumulation of autophagosomes resulted in increased γ-secretase activity and Aβ generation. Additional experiments indicated that metformin increased phosphorylation of AMP-activated protein kinase, which activates autophagy by suppressing mammalian target of rapamycin (mTOR). The suppression of mTOR then induces the abnormal accumulation of autophagosomes. We conclude that metformin, an anti-diabetes drug, may exacerbate AD pathogenesis by promoting amyloidogenic AβPP processing in autophagosomes.

%B J Alzheimers Dis %V 51 %P 1197-208 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967226?dopt=Abstract %R 10.3233/JAD-151200 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. %A Luchsinger, Jose A %A Perez, Thania %A Chang, Helena %A Mehta, Pankaj %A Steffener, Jason %A Pradabhan, Gnanavalli %A Ichise, Masanori %A Manly, Jennifer %A Devanand, Davangere P %A Bagiella, Emilia %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Brain %K Cognitive Dysfunction %K Double-Blind Method %K Female %K Follow-Up Studies %K Glucose %K Humans %K Male %K Metformin %K Middle Aged %K Nootropic Agents %K Overweight %K Peptide Fragments %K Pilot Projects %K Positron-Emission Tomography %K Psychological Tests %K Severity of Illness Index %K Treatment Outcome %X

Diabetes and hyperinsulinemia may be risk factors for Alzheimer's disease (AD). We conducted a pilot study of metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia, among persons with amnestic mild cognitive impairment (aMCI) with the goal of collecting preliminary data on feasibility, safety, and efficacy. Participants were 80 men and women aged 55 to 90 years with aMCI, overweight or obese, without treated diabetes. We randomized participants to metformin 1000 mg twice a day or matching placebo for 12 months. The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective Reminding Test (SRT) and the score of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake in the posterior cingulate-precuneus in brain fluorodeoxyglucose positron emission tomography. Change in plasma Aβ42 was an exploratory outcome. The mean age of participants was 65 years. Fifty percent of participants were women. The only baseline variable that was different between the arms was the ADAS-Cog. Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose. There were no serious adverse events related to metformin. The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms. After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7±8.5 versus 5.3±8.5; p = 0.02). Differences for other outcomes were not significant. A larger trial seems warranted to evaluate the efficacy and cognitive safety of metformin in prodromal AD.

%B J Alzheimers Dis %V 51 %P 501-14 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890736?dopt=Abstract %R 10.3233/JAD-150493 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Methods for the Specific Detection and Quantitation of Amyloid-β Oligomers in Cerebrospinal Fluid. %A Schuster, Judith %A Funke, Susanne Aileen %X

Protein misfolding and aggregation are fundamental features of the majority of neurodegenerative diseases, like Alzheimer's disease (AD), Parkinson's disease, frontotemporal dementia, and prion diseases. Proteinaceous deposits in the brain of the patient, e.g., amyloid plaques consisting of the amyloid-β (Aβ) peptide and tangles composed of tau protein, are the hallmarks of AD. Soluble oligomers of Aβ and tau play a fundamental role in disease progression, and specific detection and quantification of the respective oligomeric proteins in cerebrospinal fluid may provide presymptomatically detectable biomarkers, paving the way for early diagnosis or even prognosis. Several studies on the development of techniques for the specific detection of Aβ oligomers were published, but some of the existing tools do not yet seem to be satisfactory, and the study results are contradicting. The detection of oligomers is challenging due to their polymorphous and unstable nature, their low concentration, and the presence of competing proteins and Aβ monomers in body fluids. Here, we present an overview of the current state of the development of methods for Aβ oligomer specific detection and quantitation. The methods are divided in the three subgroups: (i) enzyme linked immunosorbent assays (ELISA), (ii) methods for single oligomer detection, and (iii) others, which are mainly biosensor based methods.

%B J Alzheimers Dis %V 53 %P 53-67 %8 2016 May 07 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163804?dopt=Abstract %R 10.3233/JAD-151029 %0 Journal Article %J J Alzheimers Dis %D 2016 %T MicroRNAs as Therapeutic Targets for Alzheimer's Disease. %A Di Meco, Antonio %A Praticò, Domenico %X

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. With increasing longevity and the absence of a cure, AD has become not only a major health problem but also a heavy social and economic burden worldwide. Given this public health challenge, and that the current approved therapy for AD is limited to symptomatic treatment (i.e., cholinesterase inhibitors and NMDA receptor antagonists), exploration of new molecular pathways as novel therapeutic targets remains an attractive option for disease modifying drug development. microRNAs (miRNAs) are short non-coding RNA that control gene expression at the post-translational level by inhibiting translation of specific mRNAs or degrading them. Dysregulation of several miRNAs has been described in AD brains. Interestingly, their molecular targets are pathways that are well-established functional players in the onset and development of AD pathogenesis. Today several molecular tools have been developed to modulate miRNA levels in vitro and in vivo. These scientific advancements are affording us for the first time with the real possibility of targeting in vivo these dysregulated miRNAs as a novel therapeutic approach against AD.

%B J Alzheimers Dis %V 53 %P 367-72 %8 2016 May 07 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163828?dopt=Abstract %R 10.3233/JAD-160203 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Midlife Physical Activity and Cognition Later in Life: A Prospective Twin Study. %A Iso-Markku, Paula %A Waller, Katja %A Vuoksimaa, Eero %A Heikkilä, Kauko %A Rinne, Juha %A Kaprio, Jaakko %A Kujala, Urho M %X

BACKGROUND: Physical activity has been associated with a reduced risk of cognitive decline but the nature of this association remains obscure.

OBJECTIVE: To study associations between midlife physical activity and cognition in old age for a prospective cohort of Finnish twins.

METHODS: Physical activity in the Finnish Twin Cohort was assessed using questionnaire responses collected in 1975 and 1981. After a mean follow-up of 25.1 years, the subjects' (n = 3050; mean age 74.2; range 66-97) cognition was evaluated with a validated telephone interview. Both participation in vigorous physical activity, and the volume of physical activity, divided into quintiles, were used as predictors of cognitive impairment. Metrics collected by TELE were used to categorize participants as: cognitively impaired, suffering mild cognitive impairment, or cognitively healthy.

RESULTS: Participation in vigorous physical activity compared to non-participation for both 1975 and 1981 was associated with a lower risk of cognitive impairment in individual-based analyses (fully adjusted OR 0.50, 95% CI 0.35-0.73). Pairwise analyses yielded similar but statistically non-significant associations. In terms of the volume of physical activity, the most active quintile of individuals (OR 0.69, 95% CI 0.46-1.04) had a reduced risk of cognitive decline compared with the most sedentary quintile in the fully adjusted model although no clear dose-response was found.

CONCLUSION: Vigorous midlife physical activity was associated with less cognitive impairment but without a clear dose-response association between the volume of physical activity and cognition.

%B J Alzheimers Dis %V 54 %P 1303-1317 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589524?dopt=Abstract %R 10.3233/JAD-160377 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Mild Cognitive Impairment and Susceptibility to Scams in Old Age. %A Han, S Duke %A Boyle, Patricia A %A James, Bryan D %A Yu, Lei %A Bennett, David A %K Aged %K Aged, 80 and over %K Aging %K Cognitive Dysfunction %K Crime Victims %K Disease Susceptibility %K Female %K Humans %K Male %K Memory, Episodic %K Middle Aged %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Residence Characteristics %K Self Report %X

BACKGROUND: Falling victim to financial scams can have a significant impact upon social and financial wellbeing and independence. A large proportion of scam victims are older adults, but whether older victims with mild cognitive impairment (MCI) are at higher risk remains unknown.

OBJECTIVE: We tested the hypothesis that older persons with MCI exhibit greater susceptibility to scams compared to those without cognitive impairment.

METHODS: Seven hundred and thirty older adults without dementia were recruited from the Rush Memory and Aging Project, a community-based epidemiologic study of aging. Participants completed a five-item self-report measure of susceptibility to scams, a battery of cognitive measures, and clinical diagnostic evaluations.

RESULTS: In models adjusted for age, education, and gender, the presence of MCI was associated with greater susceptibility to scams (B = 0.125, SE = 0.063, p-value = 0.047). Further, in analyses of the role of specific cognitive systems in susceptibility to scams among persons with MCI (n = 144), the level of performance in two systems, episodic memory and perceptual speed abilities, were associated with susceptibility.

CONCLUSIONS: Adults with MCI may be more susceptible to scams in old age than older persons with normal cognition. Lower abilities in specific cognitive systems, particularly perceptual speed and episodic memory, may contribute to greater susceptibility to scams in those with MCI.

%B J Alzheimers Dis %V 49 %P 845-51 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519434?dopt=Abstract %R 10.3233/JAD-150442 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Mindfulness in the Maintenance of Cognitive Capacities in Alzheimer's Disease: A Randomized Clinical Trial. %A Quintana-Hernández, Domingo J %A Miró-Barrachina, María T %A Ibáñez-Fernández, Ignacio J %A Pino, Angelo Santana-Del %A Quintana-Montesdeoca, María P %A Rodríguez-de Vera, Bienvenida %A Morales-Casanova, David %A Pérez-Vieitez, María Del Carmen %A Rodríguez-García, Javier %A Bravo-Caraduje, Noelia %K Age Factors %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Cognition Disorders %K Double-Blind Method %K Female %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K Mindfulness %K Neuropsychological Tests %K Treatment Outcome %X

BACKGROUND: The Canary Islands longitudinal study on non-pharmacological treatments showed the overall effectiveness of mindfulness in Alzheimer's disease (AD). However, no specific data on the maintenance of cognitive capacities were presented.

OBJECTIVE: To determine whether the practice of mindfulness modifies the course of cognitive impairment in AD.

METHODS:

DESIGN: Longitudinal, non-inferiority and equivalence, randomized clinical trial, repeated-measures design, with three experimental groups and one control group.

PARTICIPANTS: Patients with AD who voluntarily attended the Lidia García Foundation (n = 502). Only those who were treated with donepezil and MMSE ≥18 were included (n = 120).

INTERVENTION: Over a two-year period, each group carried out three weekly sessions of stimulation based on mindfulness, cognitive stimulation therapy, and progressive muscle relaxation.

MEASURES: Cognitive assessment CAMDEX-R (MMSE and CAMCOG).

STATISTICAL ANALYSIS: Repeated-measures ANOVA (p <  0.05) and the effect size Cohen's d were performed.

RESULTS: The mindfulness group showed significant scores compared with the control and muscle relaxation groups (p <  0.05), while mindfulness and cognitive stimulation therapy were equivalent (p≥0.05). Group cognitive stimulation evolved better than the control (p <  0.05) group but not better than the muscle relaxation group (p≥0.05). The effect size compared over two years was large for the mindfulness group (p≥0.80), moderate for the relaxation group (p≥0.50), and low for the cognitive stimulation group (p≥0.20).

CONCLUSION: The practice of mindfulness maintained cognitive function over a period of two years. This longitudinal study suggests that mindfulness can be used as a non-pharmacological treatment to slow cognitive impairment in AD.

%B J Alzheimers Dis %V 50 %P 217-32 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639952?dopt=Abstract %R 10.3233/JAD-143009 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Mindfulness Training for Older Adults with Subjective Cognitive Decline: Results from a Pilot Randomized Controlled Trial. %A Smart, Colette M %A Segalowitz, Sidney J %A Mulligan, Bryce P %A Koudys, Jacob %A Gawryluk, Jodie R %X

INTRODUCTION: Subjective cognitive decline (SCD) in older adults is a condition with a complex phenomenology and diverse etiologies including (but not limited to) mood, personality, and health concerns, as well as biomarkers of preclinical Alzheimer's disease such as amyloid-β deposition and gray matter volume loss. Approximately 60% of affected persons are estimated to decline to Alzheimer's dementia. Regardless of etiology, persons with SCD may be optimal targets for early intervention.

OBJECTIVE: To ascertain the feasibility and impact of mindfulness training (MT) as an early intervention in persons with SCD.

METHODS: Using a single-blind, randomized controlled trial design, older adults with (n = 14) and without (n = 22) SCD were randomized to either MT or a control condition of psychoeducation (PE) on cognitive aging. EEG/ERP (specifically, the P3 component), structural MRI, and self-report measures of psychological functioning were obtained within 4 weeks prior to and within 2 weeks following intervention.

RESULTS: MT resulted in decreased reaction time intra-individual variability for all participants, with a selective increase in the P3 event-related component for those with SCD. Compared with PE, MT also resulted in an increase in percent volume brain change in structural MRI. Finally, all SCD participants reported a decrease in cognitive complaints and increase in memory self-efficacy following intervention.

DISCUSSION: Results suggest that MT is a feasible early intervention in persons with SCD. Longer-term follow-up with larger sample sizes will determine whether MT can slow the rate of decline in persons who may be at risk for Alzheimer's dementia.

%B J Alzheimers Dis %V 52 %P 757-74 %8 2016 Apr 05 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060951?dopt=Abstract %R 10.3233/JAD-150992 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Mini-Mental State Examination in Elderly Chinese: A Population-Based Normative Study. %A Li, Hanzhi %A Jia, Jianping %A Yang, Zhiqiang %X

BACKGROUND: Chinese nationwide norms of the Mini-Mental State Examination (MMSE) have not been established despite its wide use.

OBJECTIVE: To obtain norms for the MMSE based on age, gender, education, and rural or urban residences and to determine the optimal cut-off points of the MMSE in elderly Chinese.

METHODS: A cross-sectional study was conducted in Chinese community residents aged 65 years or over selected by cluster random sampling. The MMSE was administered to 9,629 subjects (7,110 cognitively normal, 2,024 with mild cognitive impairment, and 495 with dementia). The demographic influences on MMSE scores were investigated and the norms were established considering those factors. Receiver operating characteristic (ROC) analysis was used to determine the optimal cut-off points.

RESULTS: Years of education (standardized β= 0.399), rural residence (standardized β= -0.261), age (standardized β= -0.198), and being female (standardized β= -0.101) had significant effects on MMSE scores (p < 0.001). Accordingly, we presented the demographic-stratified normative data for the MMSE. The optimal cut-off points for dementia screening were 16/17 for illiterate (sensitivity 87.6% and specificity 80.8%), 19/20 for individuals with 1-6 years of education (sensitivity 93.6% and specificity 92.7%), and 23/24 for individuals with 7 or more years of education (sensitivity 94.3% and specificity 94.3%).

CONCLUSION: We provide the age-, gender-, education-, and residence-specific reference norms for the MMSE derived from an investigation of a large-scale, multicenter, nationwide representative Chinese elderly population. It could be of great improvement for the use of the MMSE in dementia screening in Chinese elderly population.

%B J Alzheimers Dis %V 53 %P 487-96 %8 2016 May 07 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163822?dopt=Abstract %R 10.3233/JAD-160119 %0 Journal Article %J J Alzheimers Dis %D 2016 %T miR-302 Attenuates Amyloid-β-Induced Neurotoxicity through Activation of Akt Signaling. %A Li, Hsin-Hua %A Lin, Shi-Lung %A Huang, Chien-Ning %A Lu, Fung-Jou %A Chiu, Pai-Yi %A Huang, Wen-Nung %A Lai, Te-Jen %A Lin, Chih-Li %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Cell Line, Tumor %K Cell Survival %K Female %K Glycogen Synthase Kinase 3 beta %K Heme Oxygenase-1 %K Humans %K Insulin %K Male %K Membrane Potential, Mitochondrial %K MicroRNAs %K Neurons %K NF-E2-Related Factor 2 %K Oxidative Stress %K Proto-Oncogene Proteins c-akt %K PTEN Phosphohydrolase %K Reactive Oxygen Species %K Ribonucleoproteins %X

Deficiency of insulin signaling has been linked to diabetes and ageing-related neurodegenerative diseases such as Alzheimer's disease (AD). In this regard, brains exhibit defective insulin receptor substrate-1 (IRS-1) and hence result in alteration of insulin signaling in progression of AD, the most common cause of dementia. Consequently, dysregulation of insulin signaling plays an important role in amyloid-β (Aβ)-induced neurotoxicity. As the derivation of induced pluripotent stem cells (iPSC) involves cell reprogramming, it may provide a means for regaining the control of ageing-associated dysfunction and neurodegeneration via affecting insulin-related signaling. To this, we found that an embryonic stem cell (ESC)-specific microRNA, miR-302, silences phosphatase and tensin homolog (PTEN) to activate Akt signaling, which subsequently stimulates nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) elevation and hence inhibits Aβ-induced neurotoxicity. miR-302 is predominantly expressed in iPSCs and is known to regulate several important biological processes of anti-oxidative stress, anti-apoptosis, and anti-aging through activating Akt signaling. In addition, we also found that miR-302-mediated Akt signaling further stimulates Nanog expression to suppress Aβ-induced p-Ser307 IRS-1 expression and thus enhances tyrosine phosphorylation and p-Ser 473-Akt/p-Ser 9-GSK3β formation. Furthermore, our in vivo studies revealed that the mRNA expression levels of both Nanog and miR-302-encoding LARP7 genes were significantly reduced in AD patients' blood cells, providing a novel diagnosis marker for AD. Taken together, our findings demonstrated that miR-302 is able to inhibit Aβ-induced cytotoxicity via activating Akt signaling to upregulate Nrf2 and Nanog expressions, leading to a marked restoration of insulin signaling in AD neurons.

%B J Alzheimers Dis %V 50 %P 1083-98 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890744?dopt=Abstract %R 10.3233/JAD-150741 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Mismatch Negativity and Ear Laterality in Alzheimer's Disease and in Mild Cognitive Impairment. %A Idrizbegovic, Esma %A Hederstierna, Christina %A Rosenhall, Ulf %X

BACKGROUND: Cortical auditory event-related potentials (ERPs) were studied in order to measure mismatch negativity (MMN). Three groups of subjects were studied: patients with Alzheimer's disease (AD, n = 32), mild cognitive impairment (MCI, n = 44), and subjective memory complaints without cognitive decline (SMC, n = 27). A bottom up strategy was applied, and the right and left ears were stimulated monaurally.

OBJECTIVE: To investigate MMN in AD and MCI, and in a clinical reference group.

METHODS: ERPs were carried out with 500 tone pulses at 80 dBnHL. Each sequence included 80% standard tones (500 Hz) (f), and 20% deviant tones (1000 Hz) (r). MMN measurements were carried out by comparing the amplitudes of (f) and (r) recordings and to calculate the amplitude difference in μV for each group. The right and the left ears were analyzed separately.

RESULTS: A left ear advantage (LEA) of MMN amplitude was demonstrated in the two groups with better cognition (the MCI and the SMC groups), but not in the AD group.

DISCUSSION: The absence of MMN asymmetry in the AD group is possibly caused by a dysfunction to apprehend changes of tonal stimuli.

%B J Alzheimers Dis %V 53 %P 1405-10 %8 2016 Jul 01 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392868?dopt=Abstract %R 10.3233/JAD-160323 %0 Journal Article %J J Alzheimers Dis %D 2016 %T "Missed" Mild Cognitive Impairment: High False-Negative Error Rate Based on Conventional Diagnostic Criteria. %A Edmonds, Emily C %A Delano-Wood, Lisa %A Jak, Amy J %A Galasko, Douglas R %A Salmon, David P %A Bondi, Mark W %X

Mild cognitive impairment (MCI) is typically diagnosed using subjective complaints, screening measures, clinical judgment, and a single memory score. Our prior work has shown that this method is highly susceptible to false-positive diagnostic errors. We examined whether the criteria also lead to "false-negative" errors by diagnostically reclassifying 520 participants using novel actuarial neuropsychological criteria. Results revealed a false-negative error rate of 7.1%. Participants' neuropsychological performance, cerebrospinal fluid biomarkers, and rate of decline provided evidence that an MCI diagnosis is warranted. The impact of "missed" cases of MCI has direct relevance to clinical practice, research studies, and clinical trials of prodromal Alzheimer's disease.

%B J Alzheimers Dis %V 52 %P 685-91 %8 2016 Mar 31 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031477?dopt=Abstract %R 10.3233/JAD-150986 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Mitochondrial Regulatory Pathways in the Pathogenesis of Alzheimer's Disease. %A Adiele, Reginald C %A Adiele, Chiedukam A %X

Alzheimer's disease (AD) is an age-associated neurodegenerative brain disorder with progressive cognitive decline that leads to terminal dementia and death. For decades, amyloid-beta (Aβ) and neurofibrillary tangle (NFT) aggregation hypotheses have dominated studies on the pathogenesis and identification of potential therapeutic targets in AD. Little attention has been paid to the mitochondrial molecular/biochemical pathways leading to AD. Mitochondria play a critical role in cell viability and death including neurons and neuroglia, not only because they regulate energy and oxygen metabolism but also because they regulate cell death pathways. Mitochondrial impairment and oxidative stress are implicated in the pathogenesis of AD. Interestingly, current therapeutics provide symptomatic benefits to AD patients resulting in the use of preventive trials on presymptomatic subjects. This review article elucidates the pathophysiology of AD and emphasizes the need to explore the mitochondrial pathways to provide solutions to unanswered questions in the prevention and treatment of AD.

%B J Alzheimers Dis %V 53 %P 1257-70 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392851?dopt=Abstract %R 10.3233/JAD-150967 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam. %A Stockburger, Carola %A Miano, Davide %A Baeumlisberger, Marion %A Pallas, Thea %A Arrey, Tabiwang N %A Karas, Michael %A Friedland, Kristina %A Müller, Walter E %K Adenosine Triphosphate %K Aging %K Alzheimer Disease %K Animals %K Brain %K Cell Line %K Cognition Disorders %K Female %K GAP-43 Protein %K Gene Expression Regulation %K Humans %K Male %K Membrane Glycoproteins %K Mitochondria %K Mitochondrial Membrane Transport Proteins %K Nerve Tissue Proteins %K Nitroprusside %K Nootropic Agents %K Piracetam %K Proteomics %K Rats %K RNA, Small Interfering %X

Aberrant neuronal network activity associated with neuronal hyperexcitability seems to be an important cause of cognitive decline in aging and Alzheimer's disease (AD). Out of many antiepileptics, only levetiracetam improved cognitive dysfunction in AD patients and AD animal models by reducing hyperexcitability. As impaired inhibitory interneuronal function, rather than overactive neurons, seems to be the underlying cause, improving impaired neuronal function rather than quieting overactive neurons might be relevant in explaining the lack of activity of the other antiepileptics. Interestingly, improvement of cognitive deficits by levetiracetam caused by small levels of soluble Aβ was accompanied by improvement of synaptic function and plasticity. As the negative effects of Aβ on synaptic plasticity strongly correlate with mitochondrial dysfunction, wehypothesized that the effect of levetiracetam on synaptic activity might be raised by an improved mitochondrial function. Accordingly, we investigated possible effects of levetiracetam on neuronal deficits associated with mitochondrial dysfunction linked to aging and AD. Levetiracetam improved several aspects of mitochondrial dysfunction including alterations of fission and fusion balance in a cell model for aging and early late-onset AD. We demonstrate for the first time, using immunohistochemistry and proteomics, that the synaptic vesicle protein 2A (SV2a), the molecular target of levetiracetam, is expressed in mitochondria. In addition, levetiracetam shows significant effect on the opening of the mitochondrial permeability transition pore. Importantly, the effects of levetiracetam were significantly abolished when SV2a was knockdown using siRNA. In conclusion, interfering with the SV2a protein at the mitochondrial level and thereby improving mitochondrial function might represent an additional therapeutic effect of levetiracetam to improve symptoms of late-onset AD.

%B J Alzheimers Dis %V 50 %P 201-15 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639968?dopt=Abstract %R 10.3233/JAD-150687 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer's Disease: A Randomized Controlled Trial. %A Hoffmann, Kristine %A Sobol, Nanna A %A Frederiksen, Kristian S %A Beyer, Nina %A Vogel, Asmus %A Vestergaard, Karsten %A Brændgaard, Hans %A Gottrup, Hanne %A Lolk, Annette %A Wermuth, Lene %A Jacobsen, Søren %A Laugesen, Lars P %A Gergelyffy, Robert G %A Høgh, Peter %A Bjerregaard, Eva %A Andersen, Birgitte B %A Siersma, Volkert %A Johannsen, Peter %A Cotman, Carl W %A Waldemar, Gunhild %A Hasselbalch, Steen G %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition %K Depression %K Exercise %K Exercise Therapy %K Female %K Humans %K Male %K Middle Aged %K Quality of Life %K Treatment Outcome %X

BACKGROUND: Studies of physical exercise in patients with Alzheimer's disease (AD) are few and results have been inconsistent.

OBJECTIVE: To assess the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD.

METHODS: In a randomized controlled trial, we recruited 200 patients with mild AD to a supervised exercise group (60-min sessions three times a week for 16 weeks) or to a control group. Primary outcome was changed from baseline in cognitive performance estimated by Symbol Digit Modalities Test (SDMT) in the intention-to-treat (ITT) group. Secondary outcomes included changes in quality of life, ability to perform activities of daily living, and in neuropsychiatric and depressive symptoms.

RESULTS: The ITT analysis showed no significant differences between intervention and control groups in change from baseline of SDMT, other cognitive tests, quality of life, or activities of daily living. The change from baseline in Neuropsychiatric Inventory differed significantly in favor of the intervention group (mean: -3.5, 95% confidence interval (CI) -5.8 to -1.3, p = 0.002). In subjects who adhered to the protocol, we found a significant effect on change from baseline in SDMT as compared with the control group (mean: 4.2, 95% CI 0.5 to 7.9, p = 0.028), suggesting a dose-response relationship between exercise and cognition.

CONCLUSIONS: This is the first randomized controlled trial with supervised moderate-to-high intensity exercise in patients with mild AD. Exercise reduced neuropsychiatric symptoms in patients with mild AD, with possible additional benefits of preserved cognition in a subgroup of patients exercising with high attendance and intensity.

%B J Alzheimers Dis %V 50 %P 443-53 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682695?dopt=Abstract %R 10.3233/JAD-150817 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Modulation of Amyloid-β1-40 Transport by ApoA1 and ApoJ Across an in vitro Model of the Blood-Brain Barrier. %A Merino-Zamorano, Cristina %A Fernández-de Retana, Sofía %A Montañola, Alex %A Batlle, Aina %A Saint-Pol, Julien %A Mysiorek, Caroline %A Gosselet, Fabien %A Montaner, Joan %A Hernández-Guillamon, Mar %X

Amyloid-β (Aβ) accumulation in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) is likely caused by the impairment of its brain clearance that partly occurs through the blood-brain barrier (BBB). In this context, an in vitro BBB model is a valuable tool for studying the molecular mechanisms that regulate this process. This study assessed brain Aβ elimination across the BBB and its modulation by the natural chaperones Apolipoprotein A1 (ApoA1) and Apolipoprotein J/Clusterin (ApoJ). The model was based on primary cerebral endothelial cells that were cultured on Matrigel-coated Transwells and treated with fluorescently labeled-Aβ1-40 to track its efflux across the BBB, which corresponds to trafficking from the basolateral (brain) to apical (blood) compartments. We observed that the transport of basolateral Aβ1-40 was enhanced when it was complexed to rApoJ, whereas the complex formed with rApoA1 did not influence Aβ1-40 efflux. However, the presence of rApoA1 in the apical compartment was able to mobilize Aβ1-40 from the basolateral side. We also observed that both rApoA1 and rApoJ moderately crossed the monolayer (from blood to brain) through a mechanism involving the LDL receptor-related protein family. In contrast to the increased rApoJ efflux when complexed to Aβ1-40, rApoA1 trafficking was restricted when it was bound to the Aβ peptide. In summary, the present study highlights the role of ApoJ and ApoA1 in the in vitro modulation of Aβ elimination across the BBB.

%B J Alzheimers Dis %V 53 %P 677-91 %8 2016 May 25 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27232214?dopt=Abstract %R 10.3233/JAD-150976 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Modulation of miR-19 in Aluminum-Induced Neural Cell Apoptosis. %A Zhu, Mingming %A Huang, Cong %A Ma, Xiao %A Wu, Rui %A Zhu, Weiwei %A Li, Xiaoting %A Liang, Zhaofeng %A Deng, Feifei %A Zhu, Jianyun %A Xie, Wei %A Yang, Xue %A Jiang, Ye %A Wang, Shijia %A Wu, Jieshu %A Geng, Shanshan %A Xie, Chunfeng %A Zhong, Caiyun %K Aluminum %K Animals %K Apoptosis %K Brain %K Cell Line, Tumor %K Dose-Response Relationship, Drug %K Humans %K Male %K MicroRNAs %K Neurons %K Proto-Oncogene Proteins c-akt %K PTEN Phosphohydrolase %K Rats, Sprague-Dawley %K Tumor Suppressor Protein p53 %X

Neuronal cell death is an important feature of neurodegeneration. Aluminum is associated with neurodegenerative disorders, particularly Alzheimer's disease. However, the underlying mechanisms by which aluminum induces neuronal apoptosis remain to be elucidated. miR-19 is a key miRNA implicated in regulating cell survival process, while the role of miR-19 in Alzheimer's disease has not been investigated. In the present study, we showed that Aluminum maltolate (Al-malt), a lipophilic Al complex which is a common component of human diet with the ability to facilitate the entry of Al into the brain, induced apoptosis in human neuroblastoma SH-SY5Y cells, along with downregulation of miR-19a/miR-19b, upregulation of miR-19-targeted PTEN, and alterations of its downstream apoptosis related proteins including AKT, p53, Bax, and Bcl-2. miR-19 overexpression attenuated Al-malt-induced apoptosis as well as changes in the expression of apoptosis related proteins in SH-SY5Y cells. We further revealed that exposure of rats to Al-malt for 12 weeks at doses relevant to human exposure significantly elevated Al concentrations in serum and brain tissues. Al-malt dose-dependently induced apoptosis in rat brain, as evidenced by increased caspase activation and increased TUNEL staining. Consistent with in vitro results, Al-malt reduced miR-19 expression and altered the expression of apoptotic related proteins in rat brain. Taken together, our data suggest for the first time that miR-19 modulation is critically involved in Al-induced neural cell apoptosis. Findings from this study could provide new insight into the molecular mechanisms of Al-associated neurodegenerative pathogenesis.

%B J Alzheimers Dis %V 50 %P 1149-62 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836165?dopt=Abstract %R 10.3233/JAD-150763 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Molecular markers of amnestic mild cognitive impairment among Mexican Americans. %A Edwards, Melissa %A Hall, James %A Williams, Benjamin %A Johnson, Leigh %A O'Bryant, Sid %K Aged %K Alzheimer Disease %K Area Under Curve %K Biomarkers %K Cognitive Dysfunction %K Female %K Humans %K Male %K Mexican Americans %K Middle Aged %K Neuropsychological Tests %K Proteome %K Sensitivity and Specificity %K United States %X

BACKGROUND: Mexican Americans face a significant health disparity when it comes to Alzheimer's disease (AD) as they present with higher rates of the disease and develop AD at an earlier age compared to other ethnic groups. Recent work identified a proteomic profile of AD among this population; however, no work to date has sought to examine the biological profile of pre-AD among Mexican Americans.

OBJECTIVE: This study aims to identify an amnestic mild cognitive impairment (aMCI) proteomic profile among Mexican Americans.

METHODS: Data were analyzed from 284 Mexican American participants (aMCI, n = 73; normal controls, n = 211) from the Health & Aging Brain among Latino Elders study. Fasting serum samples were analyzed using a multi-plex biomarker assay platform. A biomarker profile was generated using random forest analyses.

RESULTS: Among aMCI cases, the biomarker profile was found to be largely inflammatory with the top three markers shown to include TNFα, IL10, and TARC. The overall diagnostic accuracy of the biomarkers in detecting aMCI was 96% (sensitivity = 0.82; specificity = 0.97). Inclusion of clinical variables with the selected biomarkers did not impact the overall detection accuracy (area under the curve = 0.96) but led to a slight improvement in specificity (specificity = 0.99) and decrease in sensitivity (sensitivity = 0.74).

CONCLUSION: The biomarker profile of aMCI was shown to be different from our previously generated AD profile among Mexican Americans, which was largely metabolic in nature. The findings implicate a possible interplay between inflammatory and metabolic processes and additional work is needed to further examine this.

%B J Alzheimers Dis %V 49 %P 221-8 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444793?dopt=Abstract %R 10.3233/JAD-150553 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Molecular Signaling Mechanisms of Natural and Synthetic Retinoids for Inhibition of Pathogenesis in Alzheimer's Disease. %A Chakrabarti, Mrinmay %A McDonald, Alexander J %A Will Reed, J %A Moss, Melissa A %A Das, Bhaskar C %A Ray, Swapan K %K Alzheimer Disease %K Animals %K Brain %K Humans %K Mice %K Neurons %K Retinoid X Receptors %K Retinoids %K Signal Transduction %K Tretinoin %X

Retinoids, which are vitamin A derivatives, interact through retinoic acid receptors (RARs) and retinoid X receptors (RXRs) and have profound effects on several physiological and pathological processes in the brain. The presence of retinoic acid signaling is extensively detected in the adult central nervous system, including the amygdala, cortex, hypothalamus, hippocampus, and other brain areas. Retinoids are primarily involved in neural patterning, differentiation, and axon outgrowth. Retinoids also play a key role in the preservation of the differentiated state of adult neurons. Impairment in retinoic acid signaling can result in neurodegeneration and progression of Alzheimer's disease (AD). Recent studies demonstrated severe deficiencies in spatial learning and memory in mice during retinoic acid (vitamin A) deprivation indicating its significance in preserving memory function. Defective cholinergic neurotransmission plays an important role in cognitive deficits in AD. All-trans retinoic acid is known to enhance the expression and activity of choline acetyltransferase in neuronal cell lines. Activation of RAR and RXR is also known to impede the pathogenesis of AD in mice by inhibiting accumulation of amyloids. In addition, retinoids have been shown to inhibit the expression of chemokines and pro-inflammatory cytokines in microglia and astrocytes, which are activated in AD. In this review article, we have described the chemistry and molecular signaling mechanisms of natural and synthetic retinoids and current understandings of their therapeutic potentials in prevention of AD pathology.

%B J Alzheimers Dis %V 50 %P 335-52 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682679?dopt=Abstract %R 10.3233/JAD-150450 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Monitoring Blood-Brain Barrier Integrity Following Amyloid-β Immunotherapy Using Gadolinium-Enhanced MRI in a PDAPP Mouse Model. %A Blockx, Ines %A Einstein, Steve %A Guns, Pieter-Jan %A Van Audekerke, Johan %A Guglielmetti, Caroline %A Zago, Wagner %A Roose, Dimitri %A Verhoye, Marleen %A Van der Linden, Annemie %A Bard, Frederique %X

BACKGROUND: Amyloid-related imaging abnormalities (ARIA) have been reported with some anti-amyloid-β (Aβ) immunotherapy trials. They are detected with magnetic resonance imaging (MRI) and thought to represent transient accumulation of fluid/edema (ARIA-E) or microhemorrhages (ARIA-H). Although the clinical significance and pathophysiology are unknown, it has been proposed that anti-Aβimmunotherapy may affect blood-brain barrier (BBB) integrity.

OBJECTIVE: To examine vascular integrity in aged (12-16 months) PDAPP and wild type mice (WT), we performed a series of longitudinal in vivo MRI studies.

METHODS: Mice were treated on a weekly basis using anti-Aβimmunotherapy (3D6) and follow up was done longitudinally from 1-12 weeks after treatment. BBB-integrity was assessed using both visual assessment of T1-weighted scans and repeated T1 mapping in combination with gadolinium (Gd-DOTA).

RESULTS: A subset of 3D6 treated PDAPP mice displayed numerous BBB disruptions, whereas WT and saline-treated PDAPP mice showed intact BBB integrity under the conditions tested. In addition, the contrast induced decrease in T1 value was observed in the meningeal and midline area. BBB disruption events occurred early during treatment (between 1 and 5 weeks), were transient, and resolved quickly. Finally, BBB-leakages associated with microhemorrhages were confirmed by Perls'Prussian blue histopathological analysis.

CONCLUSION: Our preclinical findings support the hypothesis that 3D6 leads to transient leakage from amyloid-positive vessels. The current study has provided valuable insights on the time course of vascular alterations during immunization treatment and supports further research in relation to the nature of ARIA and the utility of in vivo repeated T1 MRI as a translational tool.

%B J Alzheimers Dis %V 54 %P 723-35 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567811?dopt=Abstract %R 10.3233/JAD-160023 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Monophosphoryl Lipid-A: A Promising Tool for Alzheimer's Disease Toll. %A Rego, Ângela %A Viana, Sofia D %A Ribeiro, Carlos A Fontes %A Rodrigues-Santos, Paulo %A Pereira, Frederico C %X

Neuroinflammation is a two-edged sword in Alzheimer's disease (AD). A certain degree of neuroinflammation is instrumental in the clearance of amyloid-β (Aβ) peptides by activated microglia, although a sustained neuroinflammation might accelerate Aβ deposition, thus fostering the neurodegenerative process and functional decline in AD. There is an increasing body of evidence suggesting that the innate immune system via Toll-like receptor 4 (TLR4) finely orchestrates the highly regulated inflammatory cascade that takes place in AD pathology. Herein we critically review pre-clinical (in vitro and in vivo approaches) and clinical studies showing that monophosphoryl lipid A (MPL), a partial TLR4 agonist, may have beneficial effect on AD physiopathology. The in vivo data elegantly showed that MPL enhanced Aβ plaque phagocytosis thus decreasing the number and the size of Aβ deposits and soluble Aβ in brain from APPswe/PS1 mice. Furthermore, MPL also improved their cognition. The mechanism underlying this MPL effect was proposed to be microglial activation by recruiting TLR4. Additionally, it was demonstrated that MPL increased the Aβ antibody titer and showed a safe profile in mice and primates, when used as a vaccine adjuvant. Clinical studies using MPL as an adjuvant in Aβ immunotherapy are currently ongoing. Overall, we argue that the TLR4 partial agonist MPL is a potentially safe and effective new pharmacological tool in AD.

%B J Alzheimers Dis %V 52 %P 1189-202 %8 2016 Apr 12 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079716?dopt=Abstract %R 10.3233/JAD-151183 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Morroniside-Induced PP2A Activation Antagonizes Tau Hyperphosphorylation in a Cellular Model of Neurodegeneration. %A Yang, Cui-cui %A Kuai, Xue-xian %A Gao, Wen-bin %A Yu, Jian-chun %A Wang, Qi %A Li, Lin %A Zhang, Lan %K Analysis of Variance %K Cell Line %K Enzyme Inhibitors %K Gene Expression Regulation %K Glycogen Synthase Kinase 3 beta %K Glycosides %K HEK293 Cells %K Humans %K Neuroblastoma %K Okadaic Acid %K Phosphorylation %K Protein Phosphatase 2 %K RNA, Small Interfering %K tau Proteins %K Transfection %K Tyrosine %X

BACKGROUND: An accumulation of hyperphosphorylated tau in the brain is a hallmark of Alzheimer's disease (AD). Deficits in protein phosphatase 2A (PP2A) are associated with tau hyperphosphorylation in AD.

OBJECTIVE: To investigate the effects of morroniside (MOR), isolated from Cornus officinalis, on tau hyperphosphorylation and its underlying mechanisms related to PP2A.

METHODS: SK-N-SH cells were pretreated with 50-200 μM MOR for 24 h followed by 20 nM okadaic acid (OA) for 6 h. PP2Ac siRNA was transfected into HEK293 cells to determine the direct interaction of MOR with PP2A. Western blotting was used to measure the expression of proteins and enzymes. PP2A activity was measured by molybdenum blue spectrophotometry.

RESULTS: Pretreatment with MOR improved the cellular morphological damage and inhibited tau hyperphosphorylation in SK-N-SH cells induced by OA, a PP2A inhibitor. Moreover, MOR increased PP2A activity, concurrent with a decrease in the expression of demethylated PP2A at Leu309 and phosphorylated PP2A at Tyr307. MOR decreased protein phosphatase methylesterase 1 (PME-1) expression and the ratio of PME-1/leucine carboxyl methyltransferase 1 (LCMT-1). Furthermore, MOR treatment decreased the phosphorylation of Src at Tyr416, which regulates the phosphorylation of PP2A. MOR had no effect on PP2Ac expression and tau hyperphosphorylation in PP2Ac siRNA-transfected cells.

CONCLUSION: MOR attenuated OA-induced tau hyperphosphorylation via PP2A activation, and its mechanism might be related to the regulation of PP2Ac post-translational modification and upstream enzymes such as Src and PME-1.

%B J Alzheimers Dis %V 51 %P 33-44 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836014?dopt=Abstract %R 10.3233/JAD-150728 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Mortality in Mild Cognitive Impairment: A Longitudinal Study in Memory Clinics. %A Connors, Michael H %A Ames, David %A Boundy, Karyn %A Clarnette, Roger %A Kurrle, Sue %A Mander, Alastair %A Ward, John %A Woodward, Michael %A Brodaty, Henry %X

BACKGROUND: Patients with mild cognitive impairment (MCI) are at greater risk of mortality than the general population. Comparatively little research has examined predictors of mortality in MCI and no research has examined whether time-varying variables, such as change in cognition and function, predict survival.

OBJECTIVE: To identify predictors of mortality in patients with MCI.

METHODS: 185 patients with MCI were recruited from nine memory clinics around Australia. Patients completed measures of cognition, function, and neuropsychiatric symptoms over three years. Mortality data were obtained from state registries eight years after baseline.

RESULTS: 55 (30%) patients died within this period. Older age, lower cognitive and functional ability at baseline, and greater decline in functional ability over six months predicted mortality.

CONCLUSION: Easily measurable clinical data predict mortality in patients with MCI. Longitudinal assessment over time can provide additional information about patients' risk.

%B J Alzheimers Dis %V 54 %P 149-55 %8 2016 Jul 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472874?dopt=Abstract %R 10.3233/JAD-160148 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Motoric Cognitive Risk Syndrome and Falls Risk: A Multi-Center Study. %A Callisaya, Michele L %A Ayers, Emmeline %A Barzilai, Nir %A Ferrucci, Luigi %A Guralnik, Jack M %A Lipton, Richard B %A Otahal, Petr %A Srikanth, Velandai K %A Verghese, Joe %X

BACKGROUND: The Motoric Cognitive Risk Syndrome (MCR) is characterized by slow gait speed and cognitive complaints.

OBJECTIVES: The objective of this study was to determine if the presence of MCR increases the risk of falls in older people.

METHODS: Individual participant data (n = 6,204) from five longitudinal studies from three countries were used for this analysis. MCR diagnosis was defined as both the presence of objectively measured slow gait speed and subjective cognitive complaints in those without dementia or mobility disability. Falls were prospectively ascertained using phone calls or questionnaires. Log binomial regression was performed to determine if MCR increased the risk of falls separately in each cohort. Random effects meta-analysis was used to pool results from all cohorts.

RESULTS: The mean age of participants was 74.9 (SD 6.8) years and 44% (n = 2728) were male. Overall 33.9% (n = 2104) reported a fall over follow-up. Pooled relative risk of MCR with any falls was RR 1.44 95% CI 1.16, 1.79. The components of MCR, slow gait (RR 1.30 95% CI 1.14, 1.47) and cognitive complaint (RR 1.25, 95% CI 1.07, 1.46) were also associated with an increased risk of any falls. In sub-analyses MCR was associated with any fall independent of previous falls (RR 1.29 95% CI 1.09, 1.53) and with multiple falls (RR 1.77, 95% CI 1.25, 2.51).

CONCLUSION: MCR is associated with an increased risk of falls. The increase in risk was higher than for its individual components. The simplicity of the MCR makes it an attractive falls risk screening tool for the clinic.

%B J Alzheimers Dis %V 53 %P 1043-52 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340851?dopt=Abstract %R 10.3233/JAD-160230 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Moving from the Dish to the Clinical Practice: A Decade of Lessons and Perspectives from the Pre-Clinical and Clinical Stem Cell Studies for Alzheimer's Disease. %A Salem, Haitham %A Rocha, Natalia Pessoa %A Colpo, Gabriela Delevati %A Teixeira, Antonio Lucio %X

To date, there is no definitive treatment for Alzheimer's disease (AD). The realm of stem cells is very promising in regenerative medicine, particularly neurodegenerative disorders. Various types of stem cells have been used in multiple trials on AD models, trying to find an innovative management of this disease. In this systematic review, we trace the published preclinical and clinical data throughout the last decade, to show how much knowledge we gained so far in this field and the future perspectives of stem cells in AD treatment.

%B J Alzheimers Dis %V 53 %P 1209-30 %8 2016 Jul 02 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392861?dopt=Abstract %R 10.3233/JAD-160250 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Multifunctional Effect of Human Serum Albumin Reduces Alzheimer's Disease Related Pathologies in the 3xTg Mouse Model. %A Ezra, Assaf %A Rabinovich-Nikitin, Inna %A Rabinovich-Toidman, Polina %A Solomon, Beka %K Albumins %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Blood-Brain Barrier %K Brain %K Calcium %K Cell Line, Tumor %K Cognition Disorders %K Disease Models, Animal %K Drug Delivery Systems %K Encephalitis %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Neuroblastoma %K Neuropsychological Tests %K Peptide Fragments %K Presenilin-1 %K tau Proteins %X

Alzheimer's disease (AD), the prevalent dementia in the elderly, involves many related and interdependent pathologies that manifests simultaneously, eventually leading to cognitive impairment and death. No treatment is currently available; however, an agent addressing several key pathologies simultaneously has a better therapeutic potential. Human serum albumin (HSA) is a highly versatile protein, harboring multifunctional properties that are relevant to key pathologies underlying AD. This study provides insight into the mechanism for HSA's therapeutic effect. In vivo, a myriad of beneficial effects were observed by pumps infusing HSA intracerebroventricularly, for the first time in an AD 3xTg mice model. A significant effect on amyloid-β (Aβ) pathology was observed. Aβ1-42, soluble oligomers, and total plaque area were reduced. Neuroblastoma SHSY5Y cell line confirmed that the reduction in Aβ1-42 toxicity was due to direct binding rather than other properties of HSA. Total and hyperphosphorylated tau were reduced along with an increase in tubulin, suggesting increased microtubule stability. HSA treatment also reduced brain inflammation, affecting both astrocytes and microglia markers. Finally, evidence for blood-brain barrier and myelin integrity repair was observed. These multidimensional beneficial effects of intracranial administrated HSA, together or individually, contributed to an improvement in cognitive tests, suggesting a non-immune or Aβ efflux dependent means for treating AD.

%B J Alzheimers Dis %V 50 %P 175-88 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682687?dopt=Abstract %R 10.3233/JAD-150694 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Multimodal Classification of Mild Cognitive Impairment Based on Partial Least Squares. %A Wang, Pingyue %A Chen, Kewei %A Yao, Li %A Hu, Bin %A Wu, Xia %A Zhang, Jiacai %A Ye, Qing %A Guo, Xiaojuan %X

In recent years, increasing attention has been given to the identification of the conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD). Brain neuroimaging techniques have been widely used to support the classification or prediction of MCI. The present study combined magnetic resonance imaging (MRI), 18F-fluorodeoxyglucose PET (FDG-PET), and 18F-florbetapir PET (florbetapir-PET) to discriminate MCI converters (MCI-c, individuals with MCI who convert to AD) from MCI non-converters (MCI-nc, individuals with MCI who have not converted to AD in the follow-up period) based on the partial least squares (PLS) method. Two types of PLS models (informed PLS and agnostic PLS) were built based on 64 MCI-c and 65 MCI-nc from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The results showed that the three-modality informed PLS model achieved better classification accuracy of 81.40%, sensitivity of 79.69%, and specificity of 83.08% compared with the single-modality model, and the three-modality agnostic PLS model also achieved better classification compared with the two-modality model. Moreover, combining the three modalities with clinical test score (ADAS-cog), the agnostic PLS model (independent data: florbetapir-PET; dependent data: FDG-PET and MRI) achieved optimal accuracy of 86.05%, sensitivity of 81.25%, and specificity of 90.77%. In addition, the comparison of PLS, support vector machine (SVM), and random forest (RF) showed greater diagnostic power of PLS. These results suggested that our multimodal PLS model has the potential to discriminate MCI-c from the MCI-nc and may therefore be helpful in the early diagnosis of AD.

%B J Alzheimers Dis %V 54 %P 359-71 %8 2016 Aug 10 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567818?dopt=Abstract %R 10.3233/JAD-160102 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Multimodal Magnetic Resonance Imaging in Alzheimer's Disease Patients at Prodromal Stage. %A Eustache, Pierre %A Nemmi, Federico %A Saint-Aubert, Laure %A Pariente, Jérémie %A Péran, Patrice %K Aged %K Alzheimer Disease %K Biomarkers %K Brain %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Female %K Fluorodeoxyglucose F18 %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Multimodal Imaging %K Neuropsychological Tests %K Organ Size %K Positron-Emission Tomography %K Prodromal Symptoms %K Radiopharmaceuticals %X

One objective of modern neuroimaging is to identify markers that can aid in diagnosis, monitor disease progression, and impact long-term drug analysis. In this study, physiopathological modifications in seven subcortical structures of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) were characterized by simultaneously measuring quantitative magnetic resonance parameters that are sensitive to complementary tissue characteristics (e.g., volume atrophy, shape changes, microstructural damage, and iron deposition). Fourteen MCI patients and fourteen matched, healthy subjects underwent 3T-magnetic resonance imaging with whole-brain, T1-weighted, T2*-weighted, and diffusion-tensor imaging scans. Volume, shape, mean R2*, mean diffusivity (MD), and mean fractional anisotropy (FA) in the thalamus, hippocampus, putamen, amygdala, caudate nucleus, pallidum, and accumbens were compared between MCI patients and healthy subjects. Comparisons were then performed using voxel-based analyses of R2*, MD, FA maps, and voxel-based morphometry to determine which subregions showed the greatest difference for each parameter. With respect to the micro- and macro-structural patterns of damage, our results suggest that different and distinct physiopathological processes are present in the prodromal phase of AD. MCI patients had significant atrophy and microstructural changes within their hippocampi and amygdalae, which are known to be affected in the prodromal stage of AD. This suggests that the amygdala is affected in the same, direct physiopathological process as the hippocampus. Conversely, atrophy alone was observed within the thalamus and putamen, which are not directly involved in AD pathogenesis. This latter result may reflect another mechanism, whereby atrophy is linked to indirect physiopathological processes.

%B J Alzheimers Dis %V 50 %P 1035-50 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836151?dopt=Abstract %R 10.3233/JAD-150353 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Multiple Object Test as a Performance Based Tool to Assess Cognitive Driven Activity of Daily Living Function in Parkinson's Disease. %A Glonnegger, Hannah %A Beyle, Aline %A Cerff, Bernhard %A Gräber, Susanne %A Csoti, Ilona %A Berg, Daniela %A Liepelt-Scarfone, Inga %X

BACKGROUND: There is need for multidimensional quantitative assessment of cognitive driven activities of daily living (ADL) functions in Parkinson's disease (PD).

OBJECTIVE: To determine whether there is an ADL profile related to cognitive impairment in PD assessed by the Multiple Object Test (MOT). We assumed MOT performance to be lower in PD patients versus controls and in PD patients with more severe cognitive impairment.

METHODS: 50 PD patients with no cognitive impairment (PD-NC), 54 patients with PD-mild cognitive impairment (PD-MCI), 29 with Parkinson's disease dementia (PDD), and 40 healthy controls (HC) were investigated. Besides comprehensive cognitive testing, the MOT, a performance based test consisting of five routine tasks (e.g., preparing a cup of coffee), was applied. Quantitative (total errors and time) and qualitative (error type) MOT parameters were analyzed.

RESULTS: Total time and number of MOT errors was increased in PD patients compared to controls (p < 0.001). These parameters also differentiated PDD patients from other cognitive groups (p < 0.05). No control subject had ≥ 4 errors in the MOT, but 30% of PD patients, especially PDD, scored above this cut-off. Omission (p < 0.001) and mislocation (p < 0.03) errors were more prominent in PDD than other cognitive groups. Perplexity errors did not differ between PD-MCI and PDD but between PD-NC and PDD (p = 0.01). MOT parameters discriminating between cognitive groups correlated mainly with lower test performance in psychomotor speed and executive function.

CONCLUSION: Performance based testing is promising to identify quantitative and qualitative ADL aspects differentiating between different cognitive groups which might be helpful for an early detection of PDD.

%B J Alzheimers Dis %V 53 %P 1475-84 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392856?dopt=Abstract %R 10.3233/JAD-160173 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Multi-Vitamin B Supplementation Reverses Hypoxia-Induced Tau Hyperphosphorylation and Improves Memory Function in Adult Mice. %A Yu, Lixia %A Chen, Yuan %A Wang, Weiguang %A Xiao, Zhonghai %A Hong, Yan %X

Hypobaric hypoxia (HH) leads to reduced oxygen delivery to brain. It could trigger cognitive dysfunction and increase the risk of dementia including Alzheimer's disease (AD). The present study was undertaken in order to examine whether B vitamins (B6, B12, folate, and choline) could exert protective effects on hypoxia-induced memory deficit and AD related molecular events in mice. Adult male Kunming mice were assigned to five groups: normoxic control, hypoxic model (HH), hypoxia+vitamin B6/B12/folate (HB), hypoxia+choline (HC), hypoxia+vitamin B6/B12/folate+choline (HBC). Mice in the hypoxia, HB, HC, and HBC groups were exposed to hypobaric hypoxia for 8 h/day for 28 days in a decompression chamber mimicking 5500 meters of high altitude. Spatial and passive memories were assessed by radial arm and step-through passive test, respectively. Levels of tau and glycogen synthase kinase (GSK)-3β phosphorylation were detected by western blot. Homocysteine (Hcy) concentrations were determined using enzymatic cycling assay. Mice in the HH group exhibited significant spatial working and passive memory impairment, increased tau phosphorylation at Thr181, Ser262, Ser202/Thr205, and Ser396 in the cortex and hippocampus, and elevated Hcy levels compared with controls. Concomitantly, the levels of Ser9-phosphorylated GSK-3β were significantly decreased in brain after hypoxic treatment. Supplementations of vitamin B6/B12/folate+choline could significantly ameliorate the hypoxia-induced memory deficits, observably decreased Hcy concentrations in serum, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites through upregulating inhibitory Ser9-phosphorylated GSK-3β. Our finding give further insight into combined neuroprotective effects of vitamin B6, B12, folate, and choline on brain against hypoxia.

%B J Alzheimers Dis %V 54 %P 297-306 %8 2016 Aug 04 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497480?dopt=Abstract %R 10.3233/JAD-160329 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Music and Memory in Alzheimer's Disease and The Potential Underlying Mechanisms. %A Peck, Katlyn J %A Girard, Todd A %A Russo, Frank A %A Fiocco, Alexandra J %K Alzheimer Disease %K Auditory Perception %K Autonomic Nervous System %K Dopamine %K Humans %K Memory Disorders %K Music Therapy %X

With population aging and a projected exponential expansion of persons diagnosed with Alzheimer's disease (AD), the development of treatment and prevention programs has become a fervent area of research and discovery. A growing body of evidence suggests that music exposure can enhance memory and emotional function in persons with AD. However, there is a paucity of research that aims to identify specific underlying neural mechanisms associated with music's beneficial effects in this particular population. As such, this paper reviews existing anecdotal and empirical evidence related to the enhancing effects of music exposure on cognitive function and further provides a discussion on the potential underlying mechanisms that may explain music's beneficial effect. Specifically, this paper will outline the potential role of the dopaminergic system, the autonomic nervous system, and the default network in explaining how music may enhance memory function in persons with AD.

%B J Alzheimers Dis %V 51 %P 949-59 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967216?dopt=Abstract %R 10.3233/JAD-150998 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Naphthoquinone-Tryptophan Hybrid Inhibits Aggregation of the Tau-Derived Peptide PHF6 and Reduces Neurotoxicity. %A Frenkel-Pinter, Moran %A Tal, Sharon %A Scherzer-Attali, Roni %A Abu-Hussien, Malak %A Alyagor, Idan %A Eisenbaum, Tal %A Gazit, Ehud %A Segal, Daniel %K Animals %K Carrier Proteins %K Disease Models, Animal %K Drosophila %K Drosophila Proteins %K Eye %K Female %K Humans %K Immunoprecipitation %K In Vitro Techniques %K Larva %K Locomotion %K Mice, Transgenic %K Microscopy, Electron, Scanning %K Naphthoquinones %K Neurotoxicity Syndromes %K Protein Aggregates %K Retinal Pigments %K tau Proteins %K Tryptophan %X

Tauopathies, such as Alzheimer's disease (AD), are a group of disorders characterized neuropathologically by intracellular toxic accumulations of abnormal protein aggregates formed by misfolding of the microtubule-associated protein tau. Since protein self-assembly appears to be an initial key step in the pathology of this group of diseases, intervening in this process can be both a prophylactic measure and a means for modifying the course of the disease for therapeutic purposes. We and others have shown that aromatic small molecules can be effective inhibitors of aggregation of various protein assemblies, by binding to the aromatic core in aggregation-prone motifs and preventing their self-assembly. Specifically, we have designed a series of small aromatic naphthoquinone-tryptophan hybrid molecules as candidate aggregation inhibitors of β -sheet based assembly and demonstrated their efficacy toward inhibiting aggregation of the amyloid-β peptide, another culprit of AD, as well as of various other aggregative proteins involved in other protein misfolding diseases. Here we tested whether a leading naphthoquinone-tryptophan hybrid molecule, namely NQTrp, can be repurposed as an inhibitor of the aggregation of the tau protein in vitro and in vivo. We show that the molecule inhibits the in vitro assembly of PHF6, the aggregation-prone fragment of tau protein, reduces hyperphosphorylated tau deposits and ameliorates tauopathy-related behavioral defect in an established transgenic Drosophila model expressing human tau. We suggest that NQTrp, or optimized versions of it, could act as novel disease modifying drugs for AD and other tauopathies.

%B J Alzheimers Dis %V 51 %P 165-78 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836184?dopt=Abstract %R 10.3233/JAD-150927 %0 Journal Article %J J Alzheimers Dis %D 2016 %T National Trends in Outpatient Antihypertensive Prescribing in People with Dementia in the United States. %A Tan, Edwin C K %A Bell, J Simon %A Lu, Christine Y %A Toh, Sengwee %X

OBJECTIVE: The objectives were to investigate national trends in outpatient antihypertensive prescribing in people with dementia in the United States between 2006 and 2012, and to investigate clinical and demographic factors associated with different antihypertensive prescribing patterns.

METHODS: This was an analysis of the National Ambulatory Medical Care Survey (NAMCS) and the outpatient department component of the National Hospital Ambulatory Medical Care Survey (NHAMCS). Outpatient visits by people aged ≥65 years with documented dementia were analyzed. Complex samples multivariate logistic regression was conducted to estimate temporal trends and adjusted odds ratios (AORs) with 95% confidence intervals (CIs) for factors associated with prescribing of antihypertensives, multiple antihypertensives and different antihypertensive classes.

RESULTS: There was a statistically significant increase in the proportion of physician visits by older people with dementia with a documented diagnosis of hypertension from 49.3% (95% CI: 41.3% -57.4%) in 2006 to 55.7% (95% CI: 50.2% -61.2%) in 2012. There were non-significant increases in overall antihypertensive use and the use of multiple antihypertensive classes. Male sex was associated with any antihypertensive use (AOR 1.37, 95% CI 1.02-1.84) and multiple antihypertensive class use (AOR 1.52, 95% CI 1.14-2.04). Black race (AOR 2.04, 95% CI 1.12-3.71) and Midwest residence (AOR 2.03, 95% CI 1.46-2.82) were associated with multiple antihypertensive use.

CONCLUSION: There was an increase in documented hypertension in physician visits by older people with dementia from 2006 to 2012, but minimal increases in overall antihypertensive use. Various demographic and clinical factors were associated with the prescribing of antihypertensives in people with dementia.

%B J Alzheimers Dis %V 54 %P 1425-1435 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589531?dopt=Abstract %R 10.3233/JAD-160470 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer's Disease. %A Spilman, Patricia R %A Corset, Veronique %A Gorostiza, Olivia %A Poksay, Karen S %A Galvan, Veronica %A Zhang, Junli %A Rao, Rammohan %A Peters-Libeu, Clare %A Vincelette, Jon %A McGeehan, Andrew %A Dvorak-Ewell, Melita %A Beyer, Janine %A Campagna, Jesus %A Bankiewicz, Krystof %A Mehlen, Patrick %A John, Varghese %A Bredesen, Dale E %X

Recent studies have shown that inoculation of susceptible mice with amyloid-β (Aβ) peptides accelerates Aβ deposition in the brain, supporting the idea that Aβ may be self-amplifying; however, the exact mechanism is not understood. Here we provide evidence that Aβ may self-amplify, in part, by inhibiting α-secretase ADAM10 (a disintegrin and metalloprotease) cleavage of full-length Aβ precursor protein (FL AβPP) and therefore allow greater β-secretase processing, and that Aβ itself is a substrate for ADAM10. Exposure of primary neuronal cultures from PDAβPP mice to exogenous rat Aβ1- 40 resulted in increased de novo human Aβ1-42 production and exposure of cells to Aβ decreased production of ADAM10 cleavage product soluble AβPPα (sAβPPα). In a cell-free assay, Aβ decreased ADAM10 cleavage of the chimeric substrate MBP-AβPPC125 and Aβ itself was apparently cleaved by the enzyme. The axonal guidance and trophic factor netrin-1, however, reduced the Aβ1- 40-induced Aβ1-42 increase, increased sAβPPα, and reversed the Aβ-induced sAβPPα decrease in vitro. In vivo, induction of netrin-1 expression in PDAβPPSwe/Ind transgenic mice resulted in reductions in both Aβ1-42 and Aβ1- 40, and ICV delivery of netrin-1 to PDAβPPSwe/Ind mice increased sAβPPα, decreased Aβ, and improved working memory. Finally, to support further study of netrin-1's potential as a therapeutic for Alzheimer's disease, pilot gene therapy studies were performed and a netrin mimetic peptide synthesized and tested that, like netrin, can increase sAβPPα and decrease Aβ1-42in vitro. Taken together, these data provide mechanistic insights into Aβ self-amplification and the ability of netrin-1 to disrupt it.

%B J Alzheimers Dis %V 52 %P 223-42 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060954?dopt=Abstract %R 10.3233/JAD-151046 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neuritic and Diffuse Plaque Associations with Memory in Non-Cognitively Impaired Elderly. %A Malek-Ahmadi, Michael %A Perez, Sylvia E %A Chen, Kewei %A Mufson, Elliott J %X

The presence of Alzheimer's disease (AD)-related neuropathology among cognitively normal individuals has been well documented. It has been proposed that these individuals may represent a pre-clinical AD population. Previous studies have demonstrated a negative association between the presence of both amyloid-β (Aβ) plaques and neurofibrillary tangles with ante-mortem cognitive performance, a relationship which is likely influenced by a number of factors including age and APOE ɛ4 carrier status. The present study determined whether the presence of neuritic plaques (NPs) and diffuse plaques (DPs) are associated with performance in a number of cognitive domains after accounting for APOE ɛ4 carrier status and neurofibrillary tangle presence in a cohort of 123 older participants from the Rush Religious Order Study who died with a premortem clinical diagnosis of no cognitive impairment (NCI). After adjusting for age at death, education, gender, Braak stage, and APOE ɛ4 carrier status, the presence of NPs was associated with lower performance in the cognitive domains of Global Cognition (p = 0.002), Episodic Memory (p = 0.03), Semantic Memory (p = 0.009), and Visuospatial performance (p = 0.006), while DPs showed no association with any cognitive domain examined. These results suggest that decreases in cognition in elderly NCI individuals are associated with an increase in NPs and not DPs when age at death, education, gender, APOE ɛ4 status, and Braak stage are taken into consideration.

%B J Alzheimers Dis %V 53 %P 1641-52 %8 2016 Jul 14 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27540968?dopt=Abstract %R 10.3233/JAD-160365 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neurocognitive Deficits Distinguishing Mild Dementia with Lewy Bodies from Mild Alzheimer's Disease are Associated with Parkinsonism. %A Brønnick, Kolbørn %A Breitve, Monica H %A Rongve, Arvid %A Aarsland, Dag %X

BACKGROUND: The cognitive profile of mild dementia with Lewy bodies (DLB) versus mild Alzheimer's disease (AD) has not been extensively studied, and the relation of cognitive deficits to the core diagnostic criteria for DLB (fluctuations, visual hallucinations, and parkinsonism) remains poorly understood.

OBJECTIVE: To compare the cognitive profile in patients with mild DLB to patients with mild AD and investigate the relation between cognitive deficits distinguishing DLB from AD and the core diagnostic features in DLB.

METHODS: Patients with mild dementia were recruited from the southwestern part of Norway and patients diagnosed with probable AD (n = 113) or probable DLB (n = 77) were included. The DLB core diagnostic symptoms were assessed using standardized clinical measures, and standardized neurocognitive tests assessing attention, language, memory, and visuospatial functions were administered. Univariate and multivariate comparisons of cognitive tests were performed, and tests distinguishing between AD and DLB were subjected to correlational analyses with the core diagnostic symptoms.

RESULTS: DLB patients performed worse than AD patients on test of visuoconstruction, but not visual perception and on all tests involving attention and executive functions, except verbal fluency. The multivariate model distinguished between DLB and AD with a sensitivity of 74% and a specificity of 82%. Tests where DLB performed worse than AD were highly correlated with degree of parkinsonism, but not with cognitive fluctuations or visual hallucinations.

CONCLUSIONS: The cognitive profile in mild DLB can be useful in distinguishing AD from DLB. The strong relation between relative deficits in DLB and parkinsonism warrants further studies.

%B J Alzheimers Dis %V 53 %P 1277-85 %8 2016 Jun 30 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372647?dopt=Abstract %R 10.3233/JAD-160294 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neurodegeneration-Like Pathological and Behavioral Changes in an AAV9-Mediated p25 Overexpression Mouse Model. %A Zhou, Xiao %A Huang, Jianou %A Pan, Suyue %A Xu, Miaojing %A He, Rongni %A Ji, Zhong %A Hu, Yafang %X

BACKGROUND: The transgenic mice models overexpressing human p25 contribute greatly to the in vivo neurotoxic mechanism of p25 in neurodegenerative diseases. However, it is time-consuming to manipulate existing transgenic mice models.

OBJECTIVE: Here we aim to establish a novel mouse model of neurodegeneration by overexpressing p25 mediated by recombinant adeno-associated virus serotype 9 (rAAV9).

METHODS: AAV9-GFP-p25 encoding GFP-fused p25 driven by synapsin promoter, and the control, AAV9-GFP, were delivered in mice by tail-vein injection. Assessments of p25 expression, neurodegenerative pathology, and behavioral changes were performed.

RESULTS: GFP expression was detected by in vivo imaging as early as one week after virus injection. Notably, widespread expression of p25 was obviously found in cortex, hippocampus, and cerebellum in AAV9-GFP-p25 mice. Moreover, decreased hippocampus volumes in AAV9-GFP-p25 mice were detected by 7T MRI examination about one month after injection. Further, these AAV9-GFP-p25 mice exhibited progressive memory impairment from three-month to six-month after virus injection. At last, hyperphosphorylated tau, neurofibrillary tangles, activated astrocytes and microglia cells were elevated in these p25 mice at about six months after virus delivery. However, amyloid-β plaques, overt neuronal loss, and apoptosis in the hippocampus and cortex were not significantly induced by AAV9-mediated p25 overexpression.

CONCLUSION: The AAV9-mediated p25 overexpression mouse model, which is a practical model exhibiting neurodegeneration-like pathological and behavioral changes, provides an easier and time-saving method to explore the functions of p25 in vivo, as well as an alternative tool for development of drugs against neurotoxic of p25.

%B J Alzheimers Dis %V 53 %P 843-55 %8 2016 May 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258419?dopt=Abstract %R 10.3233/JAD-160191 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations. %A Luis, Elkin %A Ortiz, Alexandra %A Eudave, Luis %A Ortega-Cubero, Sara %A Borroni, Barbara %A van der Zee, Julie %A Gazzina, Stefano %A Caroppo, Paola %A Rubino, Elisa %A D'Agata, Federico %A Le Ber, Isabelle %A Santana, Isabel %A Cunha, Gil %A Almeida, Maria R %A Boutoleau-Bretonnière, Claire %A Hannequin, Didier %A Wallon, David %A Rainero, Innocenzo %A Galimberti, Daniela %A Van Broeckhoven, Christine %A Pastor, María A %A Pastor, Pau %X

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1), among other genes. Rare SQSTM1 gene mutations have been associated with Paget's disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD).

OBJECTIVE: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction.

METHODS: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD; n = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n = 20). The groups were matched according to current age, disease duration, and gender.

RESULTS: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres.

CONCLUSIONS: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern.

%B J Alzheimers Dis %V 53 %P 303-13 %8 2016 May 07 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163810?dopt=Abstract %R 10.3233/JAD-160006 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neuronal activity and amyloid plaque pathology: an update. %A Ovsepian, Saak V %A O'Leary, Valerie B %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid Precursor Protein Secretases %K Amyloidosis %K Animals %K Disease Models, Animal %K Humans %K Mice %K Mice, Transgenic %K Neurons %K Plaque, Amyloid %K Prosencephalon %K Seizures %X

A breakthrough in Alzheimer's disease (AD) research came with the discovery of the link between activity-dependent release of amyloid-β (Aβ) from neurons and formation of amyloid plaques. Along with elucidating the cellular basis of behavioral-dependent fluctuations in Aβ levels in the brain, insights have been gained toward understanding the mechanisms that warrant selective vulnerability of various forebrain circuits to amyloid pathology. The notion of elevated activity as a source of excessive Aβ production and plaque formation is, however, in conflict with ample electrophysiological data, which demonstrate exceedingly intense activity (both intrinsic and synaptic) of neurons in several brain regions that are spared or marginally affected by amyloid plaques of AD. Thus, the link between the functional load of brain circuits and their vulnerability to amyloidosis, while evident, is also complex and remains poorly understood. Here, we discuss emerging data suggestive of a major role for super-intense synchronous activity of cortical and limbic networks in excessive Aβ production and plaque formation. It is proposed that dense recurrent wiring of associative areas prone to epileptic seizures might be of critical relevance to their higher susceptibility to plaque pathology and related functional impairments.

%B J Alzheimers Dis %V 49 %P 13-9 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444792?dopt=Abstract %R 10.3233/JAD-150544 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neurophysiological assessment of Alzheimer's disease individuals by a single electroencephalographic marker. %A Lizio, Roberta %A Del Percio, Claudio %A Marzano, Nicola %A Soricelli, Andrea %A Yener, Görsev G %A Başar, Erol %A Mundi, Ciro %A De Rosa, Salvatore %A Triggiani, Antonio Ivano %A Ferri, Raffaele %A Arnaldi, Dario %A Nobili, Flavio Mariano %A Cordone, Susanna %A Lopez, Susanna %A Carducci, Filippo %A Santi, Giulia %A Gesualdo, Loreto %A Rossini, Paolo M %A Cavedo, Enrica %A Mauri, Margherita %A Frisoni, Giovanni B %A Babiloni, Claudio %K Aged %K Alzheimer Disease %K Biomarkers %K Brain Mapping %K Case-Control Studies %K Cognition Disorders %K Electroencephalography %K Female %K Humans %K Italy %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Occipital Lobe %K Rest %K ROC Curve %K Turkey %X

Here we presented a single electroencephalographic (EEG) marker for a neurophysiological assessment of Alzheimer's disease (AD) patients already diagnosed by current guidelines. The ability of the EEG marker to classify 127 AD individuals and 121 matched cognitively intact normal elderly (Nold) individuals was tested. Furthermore, its relationship to AD patients' cognitive status and structural brain integrity was examined. Low-resolution brain electromagnetic tomography (LORETA) freeware estimated cortical sources of resting state eyes-closed EEG rhythms. The EEG marker was defined as the ratio between the activity of parieto-occipital cortical sources of delta (2-4 Hz) and low-frequency alpha (8-10.5 Hz) rhythms. Results showed 77.2% of sensitivity in the recognition of the AD individuals; 65% of specificity in the recognition of the Nold individuals; and 0.75 of area under the receiver-operating characteristic curve. Compared to the AD subgroup with the EEG maker within one standard deviation of the Nold mean (EEG-), the AD subgroup with EEG+ showed lower global cognitive status, as revealed by Mini-Mental State Evaluation score, and more abnormal values of white-matter and cerebrospinal fluid normalized volumes, as revealed by structural magnetic resonance imaging. We posit that cognitive and functional status being equal, AD patients with EEG+ should receive special clinical attention due to a neurophysiological "frailty". EEG+ label can be also used in clinical trials (i) to form homogeneous groups of AD patients diagnosed by current guidelines and (ii) as end-point to evaluate intervention effects.

%B J Alzheimers Dis %V 49 %P 159-77 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444753?dopt=Abstract %R 10.3233/JAD-143042 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neuropsychological Features of Microbleeds and Cortical Microinfarct Detected by High Resolution Magnetic Resonance Imaging. %A Ueda, Yukito %A Satoh, Masayuki %A Tabei, Ken-Ichi %A Kida, Hirotaka %A Ii, Yuichiro %A Asahi, Masaru %A Maeda, Masayuki %A Sakuma, Hajime %A Tomimoto, Hidekazu %X

BACKGROUND: Lobar microbleeds (MBs) and cortical microinfarct (CMI) are caused by cerebral amyloid angiopathy in the elderly and increase in number in Alzheimer's disease.

OBJECTIVE: The aim of this study is to elucidate the effects of lobar MBs and CMIs on cognitive function.

METHODS: The subjects were outpatients who visited the memory clinic of Mie University Hospital. Among 120 subjects, 109 patients fulfilled the inclusion criteria. We quantitatively estimated MBs and CMIs using double inversion recovery and 3D FLAIR images of 3T MRI. Neuropsychological assessments included intellectual, memory, constructional, and frontal lobe function.

RESULTS: Of the 109 patients, MBs and CMIs were observed in 68 (62%) and 17 (16%) subjects, respectively. Of the 68 patients with MBs, lobar MBs were found in 28, deep MBs in 8 and mixed MBs in 31. In each age group, the number of MBs increased in patients with CMI (CMI+ group) than those without CMI (CMI- group), and MBs and CMIs additively decreased MMSE scores. In psychological screens, the MBs+ group with more than 10 MBs showed significantly lower scores of category- and letter-WF than MB- group. The CMI+ group showed significantly worse scores than CMI- group in Japanese Raven's coloured progressive matrices, Trail Making Test-A, category- and letter-word fluency and copy and drawing of figures.

CONCLUSION: Lobar MBs and CMIs in the elderly frequently coexisted with each other and additively contributed to cognitive impairment, which is mainly predisposed to frontal lobe function.

%B J Alzheimers Dis %V 53 %P 315-25 %8 2016 May 07 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163803?dopt=Abstract %R 10.3233/JAD-151008 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neuropsychological Markers of Medial Perirhinal and Entorhinal Cortex Functioning are Impaired Twelve Years Preceding Diagnosis of Alzheimer's Dementia. %A Hirni, Daniela I %A Kivisaari, Sasa L %A Krumm, Sabine %A Monsch, Andreas U %A Berres, Manfred %A Oeksuez, Fatma %A Reinhardt, Julia %A Ulmer, Stephan %A Kressig, Reto W %A Stippich, Christoph %A Taylor, Kirsten I %X

Neurofibrillary pathology in Alzheimer's dementia (AD) is associated with cognitive impairments and cortical thinning, and begins in medial perirhinal cortex (mPRC) before entering entorhinal cortex (ERC). Thus, mPRC dysfunction (e.g., semantic object memory impairments) may predate or accompany ERC (i.e., episodic memory) dysfunction in the preclinical course of typical AD. We developed formulae estimating mPRC and ERC integrity (i.e., cortical thickness) using common neuropsychological tests in 31 healthy individuals and 58 early AD patients. These formulae estimated the longitudinal courses of mPRC and ERC functioning in independent groups of 28 optimally healthy individuals who developed AD (NC-AD) over 2.8-13.4 years and 28 pairwise-matched, stable, healthy individuals (NC-NC). Mixed models demonstrated significantly worse NC-AD than NC-NC estimated mPRC and ERC functioning at the earliest observation, 12 years preceding diagnosis, and a significant decline 4 years preceding the AD diagnosis. These findings demonstrate that specific neuropsychological impairments occur early in the course of preclinical AD and that tasks measuring mPRC functioning may serve as additional, powerful markers of preclinical AD.

%B J Alzheimers Dis %V 52 %P 573-80 %8 2016 Mar 26 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031465?dopt=Abstract %R 10.3233/JAD-150158 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Non Fluent Variant of Primary Progressive Aphasia Due to the Novel GRN g.9543delA(IVS3-2delA) Mutation. %A Cioffi, Sara M G %A Galimberti, Daniela %A Barocco, Federica %A Spallazzi, Marco %A Fenoglio, Chiara %A Serpente, Maria %A Arcaro, Marina %A Gardini, Simona %A Scarpini, Elio %A Caffarra, Paolo %X

Mutations in progranulin gene (GRN) are a common cause of autosomal dominant frontotemporal lobar degeneration syndromes and are associated with a wide phenotypic heterogeneity. The majority of genetic defects in GRN consists of loss-of-function mutations, causing haploinsufficiency, and is associated with extremely low plasma progranulin levels. Herein, we describe a patient who developed language dysfunctions and memory disturbances at 63 years of age. Considering the early onset and the positive family history (sister aged 50 with non-fluent/agrammatic variant of primary progressive aphasia, father with behavioral disturbances in his sixties), a genetic analysis was carried out, showing the presence of a novel mutation [g.9543delA (IVS3-2delA)] in a predicted splicing site of GRN. Her progranulin plasma levels were under the reference threshold, as in her sister, thus supporting the causative role of the new variant. The same genetic mutation was confirmed by sequencing in her sister. Results described enlarge current knowledge on genetic causes of the disease and clinical characteristics of carriers.

%B J Alzheimers Dis %V 54 %P 717-21 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567822?dopt=Abstract %R 10.3233/JAD-160185 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Non-Catalytic Roles of Presenilin Throughout Evolution. %A Otto, Grant P %A Sharma, Devdutt %A Williams, Robin S B %X

Research into Alzheimer's disease pathology and treatment has often focused on presenilin proteins. These proteins provide the key catalytic activity of the γ-secretase complex in the cleavage of amyloid-β precursor protein and resultant amyloid tangle deposition. Over the last 25 years, screening novel drugs to control this aberrant proteolytic activity has yet to identify effective treatments for the disease. In the search for other mechanisms of presenilin pathology, several studies have demonstrated that mammalian presenilin proteins also act in a non-proteolytic role as a scaffold to co-localize key signaling proteins. This role is likely to represent an ancestral presenilin function, as it has been described in genetically distant species including non-mammalian animals, plants, and a simple eukaryotic amoeba Dictyostelium that diverged from the human lineage over a billion years ago. Here, we review the non-catalytic scaffold role of presenilin, from mammalian models to other biomedical models, and include recent insights using Dictyostelium, to suggest that this role may provide an early evolutionary function of presenilin proteins.

%B J Alzheimers Dis %V 52 %P 1177-87 %8 2016 Apr 12 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079701?dopt=Abstract %R 10.3233/JAD-150940 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Non-Fibrillar Oligomeric Amyloid-β within Synapses. %A Pickett, Eleanor K %A Koffie, Robert M %A Wegmann, Susanne %A Henstridge, Christopher M %A Herrmann, Abigail G %A Colom-Cadena, Marti %A Lleo, Alberto %A Kay, Kevin R %A Vaught, Melissa %A Soberman, Roy %A Walsh, Dominic M %A Hyman, Bradley T %A Spires-Jones, Tara L %X

Alzheimer's disease (AD) is characterized by memory loss, insidious cognitive decline, profound neurodegeneration, and the extracellular accumulation of amyloid-β (Aβ) peptide in senile plaques and intracellular accumulation of tau in neurofibrillary tangles. Loss and dysfunction of synapses are believed to underlie the devastating cognitive decline in AD. A large amount of evidence suggests that oligomeric forms of Aβ associated with senile plaques are toxic to synapses, but the precise sub-synaptic localization of Aβ and which forms are synaptotoxic remain unknown. Here, we characterize the sub-synaptic localization of Aβ oligomers using three high-resolution imaging techniques, stochastic optical reconstruction microscopy, immunogold electron microscopy, and Förster resonance energy transfer in a plaque-bearing mouse model of AD. With all three techniques, we observe oligomeric Aβ inside synaptic terminals. Further, we tested a panel of Aβ antibodies using the relatively high-throughput array tomography technique to determine which forms are present in synapses. Our results show that different oligomeric Aβ species are present in synapses and highlight the potential of array tomography for rapid testing of aggregation state specific Aβ antibodies in brain tissue.

%B J Alzheimers Dis %V 53 %P 787-800 %8 2016 May 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258414?dopt=Abstract %R 10.3233/JAD-160007 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Non-Verbal Episodic Memory Deficits in Primary Progressive Aphasias are Highly Predictive of Underlying Amyloid Pathology. %A Ramanan, Siddharth %A Flanagan, Emma %A Leyton, Cristian E %A Villemagne, Victor L %A Rowe, Christopher C %A Hodges, John R %A Hornberger, Michael %K Aged %K Alzheimer Disease %K Amyloid %K Aniline Compounds %K Aphasia, Primary Progressive %K Brain %K Diagnosis, Differential %K Female %K Humans %K Logistic Models %K Male %K Memory, Episodic %K Neuropsychological Tests %K Positron-Emission Tomography %K Radiopharmaceuticals %K Speech Perception %K Thiazoles %X

Diagnostic distinction of primary progressive aphasias (PPA) remains challenging, in particular for the logopenic (lvPPA) and nonfluent/agrammatic (naPPA) variants. Recent findings highlight that episodic memory deficits appear to discriminate these PPA variants from each other, as only lvPPA perform poorly on these tasks while having underlying amyloid pathology similar to that seen in amnestic dementias like Alzheimer's disease (AD). Most memory tests are, however, language based and thus potentially confounded by the prevalent language deficits in PPA. The current study investigated this issue across PPA variants by contrasting verbal and non-verbal episodic memory measures while controlling for their performance on a language subtest of a general cognitive screen. A total of 203 participants were included (25 lvPPA; 29 naPPA; 59 AD; 90 controls) and underwent extensive verbal and non-verbal episodic memory testing, with a subset of patients (n = 45) with confirmed amyloid profiles as assessed by Pittsburgh Compound B and PET. The most powerful discriminator between naPPA and lvPPA patients was a non-verbal recall measure (Rey Complex Figure delayed recall), with 81% of PPA patients classified correctly at presentation. Importantly, AD and lvPPA patients performed comparably on this measure, further highlighting the importance of underlying amyloid pathology in episodic memory profiles. The findings demonstrate that non-verbal recall emerges as the best discriminator of lvPPA and naPPA when controlling for language deficits in high load amyloid PPA cases.

%B J Alzheimers Dis %V 51 %P 367-76 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890745?dopt=Abstract %R 10.3233/JAD-150752 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Normal Amplitude of Electroretinography and Visual Evoked Potential Responses in AβPP/PS1 Mice. %A Leinonen, Henri %A Lipponen, Arto %A Gurevicius, Kestutis %A Tanila, Heikki %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Contrast Sensitivity %K Disease Models, Animal %K Electroencephalography %K Electroretinography %K Evoked Potentials, Visual %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Photic Stimulation %K Presenilin-1 %K Reaction Time %X

Alzheimer's disease has been shown to affect vision in human patients and animal models. This may pose the risk of bias in behavior studies and therefore requires comprehensive investigation. We recorded electroretinography (ERG) under isoflurane anesthesia and visual evoked potentials (VEP) in awake amyloid expressing AβPPswe/PS1dE9 (AβPP/PS1) and wild-type littermate mice at a symptomatic age. The VEPs in response to patterned stimuli were normal in AβPP/PS1 mice. They also showed normal ERG amplitude but slightly shortened ERG latency in dark-adapted conditions. Our results indicate subtle changes in visual processing in aged male AβPP/PS1 mice specifically at a retinal level.

%B J Alzheimers Dis %V 51 %P 21-6 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836173?dopt=Abstract %R 10.3233/JAD-150798 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Novel and Intelligent Home Monitoring System for Care Support of Elders with Cognitive Impairment. %A Lazarou, Ioulietta %A Karakostas, Anastasios %A Stavropoulos, Thanos G %A Tsompanidis, Theodoros %A Meditskos, Georgios %A Kompatsiaris, Ioannis %A Tsolaki, Magda %X

BACKGROUND: Assistive technology, in the form of a smart home environment, is employed to support people with dementia.

OBJECTIVES: To propose a system for continuous and objective remote monitoring of problematic daily living activity areas and design personalized interventions based on system feedback and clinical observations for improving cognitive function and health-related quality of life.

METHODS: The assistive technology of the proposed system, including wearable, sleep, object motion, presence, and utility usage sensors, was methodically deployed at four different home installations of people with cognitive impairment. Detection of sleep patterns, physical activity, and activities of daily living, based on the collected sensor data and analytics, was available at all times through comprehensive data visualization solutions. Combined with clinical observation, targeted psychosocial interventions were introduced to enhance the participants' quality of life and improve their cognitive functions and daily functionality. Meanwhile, participants and their caregivers were able to visualize a reduced set of information tailored to their needs.

RESULTS: Overall, paired-sample t-test analysis of monitored qualities revealed improvement for all participants in neuropsychological assessment. Moreover, improvement was detected from the beginning to the end of the trial, in physical condition and in the domains of sleep. Detecting abnormalities via the system, for example in sleep quality, such as REM sleep, has proved to be critical to assess current status, drive interventions, and evaluate improvements in a reliable manner.

CONCLUSION: It has been proved that the proposed system is suitable to support clinicians to reliably drive and evaluate clinical interventions toward quality of life improvement of people with cognitive impairment.

%B J Alzheimers Dis %V 54 %P 1561-1591 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636843?dopt=Abstract %R 10.3233/JAD-160348 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Novel Liposomal Nanoparticle for the Imaging of Amyloid Plaque by Magnetic Resonance Imaging. %A Tanifum, Eric A %A Ghaghada, Ketan %A Vollert, Craig %A Head, Elizabeth %A Eriksen, Jason L %A Annapragada, Ananth %X

Amyloid binding molecules with greater hydrophilicity than existing ligands were synthesized. The lead candidate ET6-21 bound amyloid fibrils, and amyloid deposits in dog brain and human brain tissue ex vivo. The ligand was used to prepare novel amyloid-targeted liposomal nanoparticles. The preparation was tested in the Tg2576 and TetO/APP mouse models of amyloid deposition. Gd chelates and Indocyanine green were included in the particles for visualization by MRI and near-infrared microscopy. Upon intravenous injection, the particles successfully traversed the blood-brain barrier in these mice, and bound to the plaques. Magnetic resonance imaging (T1-MRI) conducted 4 days after injection demonstrated elevated signal in the brains of mice with amyloid plaques present. No signal was observed in amyloid-negative mice, or in amyloid-positive mice injected with an untargeted version of the same agent. The MRI results were confirmed by immunohistochemical and fluorescent microscopic examination of mouse brain sections, showing colocalization of the fluorescent tags and amyloid deposits.

%B J Alzheimers Dis %V 52 %P 731-45 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031484?dopt=Abstract %R 10.3233/JAD-151124 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Novel Mutation (Gly212Val) in the PS2 Gene Associated with Early-Onset Familial Alzheimer's Disease. %A Marín-Muñoz, Juan %A Noguera-Perea, Ma Fuensanta %A Gómez-Tortosa, Estrella %A López-Motos, David %A Antequera-Torres, Martirio %A Martínez-Herrada, Begoña %A Manzanares-Sánchez, Salvadora %A Vivancos-Moreau, Laura %A Legaz-García, Agustina %A Rábano-Gutiérrez Del Arroyo, Alberto %A Antúnez-Almagro, Carmen %X

Mutations in the presenilin 2 gene (PS2) are an extremely rare cause of early-onset autosomal dominant Alzheimer's disease (AD), accounting for only 5% of these families. These cases represent a particular model of AD, and the scarcity of reports on their clinical phenotypes makes them of great interest. We report a family with early-onset autosomal dominant AD in four members, where the two living siblings were found to carry the novel PS2 mutation Gly212Val (exon 7, transmembrane domain IV) with highly predicted pathogenicity. Age at onset ranged from 60 to 65 years and three of the cases died between ages 74 and 76 years. Clinical phenotype was quite homogeneous among affected members of the family, and overall features, including cognitive decline, tau/p-tau and amyloid-β cerebrospinal fluid markers, neuroimaging, and neuropathology were consistent with typical AD. Lewy bodies were present but restricted to the amygdala.

%B J Alzheimers Dis %V 53 %P 73-8 %8 2016 Apr 25 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128372?dopt=Abstract %R 10.3233/JAD-160050 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer's Disease. %A Fà, Mauro %A Zhang, Hong %A Staniszewski, Agnieszka %A Saeed, Faisal %A Shen, Li W %A Schiefer, Isaac T %A Siklos, Marton I %A Tapadar, Subhasish %A Litosh, Vladislav A %A Libien, Jenny %A Petukhov, Pavel A %A Teich, Andrew F %A Thatcher, Gregory R J %A Arancio, Ottavio %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Cysteine Proteinase Inhibitors %K Disease Models, Animal %K Dose-Response Relationship, Drug %K Fear %K Glycoproteins %K Hippocampus %K Humans %K In Vitro Techniques %K Long-Term Potentiation %K Maze Learning %K Memory %K Mice %K Mice, Inbred ICR %K Mice, Transgenic %K Mutation %K Patch-Clamp Techniques %K Peptide Fragments %K Presenilin-1 %K Spectrin %X

Alzheimer's disease, one of the most important brain pathologies associated with neurodegenerative processes, is related to overactivation of calpain-mediated proteolysis. Previous data showed a compelling efficacy of calpain inhibition against abnormal synaptic plasticity and memory produced by the excess of amyloid-β, a distinctive marker of the disease. Moreover, a beneficial effect of calpain inhibitors in Alzheimer's disease is predictable by the occurrence of calpain hyperactivation leading to impairment of memory-related pathways following abnormal calcium influxes that might ensue independently of amyloid-β elevation. However, molecules currently available as effective calpain inhibitors lack adequate selectivity. This work is aimed at characterizing the efficacy of a novel class of epoxide-based inhibitors, synthesized to display improved selectivity and potency towards calpain 1 compared to the prototype epoxide-based generic calpain inhibitor E64. Both functional and preliminary toxicological investigations proved the efficacy, potency, and safety of the novel and selective calpain inhibitors NYC438 and NYC488 as possible therapeutics against the disease.

%B J Alzheimers Dis %V 49 %P 707-21 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484927?dopt=Abstract %R 10.3233/JAD-150618 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Novel Small Molecule Modulator of Amyloid Pathology. %A Lovell, Mark A %A Lynn, Bert C %A Fister, Shuling %A Bradley-Whitman, Melissa %A Murphy, M Paul %A Beckett, Tina L %A Norris, Christopher M %X

Because traditional approaches to drug development for Alzheimer's disease are becoming increasingly expensive and in many cases disappointingly unsuccessful, alternative approaches are required to shift the paradigm. Following leads from investigations of dihydropyridine calcium channel blockers, we observed unique properties from a class of functionalized naphthyridines and sought to develop these as novel therapeutics that minimize amyloid pathology without the adverse effects associated with current therapeutics. Our data show methyl 2,4-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carboxylate (BNC-1) significantly decreases amyloid burden in a well-established mouse model of amyloid pathology through a unique mechanism mediated by Elk-1, a transcriptional repressor of presenilin-1. Additionally, BNC-1 treatment leads to increased levels of synaptophysin and synapsin, markers of synaptic integrity, but does not adversely impact presenilin-2 or processing of Notch-1, thus avoiding negative off target effects associated with pan-gamma secretase inhibition. Overall, our data show BNC-1 significantly decreases amyloid burden and improves markers of synaptic integrity in a well-established mouse model of amyloid deposition by promoting phosphorylation and activation of Elk-1, a transcriptional repressor of presenilin-1 but not presenilin-2. These data suggest BNC-1 might be a novel, disease-modifying therapeutic that will alter the pathogenesis of Alzheimer's disease.

%B J Alzheimers Dis %V 53 %P 273-87 %8 2016 May 04 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163808?dopt=Abstract %R 10.3233/JAD-151160 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy. %A Sassi, Celeste %A Capozzo, Rosa %A Gibbs, Raphael %A Crews, Cynthia %A Zecca, Chiara %A Arcuti, Simona %A Copetti, Massimiliano %A Barulli, Maria R %A Brescia, Vincenzo %A Singleton, Andrew B %A Logroscino, Giancarlo %X

Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24 ng/ml) compared to controls (142.7 ng/ml) or family members non-carriers (82.0 ng/ml) (p-value = 0.005, Kruskal Wallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c.709-2 A>T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations.

%B J Alzheimers Dis %V 53 %P 475-85 %8 2016 May 30 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258413?dopt=Abstract %R 10.3233/JAD-151170 %0 Journal Article %J J Alzheimers Dis %D 2016 %T N-Terminal Pro-B-Type Natriuretic Peptide and Risk of Future Cognitive Impairment in the REGARDS Cohort. %A Cushman, Mary %A Callas, Peter W %A McClure, Leslie A %A Unverzagt, Frederick W %A Howard, Virginia J %A Gillett, Sarah R %A Thacker, Evan L %A Wadley, Virginia G %X

BACKGROUND: Improved understanding of the etiology of cognitive impairment is needed to develop effective preventive interventions. Higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac dysfunction associated with risk of cardiovascular diseases and stroke in apparently healthy people.

OBJECTIVE: To study the association of NT-proBNP with risk of incident cognitive impairment.

METHODS: The Reasons for Geographic and Racial Differences in Stroke is a national cohort study of 30,239 black and white Americans age 45 and older at baseline, enrolled in 2003-7. Among participants without prebaseline stroke or cognitive impairment, baseline NT-proBNP was measured in 470 cases of incident cognitive impairment and 557 controls. Cases were participants scoring below the 6th percentile of demographically-adjusted means on at least 2 of 3 serially administered tests (word list learning, word list recall and semantic fluency) over 3.5 years follow-up.

RESULTS: Adjusting for age, gender, race, region of residence, education, and income, there was an increased odds ratio of incident cognitive impairment with increasing NT-proBNP; participants in the 4th versus 1st quartile (>127 versus ≤33 pg/ml) had a 1.69-fold increased odds (95% CI 1.11-2.58). Adjustment for cardiovascular risk factors and presence of an apolipoprotein E4 allele had no substantial impact on the odds ratio. Results did not differ by age, race, gender, or presence of an apolipoprotein E4 allele.

CONCLUSION: Higher NT-pro-BNP was associated with incident cognitive impairment in this prospective study, independent of atherogenic and Alzheimer's disease risk factors. Future work should clarify pathophysiologic connections of NT-proBNP and cognitive dysfunction.

%B J Alzheimers Dis %V 54 %P 497-503 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567834?dopt=Abstract %R 10.3233/JAD-160328 %0 Journal Article %J J Alzheimers Dis %D 2016 %T N-truncated Aβ2-X starting with position two in sporadic Alzheimer's disease cases and two Alzheimer mouse models. %A Savastano, Adriana %A Klafki, Hans %A Haußmann, Ute %A Oberstein, Timo Jan %A Muller, Petr %A Wirths, Oliver %A Wiltfang, Jens %A Bayer, Thomas A %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Blotting, Western %K Brain %K Cerebral Amyloid Angiopathy %K Disease Models, Animal %K Female %K Humans %K Male %K Mice %K Mice, Transgenic %K Plaque, Amyloid %X

According to the modified amyloid hypothesis, the key event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid β-peptides (Aβs) in plaques and cerebral blood vessels. Additionally to full-length peptides, a great diversity of N-truncated Aβ variants is derived from the larger amyloid-β protein precursor (AβPP). Vast evidence suggests that Aβx-42 isoforms play an important role in triggering neurodegeneration due to their high abundance, amyloidogenic propensity and toxicity. Although N-truncated Aβ peptides and Aβx-42 species appear to be the crucial players in AD etiology, the Aβ2-X isoforms did not receive much attention yet. The present study is the first to show immunohistochemical evidence of Aβ2-X in cases of AD and its distribution in AβPP/PS1KI and 5XFAD transgenic mouse models using a novel antibody pAB77 that has been developed using Aβ2-14 as antigen. Positive plaques and congophilic amyloid angiopathy (CAA) were observed in AD cases and in both mouse models. While in AD cases, abundant CAA and less pronounced plaque pathology was evident, the two mouse models showed predominantly extracellular Aβ deposits and minor CAA staining. Western blotting and a capillary isoelectric focusing immunoassay demonstrated the high specificity of the antibody pAb77 against Aβ-variants starting with the N-terminal Alanine-2.

%B J Alzheimers Dis %V 49 %P 101-10 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26529393?dopt=Abstract %R 10.3233/JAD-150394 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Nutritional Status is Associated with Faster Cognitive Decline and Worse Functional Impairment in the Progression of Dementia: The Cache County Dementia Progression Study1. %A Sanders, Chelsea %A Behrens, Stephanie %A Schwartz, Sarah %A Wengreen, Heidi %A Corcoran, Chris D %A Lyketsos, Constantine G %A Tschanz, JoAnn T %K Age of Onset %K Aged, 80 and over %K Alzheimer Disease %K Dementia, Vascular %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K Nutritional Status %K Severity of Illness Index %K Sex Factors %K Utah %X

Nutritional status may be a modifiable factor in the progression of dementia. We examined the association of nutritional status and rate of cognitive and functional decline in a U.S. population-based sample. Study design was an observational longitudinal study with annual follow-ups up to 6 years of 292 persons with dementia (72% Alzheimer's disease, 56% female) in Cache County, UT using the Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-sb), and modified Mini Nutritional Assessment (mMNA). mMNA scores declined by approximately 0.50 points/year, suggesting increasing risk for malnutrition. Lower mMNA score predicted faster rate of decline on the MMSE at earlier follow-up times, but slower decline at later follow-up times, whereas higher mMNA scores had the opposite pattern (mMNA by time β= 0.22, p = 0.017; mMNA by time2 β= -0.04, p = 0.04). Lower mMNA score was associated with greater impairment on the CDR-sb over the course of dementia (β= 0.35, p <  0.001). Assessment of malnutrition may be useful in predicting rates of progression in dementia and may provide a target for clinical intervention.

%B J Alzheimers Dis %V 52 %P 33-42 %8 2016 02 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967207?dopt=Abstract %R 10.3233/JAD-150528 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Nutritional Status of Patients with Alzheimer's Disease and Their Caregivers. %A Tombini, Mario %A Sicari, Maura %A Pellegrino, Giovanni %A Ursini, Francesca %A Insardá, Pasqualina %A Di Lazzaro, Vincenzo %X

BACKGROUND: Malnutrition is one of the most important conditions that negatively affects the health of elder people, particularly in patients with dementia.

OBJECTIVE: To provide an assessment of nutritional status of patients affected by Alzheimer's disease (AD) living at home and of their caregivers by means of Mini Nutritional Assessment (MNA), and to explore the influence of different factors on nutrition.

METHODS: 90 patients affected by AD living at home and 90 age- and sex-matched caregivers were enrolled. Patients and caregivers, coming from an urban-rural fringe of Southern Italy, were assessed using full MNA, Mini-Mental State Examination, Geriatric Depression Scale- short form, Activity of Daily Living, and Instrumental Activities of Daily Living scales.

RESULTS: Malnutrition was found with high prevalence in patients affected by AD of different severity (more than 95% of patients were malnourished or at risk of malnutrition), and associated with reduced functional status. An altered nutrition was also recognized with high rate in the group of caregivers (23.3% were malnourished and 41.1% at risk of malnutrition) and the worse nutritional condition was correlated with higher age and lower functional and cognitive status and education. A positive correlation between MNA score of AD patients and caregivers was found.

CONCLUSION: Corrective measures should be taken in order to early identify nutritional deficiencies and risk of malnutrition observed with high rate in both groups of AD patients and their caregivers; in these subjects a nutrition education program and intervention policies are mandatory to restore nutritional status.

%B J Alzheimers Dis %V 54 %P 1619-1627 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636839?dopt=Abstract %R 10.3233/JAD-160261 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Oculodentodigital dysplasia with massive brain calcification and a new mutation of GJA1 gene. %A Tumminelli, Gemma %A Di Donato, Ilaria %A Guida, Valentina %A Rufa, Alessandra %A De Luca, Alessandro %A Federico, Antonio %K Basal Ganglia %K Calcinosis %K Connexin 43 %K Craniofacial Abnormalities %K DNA Mutational Analysis %K Eye Abnormalities %K Fingers %K Foot Deformities, Congenital %K Humans %K Male %K Middle Aged %K Mutation, Missense %K Syndactyly %K Tomography, X-Ray Computed %K Tooth Abnormalities %X

Oculodentodigital dysplasia (ODDD) [MIM 164200] is a rare disorder caused by mutations in the gap junction alpha 1 (GJA1) gene encoding for connexin 43 (Cx43). Typical signs include type III syndactyly, microphtalmia, microdontia, and neurological disturbances. We report a 59-year-old man having clinical symptoms and signs suggestive of ODDD, with some rarely reported features, that is the presence of gross calcifications of basal ganglia and cerebellar nuclei. Mutation analysis of GJA1 gene identified an unreported heterozygous missense mutation [NM_000165.3:c.124 G>C;p.(Glu42Gln)], which may be thought to alter the brain microvessels leading to massive calcifications, as in primary familial brain calcification.

%B J Alzheimers Dis %V 49 %P 27-30 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444782?dopt=Abstract %R 10.3233/JAD-150424 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Older Adults Taking AT1-Receptor Blockers Exhibit Reduced Cerebral Amyloid Retention. %A Nation, Daniel A %A Ho, Jean %A Yew, Belinda %K Aged %K Aged, 80 and over %K Aging %K Amyloid beta-Peptides %K Angiotensin Receptor Antagonists %K Antihypertensive Agents %K Chi-Square Distribution %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Peptide Fragments %K Psychiatric Status Rating Scales %K Regression Analysis %K tau Proteins %K Time Factors %X

BACKGROUND: Evidence suggests that angiotensin II AT1-receptor blockers (ARBs) may be protective against dementia, and studies in transgenic animals indicate that this may be due to improved amyloid-β (Aβ) clearance.

OBJECTIVE: We investigated whether taking ARBs was associated with an attenuation of age-related increases in cerebral Aβ retention, and reduced progression to dementia.

METHODS: Eight hundred seventy-one stroke-free and dementia-free older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study underwent baseline lumbar puncture, and a subgroup (n = 124) underwent 12 and 24 month follow-up lumbar puncture. Participants were followed at variable intervals for clinical progression to dementia. Linear mixed models and ANCOVA compared ARBs users with those taking other antihypertensives (O-antiHTN) or no antihypertensives (No-antiHTN) on cerebrospinal fluid (CSF) Aβ and phosphorylated tau (P-tau) levels. Cox regression and chi-square analyses compared groups on progression to dementia.

RESULTS: ARBs users exhibited greater vascular risk and lower educational attainment than the No-antiHTN group. Longitudinal analyses indicated higher CSF Aβ and lower P-tau in ARBs users versus other groups. Cross-sectional analyses revealed age-related decreases in CSF Aβ in other groups but not ARBs users. ARBs users were less likely to progress to dementia and showed reduced rate of progression relative to the No-antiHTN group.

DISCUSSION: Patients taking ARBs showed an attenuation of age-related decreases in CSF Aβ, a finding that is consistent with studies done in transgenic animals. These findings may partly explain why ARBs users show reduced progression to dementia despite their lower educational attainment and greater vascular risk burden.

%B J Alzheimers Dis %V 50 %P 779-89 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757036?dopt=Abstract %R 10.3233/JAD-150487 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. %A Oulhaj, Abderrahim %A Jernerén, Fredrik %A Refsum, Helga %A Smith, A David %A de Jager, Celeste A %K Aged %K Aged, 80 and over %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Fatty Acids, Omega-3 %K Female %K Humans %K Male %K Neuropsychological Tests %K Treatment Outcome %K Vitamin B Complex %X

A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD.

%B J Alzheimers Dis %V 50 %P 547-57 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757190?dopt=Abstract %R 10.3233/JAD-150777 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Online Environment: A Key Variable in the Ethical Response to Complementary and Alternative Medicine for Alzheimer's Disease. %A Robillard, Julie M %K Alzheimer Disease %K Complementary Therapies %K Humans %X

Racine et al.'s Ethics Review highlights the challenges associated with the use of complementary and alternative medicine (CAM) in the context of early diagnosis of Alzheimer's disease (AD). As CAM are increasingly promoted and sold on the Internet, the unregulated online environment has the potential to significantly impact the health and well-being of the aging demographic, and in particular of individuals concerned about AD. In this response, the ethical challenges specific to the online environment are discussed and solutions are put forward to empower the aging population to maximize the benefits of the online environment while minimizing the potential harms of misinformation, conflict of interest, and other ethical concerns.

%B J Alzheimers Dis %V 51 %P 11-3 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836156?dopt=Abstract %R 10.3233/JAD-150641 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Optimization of Statistical Single Subject Analysis of Brain FDG PET for the Prognosis of Mild Cognitive Impairment-to-Alzheimer's Disease Conversion. %A Lange, Catharina %A Suppa, Per %A Frings, Lars %A Brenner, Winfried %A Spies, Lothar %A Buchert, Ralph %K Aged %K Alzheimer Disease %K Area Under Curve %K Brain %K Cognitive Dysfunction %K Disease Progression %K Female %K Fluorodeoxyglucose F18 %K Follow-Up Studies %K Glucose %K Humans %K Image Interpretation, Computer-Assisted %K Male %K Positron-Emission Tomography %K Prognosis %K Radiopharmaceuticals %K ROC Curve %X

BACKGROUND: Positron emission tomography (PET) with the glucose analog F-18-fluorodeoxyglucose (FDG) is widely used in the diagnosis of neurodegenerative diseases. Guidelines recommend voxel-based statistical testing to support visual evaluation of the PET images. However, the performance of voxel-based testing strongly depends on each single preprocessing step involved.

OBJECTIVE: To optimize the processing pipeline of voxel-based testing for the prognosis of dementia in subjects with amnestic mild cognitive impairment (MCI).

METHODS: The study included 108 ADNI MCI subjects grouped as 'stable MCI' (n = 77) or 'MCI-to-AD converter' according to their diagnostic trajectory over 3 years. Thirty-two ADNI normals served as controls. Voxel-based testing was performed with the statistical parametric mapping software (SPM8) starting with default settings. The following modifications were added step-by-step: (i) motion correction, (ii) custom-made FDG template, (iii) different reference regions for intensity scaling, and (iv) smoothing was varied between 8 and 18 mm. The t-sum score for hypometabolism within a predefined AD mask was compared between the different settings using receiver operating characteristic (ROC) analysis with respect to differentiation between 'stable MCI' and 'MCI-to-AD converter'. The area (AUC) under the ROC curve was used as performance measure.

RESULTS: The default setting provided an AUC of 0.728. The modifications of the processing pipeline improved the AUC up to 0.832 (p = 0.046). Improvement of the AUC was confirmed in an independent validation sample of 241 ADNI MCI subjects (p = 0.048).

CONCLUSION: The prognostic value of voxel-based single subject analysis of brain FDG PET in MCI subjects can be improved considerably by optimizing the processing pipeline.

%B J Alzheimers Dis %V 49 %P 945-59 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26577523?dopt=Abstract %R 10.3233/JAD-150814 %0 Journal Article %J J Alzheimers Dis %D 2016 %T An Optimized Combination of Ginger and Peony Root Effectively Inhibits Amyloid-β Accumulation and Amyloid-β-Mediated Pathology in AβPP/PS1 Double-Transgenic Mice. %A Lim, Soonmin %A Choi, Jin Gyu %A Moon, Minho %A Kim, Hyo Geun %A Lee, Wonil %A Bak, Hyoung-Rok %A Sung, Hachang %A Park, Chi Hye %A Kim, Sun Yeou %A Oh, Myung Sook %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Analysis of Variance %K Animals %K Cyclooxygenase 2 %K Disease Models, Animal %K Dose-Response Relationship, Drug %K Ginger %K Glial Fibrillary Acidic Protein %K Humans %K Male %K Mice %K Mice, Transgenic %K Mutation %K Paeonia %K Phytotherapy %K Plant Preparations %K Plaque, Amyloid %K Presenilin-1 %X

The progressive aggregation of amyloid-β protein (Aβ) into senile plaques is a major pathological factor of Alzheimer's disease (AD) and is believed to result in memory impairment. We aimed to investigate the effect of an optimized combination of ginger and peony root (OCGP), a standardized herbal mixture of ginger and peony root, on Aβ accumulation and memory impairment in amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) double-transgenic mice. In an in vitro thioflavin T fluorescence assay, 100 μg/ml OCGP inhibited Aβ accumulation to the same extent as did 10 μM curcumin. Furthermore, AβPP/PS1 double-transgenic mice treated with OCGP (50 or 100 mg/kg/day given orally for 14 weeks) exhibited reduced Aβ plaque accumulation in the hippocampus and lower levels of glial fibrillary acid protein and cyclooxygease-2 expression compared with vehicle-treated controls. These results suggest that OCGP may prevent memory impairment in AD by inhibiting Aβ accumulation and inflammation in the brain.

%B J Alzheimers Dis %V 50 %P 189-200 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639976?dopt=Abstract %R 10.3233/JAD-150839 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Optimized Standard Operating Procedures for the Analysis of Cerebrospinal Fluid Aβ42 and the Ratios of Aβ Isoforms Using Low Protein Binding Tubes. %A Vanderstichele, Hugo Marcel Johan %A Janelidze, Shorena %A Demeyer, Leentje %A Coart, Els %A Stoops, Erik %A Herbst, Victor %A Mauroo, Kimberley %A Brix, Britta %A Hansson, Oskar %X

BACKGROUND: Reduced cerebrospinal fluid (CSF) concentration of amyloid-β1-42 (Aβ1-42) reflects the presence of amyloidopathy in brains of subjects with Alzheimer's disease (AD).

OBJECTIVE: To qualify the use of Aβ1-42/Aβ1-40 for improvement of standard operating procedures (SOP) for measurement of CSF Aβ with a focus on CSF collection, storage, and analysis.

METHODS: Euroimmun ELISAs for CSF Aβ isoforms were used to set up a SOP with respect to recipient properties (low binding, polypropylene), volume of tubes, freeze/thaw cycles, addition of detergents (Triton X-100, Tween-20) in collection or storage tubes or during CSF analysis. Data were analyzed with linear repeated measures and mixed effects models.

RESULTS: Optimization of CSF analysis included a pre-wash of recipients (e.g., tubes, 96-well plates) before sample analysis. Using the Aβ1-42/Aβ1-40 ratio, in contrast to Aβ1-42, eliminated effects of tube type, additional freeze/thaw cycles, or effect of CSF volumes for polypropylene storage tubes. 'Low binding' tubes reduced the loss of Aβ when aliquoting CSF or in function of additional freeze/thaw cycles. Addition of detergent in CSF collection tubes resulted in an almost complete absence of variation in function of collection procedures, but affected the concentration of Aβ isoforms in the immunoassay.

CONCLUSION: The ratio of Aβ1-42/Aβ1-40 is a more robust biomarker than Aβ1-42 toward (pre-) analytical interfering factors. Further, 'low binding' recipients and addition of detergent in collection tubes are able to remove effects of SOP-related confounding factors. Integration of the Aβ1-42/Aβ1-40 ratio and 'low-binding tubes' into guidance criteria may speed up worldwide standardization of CSF biomarker analysis.

%B J Alzheimers Dis %V 53 %P 1121-32 %8 2016 May 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258423?dopt=Abstract %R 10.3233/JAD-160286 %0 Journal Article %J J Alzheimers Dis %D 2016 %T An Oral Aβ Vaccine Using a Recombinant Adeno-Associated Virus Vector in Aged Monkeys: Reduction in Plaque Amyloid and Increase in Aβ Oligomers. %A Hara, Hideo %A Ono, Fumiko %A Nakamura, Shinichiro %A Matsumoto, Shin-Ei %A Jin, Haifeng %A Hattori, Nobutaka %A Tabira, Takeshi %X

With the objective to improve the amyloid-β (Aβ) targeting immunotherapy, we investigated the safety and efficacy of an oral vaccine with recombinant adeno-associated virus vector carrying a signal sequence and Aβ1-43 cDNA (rAAV/Aβ) in old non-human primates, 12 African green and 10 cynomolgus monkeys. The enteric-dissolving coated capsules containing rAAV/Aβ were orally administered once or twice, then monkeys' conditions were carefully observed with complete blood count and laboratory examinations of the sera. General conditions, food intake, water intake, stool conditions, body weight changes, and menstruation cycles were not significantly altered, and laboratory tests and pathological examinations of the systemic organs were unremarkable. Pathological examinations of the brain showed significant reduction of the amyloid plaque burden and intracellular Aβ without inflammatory or hemorrhagic changes in the brain. However, soluble Aβ and some Aβ oligomers were increased in rAAV-treated monkey brains without changes of the neuronal density and vascular amyloidosis. Thus, this vaccine seems to be safe in general, but we must be cautious about the increase of Aβ oligomers after vaccination. This vaccine may be recommended at a very early stage of Alzheimer's disease when little amyloid is deposited.

%B J Alzheimers Dis %V 54 %P 1047-1059 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567868?dopt=Abstract %R 10.3233/JAD-160514 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Oral Infections and Cytokine Levels in Patients with Alzheimer's Disease and Mild Cognitive Impairment Compared with Controls. %A Cestari, José Augusto Ferrari %A Fabri, Gisele Maria Campos %A Kalil, Jorge %A Nitrini, Ricardo %A Jacob-Filho, Wilson %A de Siqueira, José Tadeu Tesseroli %A Siqueira, Silvia Regina D T %X

BACKGROUND: Oral infections are prevalent in the adult population. Their impact includes the implication as a risk factor for Alzheimer's disease (AD), altering its progression. One of the potential mechanisms involves immune mediators such as circulating cytokines.

OBJECTIVE: The goal of the present study was to investigate the prevalence of oral infections and blood levels of IL-1β, TNF-α, and IL-6 in patients with AD, mild cognitive impairment (MCI), and controls.

METHODS: Sixty-five elderly were evaluated (25 AD, 19 MCI, and 21 controls) by the following methods: Mini Mental State Exam, Questionnaire of Functional Activities, periodontal and oral evaluation, and blood concentrations of IL-1β, TNF-α and IL-6.

RESULTS: Patients with AD had high serum IL-6 levels (p = 0.029), and patients with periodontitis had high serum TNF-α levels (p = 0.005). There was an association between IL-6 and TNF-α in patients with AD/MCI and periodontitis (p = 0.023).

CONCLUSION: The increased levels of TNF-α and IL-6 in this study suggests their implication in the overlapping mechanisms between oral infections and AD. Longitudinal studies are necessary for further investigation.

%B J Alzheimers Dis %V 52 %P 1479-85 %8 2016 Apr 19 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104907?dopt=Abstract %R 10.3233/JAD-160212 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Oral Iron Chelator, Deferasirox, Reverses the Age-Dependent Alterations in Iron and Amyloid-β Homeostasis in Rat Brain: Implications in the Therapy of Alzheimer's Disease. %A Banerjee, Priyanjalee %A Sahoo, Arghyadip %A Anand, Shruti %A Bir, Aritri %A Chakrabarti, Sasanka %K Administration, Oral %K Aging %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Benzoates %K Brain %K Ferritins %K Gene Expression Regulation %K Iron %K Iron Chelating Agents %K Neprilysin %K NF-kappa B %K Oxidative Stress %K Peptide Fragments %K Protein Carbonylation %K Rats %K Rats, Wistar %K Receptors, Transferrin %K Spectrophotometry %K Triazoles %X

The altered metabolism of iron impacts the brain function in multiple deleterious ways during normal aging as well as in Alzheimer's disease. We have shown in this study that chelatable iron accumulates in the aged rat brain along with overexpression of transferrin receptor 1 (TfR1) and ferritin, accompanied by significant alterations in amyloid-β (Aβ) peptide homeostasis in the aging brain, such as an increased production of the amyloid-β protein precursor, a decreased level of neprilysin, and increased accumulation of Aβ42. When aged rats are given daily the iron chelator, deferasirox, over a period of more than 4 months starting from the 18th month, the age-related accumulation of iron and overexpression of TfR1 and ferritin in the brain are significantly prevented. More interestingly, the chelator treatment also considerably reverses the altered Aβ peptide metabolism in the aging brain implying a significant role of iron in the latter phenomenon. Further, other results indicate that iron accumulation results in oxidative stress and the activation of NF-κB in the aged rat brain, which are also reversed by the deferasirox treatment. The analysis of the results together suggests that iron accumulation and oxidative stress interact at multiple levels that include transcriptional and post-transcriptional mechanisms to bring about changes in the expression levels of TfR1 and ferritin and also alterations in Aβ peptide metabolism in the aging rat brain. The efficacy of deferasirox in preventing age-related changes in iron and Aβ peptide metabolism in the aging brain, as shown here, has obvious therapeutic implications for Alzheimer's disease.

%B J Alzheimers Dis %V 49 %P 681-93 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484920?dopt=Abstract %R 10.3233/JAD-150514 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Outstanding Phenotypic Differences in the Profile of Amyloid-β between Tg2576 and APPswe/PS1dE9 Transgenic Mouse Models of Alzheimer's Disease. %A Allué, José Antonio %A Sarasa, Leticia %A Izco, María %A Pérez-Grijalba, Virginia %A Fandos, Noelia %A Pascual-Lucas, María %A Ogueta, Samuel %A Pesini, Pedro %A Sarasa, Manuel %X

APPswe/PS1dE9 and Tg2576 are very common transgenic mouse models of Alzheimer's disease (AD), used in many laboratories as tools to research the mechanistic process leading to the disease. In order to augment our knowledge about the amyloid-β (Aβ) isoforms present in both transgenic mouse models, we have developed two chromatographic methods, one acidic and the other basic, for the characterization of the Aβ species produced in the brains of the two transgenic mouse models. After immunoprecipitation and micro-liquid chromatography-electrospray ionization mass spectrometry/mass spectrometry, 10 species of Aβ, surprisingly all of human origin, were detected in the brain of Tg2576 mouse, whereas 39 species, of both murine and human origin, were detected in the brain of the APP/PS1 mouse. To the best of our knowledge, this is the first study showing the identification of such a high number of Aβ species in the brain of the APP/PS1 transgenic mouse, whereas, in contrast, a much lower number of Aβ species were identified in the Tg2576 mouse. Therefore, this study brings to light a relevant phenotypic difference between these two popular mice models of AD.

%B J Alzheimers Dis %V 53 %P 773-85 %8 2016 May 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258422?dopt=Abstract %R 10.3233/JAD-160280 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Overexpression of Metallothionein-1 Modulates the Phenotype of the Tg2576 Mouse Model of Alzheimer's Disease. %A Manso, Yasmina %A Comes, Gemma %A López-Ramos, Juan C %A Belfiore, Mónica %A Molinero, Amalia %A Giralt, Mercedes %A Carrasco, Javier %A Adlard, Paul A %A Bush, Ashley I %A Delgado-García, José María %A Hidalgo, Juan %K Age Factors %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Anxiety %K Disease Models, Animal %K Exploratory Behavior %K Female %K Gene Expression Regulation %K Humans %K Male %K Matrix Metalloproteinase 16 %K Maze Learning %K Metallothionein %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Motor Activity %K Mutation %K Phenotype %K Psychomotor Disorders %X

Alzheimer's disease (AD) is the most commonly diagnosed dementia, where signs of neuroinflammation and oxidative stress are prominent. In this study we intend to further characterize the roles of the antioxidant, anti-inflammatory, and heavy metal binding protein, metallothionein-1 (MT-1), by crossing Mt1 overexpressing mice with a well-known mouse model of AD, Tg2576 mice, which express the human amyloid-β protein precursor (hAβPP) with the Swedish K670N/M671L mutations. Mt1 overexpression increased overall perinatal survival, but did not affect significantly hAβPP-induced mortality and weight loss in adult mice. Amyloid plaque burden in ∼14-month-old mice was increased by Mt1 overexpression in the hippocampus but not the cortex. Despite full length hAβPP levels and amyloid plaques being increased by Mt1 overexpression in the hippocampus of both sexes, oligomeric and monomeric forms of Aβ, which may contribute more to toxicity, were decreased in the hippocampus of females and increased in males. Several behavioral traits such as exploration, anxiety, and learning were altered in Tg2576 mice to various degrees depending on the age and the sex. Mt1 overexpression ameliorated the effects of hAβPP on exploration in young females, and potentiated those on anxiety in old males, and seemed to improve the rate of spatial learning (Morris water maze) and the learning elicited by a classical conditioning procedure (eye-blink test). These results clearly suggest that MT-1 may be involved in AD pathogenesis.

%B J Alzheimers Dis %V 51 %P 81-95 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836194?dopt=Abstract %R 10.3233/JAD-151025 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Pain Assessment in Elderly with Behavioral and Psychological Symptoms of Dementia. %A Malara, Alba %A De Biase, Giuseppe Andrea %A Bettarini, Francesco %A Ceravolo, Francesco %A Di Cello, Serena %A Garo, Michele %A Praino, Francesco %A Settembrini, Vincenzo %A Sgrò, Giovanni %A Spadea, Fausto %A Rispoli, Vincenzo %K Affect %K Aged, 80 and over %K Analgesics %K Anxiety %K Dementia %K Depression %K Female %K Humans %K Italy %K Logistic Models %K Long-Term Care %K Male %K Multivariate Analysis %K Nursing Homes %K Pain %K Pain Measurement %K Prevalence %K Prospective Studies %K Psychiatric Status Rating Scales %K Self Report %K Severity of Illness Index %X

BACKGROUND: Pain is under-detected and undertreated in people with dementia. The present study investigates the prevalence of pain in people with dementia hospitalized in nursing homes that are members of National Association of Third Age Residences (ANASTE) Calabria, and evaluates the association among pain, mood, and behavioral and psychological symptoms of dementia (BPSD).

OBJECTIVE: The aim of this study is to define the prevalence of pain in people with dementia in long term care facilities using scales of self-reporting and observational tools and, particularly, to study the relationship between pain and BPSD.

METHODS: A prospective observational study was carried out on 233 patients. Pain assessment was performed using self-reporting tools such as the Numeric Rating Scale (NRS) for patients with slight cognitive impairment or no cognitive impairment and observational tools such as Pain Assessment In Advanced Dementia Scale (PAINAD) for patients with moderate or severe cognitive impairment. Mood was evaluated through the Cornell Scale for Depression in Dementia (CSDD) while behavioral problems were assessed through the Cohen-Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory (NPI).

RESULTS: Only 42.5% of patients evaluated by NRS provided a reliable answer; of these, 20.4% reported no pain. The percentage of pain evaluated by PAINAD was 51.8% . Analysis of data showed a statistically significant correlation between diagnosis of pain and depressive symptoms, assessed with CSDD (p = 0.0113), as well as by single items of NPI, such as anxiety (p = 0.0362) and irritability (p = 0.0034), and F1 profile (Aggression) of CMAI (p = 0.01).

CONCLUSION: This study confirms that self-report alone is not sufficient to assess pain in elderly people with dementia; the observational tool is a necessary and suitable way of assessing pain in patients with cognitive impairment. If not adequately treated, chronic pain can cause depression, agitation, and aggression in patients with dementia.

%B J Alzheimers Dis %V 50 %P 1217-25 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757042?dopt=Abstract %R 10.3233/JAD-150808 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Paired Studies Comparing Clinical Profiles of Lewy Body Dementia with Alzheimer's and Parkinson's Diseases. %A Scharre, Douglas W %A Chang, Shu-Ing %A Nagaraja, Haikady N %A Park, Ariane %A Adeli, Anahita %A Agrawal, Punit %A Kloos, Anne %A Kegelmeyer, Deb %A Linder, Shannon %A Fritz, Nora %A Kostyk, Sandra K %A Kataki, Maria %X

Limited data compares clinical profiles of Lewy Body Dementia (LBD) with Alzheimer's disease (AD) and Parkinson's disease (PD). Twenty-one mildly demented ambulatory LBD subjects were individually matched by MMSE score with 21 AD subjects and by UPDRS motor score with 21 PD subjects. Matched by age, gender, education, and race, pairs were compared using cognitive, functional, behavioral, and motor measures. LBD group performed worse than PD on axial motor, gait, and balance measures. AD had more amnesia and orientation impairments, but less executive and visuospatial deficits than LBD subjects. LBD group had more sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea than AD or PD. Axial motor, gait, and balance disturbances correlated with executive, visuospatial, and global cognition deficits. LBD is differentiated from AD and PD by retrieval memory, visuospatial, and executive deficits; axial motor, gait and balance impairments; sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea.

%B J Alzheimers Dis %V 54 %P 995-1004 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567844?dopt=Abstract %R 10.3233/JAD-160384 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Palmomental Reflex a Relevant Sign in Early Alzheimer's Disease Diagnosis? %A Gabelle, Audrey %A Gutierrez, Laure-Anne %A Dartigues, Jean-François %A Ritchie, Karen %A Touchon, Jacques %A Berr, Claudine %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cohort Studies %K Early Diagnosis %K Female %K Follow-Up Studies %K France %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Reflex %X

BACKGROUND: Sophisticated and expensive biomarkers are proposed for the diagnostic of Alzheimer's disease (AD). The amyloid process seems to be early in AD, and brain amyloid load affects the frontal lobe.

OBJECTIVE: To determine if certain simple clinical signs, especially frontal-related signs, could help reach an earlier and better diagnosis.

METHODS: In the frame of the 3-City cohort, we conducted a nested case-control study comparing incident cases of AD to controls matched for age, gender, and education. The standardized neurological exam included extrapyramidal signs (akinesia, rigidity, rest tremor), pyramidal symptoms (spastic rigidity, Babinski reflex), primitive reflexes (snout, palmomental reflex grasping), and tremor (essential, intentional, head) at the time of diagnosis and two years before.

RESULTS: We compared 106 incident AD subjects (mean age at diagnosis 82.2 (SD = 5.9); median MMSE at diagnosis = 23) to 208 matched controls. In patients younger than 80, palmomental reflexes were more frequent in AD than controls, two years before diagnosis (25.0 versus 7.0% , p = 0.03) and at time of diagnosis (30.3 versus 12.3% , p = 0.02). No difference was observed for other signs two years before diagnosis or for patients older than 80.

CONCLUSION: Before diagnosis, the clinical examination of AD patients is not strictly normal; the primitive reflexes appear to be pathological. It might be in connection with the frontal amyloid load at an early stage of the disease. Clinical examination can reveal simple and interesting signs that deserve consideration as well as the other more invasive and expensive biomarkers.

%B J Alzheimers Dis %V 49 %P 1135-41 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639955?dopt=Abstract %R 10.3233/JAD-150436 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Parkinsonism Differentiates Idiopathic Normal Pressure Hydrocephalus from Its Mimics. %A Allali, Gilles %A Garibotto, Valentina %A Assal, Frèdèric %X

BACKGROUND: Parkinsonism is frequent in neurological conditions affecting gait and cognition, such as idiopathic normal pressure hydrocephalus (iNPH) and iNPH mimics, but its discriminating value between these two groups is still unidentified.

OBJECTIVE: This study aims to compare the prevalence of parkinsonism between iNPH and iNPH mimics and its discriminating value.

METHODS: Among 141 patients with suspicion of iNPH (75.7±7.1 years; 31.2% women), seventy-nine presented a possible or probable iNPH according to standardized diagnostic criteria and the remaining sixty-two were classified as iNPH mimics. Presence of parkinsonism and other seminal clinical symptoms of iNPH were systematically evaluated by a board-certified neurologist. Covariates include age, gender, comorbidities, and white matter disease burden using the age-related white matter changes scale. Logistic regressions were used to assess the association between parkinsonism and diagnostic groups.

RESULTS: Parkinsonism was present in 40.3% of iNPH mimics and 20.3% of iNPH (p-value: 0.015). The presence of parkinsonism, but not iNPH symptoms, was associated with the diagnosis of mimics in the adjusted model (adjusted odds ratio: 2.28; 95% CI: 1.06-4.93), even when age-related white matter changes were accounted for.

CONCLUSION: Compared to iNPH, the increased prevalence of parkinsonism in patients with iNPH mimics in the absence of significant white matter disease suggest an underlying neurodegenerative mechanism.

%B J Alzheimers Dis %V 54 %P 123-7 %8 2016 Jul 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472883?dopt=Abstract %R 10.3233/JAD-160428 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Partial Amelioration of Synaptic and Cognitive Deficits by Inhibiting Cofilin Dephosphorylation in an Animal Model of Alzheimer's Disease. %A Deng, Yulei %A Wei, Jing %A Cheng, Jia %A Zhong, Ping %A Xiong, Zhe %A Liu, Aiyi %A Lin, Lin %A Chen, Shengdi %A Yan, Zhen %X

The loss of synaptic structure and function has been linked to the cognitive impairment of Alzheimer's disease (AD). Dysregulation of the actin cytoskeleton, which plays a key role in regulating the integrity of synapses and the transport of synaptic proteins, has been suggested to contribute to the pathology of AD. In this study, we found that glutamate receptor surface expression and synaptic function in frontal cortical neurons were significant diminished in a familial AD (FAD) model, which was correlated with the reduction of phosphorylated cofilin, a key protein regulating the dynamics of actin filaments. Injecting a cofilin dephosphorylation inhibitory peptide to FAD mice led to the partial rescue of the surface expression of AMPA and NMDA receptor subunits, as well as the partial restoration of AMPAR- and NMDAR-mediated synaptic currents. Moreover, the impaired working memory and novel object recognition memory in FAD mice were partially ameliorated by injections of the cofilin dephosphorylation inhibitory peptide. These results suggest that targeting the cofilin-actin signaling holds promise to mitigate the physiological and behavioral abnormality in AD.

%B J Alzheimers Dis %V 53 %P 1419-32 %8 2016 Jun 28 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372643?dopt=Abstract %R 10.3233/JAD-160167 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Pathway Based Classification Method for Analyzing Gene Expression for Alzheimer's Disease Diagnosis. %A Voyle, Nicola %A Keohane, Aoife %A Newhouse, Stephen %A Lunnon, Katie %A Johnston, Caroline %A Soininen, Hilkka %A Kloszewska, Iwona %A Mecocci, Patrizia %A Tsolaki, Magda %A Vellas, Bruno %A Lovestone, Simon %A Hodges, Angela %A Kiddle, Steven %A Dobson, Richard Jb %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoproteins E %K Cohort Studies %K Datasets as Topic %K Female %K Gene Expression %K Gene Expression Profiling %K Humans %K Male %K Models, Genetic %K Oligonucleotide Array Sequence Analysis %K Signal Transduction %X

BACKGROUND: Recent studies indicate that gene expression levels in blood may be able to differentiate subjects with Alzheimer's disease (AD) from normal elderly controls and mild cognitively impaired (MCI) subjects. However, there is limited replicability at the single marker level. A pathway-based interpretation of gene expression may prove more robust.

OBJECTIVES: This study aimed to investigate whether a case/control classification model built on pathway level data was more robust than a gene level model and may consequently perform better in test data. The study used two batches of gene expression data from the AddNeuroMed (ANM) and Dementia Case Registry (DCR) cohorts.

METHODS: Our study used Illumina Human HT-12 Expression BeadChips to collect gene expression from blood samples. Random forest modeling with recursive feature elimination was used to predict case/control status. Age and APOE ɛ4 status were used as covariates for all analysis.

RESULTS: Gene and pathway level models performed similarly to each other and to a model based on demographic information only.

CONCLUSIONS: Any potential increase in concordance from the novel pathway level approach used here has not lead to a greater predictive ability in these datasets. However, we have only tested one method for creating pathway level scores. Further, we have been able to benchmark pathways against genes in datasets that had been extensively harmonized. Further work should focus on the use of alternative methods for creating pathway level scores, in particular those that incorporate pathway topology, and the use of an endophenotype based approach.

%B J Alzheimers Dis %V 49 %P 659-69 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484910?dopt=Abstract %R 10.3233/JAD-150440 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Patients that have Undergone Hemodialysis Exhibit Lower Amyloid Deposition in the Brain: Evidence Supporting a Therapeutic Strategy for Alzheimer's Disease by Removal of Blood Amyloid. %A Sakai, Kazuyoshi %A Senda, Takao %A Hata, Ryuji %A Kuroda, Makoto %A Hasegawa, Midori %A Kato, Masao %A Abe, Masato %A Kawaguchi, Kazunori %A Nakai, Shigeru %A Hiki, Yoshiyuki %A Yuzawa, Yukio %A Kitaguchi, Nobuya %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Autopsy %K Brain %K Case-Control Studies %K Humans %K Kidney Diseases %K Plaque, Amyloid %K Renal Dialysis %K Silver Staining %K Statistics, Nonparametric %X

As a proof of concept that removal of blood amyloid-β (Aβ) can reduce Aβ deposition in the brains of patients with Alzheimer's disease, cortices of patients who had undergone hemodialysis (HD), which removes Aβ from the blood, were histochemically analyzed; postmortem brain sections were stained with anti-Aβ antibodies. Brains from patients who had undergone HD had significantly fewer senile plaques than those of patient who had not undergone HD. This significant difference was also confirmed by silver staining. Our findings suggest that removal of blood Aβ by hemodialysis results in lower accumulation of Aβ in the brain.

%B J Alzheimers Dis %V 51 %P 997-1002 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923028?dopt=Abstract %R 10.3233/JAD-151139 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Patients with Amyloid-Negative Mild Cognitive Impairment have Cortical Hypometabolism but the Hippocampus is Preserved. %A Hanseeuw, Bernard %A Dricot, Laurence %A Lhommel, Renaud %A Quenon, Lisa %A Ivanoiu, Adrian %X

BACKGROUND: Patients with mild cognitive impairment (MCI) are at risk for Alzheimer's dementia but the presence of amyloid (Aβ) strongly increases this risk. In clinical settings, when Aβ status is not available, different neurodegenerative markers are used to characterize MCI. The accuracy of these markers to discriminate between Aβ-and Aβ+ MCI is not yet determined.

OBJECTIVE: To compare different markers of neurodegeneration in Aβ-and Aβ+ MCI, with an Aβ-elderly control (EC) group.

METHODS: Patients with MCI (n = 39) and EC (n = 28) underwent MRI, 18F-FDG PET, and Aβ PET (18F-flutemetamol). We compared FDG and MRI biomarker values in cortical and hippocampal regions of interest, and using voxel-wise surface maps. We computed ROC curves discriminating between the three groups for each biomarker.

RESULTS: All biomarker values were reduced in Aβ+ MCI compared to EC (p < 0.001). Aβ-MCI had low cortical metabolism (p = 0.002), but hippocampal volume, cortical thickness, and hippocampal metabolism were not significantly different between Aβ-MCI and EC (p > 0.40). Cortical metabolism best discriminated between MCI and EC (AUC = 0.92/0.86, Aβ+/Aβ-) while hippocampal volume best discriminated between Aβ-MCI and Aβ+ MCI (AUC = 0.79).

CONCLUSIONS: Cortical hypometabolism was observed in both Aβ-MCI and Aβ+ MCI whereas hippocampal atrophy was mostly found in Aβ+ MCI. For MCI patients without available Aβ information, hippocampal atrophy is thus more informative about Aβ status than cortical hypometabolism.

%B J Alzheimers Dis %V 53 %P 651-60 %8 2016 May 23 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27232217?dopt=Abstract %R 10.3233/JAD-160204 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Patients with Mild Alzheimer's Disease Fail When Using Their Working Memory: Evidence from the Eye Tracking Technique. %A Fernández, Gerardo %A Manes, Facundo %A Politi, Luis E %A Orozco, David %A Schumacher, Marcela %A Castro, Liliana %A Agamennoni, Osvaldo %A Rotstein, Nora P %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Eye Movements %K Female %K Humans %K Linear Models %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Memory, Short-Term %K Mental Recall %K Mental Status Schedule %K Predictive Value of Tests %K Semantics %K Verbal Learning %X

Patients with Alzheimer's disease (AD) develop progressive language, visuoperceptual, attentional, and oculomotor changes that can have an impact on their reading comprehension. However, few studies have examined reading behavior in AD, and none have examined the contribution of predictive cueing in reading performance. For this purpose we analyzed the eye movement behavior of 35 healthy readers (Controls) and 35 patients with probable AD during reading of regular and high-predictable sentences. The cloze predictability of words N - 1, and N + 1 exerted an influence on the reader's gaze duration. The predictabilities of preceding words in high-predictable sentences served as task-appropriate cues that were used by Control readers. In contrast, these effects were not present in AD patients. In Controls, changes in predictability significantly affected fixation duration along the sentence; noteworthy, these changes did not affect fixation durations in AD patients. Hence, only in healthy readers did predictability of upcoming words influence fixation durations via memory retrieval. Our results suggest that Controls used stored information of familiar texts for enhancing their reading performance and imply that contextual-word predictability, whose processing is proposed to require memory retrieval, only affected reading behavior in healthy subjects. In AD patients, this loss reveals impairments in brain areas such as those corresponding to working memory and memory retrieval. These findings might be relevant for expanding the options for the early detection and monitoring in the early stages of AD. Furthermore, evaluation of eye movements during reading could provide a new tool for measuring drug impact on patients' behavior.

%B J Alzheimers Dis %V 50 %P 827-38 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836011?dopt=Abstract %R 10.3233/JAD-150265 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Patterns of Brain Iron Accumulation in Vascular Dementia and Alzheimer's Dementia Using Quantitative Susceptibility Mapping Imaging. %A Moon, Yeonsil %A Han, Seol-Heui %A Moon, Won-Jin %K Aged %K Aging %K Alzheimer Disease %K Brain %K Brain Mapping %K Cognition %K Dementia, Vascular %K Female %K Humans %K Imaging, Three-Dimensional %K Iron %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Retrospective Studies %K Severity of Illness Index %X

BACKGROUND: Emerging evidence suggests that the excessive accumulation of iron in subcortical and deep gray matter has been related to dementia. However, the presence and pattern of iron accumulation in vascular dementia (VaD) and Alzheimer's disease (AD) are rarely investigated.

OBJECTIVE: To examine and compare the pattern and presence of brain iron accumulation of VaD and AD using quantitative susceptibility mapping (QSM).

MATERIALS AND METHODS: Twelve patients with VaD, 27 patients with AD, and 18 control subjects were recruited in this institutional review-board approved study. Susceptibility maps were reconstructed from a three-dimensional multiecho spoiled gradient-echo sequence. Four regions of interest were drawn manually on QSM images, namely the globus pallidus, putamen, caudate nucleus, and pulvinar nucleus of the thalamus. Comparisons of patient demographics, and iron concentrations among the VaD, AD, and control subjects were assessed using analysis of variance and post-hoc analyses. The relationships of age and cognitive state with susceptibility values were assessed using partial correlation analysis.

RESULTS: In VaD and AD, overall susceptibility values were higher than those of control subjects. A significant difference in susceptibility values was found in the putamen and caudate nucleus (p <  0.001 and p = 0.002, respectively). However, susceptibility values did not differ between VaD and AD. Age and cognitive deficit severity were not related to susceptibility values in the VaD and AD groups.

CONCLUSION: Increased iron deposition in the putamen and caudate nucleus in VaD and AD patients was not associated with age or the severity of cognitive deficits. Further evaluations are needed to determine the temporal changes in iron load and their diagnostic role in dementia pathology.

%B J Alzheimers Dis %V 51 %P 737-45 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890777?dopt=Abstract %R 10.3233/JAD-151037 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Pauses During Autobiographical Discourse Reflect Episodic Memory Processes in Early Alzheimer's Disease. %A Pistono, Aurélie %A Jucla, Mélanie %A Barbeau, Emmanuel J %A Saint-Aubert, Laure %A Lemesle, Béatrice %A Calvet, Benjamin %A Köpke, Barbara %A Puel, Michèle %A Pariente, Jérémie %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Brain %K Female %K Humans %K Male %K Memory Disorders %K Memory, Episodic %K Mental Status Schedule %K Neuropsychological Tests %K Positron-Emission Tomography %K Statistics as Topic %X

There is a large body of research on discourse production in Alzheimer's disease (AD). Some studies have focused on pause production, revealing that patients make extensive use of pauses during speech. This has been attributed to lexical retrieval difficulties, but pausing may also reflect other forms of cognitive impairment as it increases with cognitive load. The aim of the present study was to analyze autobiographical discourse impairment in AD from a broad perspective, looking at pausing behavior (frequency, duration, and location). Our first objective was to characterize discourse changes in mild cognitive impairment (MCI) due to AD. Our second objective was to determine the cognitive and neuroanatomical correlates of these changes. Fifteen patients with MCI due to AD and 15 matched cognitively normal controls underwent an ecological episodic memory task, a full neuropsychological assessment, and a 3D T1-weighted MRI scans. Autobiographical discourse collected from the ecological episodic memory task was recorded, transcribed, and analyzed, focusing on pausing. Intergroup comparisons showed that although patients did not produce more pauses than controls overall, they did make more between-utterance pauses. The number of these specific pauses was positively correlated with patients' episodic memory performance. Furthermore, neuroimaging analysis showed that, in the patient group, their use was negatively correlated with frontopolar area (BA 10) grey matter density. This region may therefore play an important role in the planning of autobiographical discourse production. These findings demonstrate that pauses in early AD may reflect a compensatory mechanism for improving mental time travel and memory retrieval.

%B J Alzheimers Dis %V 50 %P 687-98 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757034?dopt=Abstract %R 10.3233/JAD-150408 %0 Journal Article %J J Alzheimers Dis %D 2016 %T PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease. %A Teich, Andrew F %A Sakurai, Mikako %A Patel, Mitesh %A Holman, Cameron %A Saeed, Faisal %A Fiorito, Jole %A Arancio, Ottavio %K Blotting, Western %K Brain %K Cyclic Nucleotide Phosphodiesterases, Type 5 %K DNA Primers %K Enzyme-Linked Immunosorbent Assay %K Humans %K Immunohistochemistry %K Nervous System Diseases %K Neurons %K Phosphodiesterase 5 Inhibitors %K Polymerase Chain Reaction %K RNA, Messenger %X

Phosphodiesterase 5 (PDE5) is a critical component of the cGMP-PKG axis of cellular signaling in neurons, and inhibition of PDE5 has been shown to be therapeutic in a wide range of neurologic conditions in animal models. However, enthusiasm for PDE5 inhibitors in humans is limited by data suggesting that PDE5 may not exist in human neurons. Here, we first show that past attempts to quantify PDE5 mRNA were flawed due to the use of incorrect primers, and that when correct primers are used, PDE5 mRNA is detectable in human brain tissue. We then show that PDE5 protein exists in human brain by western blot and ELISA. Most importantly, we performed immunohistochemistry and demonstrate that PDE5 is present in human neurons. We hope that this work will trigger a renewed interest in the development of PDE5 inhibitors for neurologic disease.

%B J Alzheimers Dis %V 52 %P 295-302 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967220?dopt=Abstract %R 10.3233/JAD-151104 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Performance Evaluation of an Automated ELISA System for Alzheimer's Disease Detection in Clinical Routine. %A Chiasserini, Davide %A Biscetti, Leonardo %A Farotti, Lucia %A Eusebi, Paolo %A Salvadori, Nicola %A Lisetti, Viviana %A Baschieri, Francesca %A Chipi, Elena %A Frattini, Giulia %A Stoops, Erik %A Vanderstichele, Hugo %A Calabresi, Paolo %A Parnetti, Lucilla %X

The variability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers undermines their full-fledged introduction into routine diagnostics and clinical trials. Automation may help to increase precision and decrease operator errors, eventually improving the diagnostic performance. Here we evaluated three new CSF immunoassays, EUROIMMUNtrademark amyloid-β 1-40 (Aβ1-40), amyloid-β 1-42 (Aβ1-42), and total tau (t-tau), in combination with automated analysis of the samples. The CSF biomarkers were measured in a cohort consisting of AD patients (n = 28), mild cognitive impairment (MCI, n = 77), and neurological controls (OND, n = 35). MCI patients were evaluated yearly and cognitive functions were assessed by Mini-Mental State Examination. The patients clinically diagnosed with AD and MCI were classified according to the CSF biomarkers profile following NIA-AA criteria and the Erlangen score. Technical evaluation of the immunoassays was performed together with the calculation of their diagnostic performance. Furthermore, the results for EUROIMMUN Aβ1-42 and t-tau were compared to standard immunoassay methods (INNOTESTtrademark). EUROIMMUN assays for Aβ1-42 and t-tau correlated with INNOTEST (r = 0.83, p < 0.001 for both) and allowed a similar interpretation of the CSF profiles. The Aβ1-42/Aβ1-40 ratio measured with EUROIMMUN was the best parameter for AD detection and improved the diagnostic accuracy of Aβ1-42 (area under the curve = 0.93). In MCI patients, the Aβ1-42/Aβ1-40 ratio was associated with cognitive decline and clinical progression to AD.The diagnostic performance of the EUROIMMUN assays with automation is comparable to other currently used methods. The variability of the method and the value of the Aβ1-42/Aβ1-40 ratio in AD diagnosis need to be validated in large multi-center studies.

%B J Alzheimers Dis %V 54 %P 55-67 %8 2016 Jul 22 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27447425?dopt=Abstract %R 10.3233/JAD-160298 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Performance of Hippocampus Volumetry with FSL-FIRST for Prediction of Alzheimer's Disease Dementia in at Risk Subjects with Amnestic Mild Cognitive Impairment. %A Suppa, Per %A Hampel, Harald %A Kepp, Timo %A Lange, Catharina %A Spies, Lothar %A Fiebach, Jochen B %A Dubois, Bruno %A Buchert, Ralph %K Aged %K Aging %K Alzheimer Disease %K Area Under Curve %K Cognitive Dysfunction %K Databases, Factual %K Disease Progression %K Hippocampus %K Humans %K Image Interpretation, Computer-Assisted %K Magnetic Resonance Imaging %K Neuropsychological Tests %K Organ Size %K Pattern Recognition, Automated %K Prognosis %K Reproducibility of Results %K Risk %K ROC Curve %K Sensitivity and Specificity %K Time Factors %X

MRI-based hippocampus volume, a core feasible biomarker of Alzheimer's disease (AD), is not yet widely used in clinical patient care, partly due to lack of validation of software tools for hippocampal volumetry that are compatible with routine workflow. Here, we evaluate fully-automated and computationally efficient hippocampal volumetry with FSL-FIRST for prediction of AD dementia (ADD) in subjects with amnestic mild cognitive impairment (aMCI) from phase 1 of the Alzheimer's Disease Neuroimaging Initiative. Receiver operating characteristic analysis of FSL-FIRST hippocampal volume (corrected for head size and age) revealed an area under the curve of 0.79, 0.70, and 0.70 for prediction of aMCI-to-ADD conversion within 12, 24, or 36 months, respectively. Thus, FSL-FIRST provides about the same power for prediction of progression to ADD in aMCI as other volumetry methods.

%B J Alzheimers Dis %V 51 %P 867-73 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923010?dopt=Abstract %R 10.3233/JAD-150804 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Performance on Specific Cognitive Domains and Cause of Death: A Prospective Population-Based Study in Non-Demented Older Adults (NEDICES). %A Benito-León, Julián %A Contador, Israel %A Mitchell, Alex J %A Domingo-Santos, Ángela %A Bermejo-Pareja, Félix %K Aged %K Cause of Death %K Cerebrovascular Disorders %K Cognitive Aging %K Dementia %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Intelligence %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Prospective Studies %K Risk %K Spain %X

Evidence regarding the relationship between performance on specific cognitive domains and cause of death is scarce. We assessed whether specific cognitive domains predicted mortality and the presence of any association with specific causes of death in a population-dwelling sample of non-demented older adults. In this population-based, prospective study (NEDICES), 2,390 non-demented subjects ≥65 years completed a brief neuropsychological battery. Cox's proportional hazards models, adjusted by sociodemographic and comorbidity factors, global cognitive performance, educational level, and premorbid intelligence were used to assess the risk of death. Participants were followed for a median of 9.2 years (range 0.01-10.7), after which the death certificates of those who died were examined. 880 (36.8%) of 2,390 participants died over a median follow-up of 5.5 years (range 0.01-10.5). Using adjusted Cox regression models, we found that hazard ratios for mortality in participants within the lowest tertiles (worse performance) were 1.31 (speed of cognitive processing, p = 0.03); 1.22 (semantic fluency, p = 0.04), 1.32 (delayed free recall, p = 0.003), and 1.23 (delayed logical memory, p = 0.03). Poor performance on delayed recall and speed of cognitive processing tests were associated with dementia and cerebrovascular disease mortality, respectively. Further, poor performance on semantic fluency was associated with decreased cancer mortality. In this study of community dwelling non-demented older adults, worse neuropsychological performance was associated with increased risk of mortality. Performance on specific cognitive domains were related to different causes of death. Of particular note there appears to be an inverse association between poor semantic fluency and cancer mortality.

%B J Alzheimers Dis %V 51 %P 533-44 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890757?dopt=Abstract %R 10.3233/JAD-150875 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Perfusion Neuroimaging Abnormalities Alone Distinguish National Football League Players from a Healthy Population. %A Amen, Daniel G %A Willeumier, Kristen %A Omalu, Bennet %A Newberg, Andrew %A Raghavendra, Cauligi %A Raji, Cyrus A %X

BACKGROUND: National Football League (NFL) players are exposed to multiple head collisions during their careers. Increasing awareness of the adverse long-term effects of repetitive head trauma has raised substantial concern among players, medical professionals, and the general public.

OBJECTIVE: To determine whether low perfusion in specific brain regions on neuroimaging can accurately separate professional football players from healthy controls.

METHOD: A cohort of retired and current NFL players (n = 161) were recruited in a longitudinal study starting in 2009 with ongoing interval follow up. A healthy control group (n = 124) was separately recruited for comparison. Assessments included medical examinations, neuropsychological tests, and perfusion neuroimaging with single photon emission computed tomography (SPECT). Perfusion estimates of each scan were quantified using a standard atlas. We hypothesized that hypoperfusion particularly in the orbital frontal, anterior cingulate, anterior temporal, hippocampal, amygdala, insular, caudate, superior/mid occipital, and cerebellar sub-regions alone would reliably separate controls from NFL players. Cerebral perfusion differences were calculated using a one-way ANOVA and diagnostic separation was determined with discriminant and automatic linear regression predictive models.

RESULTS: NFL players showed lower cerebral perfusion on average (p < 0.01) in 36 brain regions. The discriminant analysis subsequently distinguished NFL players from controls with 90% sensitivity, 86% specificity, and 94% accuracy (95% CI 95-99). Automatic linear modeling achieved similar results. Inclusion of age and clinical co-morbidities did not improve diagnostic classification.

CONCLUSION: Specific brain regions commonly damaged in traumatic brain injury show abnormally low perfusion on SPECT in professional NFL players. These same regions alone can distinguish this group from healthy subjects with high diagnostic accuracy. This study carries implications for the neurological safety of NFL players.

%B J Alzheimers Dis %V 53 %P 237-41 %8 2016 Apr 25 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128374?dopt=Abstract %R 10.3233/JAD-160207 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Peripheral Administration of GSK-3β Antisense Oligonucleotide Improves Learning and Memory in SAMP8 and Tg2576 Mouse Models of Alzheimer's Disease. %A Farr, Susan A %A Sandoval, Karin E %A Niehoff, Michael L %A Witt, Ken A %A Kumar, Vijaya B %A Morley, John E %X

Glycogen synthase kinase (GSK)-3β is a multifunctional protein that has been implicated in the pathological characteristics of Alzheimer's disease (AD), including the heightened levels of neurofibrillary tangles, amyloid-beta (Aβ), and neurodegeneration. We have previously shown that an antisense oligonucleotide directed at the Tyr 216 site on GSK-3β (GAO) when injected centrally can decrease GSK-3β levels, improve learning and memory, and decrease oxidative stress. In addition, we showed that GAO can cross the blood-brain barrier. Herein the impact of peripherally administered GAO in both the non-transgenic SAMP8 and transgenic Tg2576 (APPswe) models of AD were examined respective to learning and memory. Brain tissues were then evaluated for expression changes in the phosphorylated-Tyr 216 residue, which leads to GSK-3β activation, and the phosphorylated-Ser9 residue, which reduces GSK-3β activity. SAMP8 GAO-treated mice showed improved acquisition and retention using aversive T-maze, and improved declarative memory as measured by the novel object recognition (NOR) test. Expression of the phosphorylated-Tyr 216 was decreased and the phosphorylated-Ser9 was increased in GAO-treated SAMP8 mice. Tg2576 GAO-treated mice improved acquisition and retention in both the T-maze and NOR tests, with an increased phosphorylated-Ser9 GSK-3β expression. Results demonstrate that peripheral administration of GAO improves learning and memory, corresponding with alterations in GSK-3β phosphorylation state. This study supports peripherally administered GAO as a viable means to mediate GSK-3β activity within the brain and a possible treatment for AD.

%B J Alzheimers Dis %V 54 %P 1339-1348 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589526?dopt=Abstract %R 10.3233/JAD-160416 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Perlecan Domain V Inhibits Amyloid-β Induced Activation of the α2β1 Integrin-Mediated Neurotoxic Signaling Cascade. %A Parham, Christi L %A Shaw, Courtney %A Auckland, Lisa D %A Dickeson, S Kent %A Griswold-Prenner, Irene %A Bix, Gregory %X

Alzheimer's disease (AD) is characterized by neuronal death, neurofibrillary tangles, and senile plaques. Amyloid-beta (Aβ) is the major component of plaques and consists of two prominent isoforms, Aβ40 and Aβ42. As many risk factors for AD are vascular in origin and blood vessel defects in clearing Aβ from the brain are a potential key component of AD pathology, we have focused on the neuron-blood vessel interface, and in particular, the vascular basement membrane, which coats blood vessels and physically separates them from neurons. A prominent component of the vascular basement membrane is the extracellular matrix proteoglycan perlecan. Domain V (DV) is the C-terminal domain and is generated by perlecan proteolysis. DV interacts with the α2 integrin and Aβ is a ligand for both α2β1 and αvβ1. Due to the known interaction of DV with α2β1 and α2β1's requirement for Aβ deposition and neurotoxicity, we hypothesized that DV and/or its C-terminal domain, LG3, might alter neurotoxic signaling pathways by directly blocking or otherwise interfering with α2β1 binding by Aβ. Our study suggests that α2β1 mediates Aβ-induced activation of c-Jun and caspase-3, key components of the neurotoxic pathway, in primary cortical and hippocampal neurons. We further demonstrate that DV and/or LG3 may therapeutically modulate these α2β1 mediated neurotoxic effects suggesting that they or other α2β1 integrin modulators could represent a novel approach to treat AD. Finally, our results suggest different neurotoxicity susceptibilities between cortical and hippocampal neurons to Aβ40 and Aβ42 as further underscored by differing neuroprotective potencies of LG3 in each cell type.

%B J Alzheimers Dis %V 54 %P 1629-1647 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636841?dopt=Abstract %R 10.3233/JAD-160290 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Pharmacological Agents Targeting γ-Secretase Increase Risk of Cancer and Cognitive Decline in Alzheimer's Disease Patients: A Systematic Review and Meta-Analysis. %A Penninkilampi, Ross %A Brothers, Holly M %A Eslick, Guy D %X

BACKGROUND: Drugs targeting γ-secretase in Alzheimer's disease (AD) have failed to demonstrate efficacy in clinical trials.

OBJECTIVE: To perform a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of drugs targeting γ-secretase in AD.

METHODS: Ten trials were identified involving 5,227 patients using electronic databases and manual review of reference lists. RCTs of at least two weeks duration involving a drug targeting γ-secretase were eligible. The main outcomes examined were adverse events and cognitive measures (ADAS-cog, MMSE, ADCS-ADL, and CDR-sb). A sub-group analysis was performed, excluding the γ-secretase modulator tarenflurbil, to evaluate the safety and efficacy of γ-secretase inhibitors only.

RESULTS: There was an increased risk of adverse events (Odds Ratio (OR) 1.38, 95% CI 1.09-1.73; p = 0.01), serious adverse events (OR 1.50, 95% CI 1.22-1.84; p < 0.001), and skin cancers (OR 4.77, 95% CI 2.83-8.06; p < 0.001). There was significantly increased risk of infections (OR 1.36, 95% CI 1.13-1.63; p < 0.001) in the subgroup analysis excluding tarenflurbil. Pooled results also revealed a worsening in ADAS-cog (difference in means 1.33, 95% CI 0.58-2.08; p < 0.001) and MMSE (difference in means -0.66, 95% CI -0.96 to 0.35; p < 0.001), but not ADCS-ADL or CDR-sb.

CONCLUSION: The use of γ-secretase inhibitors is associated with significantly increased risk of serious adverse events including skin cancers, and worsening in cognitive indicators. This evidence indicates that γ-secretase may not be an appropriate target for clinical treatment of AD.

%B J Alzheimers Dis %V 53 %P 1395-404 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392862?dopt=Abstract %R 10.3233/JAD-160275 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Pharmacological Modulations of the Serotonergic System in a Cell-Model of Familial Alzheimer's Disease. %A Tajeddinn, Walid %A Persson, Torbjörn %A Calvo-Garrido, Javier %A Seed Ahmed, Mohammed %A Maioli, Silvia %A Vijayaraghavan, Swetha %A Kazokoglu, Mehmet Selim %A Parrado-Fernández, Cristina %A Yoshitake, Takashi %A Kehr, Jan %A Francis, Paul %A Winblad, Bengt %A Höglund, Kina %A Cedazo-Minguez, Angel %A Aarsland, Dag %X

Serotonin (5-HT) plays a central role in the integrity of different brain functions. The 5-HT homeostasis is regulated by many factors, including serotonin transporter (SERT), monoamine oxidase enzyme (MAO), and several 5-HT receptors, including the 5-HT1B. There is little knowledge how the dynamics of this system is affected by the amyloid-β (Aβ) burden of Alzheimer's disease (AD) pathology. SH-SY5Y neuroblastoma cells transfected with the amyloid precursor protein (APP) gene containing the Swedish mutations causing familial AD (APPswe), were used as a model to explore the effect of Aβ pathology on 5-HT1B and related molecules including the receptor adaptor protein (p11), SERT and MAOA gene expression, and MAOA activity after treatment with selective serotonin reuptake inhibitor (SSRI) (sertraline), and a 5-HT1B receptor antagonist. Sertraline led more than 70 fold increase of 5-HT1B gene expression (p < 0.001), an increased serotonin turnover in both APPswe and control cells and reduced intracellular serotonin levels by 75% in APPswe cells but not in controls (p > 0.05). Treatment with the 5-HT1B receptor antagonist increased SERT gene-expression in control cells but not in the APPswe cells. 5-HT and 5-HT1B antagonist treatment resulted in different p11 expression patterns in APPswe cells compared to controls. Although MAOA gene expression was not changed by APPswe overexpression, adding 5-HT lead to a significant increase in MAOA gene expression in APPswe but not control cells. These findings suggest that the sensitivity of the 5-HT1B receptor and related systems is affected by APPswe overexpression, with potential relevance for pharmacologic intervention in AD. This may at least partly explain the lack of effect of SSRIs in patients with AD and depression.

%B J Alzheimers Dis %V 53 %P 349-61 %8 2016 May 07 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163814?dopt=Abstract %R 10.3233/JAD-160046 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Safety, Pharmacokinetics, and Biomarker Results of Subcutaneous Bapineuzumab in Patients with mild to moderate Alzheimer's disease. %A Brody, Mark %A Liu, Enchi %A Di, Jianing %A Lu, Ming %A Margolin, Richard A %A Werth, John L %A Booth, Kevin %A Shadman, Anna %A Brashear, H Robert %A Novak, Gerald %X

BACKGROUND: Bapineuzumab, a humanized monoclonal antibody, targets amyloid-β (Aβ1-40/1 -42) that is believed to play a key role in the pathogenesis of Alzheimer disease (AD).

OBJECTIVES: To assess the effects of monthly subcutaneous (SC) bapineuzumab versus placebo on cerebral amyloid signal in amyloid-positive patients with mild to moderate AD. The incidence of amyloid-related imaging abnormalities-edema/effusion (ARIA-E), pharmacokinetics, pharmacodynamics, immunogenicity, and other safety aspects of bapineuzumab were also evaluated.

METHODS: In this multicenter, double-blind study, 146 patients were randomized (1 : 1:1 : 1) to SC bapineuzumab 2, 7, or 20 mg/month or placebo. Lack of efficacy of intravenous (IV) bapineuzumab in Phase III studies led to truncation of the treatment duration from 24 months to 12 months. Primary endpoint: change from baseline to month 12 in brain amyloid signal as measured by standardized uptake value ratio (SUVR) using florbetapir positron emission tomography (PET).

RESULTS: Florbetapir PET SUVR decreased significantly (p = 0.038) from baseline to month 12 for the bapineuzumab 7 mg/month group only; reductions versus placebo were not significant for any dosage. One patient each in bapineuzumab 2 mg/month and 20 mg/month groups had ARIA-E. The percentages of patients with treatment-emergent adverse events were similar in placebo (77.8%) and bapineuzumab 2 mg/month (78.4%) group, but higher in 7 mg/month (94.4%) and 20 mg/month (89.2%) groups.

CONCLUSION: Bapineuzumab SC once-monthly did not demonstrate significant treatment difference over placebo on cerebral amyloid signal at one year but was well-tolerated. There was less ARIA-E than had been expected based on prior experience with comparable exposure on IV bapineuzumab.

%B J Alzheimers Dis %V 54 %P 1509-1519 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589523?dopt=Abstract %R 10.3233/JAD-160369 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease. %A Lozano, Andres M %A Fosdick, Lisa %A Chakravarty, M Mallar %A Leoutsakos, Jeannie-Marie %A Munro, Cynthia %A Oh, Esther %A Drake, Kristen E %A Lyman, Christopher H %A Rosenberg, Paul B %A Anderson, William S %A Tang-Wai, David F %A Pendergrass, Jo Cara %A Salloway, Stephen %A Asaad, Wael F %A Ponce, Francisco A %A Burke, Anna %A Sabbagh, Marwan %A Wolk, David A %A Baltuch, Gordon %A Okun, Michael S %A Foote, Kelly D %A McAndrews, Mary Pat %A Giacobbe, Peter %A Targum, Steven D %A Lyketsos, Constantine G %A Smith, Gwenn S %X

BACKGROUND: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown.

OBJECTIVE: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer's disease (AD).

METHODS: We evaluated active "on" versus sham "off" bilateral DBS directed at the fornix-a major fiber bundle in the brain's memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation.

RESULTS: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the "on" versus "off" stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients 

CONCLUSION: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.

%B J Alzheimers Dis %V 54 %P 777-87 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567810?dopt=Abstract %R 10.3233/JAD-160017 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Phase IIa Randomized Control Trial of VEL015 (Sodium Selenate) in Mild-Moderate Alzheimer's Disease. %A Malpas, Charles B %A Vivash, Lucy %A Genc, Sila %A Saling, Michael M %A Desmond, Patricia %A Steward, Christopher %A Hicks, Rodney J %A Callahan, Jason %A Brodtmann, Amy %A Collins, Steven %A Macfarlane, Stephen %A Corcoran, Niall M %A Hovens, Christopher M %A Velakoulis, Dennis %A O'Brien, Terence J %X

BACKGROUND: There is increasing interest in targeting hyperphosphorylated tau (h-tau) as a disease modifying approach for Alzheimer's disease (AD). Sodium selenate directly stimulates the activity of PP2A, the main enzyme responsible for h-tau dephosphorylation in the brain.

OBJECTIVE: This study assessed the safety and tolerability of 24-week treatment with VEL015 (sodium selenate) in AD. Investigating the effects of VEL015 on cognitive, CSF, and neuroimaging biomarkers of AD were secondary, exploratory objectives. Data were used to identify biomarkers showing most promise for use in subsequent efficacy trials.

METHODS: A 24-week, multicenter, Phase IIa, double-blinded randomized controlled trial. Forty patients aged ≥55 y with mild-moderate AD (MMSE 14-26) were randomized to supranutritional (VEL015 10 mg tds [n = 20]) and control (VEL015 320μg tds [n = 10] or placebo [n = 10]) groups. Patients were regularly monitored for safety, adverse events (AEs), and protocol compliance. Exploratory biomarkers included cognitive tests, neuroimaging (diffusion MR), and CSF (p-tau, t-tau, and Aβ1-42).

RESULTS: Thirty-six (90%; [supranutritional n = 18, control/placebo n = 18]) patients completed the trial. There were no differences in the incidence of specific AEs between groups. Only one secondary biomarker, diffusion MR measures, showed group differences, with less deterioration in the supranutritional group (p < 0.05).

CONCLUSION: Treatment with VEL015 at doses up to 30 mg per day for 24 weeks was safe and well-tolerated in patients with AD. Diffusion MR measures appear to be the most sensitive biomarkers to assess disease progression over 24 weeks.

%B J Alzheimers Dis %V 54 %P 223-32 %8 2016 Jul 22 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27447428?dopt=Abstract %R 10.3233/JAD-160544 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Phenomenological Reliving and Visual Imagery During Autobiographical Recall in Alzheimer's Disease. %A El Haj, Mohamad %A Kapogiannis, Dimitrios %A Antoine, Pascal %B J Alzheimers Dis %V 52 %P 421-31 %8 03/2016 %G eng %N 2 %R 10.3233/JAD-151122 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Physical and Cognitive Stimulation Using an Exergame in Subjects with Normal Aging, Mild and Moderate Cognitive Impairment. %A Ben-Sadoun, Grégory %A Sacco, Guillaume %A Manera, Valeria %A Bourgeois, Jérémy %A König, Alexandra %A Foulon, Pierre %A Fosty, Baptiste %A Bremond, François %A d'Arripe-Longueville, Fabienne %A Robert, Philippe %X

BACKGROUND: The use of Serious exerGames (SeG) as enriched environments (EE), which promotes cognitive simulation with physical activity in a positive emotional context, has been proposed to represent a powerful method to slow down the decline due to neurodegenerative diseases (ND), such as Alzheimer's disease (AD). However, so far, no SeG targeting EE has been tested in ND subjects.

OBJECTIVE: This study aimed at evaluating the usability and short-term training effects of X-Torp, an action SeG designed for elderly ND subjects with mild cognitive impairment (MCI) and AD.

METHODS: X-Torp is a SeG played using the Microsoft® Kinect™. 10 ND subjects and 8 healthy elderly controls (HEC) were enrolled in a 1-month program with three training sessions per week. Usability was evaluated through game time, game performance, the aerobic intensity level reached, perceived emotions, and perceived usability.

RESULTS: All participants successfully completed the training program. ND subjects played less and had a lower game performance compared to HEC. During the sessions, ND subjects maintained a light intensity of aerobic activity, while HEC maintained a moderate intensity. Both groups experienced only positive emotions, and reported a 'moderate' to 'high' perceived competence, a 'moderate' game difficulty, and a 'high' interest in the game.

CONCLUSION: Usability results suggest that X-Torp represents a usable EE for healthy subjects and persons with MCI and AD. However, in order to reach moderate or high intensity of aerobic activity, X-Torp control modes should be adapted to become more physically stimulating.

%B J Alzheimers Dis %V 53 %P 1299-314 %8 2016 Jun 30 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372645?dopt=Abstract %R 10.3233/JAD-160268 %0 Journal Article %J J Alzheimers Dis %D 2016 %T PiB-PET Imaging-Based Serum Proteome Profiles Predict Mild Cognitive Impairment and Alzheimer's Disease. %A Kang, Seokjo %A Jeong, Hyobin %A Baek, Je-Hyun %A Lee, Seung-Jin %A Han, Sun-Ho %A Cho, Hyun Jin %A Kim, Hee %A Hong, Hyun Seok %A Kim, Young Ho %A Yi, Eugene C %A Seo, Sang Won %A Na, Duk L %A Hwang, Daehee %A Mook-Jung, Inhee %X

Development of a simple, non-invasive early diagnosis platform of Alzheimer's disease (AD) using blood is urgently required. Recently, PiB-PET imaging has been shown to be powerful to quantify amyloid-β plaque loads leading to pathophysiological alterations in AD brains. Thus, there has been a need for serum biomarkers reflecting PiB-PET imaging data as an early diagnosis platform of AD. Here, using LC-MS/MS analysis coupled with isobaric tagging, we performed comprehensive proteome profiling of serum samples from cognitively normal controls, mild cognitive impairment (MCI), and AD patients, who were selected using PiB-PET imaging. Comparative analysis of the proteomes revealed 79 and 72 differentially expressed proteins in MCI and AD, respectively, compared to controls. Integrated analysis of these proteins with genomic and proteomic data of AD brain tissues, together with network analysis, identified three biomarker candidates representing the altered proteolysis-related process in MCI or AD: proprotein convertase subtilisin/kexin type 9 (PCSK9), coagulation factor XIII, A1 polypeptide (F13A1), and dermcidin (DCD). In independent serum samples of MCI and AD, we confirmed the elevation of the candidates using western blotting and ELISA. Our results suggest that these biomarker candidates can serve as a potential non-invasive early diagnosis platform reflecting PiB-PET imaging for MCI and AD.

%B J Alzheimers Dis %V 53 %P 1563-76 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392853?dopt=Abstract %R 10.3233/JAD-160025 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Pilot Study Measuring Aluminum in Bone in Alzheimer's Disease and control Subjects Using in vivo Neutron Activation Analysis. %A Mohseni, Hedieh K %A Cowan, David %A Chettle, David R %A Milić, Ana Pejović %A Priest, Nicholas %A Matysiak, Witold %A Atanackovic, Jovica %A Byun, Soo Hyun %A Prestwich, William V %X

Aluminum, being the most abundant metal in the earth's crust, is widely distributed in the environment, and is routinely taken up by the human body through ingestion and inhalation. Aluminum is not considered an essential element and it can be toxic in high concentrations. Most of the body burden of aluminum is stored in the bones. Aluminum has been postulated to be involved in the causality of Alzheimer's disease. A system for non-invasive measurement of bone aluminum using the in vivo neutron activation analysis technique has been developed and previously reported in the literature by our group. The results are reported as ratio of Al to Ca in order to eliminate the variations in beam parameters and geometry as well as the physical variations among the subjects such as size of the hand and bone structure. This pilot study included 30 subjects, 15 diagnosed with Alzheimer's disease in mild and moderate stages and 15 control subjects, all of whom were 60 years of age or older. The mean value of aluminum for the control group was 2.7±8.2μg Al/g Ca (inverse-variance weighted mean 3.5±0.9μg Al/g Ca) and for the Alzheimer's disease subjects was 12.5±13.1μg Al/g Ca (inverse-variance weighted mean 7.6±0.6μg Al/g Ca). The difference between the mean of the Alzheimer's disease group and the mean of the control group was 9.8±15.9μg Al/g Ca, with a p-value of 0.02. An age-dependent linear increase in bone aluminum concentration was observed for all subjects. The difference in serum aluminum levels between the two groups did not reach significance.

%B J Alzheimers Dis %V 53 %P 933-42 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340850?dopt=Abstract %R 10.3233/JAD-160194 %0 Journal Article %J J Alzheimers Dis %D 2016 %T PKC Activation Counteracts ADAM10 Deficit in HuD-Silenced Neuroblastoma Cells. %A Marchesi, Nicoletta %A Amadio, Marialaura %A Colombrita, Claudia %A Govoni, Stefano %A Ratti, Antonia %A Pascale, Alessia %X

Neuronal ELAV/Hu (nELAV) are RNA-binding proteins that mainly regulate gene expression by increasing the stability and/or translation rate of target mRNAs bearing ARE (adenine and uracil-rich elements) sequences. Among nELAV target transcripts there is ADAM10, an α-secretase involved in the non-amyloidogenic processing of the amyloid-β protein precursor (AβPP) which leads to the production of the neuroprotective sAβPPα peptide. The aim of this study was to evaluate if nELAV depletion affects ADAM10 expression in human SH-SY5Y neuroblastoma cells. We also studied the effects of Bryostatin-1, a molecule able to activate nELAV protein cascade. The specific HuD/nELAV gene silencing decreased both nELAV and ADAM10 protein contents; similar results were obtained by Aβ40 treatment in wild-type SH-SY5Y cells. In HuD-silenced cells, the exposure to Bryostatin-1 counteracted both nELAV and ADAM10 proteins downregulation, by restoring nELAV/ADAM10 basal levels. We also found that sAβPPα release, which seemed not to be compromised by Aβ40 challenge or HuD-silencing, was favored by Bryostatin-1. Overall, these findings strongly suggest that a deficiency in nELAV content negatively affects ADAM10 expression and may play a role in neurodegenerative diseases, which may benefit by molecules activating ELAV cascade.

%B J Alzheimers Dis %V 54 %P 535-47 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472877?dopt=Abstract %R 10.3233/JAD-160299 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Plasma Ceramides and Neuropsychiatric Symptoms of Alzheimer's Disease. %A Xing, Yi %A Tang, Yi %A Zhao, Lina %A Wang, Qi %A Qin, Wei %A Zhang, Jin-Lan %A Jia, Jianping %X

BACKGROUND: Various evidence demonstrates the influences of ceramides on Alzheimer's disease (AD) pathogenesis. Furthermore, increased ceramides were also suggested to be related to cognitive decline. However, the association between ceramides and neuropsychiatric symptoms of AD remains unclear.

OBJECTIVE: This study sought to investigate the association between plasma ceramide levels and multiple neuropsychiatric symptoms in AD.

METHODS: A total of 98 patients and 92 cognitively normal controls participated in this study, including 56 with mild AD and 42 with moderate to severe AD. The Neuropsychiatric Inventory (NPI) was used to assess neuropsychiatric symptoms. Considering the influences of dementia severity on ceramide levels and neuropsychiatric symptoms, a subgroup analysis was conducted by dementia severity.

RESULTS: Except for C24 : 0, all ceramide species were significantly higher in AD patients than in controls. After controlling for confounding factors, the C16 : 0 and C20 : 0 levels were positively associated with delusions, and the quartiles of C22 : 0 and C24 : 0 were positively associated with depression. In the subgroup analysis, association between ceramide species and delusions were only observed in mild AD, and the association between ceramides and depression were prominent in moderate to severe AD. In mild AD, after controlling for age, gender, anti-dementia medications, diabetes status, and ApoE ɛ4 status, the C16 : 0, C20 : 0, and quartiles of C24 : 1 were associated with delusions. In moderate to severe AD, depression was associated with C22 : 0 and C24 : 0.

CONCLUSION: There were stage-specific associations between ceramides and neuropsychiatric symptoms of AD. The potential mechanisms deserve further investigation.

%B J Alzheimers Dis %V 52 %P 1029-35 %8 2016 Apr 12 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079712?dopt=Abstract %R 10.3233/JAD-151158 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Plasma Phospholipid and Sphingolipid Alterations in Presenilin1 Mutation Carriers: A Pilot Study. %A Chatterjee, Pratishtha %A Lim, Wei L F %A Shui, Guanghou %A Gupta, Veer B %A James, Ian %A Fagan, Anne M %A Xiong, Chengjie %A Sohrabi, Hamid R %A Taddei, Kevin %A Brown, Belinda M %A Benzinger, Tammie %A Masters, Colin %A Snowden, Stuart G %A Wenk, Marcus R %A Bateman, Randall J %A Morris, John C %A Martins, Ralph N %K Adult %K Alzheimer Disease %K Apolipoproteins E %K Female %K Humans %K Linear Models %K Male %K Middle Aged %K Mutation %K Phospholipids %K Pilot Projects %K Presenilin-1 %K Sphingolipids %X

BACKGROUND AND OBJECTIVE: Aberrant lipid metabolism has been implicated in sporadic Alzheimer's disease (AD). The current study investigated plasma phospholipid and sphingolipid profiles in individuals carrying PSEN1 mutations responsible for autosomal dominant AD (ADAD).

METHODS: Study participants evaluated were from the Perth and Melbourne sites of the Dominantly Inherited Alzheimer Network (DIAN) study. Plasma phospholipid and sphingolipid profiles were measured using liquid chromatography coupled with mass spectrometry in 20 PSEN1 mutation carriers (MC; eight of whom were symptomatic and twelve asymptomatic, based on Clinical Dementia Rating scores) and compared with six non carriers (NC) using linear mixed models. Further, AD gold standard biomarker data obtained from the DIAN database were correlated with lipid species significantly altered between MC and NC, using Spearman's correlation coefficient.

RESULTS: One-hundred and thirty-nine plasma phospholipid and sphingolipid species were measured. Significantly altered species in MC compared to NC primarily belonged to choline and ethanolamine containing phospholipid classes and ceramides. Further phosphatidylcholine species (34:6, 36:5, 40:6) correlated with cerebrospinal fluid tau (p <  0.05), and plasmalogen ethanolamine species (34:2, 36:,4) correlated with both cerebrospinal fluid tau and brain amyloid load within the MC group (p <  0.05).

CONCLUSION: These findings indicate altered phospholipid and sphingolipid metabolism in ADAD and provide insight into the pathomolecular changes occurring with ADAD pathogenesis. Further, findings reported in this study allow comparison of lipid alterations in ADAD with those reported previously in sporadic AD. The findings observed in the current pilot study warrant validation in the larger DIAN cohort.

%B J Alzheimers Dis %V 50 %P 887-94 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836186?dopt=Abstract %R 10.3233/JAD-150948 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Plasma Screening for Progranulin Mutations in Patients with Progressive Supranuclear Palsy and Corticobasal Syndromes. %A Galimberti, Daniela %A Bertram, Kelly %A Formica, Alessandra %A Fenoglio, Chiara %A Cioffi, Sara M G %A Arighi, Andrea %A Scarpini, Elio %A Colosimo, Carlo %X

Progranulin gene (GRN) mutations are characterized by heterogeneous presentations. Corticobasal syndrome (CBS) is often associated with GRN mutations, whereas association with progressive supranuclear palsy syndrome (PSPS) is rare. Plasma progranulin levels were evaluated in 34 patients, including 19 with PSPS, 12 with CBS, and 3 with mixed signs, with the purpose to screen for the presence of causal mutations, associated with low levels. We found undetectable levels in a patient with CBS. Sequencing confirmed the presence of the Thr272fs deletion. Progranulin mutation screening is suggested in cases of CBS, even in the absence of positive family history for dementia and/or movement disorders.

%B J Alzheimers Dis %V 53 %P 445-9 %8 2016 May 04 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163816?dopt=Abstract %R 10.3233/JAD-160073 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Platelet Membrane β-Secretase Activity in Mild Cognitive Impairment and Conversion to Dementia: a Longitudinal Study. %A McGuinness, Bernadette %A Fuchs, Marc %A Barrett, Suzanne L %A Passmore, A Peter %A Johnston, Janet A %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid Precursor Protein Secretases %K Biomarkers %K Blood Platelets %K Cholesterol %K Cognitive Dysfunction %K Cross-Sectional Studies %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Neuropsychological Tests %K Sensitivity and Specificity %X

A blood-based biomarker to complement the clinical and neuropsychological assessments used to evaluate the risk of individuals with mild cognitive impairment (MCI) developing Alzheimer's disease (AD) would be invaluable. Previous pilot studies by our group identified elevated platelet membrane β-secretase activity in patients with AD and MCI, as compared to controls, and this activity was influenced by membrane cholesterol levels. The present study investigated baseline platelet membrane β-secretase activity and cholesterol levels in 97 MCI participants and 85 controls and explored whether these parameters differed in individuals with stable MCI, as compared to those who subsequently developed AD. To evaluate signal specificity, β-secretase activity assays were conducted in the presence and absence of beta-site amyloid-β protein precursor-cleaving enzyme (BACE) inhibitors. Baseline platelet membrane β-secretase activity did not differ significantly in MCI participants, as compared to controls, and platelet membrane cholesterol levels were significantly lower in the MCI group. The longitudinal study indicated that the activities inhibited by two different BACE inhibitors did not predict conversion to AD; however, the activity that was not affected by BACE inhibitors was significantly (40%) higher in individuals with stable MCI, as compared with those who subsequently developed AD. These findings indicated that further research into the source of this activity could contribute to a measure facilitating prediction of the risk of conversion from MCI to AD.

%B J Alzheimers Dis %V 49 %P 1095-103 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639974?dopt=Abstract %R 10.3233/JAD-150795 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Polyphenol Oleuropein Aglycone Modulates the PARP1-SIRT1 Interplay: An In Vitro and In Vivo Study. %A Luccarini, Ilaria %A Pantano, Daniela %A Nardiello, Pamela %A Cavone, Leonardo %A Lapucci, Andrea %A Miceli, Caterina %A Nediani, Chiara %A Berti, Andrea %A Stefani, Massimo %A Casamenti, Fiorella %X

Poly(ADP-ribose) polymerase-1 (PARP1) activation contributes to the cascade of events initiated by amyloid-β (Aβ) peptide eventually leading to cell death in Alzheimer's disease brain. A significant accumulation of PAR polymers and increase of PARP1 expression were detected in the cortex at the early (3.5 months) and intermediate (6 months) stage of Aβ deposition in the TgCRND8 mouse model. Our previous data highlighted the beneficial effects of oleuropein aglycone (OLE), the main polyphenol found in the olive oil, against neurodegeneration both in cultured cells and in model organisms. Here we found that 8-week OLE treatment (50 mg/kg of diet) to 6-month-old TgCRND8 mice rescued to control values PARP1 activation and the levels of its product, PAR. In N2a neuroblastoma cells, PARP1 activation and PAR formation upon exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were abolished by pretreatment for 24 h with either OLE (100μM) or PARP inhibitors. A significant reduction of the NAD+ content, compared to controls, was found in N2a cells exposed to MNNG (100μM) for 90 min; the latter was slightly attenuated by cell treatment for 24 h with PJ-34 or with OLE. In vitro and in vivo, the OLE-induced reduction of PARP1 activation was paralleled by the overexpression of Sirtuin1 (SIRT1), and, in vivo, by a decrease of NF-κB and the pro-apoptotic marker p53. In N2a cells, we also found that OLE potentiates the MNNG-induced increase of Beclin1 levels. In conclusion, our data show that OLE treatment counteracts neuronal damage through modulation of the PARP1-SIRT1 interplay.

%B J Alzheimers Dis %V 54 %P 737-50 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567859?dopt=Abstract %R 10.3233/JAD-160471 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Possible Involvement of Adiponectin, the Anti-Diabetes Molecule, in the Pathogenesis of Alzheimer's Disease. %A Waragai, Masaaki %A Adame, Anthony %A Trinh, Ivy %A Sekiyama, Kazunari %A Takamatsu, Yoshiki %A Une, Kaori %A Masliah, Eliezer %A Hashimoto, Makoto %X

Adiponectin (APN) is protective in animal models of neurodegenerative diseases, but the role of APN in human brain has not been established. Using an enzyme-linked immunosorbent assay, we found that APN was significantly decreased in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), compared to those in patients with mild cognitive impairment (MCI) and in normal controls (NC), despite elevation of APN in serum of patients with MCI and AD compared to that in NC. The discrepancy of CSF APN from serum APN in AD may suggest some critical actions of APN in the pathogenesis of AD. Indeed, it was histologically observed that APN was co-localized with tau in neurofibrillary tangles and immunoblot analysis showed that the functional trimers of APN were significantly decreased in AD compared to those in NC. Collectively, a loss of function of APN may be involved in the pathogenesis of AD.

%B J Alzheimers Dis %V 52 %P 1453-9 %8 2016 Apr 08 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079710?dopt=Abstract %R 10.3233/JAD-151116 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Post Hoc Analyses of ApoE Genotype-Defined Subgroups in Clinical Trials. %A Kennedy, Richard E %A Cutter, Gary R %A Wang, Guoqiao %A Schneider, Lon S %K Alzheimer Disease %K Apolipoprotein E4 %K Clinical Trials as Topic %K Cognitive Dysfunction %K Data Interpretation, Statistical %K Humans %K Research Design %X

BACKGROUND: Many post hoc analyses of clinical trials in Alzheimer's disease (AD) and mild cognitive impairment (MCI) are in small Phase 2 trials. Subject heterogeneity may lead to statistically significant post hoc results that cannot be replicated in larger follow-up studies.

OBJECTIVE: We investigated the extent of this problem using simulation studies mimicking current trial methods with post hoc analyses based on ApoE4 carrier status.

METHODS: We used a meta-database of 24 studies, including 3,574 subjects with mild AD and 1,171 subjects with MCI/prodromal AD, to simulate clinical trial scenarios. Post hoc analyses examined if rates of progression on the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) differed between ApoE4 carriers and non-carriers.

RESULTS: Across studies, ApoE4 carriers were younger and had lower baseline scores, greater rates of progression, and greater variability on the ADAS-cog. Up to 18% of post hoc analyses for 18-month trials in AD showed greater rates of progression for ApoE4 non-carriers that were statistically significant but unlikely to be confirmed in follow-up studies. The frequency of erroneous conclusions dropped below 3% with trials of 100 subjects per arm. In MCI, rates of statistically significant differences with greater progression in ApoE4 non-carriers remained below 3% unless sample sizes were below 25 subjects per arm.

CONCLUSIONS: Statistically significant differences for ApoE4 in post hoc analyses often reflect heterogeneity among small samples rather than true differential effect among ApoE4 subtypes. Such analyses must be viewed cautiously. ApoE genotype should be incorporated into the design stage to minimize erroneous conclusions.

%B J Alzheimers Dis %V 50 %P 1205-15 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836180?dopt=Abstract %R 10.3233/JAD-150847 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Posterior Accumulation of Tau and Concordant Hypometabolism in an Early-Onset Alzheimer's Disease Patient with Presenilin-1 Mutation. %A Smith, Ruben %A Wibom, Moa %A Olsson, Tomas %A Hägerström, Douglas %A Jögi, Jonas %A Rabinovici, Gil D %A Hansson, Oskar %K Adult %K Age of Onset %K Alzheimer Disease %K Amyloid beta-Peptides %K Aniline Compounds %K Benzothiazoles %K Brain %K Brain Mapping %K Fluorodeoxyglucose F18 %K Humans %K Magnetic Resonance Imaging %K Male %K Positron-Emission Tomography %K Presenilin-1 %K Radiopharmaceuticals %K tau Proteins %X

It is unclear whether the distribution of tau pathology differs between cases with early-onset familial Alzheimer's disease (AD) and sporadic AD. We present positron emission tomography (PET) data from a young patient with a presenilin-1 mutation (Thr116Asn). 18F-flutemetamol PET showed a distribution of amyloid-β fibrils similar to sporadic AD. However, the pattern of tau pathology, revealed using 18F-AV1451 PET, showed higher uptake in posterior cingulate, precuneus, parietal and occipital cortices compared to late-onset sporadic AD. Further, the tau pathology, but not amyloid pathology, exhibited a very clear inverse relationship with 18F-fluorodeoxyglucose-metabolism, indicating neuronal hypometabolism in regions affected by tau aggregates.

%B J Alzheimers Dis %V 51 %P 339-43 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836192?dopt=Abstract %R 10.3233/JAD-151004 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Posterior Ventricular Enlargement to Differentiate Dementia with Lewy Bodies from Alzheimer's Disease. %A Ye, Byoung Seok %A Lee, Yoonju %A Kwak, Kichang %A Park, Yeong-Hun %A Ham, Jee Hyun %A Lee, Jae Jung %A Shin, Na-Young %A Lee, Jong-Min %A Sohn, Young H %A Lee, Phil Hyu %X

BACKGROUND: Enlargement of the lateral ventricle is observed in dementia associated with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB).

OBJECTIVE: The degree of anteroposterior ventricular enlargement and its correlation with clinical and neuropsychological features were investigated in DLB patients.

METHODS: Forty-eight patients with DLB, 76 with AD, and 45 subjects with normal cognition (NC) underwent structural brain MRI and detailed neuropsychological tests. Ventricular shape was compared among the groups by visual inspection. Posterior ventricle enlargement (PVE) was defined as the ratio of the distance between the temporal and occipital horns of the lateral ventricle to the distance between the temporal horn of the lateral ventricle and occipital pole of the brain.

RESULTS: After controlling for age, sex, and education, higher PVE was observed in the DLB group than in the AD group (68.5 ± 7.9% versus 62.8 ± 9.0%, respectively; p = 0.001) or the NC group (61.9 ± 9.9%, p = 0.002). However, higher PVE was not associated with poorer neuropsychological performance, nor was it associated with any clinical features in the DLB group after controlling for age, sex, and education.

CONCLUSION: PVE occurs more often in DLB than in AD and NC. However, it is unclear how PVE is related to the clinical and neuropsychological features of DLB.

%B J Alzheimers Dis %V 52 %P 1237-43 %8 2016 Apr 21 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104902?dopt=Abstract %R 10.3233/JAD-160062 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Postmortem Adult Human Microglia Proliferate in Culture to High Passage and Maintain Their Response to Amyloid-β. %A Guo, Ling %A Rezvanian, Aras %A Kukreja, Lokesh %A Hoveydai, Ramez %A Bigio, Eileen H %A Mesulam, M-Marsel %A El Khoury, Joseph %A Geula, Changiz %X

Microglia are immune cells of the brain that display a range of functions. Most of our knowledge about microglia biology and function is based on cells from the rodent brain. Species variation in the complexity of the brain and differences in microglia response in the primate when compared with the rodent, require use of adult human microglia in studies of microglia biology. While methods exist for isolation of microglia from postmortem human brains, none allow culturing cells to high passage. Thus cells from the same case could not be used in parallel studies and multiple conditions. Here we report a method, which includes use of growth factors such as granulocyte macrophage colony stimulating factor, for successful culturing of adult human microglia from postmortem human brains up to 28 passages without significant loss of proliferation. Such cultures maintained their phenotype, including uptake of the scavenger receptor ligand acetylated low density lipoprotein and response to the amyloid-β peptide, and were used to extend in vivo studies in the primate brain demonstrating that inhibition of microglia activation protects neurons from amyloid-β toxicity. Significantly, microglia cultured from brains with pathologically confirmed Alzheimer's disease displayed the same characteristics as microglia cultured from normal aged brains. The method described here provides the scientific community with a new and reliable tool for mechanistic studies of human microglia function in health from childhood to old age, and in disease, enhancing the relevance of the findings to the human brain and neurodegenerative conditions.

%B J Alzheimers Dis %V 54 %P 1157-1167 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567845?dopt=Abstract %R 10.3233/JAD-160394 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Potential VEP Biomarker for Mild Cognitive Impairment: Evidence from Selective Visual Deficit of Higher-Level Dorsal Pathway. %A Yamasaki, Takao %A Horie, Shizuka %A Ohyagi, Yasumasa %A Tanaka, Eri %A Nakamura, Norimichi %A Goto, Yoshinobu %A Kanba, Shigenobu %A Kira, Jun-Ichi %A Tobimatsu, Shozo %X

Visual dysfunctions are common in Alzheimer's disease (AD). Our aim was to establish a neurophysiological biomarker for amnestic mild cognitive impairment (aMCI). Visual evoked potentials (VEPs) were recorded in aMCI patients who later developed AD (n = 15) and in healthy older (n = 15) and younger controls (n = 15). Visual stimuli were optimized to separately activate lower and higher levels of the ventral and dorsal streams. We compared VEP parameters across the three groups of participants and conducted a linear correlation analysis between VEPs and data from neuropsychological tests. We then used a receiver operating characteristic (ROC) analysis to discriminate those with aMCI from those who were healthy older adults. The latency and phase of VEPs to lower-level stimuli (chromatic and achromatic gratings) were significantly affected by age but not by cognitive decline. Conversely, VEP latencies for higher-ventral (faces and kanji-words) and dorsal (kana-words and optic flow motion) stimuli were not affected by age, but they were significantly prolonged in aMCI patients. Interestingly, VEPs for higher-dorsal stimuli were related to outcomes of neuropsychological tests. Furthermore, the ROC analysis showed that the highest areas under the curve were obtained for VEP latencies in response to higher-dorsal stimuli. These results suggest aMCI-related functional impairment specific to higher-level visual processing. Further, dysfunction in the higher-level of the dorsal stream could be an early indicator of cognitive decline. Therefore, we conclude that VEPs associated with higher-level dorsal stream activity can be a sensitive biomarker for early detection of aMCI.

%B J Alzheimers Dis %V 53 %P 661-76 %8 2016 May 23 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27232213?dopt=Abstract %R 10.3233/JAD-150939 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Potentially Inappropriate Prescribing Among People with Dementia in Primary Care: A Retrospective Cross-Sectional Study Using the Enhanced Prescribing Database. %A Barry, Heather E %A Cooper, Janine A %A Ryan, Cristín %A Passmore, A Peter %A Robinson, A Louise %A Molloy, Gerard J %A Darcy, Carmel M %A Buchanan, Hilary %A Hughes, Carmel M %X

BACKGROUND: Little is known about prescribing appropriateness for community-dwelling people with dementia (PWD).

OBJECTIVE: To estimate potentially inappropriate prescribing (PIP) prevalence among PWD in primary care in Northern Ireland, and to investigate associations between PIP, polypharmacy, age, and gender.

METHODS: A retrospective cross-sectional study was conducted, using data from the Enhanced Prescribing Database. Patients were eligible if a medicine indicated for dementia management was dispensed to them during 1 January 2013-31 December 2013. Polypharmacy was indicated by use of ≥4 repeat medications from different drug groups. A subset of the Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) criteria, comprising 36 indicators, was applied to the dataset. Overall prevalence of PIP and the prevalence per each STOPP criterion was calculated as a proportion of all eligible persons in the dataset. Logistic regression was used to investigate associations between PIP, polypharmacy, age, and gender.

RESULTS: The study population comprised 6826 patients. Polypharmacy was observed in 81.5% (n = 5564) of patients. PIP prevalence during the study period was 64.4% (95% CI 63.2- 65.5; n = 4393). The most common instance of PIP was the use of anticholinergic/antimuscarinic medications (25.2%; 95% CI 24.2-26.2; n = 1718). In multivariable analyses, both polypharmacy and gender (being female) were associated with PIP, with odds ratios of 7.6 (95% CI 6.6-8.7) and 1.3 (95% CI 1.2-1.4), respectively. No association was observed between PIP and age, after adjustments for gender and polypharmacy.

CONCLUSION: This study identified a high prevalence of PIP in community-dwelling PWD. Future interventions may need to focus on certain therapeutic categories and polypharmacy.

%B J Alzheimers Dis %V 52 %P 1503-13 %8 2016 Apr 11 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079714?dopt=Abstract %R 10.3233/JAD-151177 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prediction of Alzheimer's Disease in Amnestic Mild Cognitive Impairment Subtypes: Stratification Based on Imaging Biomarkers. %A Ota, Kenichi %A Oishi, Naoya %A Ito, Kengo %A Fukuyama, Hidenao %X

BACKGROUND: Prediction of progression to Alzheimer's disease (AD) in amnestic mild cognitive impairment (MCI) is challenging because of its heterogeneity.

OBJECTIVE: To evaluate a stratification method on different cohorts and to investigate whether stratification in amnestic MCI could improve prediction accuracy.

METHODS: We identified 80 and 79 patients with amnestic MCI from different cohorts, respectively. They underwent baseline magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans. We performed hierarchical clustering with three imaging biomarkers: Brain volume on MRI, left hippocampus grey matter loss on MRI, and left inferior temporal gyrus glucose hypometabolism on FDG-PET. Regions-of-interest for biomarkers were defined by the Automated Anatomical Labeling atlas. We performed voxel-wise statistical parametric mapping to explore differences between clusters in patterns of grey matter loss and glucose hypometabolism. We compared time to progression using an interval-censored parametric model. We evaluated predictive performance using logistic regression.

RESULTS: Similar clusters were found in different cohorts. MCI1 had the healthiest biomarker profile of cognitive performance and imaging biomarkers. MCI2 had cognitive performance and MRI measures intermediate between those of nonconverters and converters. MCI3 showed the severest reduction in brain volume and left hippocampal atrophy. MCI4 showed remarkable glucose hypometabolism in the left inferior temporal gyrus, and also demonstrated significant decreases in most cognitive scores, including non-memory functions. MCI4 showed the highest risk for progression. The prediction of progression of MCI2 especially benefited from the stratification.

CONCLUSION: Stratification with imaging biomarkers in amnestic MCI can be a good approach for improving predictive performance.

%B J Alzheimers Dis %V 52 %P 1385-401 %8 2016 Apr 12 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079727?dopt=Abstract %R 10.3233/JAD-160145 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prediction of Progressive Mild Cognitive Impairment by Multi-Modal Neuroimaging Biomarkers. %A Xu, Lele %A Wu, Xia %A Li, Rui %A Chen, Kewei %A Long, Zhiying %A Zhang, Jiacai %A Guo, Xiaojuan %A Yao, Li %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Aniline Compounds %K Biomarkers %K Brain %K Cognitive Dysfunction %K Disease Progression %K Ethylene Glycols %K Female %K Fluorodeoxyglucose F18 %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Positron-Emission Tomography %K Predictive Value of Tests %K Psychiatric Status Rating Scales %K Sensitivity and Specificity %X

For patients with mild cognitive impairment (MCI), the likelihood of progression to probable Alzheimer's disease (AD) is important not only for individual patient care, but also for the identification of participants in clinical trial, so as to provide early interventions. Biomarkers based on various neuroimaging modalities could offer complementary information regarding different aspects of disease progression. The current study adopted a weighted multi-modality sparse representation-based classification method to combine data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, from three imaging modalities: Volumetric magnetic resonance imaging (MRI), fluorodeoxyglucose (FDG) positron emission tomography (PET), and florbetapir PET. We included 117 normal controls (NC) and 110 MCI patients, 27 of whom progressed to AD within 36 months (pMCI), while the remaining 83 remained stable (sMCI) over the same time period. Modality-specific biomarkers were identified to distinguish MCI from NC and to predict pMCI among MCI. These included the hippocampus, amygdala, middle temporal and inferior temporal regions for MRI, the posterior cingulum, precentral, and postcentral regions for FDG-PET, and the hippocampus, amygdala, and putamen for florbetapir PET. Results indicated that FDG-PET may be a more effective modality in discriminating MCI from NC and in predicting pMCI than florbetapir PET and MRI. Combining modality-specific sensitive biomarkers from the three modalities boosted the discrimination accuracy of MCI from NC (76.7%) and the prediction accuracy of pMCI (82.5%) when compared with the best single-modality results (73.6% for MCI and 75.6% for pMCI with FDG-PET).

%B J Alzheimers Dis %V 51 %P 1045-56 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923024?dopt=Abstract %R 10.3233/JAD-151010 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Predictive factors for disease progression in patients with early-onset Alzheimer's disease. %A Yoon, Bora %A Shim, Yong S %A Park, Hee-Kyung %A Park, Sun Ah %A Choi, Seong Hye %A Yang, Dong Won %K Activities of Daily Living %K Adult %K Age Factors %K Aged %K Alleles %K Alzheimer Disease %K Apolipoproteins E %K Disease Progression %K Female %K Genotype %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Middle Aged %K Neuropsychological Tests %K Risk Factors %K Sex Factors %X

BACKGROUND: Only a few studies have investigated disease progression in patients with early-onset Alzheimer's disease (EOAD). Therefore, the aim of this study was to investigate disease progression in patients with EOAD and the influence of various factors, such as gender, education, and apolipoprotein E (APOE) genotype on disease progression.

METHODS: A total of 288 EOAD patients were enrolled in the study. Linear mixed models were used to investigate the rate of cognitive and functional decline in terms of age at onset, gender, education, follow-up period, and APOE genotype.

RESULTS: EOAD patients showed an annual decline of -1.54 points/years in the Korean version mini-mental examination score, an annual increase of 3.46 points/year in the Seoul instrumental activities of daily living (SIADL) score, and an annual increase of 1.15 points/year in the clinical dementia rating scale-sum of boxes score. After stratification, higher educated patients showed faster disease progression in all three parameters, and female patients demonstrated faster disease progression as assessed by the SIADL score. Age at onset and APOE genotype had no influence on disease progression.

CONCLUSION: We confirmed the rate of disease progression in Korean patients with EOAD in real-life hospital-based clinical practice. The results of this study suggest that education and female gender, not APOE genotype, may be important as independent strong predictive factors for disease progression in patients with EOAD.

%B J Alzheimers Dis %V 49 %P 85-91 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444786?dopt=Abstract %R 10.3233/JAD-150462 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Predictive Value of Cerebrospinal Fluid Visinin-Like Protein-1 Levels for Alzheimer's Disease Early Detection and Differential Diagnosis in Patients with Mild Cognitive Impairment. %A Babić Leko, Mirjana %A Borovečki, Fran %A Dejanović, Nenad %A Hof, Patrick R %A Šimić, Goran %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Diagnosis, Differential %K Disease Progression %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neurocalcin %K Peptide Fragments %K Predictive Value of Tests %K ROC Curve %K Statistics as Topic %K tau Proteins %X

Visinin-like protein 1 (VILIP-1) recently emerged as a potential biomarker of Alzheimer's disease (AD). This neuronal calcium sensor protein previously used as a marker of acute ischemic stroke is elevated in the cerebrospinal fluid (CSF) of AD patients. The goal of this study was to assess CSF VILIP-1 potential in early AD diagnosis and in differentiating mild cognitive impairment (MCI) patients with and without risk of AD. Additionally, we tested VILIP-1 ability to differentiate AD from other primary causes of dementia, and predict the progression of AD-related cognitive decline. VILIP-1 levels were compared with five CSF AD biomarkers (t-tau, Aβ1-42, p-tau181, p-tau199, and p-tau231). VILIP-1 successfully differentiated two MCI patient groups characterized by absence or presence of pathological levels of these CSF biomarkers, except for t-tau. VILIP-1/Aβ(1-42) and VILIP-1/p-tau181 ratios also differentiated MCI patients with pathological CSF biomarker levels. However, there was no difference in VILIP-1 levels between AD and MCI patients. VILIP-1/Aβ(1-42) and VILIP-1/p-tau231 ratios reached high sensitivities (above 70%) and very high specificities (above 85%) in differentiating AD patients from HC. Additionally, VILIP-1 differentiated AD from patients with Lewy body disease with 77.1% sensitivity and 100% specificity. VILIP-1 potential as a prognostic biomarker of cognitive decline in AD was also proved since VILIP-1/t-tau, VILIP-1/p-tau181, and VILIP-1/p-tau231 ratios correlated with MMSE scores. These data indicate that VILIP-1 alone or in combination with other AD CSF biomarkers represent a valuable marker for the early diagnosis of AD, recognition of MCI patients at higher risk to develop dementia, and in differentiating AD from LBD.

%B J Alzheimers Dis %V 50 %P 765-78 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836160?dopt=Abstract %R 10.3233/JAD-150705 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Predictors and Moderators of Quality of Life in Alzheimer's Disease Patients. %A Lima, Sara %A Gago, Miguel %A Garrett, Carolina %A Pereira, M Graça %X

BACKGROUND: Alzheimer's disease (AD) is a chronic degenerative disease leading to global cognitive and functional decline. Quality of Life (QOL) is an important variable in the effectiveness of intervention programs in dementia.

OBJECTIVE: This study analyzed the relationships between gender, psychological variables and QOL, the predictors of QOL, and the role of spirituality as a moderator between functionality and QOL.

METHOD: A cross-sectional study was conducted with 128 patients with mild AD.

RESULTS: Being a male, good social support, and high functionality were significant predictors of better QOL. Spirituality was a moderator in the relationship between functionality and QOL.

CONCLUSION: These results reinforce the importance of gender, psychological morbidity, social support, and functionality, with special emphasis on the role of spirituality, regarding intervention programs that promote QOL, in patients with mild AD.

%B J Alzheimers Dis %V 54 %P 1113-1121 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567826?dopt=Abstract %R 10.3233/JAD-160256 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Predictors of Mortality in Dementia: The PRIME Study. %A Connors, Michael H %A Ames, David %A Boundy, Karyn %A Clarnette, Roger %A Kurrle, Sue %A Mander, Alastair %A Ward, John %A Woodward, Michael %A Brodaty, Henry %X

BACKGROUND: Dementia is a terminal illness. While various baseline characteristics of patients, such as age, sex, and dementia severity, are known to predict mortality, little research has examined how changes in patients' symptoms over time predict survival. There are also limited data on patients seen in memory clinics, as opposed to other health care settings, and whether antipsychotic medications are associated with mortality in dementia once patients' demographic and clinical features are controlled for.

OBJECTIVE: To identify predictors of mortality in patients with dementia.

METHOD: Of 970 patients recruited from nine memory clinics around Australia, 779 patients had dementia at baseline. Patients completed measures of dementia severity, cognition, functional ability, neuropsychiatric symptoms, caregiver burden, and medication use at baseline and at regular intervals over a three-year period. Mortality data were obtained from state registries eight years after baseline.

RESULTS: Overall, 447 (57.4%) of the patients with dementia died within the eight years. Older age, male sex, more severe dementia and functional impairment at baseline, greater decline in dementia severity and functional impairment over six months, taking a larger number of medications, and use of atypical antipsychotic medication predicted earlier mortality.

CONCLUSIONS: The findings confirm that demographic and diagnostic features predict the survival of patients with dementia. Importantly, the findings indicate that changes in dementia severity and functional impairment over time predict mortality independently of baseline levels, and provide further evidence for the higher mortality risk of patients taking antipsychotic medications.

%B J Alzheimers Dis %V 52 %P 967-74 %8 2016 Apr 12 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079702?dopt=Abstract %R 10.3233/JAD-150946 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Predictors of Response to Cholinesterase Inhibitors Treatment of Alzheimer's Disease: Date Mining from the TREDEM Registry. %A Gallucci, Maurizio %A Spagnolo, Pierpaolo %A Aricò, Maria %A Grossi, Enzo %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cerebrovascular Disorders %K Cholinesterase Inhibitors %K Female %K Humans %K Life Style %K Male %K Marital Status %K Mental Status Schedule %K Neural Networks (Computer) %K Neuropsychological Tests %K Occupations %K Outpatients %K Prognosis %K Registries %K Treatment Outcome %X

BACKGROUND: The pharmacological treatment of Alzheimer's disease (AD) is based largely on cholinesterase inhibitors (ChEI).

OBJECTIVE: To investigate whether or not some non-pharmacological and contextual factors measured prior to starting treatment such as past occupation, lifestyles, marital status, degree of autonomy and cognitive impairment, living alone or with others, and the degree of brain atrophy are associated with a better response to ChEI treatment.

METHODS: Eighty-four AD and six AD with cerebrovascular disease (AD + CVD) outpatients of Treviso Dementia (TREDEM) Registry, with an average cholinesterase inhibitors treatment length of four years, were considered. The outpatients had undergone a complete evaluation and some non-pharmacological and contextual factors were collected. We defined responder a patient with a delta score T0 - T1 equal or inferior to 2.0 points per year of MMSE and a non-responder a patient with a delta score T0 - T1 superior to 2.0 points per year. In order to identify hidden relationships between variables related to response and non-response, we use a special kind of artificial neural network called Auto-CM, able to create a semantic connectivity map of the variables considered in the study.

RESULTS: A higher cognitive profile, a previous intellectual occupation, healthier lifestyles, being married and not living alone, a higher degree of autonomy, and lower degree of brain atrophy at baseline resulted in affecting the response to long-term ChEI therapy.

CONCLUSION: Non-pharmacological and contextual factors appear to influence the effectiveness of treatment with ChEI in the long term.

%B J Alzheimers Dis %V 50 %P 969-79 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836164?dopt=Abstract %R 10.3233/JAD-150747 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy. %A Stern, Robert A %A Tripodis, Yorghos %A Baugh, Christine M %A Fritts, Nathan G %A Martin, Brett M %A Chaisson, Christine %A Cantu, Robert C %A Joyce, James A %A Shah, Sahil %A Ikezu, Tsuneya %A Zhang, Jing %A Gercel-Taylor, Cicek %A Taylor, Douglas D %K Adult %K Aged %K Analysis of Variance %K Case-Control Studies %K Chronic Traumatic Encephalopathy %K Extracellular Vesicles %K Humans %K Male %K Middle Aged %K Plasma %K tau Proteins %X

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer's disease, there is a need for methods to diagnose CTE during life through objective biomarkers.

OBJECTIVE: The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker.

METHODS: Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau.

RESULTS: The NFL group had higher exosomal tau than the control group (p <  0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093).

CONCLUSION: These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.

%B J Alzheimers Dis %V 51 %P 1099-109 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890775?dopt=Abstract %R 10.3233/JAD-151028 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Presence of Select Tau Species in Human Peripheral Tissues and Their Relation to Alzheimer's Disease. %A Dugger, Brittany N %A Whiteside, Charisse M %A Maarouf, Chera L %A Walker, Douglas G %A Beach, Thomas G %A Sue, Lucia I %A Garcia, Angelica %A Dunckley, Travis %A Meechoovet, Bessie %A Reiman, Eric M %A Roher, Alex E %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Blotting, Western %K Colon %K Enzyme-Linked Immunosorbent Assay %K Female %K Frontal Lobe %K Gray Matter %K Humans %K Immunohistochemistry %K Liver %K Male %K Neurofibrillary Tangles %K Phosphorylation %K Severity of Illness Index %K Sex Characteristics %K Skin %K Submandibular Gland %K tau Proteins %X

Tau becomes excessively phosphorylated in Alzheimer's disease (AD) and is widely studied within the brain. Further examination of the extent and types of tau present in peripheral tissues and their relation to AD is warranted given recent publications on pathologic spreading. Cases were selected based on the presence of pathological tau spinal cord deposits (n = 18). Tissue samples from sigmoid colon, scalp, abdominal skin, liver, and submandibular gland were analyzed by western blot and enzyme-linked immunosorbent assays (ELISAs) for certain tau species; frontal cortex gray matter was used for comparison. ELISAs revealed brain to have the highest total tau levels, followed by submandibular gland, sigmoid colon, liver, scalp, and abdominal skin. Western blots with antibodies recognizing tau phosphorylated at threonine 231(pT231), serine 396 and 404 (PHF-1), and an unmodified total human tau between residues 159 and 163 (HT7) revealed multiple banding patterns, some of which predominated in peripheral tissues. As submandibular gland had the highest levels of peripheral tau, a second set of submandibular gland samples were analyzed (n = 36; 19 AD, 17 non-demented controls). ELISAs revealed significantly lower levels of pS396 (p = 0.009) and pT231 (p = 0.005) in AD cases but not total tau (p = 0.18). Furthermore, pT231 levels in submandibular gland inversely correlated with Braak neurofibrillary tangle stage (p = 0.04), after adjusting for age at death, gender, and postmortem interval. These results provide evidence that certain tau species are present in peripheral tissues. Of potential importance, submandibular gland pT231 is progressively less abundant with increasing Braak neurofibrillary tangle stage.

%B J Alzheimers Dis %V 51 %P 345-56 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890756?dopt=Abstract %R 10.3233/JAD-150859 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prevalence and Risk Factor of Cognitive Impairment were Different between Urban and Rural Population: A Community-Based Study. %A Tang, Hui-Dong %A Zhou, Yi %A Gao, Xiang %A Liang, Liang %A Hou, Miao-Miao %A Qiao, Yuan %A Ma, Jian-Fang %A Chen, Sheng-Di %K Aged %K Aged, 80 and over %K China %K Cognition Disorders %K Female %K Humans %K Logistic Models %K Male %K Mental Status Schedule %K Middle Aged %K Multivariate Analysis %K Prevalence %K Risk Factors %K Rural Population %K Urban Population %X

BACKGROUND: China is facing a continuously rising numbers of people with cognitive impairment (CI).

OBJECTIVES: To investigate the prevalence and risk factors of CI among elderly people living in rural and urban communities.

METHODS: We conducted a face-to-face survey of CI on 7,900 individuals aged 50 years or older meeting inclusion criteria in the Malu (rural community, n = 4,429) and Wuliqiao (urban community, n = 3,471) communities of Shanghai. The Mini-Mental State Examination (MMSE) was used to evaluate the cognitive function. Information on demographic features and potential risk factors for CI was collected during the interview. Multivariate logistic regression was performed to identify risk factors associated with CI.

RESULTS: Based on the education modified MMSE score, we identified 329 CI cases in rural community and 227 in urban community. The prevalence of CI was 7.43% in rural population and 6.54% in urban population (p = 0.13). In the urban population, risk of having CI was associated with age (OR = 1.04; 95% CI: 1.01-1.08), lack of physical activities (OR = 2.25; 95% CI: 1.11-4.57), presence of diabetes mellitus (OR = 1.79; 95% CI: 1.04-3.07), and having three or more children (OR = 2.39; 95% CI: 1.27-4.50). In contrast, factors associated with rural populations included female gender (OR = 2.03; 95% CI: 1.08-3.82), age (OR = 1.06; 95% CI: 1.03-1.08), exposure to pesticides (OR = 4.68; 95% CI: 1.27-17.21), history of encephalitis or meningitis (OR = 6.02; 95% CI: 1.92-18.85) and head trauma (OR = 1.89; 95% CI: 1.10-3.24).

CONCLUSIONS: Urban rural and populations showed different risk factors for CI, suggesting that different preventive strategies in these areas should be performed.

%B J Alzheimers Dis %V 49 %P 917-25 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519443?dopt=Abstract %R 10.3233/JAD-150748 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prevention Trials in Alzheimer's Disease: Current Status and Future Perspectives. %A Wang, Jun %A Tan, Lan %A Yu, Jin-Tai %K Alzheimer Disease %K Biomarkers %K Clinical Trials as Topic %K Humans %X

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Over the past 20 years, both pharmacological and lifestyle interventions have been studied for AD prevention, but the overall results have been disappointing. The majority of disappointing results have raised questions and great challenges for the future of AD prevention trials. Ongoing advances in the knowledge of pathogenesis, in the identification of novel targets, in improved outcome measures, and in identification and validation of biomarkers may lead to effective strategies for AD prevention. In this paper, we review the selection of participants and interventions, trial design, outcome assessments, and promising biomarkers in prevention trials, and summarize the lessons learned from completed trials and perspectives from ongoing trials in AD prevention. Selection of optimal participants and interventions, coupled with more refined outcomes and more efficient trial design, may have the capacity to deliver a new era of preventive discovery in this challenging area.

%B J Alzheimers Dis %V 50 %P 927-45 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836177?dopt=Abstract %R 10.3233/JAD-150826 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Primary Progressive Aphasia in the Network of French Alzheimer Plan Memory Centers. %A Magnin, Eloi %A Démonet, Jean-François %A Wallon, David %A Dumurgier, Julien %A Troussière, Anne-Cécile %A Jager, Alain %A Duron, Emmanuelle %A Gabelle, Audrey %A de la Sayette, Vincent %A Volpe-Gillot, Lisette %A Tio, Gregory %A Evain, Sarah %A Boutoleau-Bretonnière, Claire %A Enderle, Adeline %A Mouton-Liger, François %A Robert, Philippe %A Hannequin, Didier %A Pasquier, Florence %A Hugon, Jacques %A Paquet, Claire %X

BACKGROUND: Few demographical data about primary progressive aphasia (PPA) are available, and most knowledge regarding PPA is based on tertiary centers' results.

OBJECTIVE: Our aims were to describe demographical characteristics of the PPA population in a large sample of PPA patients from the network of French Alzheimer plan memory centers (Sample 1), and to describe the stratification of cerebrospinal fluid (CSF) biomarkers in two different samples of PPA patients (Samples 2 and 3).

METHODS: All registered PPA patients in the French Alzheimer's disease (AD) databank (Sample 1: n = 2,035) and a subsample (Sample 2: n = 65) derived from a multicentric prospective cohort with CSF biomarker analysis were analyzed. A multicentric retrospective cohort from language expert tertiary centers (Sample 3: n = 97) with CSF biomarker analysis was added. Sample 3 was added to replicate the CSF results of the Sample 2 and to evaluate repartition of AD pathology in the three variant of PPA according to the latest classification.

RESULTS: Non-Fluent/Agrammatic, Logopenic, and Unclassifiable PPA patients (NF/A-Logo-Unclass PPA) were older and more frequent than Semantic PPA patients (2.2 versus 0.8/100,000 inhabitants; p < 0.00001). Male predominance occurred after the age of 80 (p < 0.00001). A higher level of education was observed in the PPA population compared to a typical amnesic AD group. No demographical significant difference between PPA due to AD and not due to AD was observed. The Logopenic variant was most frequent with 85% of AD CSF biomarker profiles (35% in NF/A PPA; 20% in Semantic PPA).

CONCLUSION: PPA occurs also in an elderly population, especially in male patients over 80. CSF biomarkers are useful to stratify PPA. The epidemiology of PPA should be further investigated to confirm gender and cognitive reserve role in PPA to better understand the factors and mechanisms leading to this language-predominant deficit during neurodegenerative diseases.

%B J Alzheimers Dis %V 54 %P 1459-1471 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589533?dopt=Abstract %R 10.3233/JAD-160536 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Primary Progressive Orofacial Apraxia: A Ten-Year Long Follow-Up Case Report. %A Trebbastoni, Alessandro %A D'Antonio, Fabrizia %A de Lena, Carlo %A Onesti, Emanuela %A John, Bev %A Inghilleri, Maurizio %X

Orofacial apraxia (OA) as the main symptom in neurodegenerative disorders has not been yet reported. We present the case of a woman with a 22-month long history of isolated OA, studied with cerebrospinal fluid biomarkers and repeated clinical, neuropsychological, and morpho-functional evaluations. Baseline morpho-functional neuroimages revealed a left frontal operculum hypoperfusion with a widespread fronto-temporal involvement at follow-up. Cerebrospinal fluid concentrations of tau and amyloid-β were normal. The ten-year long clinical observation disclosed progressive OA worsening and the late onset of frontal functions impairment and extrapyramidal signs. The early and late stages of a neurodegenerative syndrome with OA as the main clinical feature were characterized.

%B J Alzheimers Dis %V 54 %P 1039-1045 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567870?dopt=Abstract %R 10.3233/JAD-160525 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prion Protein-Hemin Interaction Upregulates Hemoglobin Synthesis: Implications for Cerebral Hemorrhage and Sporadic Creutzfeldt-Jakob Disease. %A Tripathi, Ajai K %A Singh, Neena %K Animals %K Brain %K Cell Line, Tumor %K Creutzfeldt-Jakob Syndrome %K Endocytosis %K Ferritins %K Green Fluorescent Proteins %K Hemin %K Hemoglobins %K Humans %K In Vitro Techniques %K Leukemia, Erythroblastic, Acute %K Mice %K Mice, Transgenic %K Neuroblastoma %K Neuroglia %K Neurons %K Organ Culture Techniques %K Prion Proteins %K Transfection %K Up-Regulation %X

Hemin is known to induce endocytosis of prion-protein (PrP(C)) from the neuronal plasma membrane, potentially limiting propagation of the disease causing PrP-scrapie (PrP(Sc)) isoform. Hemin is therefore an attractive disease-modifying option for sporadic Creutzfeldt-Jakob disease (sCJD), a human prion disorder with no effective treatment. The hemin-PrP(C) interaction is also of interest in cerebral-hemorrhage (CH), a condition where potentially toxic hemin molecules come in contact with neuronal PrP(C). Interestingly, PrP(C) is upregulated in penumbric neurons surrounding CH and is known to confer neuroprotection in a dose-dependent manner. The underlying mechanism, however, is not clear. Here, we report that hemin binds PrP(C) on diverse cell lines, resulting in its aggregation or degradation in a cell-type specific manner. Surprisingly, the hemin-PrP(C) interaction upregulates Hb synthesis in hematopoietic cells, a response reversed by deleting the hemin-binding octa-peptide repeat region of PrP(C). A similar response is noted in brain organotypic cultures where exposure to hemin induces significantly more α-globin in wild-type (PrP(+/+)) relative to PrP-knock-out (PrP(-/-)) samples. Furthermore, red blood cells and brain tissue from PrP(-/-) mice show significantly less α-globin relative to PrP(+/+) controls, indicating a positive effect of PrP(C) on Hb synthesis under physiological conditions as well. Surprisingly, levels of α-globin are significantly higher in sCJD brain tissue relative to controls, suggesting compensatory upregulation of Hb synthesis by surviving neurons or misregulation in diseased brains. These observations reveal a unique function of PrP(C) that is likely to impact the therapeutic management of CH and sCJD.

%B J Alzheimers Dis %V 51 %P 107-21 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836195?dopt=Abstract %R 10.3233/JAD-151039 %0 Journal Article %J J Alzheimers Dis %D 2016 %T PRNP P39L Variant is a Rare Cause of Frontotemporal Dementia in Italian Population. %A Oldoni, Emanuela %A Fumagalli, Giorgio G %A Serpente, Maria %A Fenoglio, Chiara %A Scarioni, Marta %A Arighi, Andrea %A Bruno, Giuseppe %A Talarico, Giuseppina %A Confaloni, Annamaria %A Piscopo, Paola %A Nacmias, Benedetta %A Sorbi, Sandro %A Rainero, Innocenzo %A Rubino, Elisa %A Pinessi, Lorenzo %A Binetti, Giuliano %A Ghidoni, Roberta %A Benussi, Luisa %A Grande, Giulia %A Arosio, Beatrice %A Bursey, Devan %A Kauwe, John S %A Cioffi, Sara Mg %A Arcaro, Marina %A Mari, Daniela %A Mariani, Claudio %A Scarpini, Elio %A Galimberti, Daniela %K Aged %K Atrophy %K Frontal Lobe %K Frontotemporal Dementia %K Genetic Predisposition to Disease %K Humans %K Italy %K Language %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Memory, Short-Term %K Neuropsychological Tests %K Prion Proteins %K Prions %K Temporal Lobe %X

The missense P39L variant in the prion protein gene (PRNP) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may be an extremely rare cause of FTD (0.13%).

%B J Alzheimers Dis %V 50 %P 353-7 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757195?dopt=Abstract %R 10.3233/JAD-150863 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Profiling of p5, a 24 Amino Acid Inhibitory Peptide Derived from the CDK5 Activator, p35 CDKR1 Against 70 Protein Kinases. %A Binukumar, B K %A Pelech, Steven L %A Sutter, Catherine %A Shukla, Varsha %A Amin, Niranjana D %A Grant, Philip %A Bhaskar, Manju %A Skuntz, Suzanne %A Steiner, Joseph %A Pant, Harish C %X

Cyclin-dependent kinase 5 (CDK5) is a multifunctional serine/threonine kinase that regulates a large number of neuronal processes essential for nervous system development and function with its activator p35 CDK5R1. Upon neuronal insults, p35 is proteolyzed and cleaved to p25 producing deregulation and hyperactivation of CDK5 (CDK5/p25), implicated in tau hyperphosphorylation, a pathology in some neurodegenerative diseases. A truncated, 24 amino acid peptide, p5, derived from p35 inhibits the deregulated CDK5 phosphotransferase activity and ameliorates Alzheimer's disease (AD) phenotypes in AD model mice. In the present study, we have screened a diverse panel of 70 human protein kinases for their sensitivities to p5, and a subset of these to p35. At least 16 of the tested protein kinases exhibited IC50 values that were 250 μM or less, with CAMK4, ZAP70, SGK1, and PIM1 showing greater sensitivity to inhibition by p5 than CDK5/p35 and CDK5/p25. In contrast, the p5 peptide modestly activated LKB1 and GSK3β. A sub set of kinases screened against p35 showed that activity of CAMK4 in the absence of calcium and calmodulin was also markedly inhibited by p35. The Cyclin Y-dependent kinases PFTK1 (CDK14) and PCTK1 (CDK16) were activated by p35 at least 10-fold in the absence of Cyclin Y and by approximately 50% in its presence. These findings provide additional insights into the mechanisms of action for p5 and p35 in the regulation of protein phosphorylation in the nervous system.

%B J Alzheimers Dis %V 54 %P 525-33 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567857?dopt=Abstract %R 10.3233/JAD-160458 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prognostic Significance of Mild Cognitive Impairment Subtypes for Dementia and Mortality: Data from the NEDICES Cohort. %A Bermejo-Pareja, Félix %A Contador, Israel %A Trincado, Rocío %A Lora, David %A Sánchez-Ferro, Álvaro %A Mitchell, Alex J %A Boycheva, Elina %A Herrero, Alejandro %A Hernández-Gallego, Jesús %A Llamas, Sara %A Villarejo Galende, Alberto %A Benito-León, Julián %K Aged %K Aged, 80 and over %K Algorithms %K Cognitive Dysfunction %K Cohort Studies %K Dementia %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Predictive Value of Tests %K Prognosis %K Proportional Hazards Models %K Spain %X

BACKGROUND: The predictive value of diverse subtypes of mild cognitive impairment (MCI) for dementia and death is highly variable.

OBJECTIVE: To compare the predictive value of several MCI subtypes in progression to dementia and/or mortality in the NEDICES (Neurological Disorders in Central Spain) elderly cohort.

METHODS: Retrospect algorithmic MCI subgroups were established in a non-dementia baseline NEDICES cohort using Spanish adaptations of the original Mini-Mental State Examination (MMSE-37) and Pfeffer's Functional Activities Questionnaire (Pfeffer-11). The presence of MCI was defined according two cognitive criteria: using two cut-offs points on the total MMSE-37 score. Five cognitive domains were used to establish the MCI subtypes. Functional capacity (Pfeffer-11) was preserved or minimally impaired in all MCI participants. The incident dementia diagnoses were established by specialists and the mortality data obtained from Spanish official registries.

RESULTS: 3,411 participants without dementia were assessed in 1994-5. The baseline prevalence of MCI varied according to the MCI definition (4.3%-31.8%). The follow-up was a mean of 3.2 years (1997-8). The dementia incidence varied between 14.9 and 71.8 per 1,000/person-years. The dementia conversion rate was increased in almost all MCI subgroups (p >  0.01), and mortality rate was raised only in four MCI subtypes. The amnestic-multi-domain MCI (aMd-MCI) had the best dementia predictive accuracy (highest positive likelihood ratio and highest clinical utility when negative).

CONCLUSIONS: Those with aMd-MCI were at greatest risk of progression to dementia, as in other surveys and might be explored with increased attention in MCI research and in dementia preventive trials.

%B J Alzheimers Dis %V 50 %P 719-31 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757038?dopt=Abstract %R 10.3233/JAD-150625 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Progranulin Protein Levels in Cerebrospinal Fluid in Primary Neurodegenerative Dementias. %A Morenas-Rodriguez, Estrella %A Cervera-Carles, Laura %A Vilaplana, Eduard %A Alcolea, Daniel %A Carmona-Iragui, María %A Dols-Icardo, Oriol %A Ribosa-Nogué, Roser %A Muñoz-Llahuna, Laia %A Sala, Isabel %A Belén Sánchez-Saudinós, M %A Blesa, Rafael %A Clarimón, Jordi %A Fortea, Juan %A Lleo, Alberto %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Biomarkers %K Dementia %K Female %K Humans %K Intercellular Signaling Peptides and Proteins %K Male %K Middle Aged %K Neurodegenerative Diseases %K Polymorphism, Single Nucleotide %K tau Proteins %X

BACKGROUND: Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerative disorders is unknown.

OBJECTIVE: To investigate the levels of progranulin (PGRN) in cerebrospinal fluid (CSF) in different neurodegenerative dementias and their correlation with levels in plasma in cognitively normal subjects.

METHODS: We measured PGRN in CSF in 229 patients with amnestic mild cognitive impairment, Alzheimer's disease dementia, sporadic FTD, dementia with Lewy bodies, corticobasal syndrome, or progressive supranuclear palsy. We also measured PGRN in CSF and plasma in 74 cognitively normal individuals. We examined the correlation between PGRN levels in CSF and diagnosis, cortical thickness, genetic factors and other CSF biomarkers. We also investigated the correlation between plasma and CSF levels of PGRN in cognitively normal individuals.

RESULTS: CSF levels did not differ across diagnoses or correlate with cortical thickness. Polymorphism rs5848 in GRN influenced CSF PGRN levels, but APOEɛ4 allele did not. Amyloid-β42, t-tau, p-tau, and YKL-40 levels correlated weakly with PGRN in CSF. We found a weak correlation (r = 0.362) between plasma and CSF PGRN levels in cognitively normal individuals.

CONCLUSIONS: Our findings do not support a diagnostic value of CSF PGRN in neurodegenerative diseases. Our data confirm that levels of PGRN in plasma do not reflect accurately levels in CSF in cognitively normal controls. These data should be considered in clinical trials aiming to increase PGRN.

%B J Alzheimers Dis %V 50 %P 539-46 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682689?dopt=Abstract %R 10.3233/JAD-150746 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Progression of Extrapyramidal Signs in Alzheimer's Disease: Clinical and Neuropathological Correlates. %A Tosto, Giuseppe %A Monsell, Sarah E %A Hawes, Stephen E %A Bruno, Giuseppe %A Mayeux, Richard %K Aged %K Algorithms %K Alzheimer Disease %K Cluster Analysis %K Databases, Factual %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Severity of Illness Index %X

BACKGROUND: Extrapyramidal signs (EPS) are frequent in Alzheimer's disease (AD) and core manifestation of related diseases, i.e., dementia with Lewy bodies and Parkinson's disease; furthermore, Lewy bodies and AD-type pathology occur in all three conditions.

OBJECTIVE: To identify clusters of EPS progression over time and their clinical and neuropathological correlates.

METHODS: 3,502 AD patients with longitudinal assessment from the National Alzheimer's Coordinating Center database were included; 394 provided neuropathological data. k-means algorithm was employed to identify clusters of EPS progression and those were compared in terms of cognitive profile, neuropsychiatric features and neuropathological findings.

RESULTS: Three clusters of EPS progression were identified: no/low (n = 1,583), medium (n = 1,259), and high (n = 660) EPS burden. Compared to those with no/low and medium EPS, those with high EPS had greater cognitive and neuropsychiatric impairment, specifically hallucinations. Despite similar AD-pathology across the three clusters, the high EPS cluster had a significantly number of subjects diagnosed with dementia with Lewy bodies.

CONCLUSIONS: Cluster analysis of EPS progression over time identified different subgroups of AD patients with distinct clinical and neuropathological features.

%B J Alzheimers Dis %V 49 %P 1085-93 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599050?dopt=Abstract %R 10.3233/JAD-150244 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prolonged Visual Facial Grasp in Frontotemporal Dementia. %A Paholpak, Pongsatorn %A Li-Jung, Liang %A Carr, Drew R %A Jimenez, Elvira %A Barrows, Robin J %A Sabodash, Valeiry %A Mendez, Mario F %X

BACKGROUND: Gaze and eye contact is a critical aspect of social interaction. Patients with behavioral variant frontotemporal dementia (bvFTD) may exhibit abnormally prolonged stare toward human faces.

OBJECTIVE: To study characteristics of social gaze in patients with bvFTD compared to age and education matched-patients with early-onset Alzheimer's disease (eAD) and healthy controls (HC).

METHOD: Fifty picture stimuli were presented to each participant (bvFTD = 12, eAD = 18, HC = 13). Each stimuli contained two properties: face (facial versus non-facial) and valence (positive, negative, and neutral). The "facial" stimuli contained human faces. The participants Visual Fixation Time (VFT) was measured for each picture stimuli of interest (per facial expressions on the Facial Action Coding System). A linear mixed-effects regression model with participant-level of random effects was used to compare VFTs between groups.

RESULTS: The patients with bvFTD showed significantly prolonged VFTs to faces than the patients with eAD and the HC, regardless of valence (all p < 0.01). There were no differences in VFTs for non-facial stimuli between patients with bvFTD and eAD. However, patients with bvFTD and eAD had significantly prolonged VFTs to negative non-facial stimuli than the HC (p = 0.006 and 0.019, respectively).

CONCLUSION: Patients with bvFTD exhibited a prolonged stare toward human faces. This prolonged visual facial grasp may contribute to the disturbed social interactions of patients with bvFTD and can help distinguish them from those with Alzheimer's disease and other conditions. Additionally, both dementia groups tended to stare at negative stimuli whether faces or non-faces.

%B J Alzheimers Dis %V 53 %P 327-35 %8 2016 May 07 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163801?dopt=Abstract %R 10.3233/JAD-150864 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Promising Role of Neuromodulation in Predicting the Progression of Mild Cognitive Impairment to Dementia. %A Naro, Antonino %A Corallo, Francesco %A De Salvo, Simona %A Marra, Angela %A Di Lorenzo, Giuseppe %A Muscarà, Nunzio %A Russo, Margherita %A Marino, Silvia %A De Luca, Rosaria %A Bramanti, Placido %A Calabrò, Rocco Salvatore %X

The differential diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD) is not always straightforward, and the rate of progression of MCI to dementia is not negligible. Thus, there is a need for para-clinical approaches that can improve the differential diagnosis and identify patients that are at risk of progression. There is a growing interest, at present, in the role of the deterioration of brain oscillations as a predictor of MCI-to-AD conversion. For this reason, we experimentally modulated γ-band oscillations (GBO) in a sample of MCI and AD patients and an age-matched healthy elderly group, using a transcranial alternating current stimulation (tACS) protocol that was applied to different cortical sites. We correlated the after-effects of tACS on the GBO and the neuropsychological data, in an attempt to differentiate MCI from AD patients and identify, among the MCI patients, those that could be at potential risk of MCI-to-dementia conversion. MCI patients showed a partial GBO increase and improvement in some neuropsychological tests whereas AD individuals did not show significant tACS after-effects. Notably, some MCI subjects lacked significant neuropsychological and electrophysiological after-effects, similar to AD individuals. In a two-year follow-up, such MCI individuals had converted into AD. Therefore, our data suggest that tACS may support the clinical differential diagnosis of MCI and AD and identify MCI patients who could be at risk of developing dementia. This prediction index may help the clinician to adopt a better prevention/follow-up strategy in such a disabling neurodegenerative disease.

%B J Alzheimers Dis %V 53 %P 1375-88 %8 2016 Jul 01 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392866?dopt=Abstract %R 10.3233/JAD-160305 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prospective Memory Impairments in Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia: Clinical and Neural Correlates. %A Dermody, Nadene %A Hornberger, Michael %A Piguet, Olivier %A Hodges, John R %A Irish, Muireann %K Aged %K Alzheimer Disease %K Atrophy %K Brain %K Brain Mapping %K Female %K Frontotemporal Dementia %K Humans %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Memory, Episodic %K Middle Aged %K Neuropsychological Tests %X

BACKGROUND: Prospective memory (PM) refers to a future-oriented form of memory in which the individual must remember to execute an intended action either at a future point in time (Time-based) or in response to a specific event (Event-based). Lapses in PM are commonly exhibited in neurodegenerative disorders including Alzheimer's disease (AD) and frontotemporal dementia (FTD), however, the neurocognitive mechanisms driving these deficits remain unknown.

OBJECTIVE: To investigate the clinical and neural correlates of Time- and Event-based PM disruption in AD and the behavioral-variant FTD (bvFTD).

METHODS: Twelve AD, 12 bvFTD, and 12 healthy older Control participants completed a modified version of the Cambridge Prospective Memory test, which examines Time- and Event-based aspects of PM. All participants completed a standard neuropsychological assessment and underwent whole-brain structural MRI.

RESULTS: AD and bvFTD patients displayed striking impairments across Time- and Event-based PM relative to Controls, however, Time-based PM was disproportionately affected in the AD group. Episodic memory dysfunction and hippocampal atrophy were found to correlate strongly with PM integrity in both patient groups, however, dissociable neural substrates were also evident for PM performance across dementia syndromes.

CONCLUSION: Our study reveals the multifaceted nature of PM dysfunction in neurodegenerative disorders, and suggests common and dissociable neurocognitive mechanisms, which subtend these deficits in each patient group. Future studies of PM disturbance in dementia syndromes will be crucial for the development of successful interventions to improve functional independence in the patient's daily life.

%B J Alzheimers Dis %V 50 %P 425-41 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682697?dopt=Abstract %R 10.3233/JAD-150871 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Protective Effect of Amyloid-β Peptides Against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model. %A Bourgade, Karine %A Le Page, Aurélie %A Bocti, Christian %A Witkowski, Jacek M %A Dupuis, Gilles %A Frost, Eric H %A Fülöp, Tamás %K Amyloid beta-Peptides %K Amyloid Precursor Protein Secretases %K Cell Line, Tumor %K Coculture Techniques %K Culture Media, Conditioned %K Herpes Simplex %K Herpesvirus 1, Human %K Humans %K Interferon-alpha %K Interleukin-1beta %K Neuroglia %K Neurons %K Peptide Fragments %K Tumor Necrosis Factor-alpha %K Virus Replication %X

Senile amyloid plaques are one of the main hallmarks of Alzheimer's disease (AD). They correspond to insoluble deposits of amyloid-β peptides (Aβ) and are responsible for the inflammatory response and neurodegeneration that lead to loss of memory. Recent data suggest that Aβ possess antimicrobial and anti-viral activity in vitro. Here, we have used cocultures of neuroglioma (H4) and glioblastoma (U118-MG) cells as a minimal in vitro model to investigate whether Aβ is produced by neuroglioma cells and whether this could result in protective anti-viral activity against HSV-1 infection. Results showed that H4 cells secreted Aβ42 in response to HSV-1 challenge and that U118-MG cells could rapidly internalize Aβ42. Production of pro-inflammatory cytokines TNFα and IL-1β by H4 and U118-MG cells occurred under basal conditions but infection of the cells with HSV-1 did not significantly upregulate production. Both cell lines produced low levels of IFNα. However, extraneous Aβ42 induced strong production of these cytokines. A combination of Aβ42 and HSV-1 induced production of pro-inflammatory cytokines TNFα and IL-1β, and IFNα in the cell lines. The reported anti-viral protection of Aβ42 was revealed in transfer experiments involving conditioned medium (CM) of HSV-1-infected H4 cells. CM conferred Aβ-dependent protection against HSV-1 replication in de novo cultures of H4 cells challenged with HSV-1. Type 1 interferons did not play a role in these assays. Our data established that H4 neuroglioma cells produced Aβ42 in response to HSV-1 infection thus inhibiting secondary replication. This mechanism may play a role in the etiology of AD.

%B J Alzheimers Dis %V 50 %P 1227-41 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836158?dopt=Abstract %R 10.3233/JAD-150652 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Protein Kinase Activity Decreases with Higher Braak Stages of Alzheimer's Disease Pathology. %A Rosenberger, Andrea F N %A Hilhorst, Riet %A Coart, Elisabeth %A García Barrado, Leandro %A Naji, Faris %A Rozemuller, Annemieke J M %A van der Flier, Wiesje M %A Scheltens, Philip %A Hoozemans, Jeroen J M %A van der Vies, Saskia M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cohort Studies %K Female %K Hippocampus %K Humans %K Male %K Middle Aged %K Phosphorylation %K Protein Kinases %K Protein-Serine-Threonine Kinases %K Severity of Illness Index %X

Alzheimer's disease (AD) is characterized by a long pre-clinical phase (20-30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform. We observed an overall decrease of protein kinase activity that correlated with disease progression. The phosphorylation of 96.7% of the serine/threonine peptides and 37.5% of the tyrosine peptides on the microarray decreased significantly with increased Braak stage (p-value <0.01). Decreased activity was evident at pre-clinical stages of AD pathology (Braak I-II). Increased phosphorylation was not observed for any peptide. STRING analysis in combination with pathway analysis and identification of kinases responsible for peptide phosphorylation showed the interactions between well-known proteins in AD pathology, including the Ephrin-receptor A1 (EphA1), a risk gene for AD, and sarcoma tyrosine kinase (Src), which is involved in memory formation. Additionally, kinases that have not previously been associated with AD were identified, e.g., protein tyrosine kinase 6 (PTK6/BRK), feline sarcoma oncogene kinase (FES), and fyn-associated tyrosine kinase (FRK). The identified protein kinases are new biomarkers and potential drug targets for early (pre-clinical) intervention.

%B J Alzheimers Dis %V 49 %P 927-43 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519433?dopt=Abstract %R 10.3233/JAD-150429 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Protein Misfolding in Prion and Prion-Like Diseases: Reconsidering a Required Role for Protein Loss-of-Function. %A Leighton, Patricia L A %A Allison, W Ted %X

Prion disease research has contributed much toward understanding other neurodegenerative diseases, including recent demonstrations that Alzheimer's disease (AD) and other neurodegenerative diseases are prion-like. Prion-like diseases involve the spread of degeneration between individuals and/or among cells or tissues via template directed misfolding, wherein misfolded protein conformers propagate disease by causing normal proteins to misfold. Here we use the premise that AD, amyotrophic lateral sclerosis, Huntington's disease, and other similar diseases are prion-like and ask: Can we apply knowledge gained from studies of these prion-like diseases to resolve debates about classical prion diseases? We focus on controversies about what role(s) protein loss-of-function might have in prion diseases because this has therapeutic implications, including for AD. We examine which loss-of-function events are recognizable in prion-like diseases by considering the normal functions of the proteins before their misfolding and aggregation. We then delineate scenarios wherein gain-of-function and/or loss-of-function would be necessary or sufficient for neurodegeneration. We consider roles of PrPC loss-of-function in prion diseases and in AD, and conclude that the conventional wisdom that prion diseases are 'toxic gain-of-function diseases' has limitations. While prion diseases certainly have required gain-of-function components, we propose that disease phenotypes are predominantly caused by deficits in the normal physiology of PrPC and its interaction partners as PrPC converts to PrPSc. In this model, gain-of-function serves mainly to spread disease, and loss-of-function directly mediates neuron dysfunction. We propose experiments and predictions to assess our conclusion. Further study on the normal physiological roles of these key proteins is warranted.

%B J Alzheimers Dis %V 54 %P 3-29 %8 2016 Jul 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392869?dopt=Abstract %R 10.3233/JAD-160361 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Psychometric Properties of the Memory Binding Test: Test-Retest Reliability and Convergent Validity. %A Gramunt, Nina %A Sánchez-Benavides, Gonzalo %A Buschke, Herman %A Lipton, Richard B %A Masramon, Xavier %A Gispert, Juan D %A Peña-Casanova, Jordi %A Fauria, Karine %A Molinuevo, José L %K Aged %K Alzheimer Disease %K Female %K Humans %K Male %K Memory %K Middle Aged %K Psychological Tests %K Psychometrics %K Reproducibility of Results %X

BACKGROUND: Episodic memory testing is fundamental for the diagnosis of Alzheimer's disease (AD). Although the Free and Cued Selective Reminding Test (FCSRT) is widely used for this purpose, it may not be sensitive enough for early detection of subtle decline in preclinical AD. The Memory Binding Test (MBT) intends to overcome this limitation.

OBJECTIVES: To analyze the test-retest reliability of the MBT and its convergent validity with the FCRST.

METHODS: 36 cognitively healthy participants of the ALFA Study, aged 45 to 65, were included for the test-retest study and 69 for the convergent analysis. They were visited twice in a period of 6 ± 2 weeks. Test-retest reliability was determined by the calculation of the intra-class correlation coefficient (ICC). Score differences were studied by computing the mean percentage of score variation between visits and visualized by Bland-Altman plots. Convergent validity was determined by Pearson's correlations.

RESULTS: ICC values in the test-retest reliability analysis of the MBT direct scores ranged from 0.64 to 0.76. Subjects showed consistent practice effects, with mean amounts of score increasing between 10% and 26%. Pearson correlation between MBT and FCSRT direct scores showed r values between 0.40 and 0.53. The FCSRT displayed ceiling effects not observed in the MBT.

CONCLUSIONS: The MBT shows adequate test-retest reliability and overall moderate convergent validity with the FCSRT. Unlike the FCSRT, the MBT does not have ceiling effects and it may therefore be especially useful in longitudinal studies, facilitating the measurement of subtle memory performance decline and the detection of very early AD.

%B J Alzheimers Dis %V 50 %P 999-1010 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836167?dopt=Abstract %R 10.3233/JAD-150776 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Psychotropic Drug Prescription in Patients with Dementia: Nursing Home Residents Versus Patients Living at Home. %A Jacquin-Piques, Agnès %A Sacco, Guillaume %A Tavassoli, Neda %A Rouaud, Olivier %A Bejot, Yannick %A Giroud, Maurice %A Robert, Philippe %A Vellas, Bruno %A Bonin-Guillaume, Sylvie %K Aged %K Aged, 80 and over %K Chi-Square Distribution %K Cross-Sectional Studies %K Databases, Factual %K Dementia %K Drug Prescriptions %K Female %K Humans %K Male %K Nursing Homes %K Psychotropic Drugs %K Residence Characteristics %X

BACKGROUND: Psychotropic drugs are frequently prescribed in nursing homes (NH). Nonetheless, we hoped that institutionalization decreases the number of psychotropic drug classes prescribed, because NH residents may have more psychosocial interventions than patients living at home.

OBJECTIVE: The aim was to compare the type and number of psychotropic drugs prescribed in elderly NH residents with dementia with those in community-living patients.

METHODS: This cross-sectional study included elderly patients (at least 75 years old) with dementia recorded in the National Alzheimer's data Bank ("Banque Nationale Alzheimer") during the year 2012 and who were taking at least one psychotropic drug. Psychotropic drugs were classified as follows: antidepressant, anxiolytic, hypnotic, and antipsychotic drugs. Patients were classified into three categories of dementia severity according to the MMSE score.

RESULTS: Among the 50,932 patients with dementia recorded in the BNA, 40.1% had at least one psychotropic drug prescribed. Most of the patients who were treated by at least one psychotropic drug class had antidepressant therapy (69.0%), whatever their residence type, and 16.1% were treated with antipsychotics. Among the study population, 51.9% of the NH residents and 67.4% of the patients living at home had only one psychotropic drug class prescribed. Living in a NH was significantly associated with the more frequent prescription of anxiolytic, hypnotic, and antipsychotic drugs, and with a greater number of psychotropic drug classes prescribed, whatever the severity of the dementia.

CONCLUSION: We underlined the more frequent prescription of psychotropic drugs in NH residents regardless of MMSE scores.

%B J Alzheimers Dis %V 49 %P 671-80 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484903?dopt=Abstract %R 10.3233/JAD-150280 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Puerarin Ameliorates D-Galactose Induced Enhanced Hippocampal Neurogenesis and Tau Hyperphosphorylation in Rat Brain. %A Hong, Xiao-Ping %A Chen, Tao %A Yin, Ni-Na %A Han, Yong-Ming %A Yuan, Fang %A Duan, Yan-Jun %A Shen, Feng %A Zhang, Yan-Hong %A Chen, Ze-Bin %K Animals %K Cognition Disorders %K Disease Models, Animal %K Fibroblast Growth Factor 2 %K Galactose %K Glycogen Synthase Kinase 3 %K Hippocampus %K Isoflavones %K Male %K Maze Learning %K Neurogenesis %K Neurons %K Neuroprotective Agents %K Phosphorylation %K Random Allocation %K Rats, Sprague-Dawley %K Signal Transduction %K Spatial Memory %K tau Proteins %X

Enhanced neurogenesis has been reported in the hippocampus of patients with Alzheimer's disease (AD), the most common neurodegenerative disorder characterized with amyloid-β (Aβ) aggregation, tau hyperphosphorylation, and progressive neuronal loss. Previously we reported that tau phosphorylation played an essential role in adult hippocampal neurogenesis, and activation of glycogen synthase kinase (GSK-3), a crucial tau kinase, could induce increased hippocampal neurogenesis. In the present study, we found that treatment of D-galactose rats with Puerarin could significantly improve behavioral performance and ameliorate the enhanced neurogenesis and microtubule-associated protein tau hyperphosphorylation in the hippocampus of D-galactose rat brains. FGF-2/GSK-3 signaling pathway might be involved in the effects of Puerarin on hippocampal neurogenesis and tau hyperphosphorylation. Our finding provides primary in vivo evidence that Puerarin can attenuate AD-like enhanced hippocampal neurogenesis and tau hyperphosphorylation. Our finding also suggests Puerarin can be served as a treatment for age-related neurodegenerative disorders, such as AD.

%B J Alzheimers Dis %V 51 %P 605-17 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890737?dopt=Abstract %R 10.3233/JAD-150566 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Purported Interactions of Amyloid-β and Glucocorticoids in Cytotoxicity and Genotoxicity: Implications in Alzheimer's Disease. %A Bengoetxea, Xabier %A de Cerain, Adela López %A Azqueta, Amaya %A Ramirez, Maria J %X

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the presence of aggregates of the amyloid-β peptide (Aβ) that are believed to be neurotoxic. One of the purposed damaging mechanisms of Aβ is oxidative insult, which eventually could damage the cellular genome. Stress and associated increases in glucocorticoids (GCs) have been described as a risk factor for the development of AD, although the purported genotoxic effects of GCs have not been fully characterized. Therefore, it is possible to speculate about purported synergistic effects of GCs on the Aβ-driven genotoxic damage. This in vitro study addresses the single and combined cyto/genotoxic effects of Aβ and GCs in SH-SY5Y cells. Cytotoxicity was determined by the MTT assay, and the genotoxic effects were studied using the comet assay. A comet assay derivation allows for measuring the presence of the FPG-sensitive sites (mainly 8-oxoguanines) in the DNA, apart from the DNA strand breaks. Treatment with Aβ (10 μM, 72 h) induced cytotoxicity (35% decrease in cell viability) and DNA strand breaks, but had no significant effect on oxidative DNA damage (FPG sites). Corticosterone showed no effect on cell viability, genotoxicity, or reparation processes. Corticosterone was unable to neither reverse nor potentiate Aβ driven effects. The present results suggest the existence of alternative mechanisms for the Aβ driven damage, not involving oxidative damage of DNA. In addition, could be suggested that the interaction between Aβ and GCs in AD does not seem to involve DNA damage.

%B J Alzheimers Dis %V 54 %P 1085-1094 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589535?dopt=Abstract %R 10.3233/JAD-160636 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Qualitative Impairment in Face Perception in Alzheimer's Disease: Evidence from a Reduced Face Inversion Effect. %A Lavallée, Marie Maxime %A Gandini, Delphine %A Rouleau, Isabelle %A Vallet, Guillaume T %A Joannette, Maude %A Kergoat, Marie-Jeanne %A Busigny, Thomas %A Rossion, Bruno %A Joubert, Sven %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Face %K Facial Recognition %K Female %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Orientation %K Pattern Recognition, Visual %K Perceptual Disorders %K Photic Stimulation %K Psychiatric Status Rating Scales %K Reaction Time %K Statistics as Topic %X

Prevalent face recognition difficulties in Alzheimer's disease (AD) have typically been attributed to the underlying episodic and semantic memory impairment. The aim of the current study was to determine if AD patients are also impaired at the perceptual level for faces, more specifically at extracting a visual representation of an individual face. To address this question, we investigated the matching of simultaneously presented individual faces and of other nonface familiar shapes (cars), at both upright and inverted orientation, in a group of mild AD patients and in a group of healthy older controls matched for age and education. AD patients showed a reduced inversion effect (i.e., larger performance for upright than inverted stimuli) for faces, but not for cars, both in terms of error rates and response times. While healthy participants showed a much larger decrease in performance for faces than for cars with inversion, the inversion effect did not differ significantly for faces and cars in AD. This abnormal inversion effect for faces was observed in a large subset of individual patients with AD. These results suggest that AD patients have deficits in higher-level visual processes, more specifically at perceiving individual faces, a function that relies on holistic representations specific to upright face stimuli. These deficits, combined with their memory impairment, may contribute to the difficulties in recognizing familiar people that are often reported in patients suffering from the disease and by their caregivers.

%B J Alzheimers Dis %V 51 %P 1225-36 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967217?dopt=Abstract %R 10.3233/JAD-151027 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Quantitative Neuroimaging Software for Clinical Assessment of Hippocampal Volumes on MR Imaging. %A Ahdidan, Jamila %A Raji, Cyrus A %A DeYoe, Edgar A %A Mathis, Jedidiah %A Noe, Karsten Ø %A Rimestad, Jens %A Kjeldsen, Thomas K %A Mosegaard, Jesper %A Becker, James T %A Lopez, Oscar %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Female %K Hippocampus %K Humans %K Image Interpretation, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Software %X

BACKGROUND: Multiple neurological disorders including Alzheimer's disease (AD), mesial temporal sclerosis, and mild traumatic brain injury manifest with volume loss on brain MRI. Subtle volume loss is particularly seen early in AD. While prior research has demonstrated the value of this additional information from quantitative neuroimaging, very few applications have been approved for clinical use. Here we describe a US FDA cleared software program, NeuroreaderTM, for assessment of clinical hippocampal volume on brain MRI.

OBJECTIVE: To present the validation of hippocampal volumetrics on a clinical software program.

METHOD: Subjects were drawn (n = 99) from the Alzheimer Disease Neuroimaging Initiative study. Volumetric brain MR imaging was acquired in both 1.5 T (n = 59) and 3.0 T (n = 40) scanners in participants with manual hippocampal segmentation. Fully automated hippocampal segmentation and measurement was done using a multiple atlas approach. The Dice Similarity Coefficient (DSC) measured the level of spatial overlap between NeuroreaderTM and gold standard manual segmentation from 0 to 1 with 0 denoting no overlap and 1 representing complete agreement. DSC comparisons between 1.5 T and 3.0 T scanners were done using standard independent samples T-tests.

RESULTS: In the bilateral hippocampus, mean DSC was 0.87 with a range of 0.78-0.91 (right hippocampus) and 0.76-0.91 (left hippocampus). Automated segmentation agreement with manual segmentation was essentially equivalent at 1.5 T (DSC = 0.879) versus 3.0 T (DSC = 0.872).

CONCLUSION: This work provides a description and validation of a software program that can be applied in measuring hippocampal volume, a biomarker that is frequently abnormal in AD and other neurological disorders.

%B J Alzheimers Dis %V 49 %P 723-32 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484924?dopt=Abstract %R 10.3233/JAD-150559 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Quantitative phosphoproteomic analyses of the inferior parietal lobule from three different pathological stages of Alzheimer's disease. %A Triplett, Judy C %A Swomley, Aaron M %A Cai, Jian %A Klein, Jon B %A Butterfield, D Allan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Male %K Memory %K Neurofibrillary Tangles %K Oxidative Stress %K Parietal Lobe %K Phosphorylation %K Plaque, Amyloid %K Proteome %X

Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is clinically characterized by progressive neuronal loss resulting in loss of memory and dementia. AD is histopathologically characterized by the extensive distribution of senile plaques and neurofibrillary tangles, and synapse loss. Amnestic mild cognitive impairment (MCI) is generally accepted to be an early stage of AD. MCI subjects have pathology and symptoms that fall on the scale intermediately between 'normal' cognition with little or no pathology and AD. A rare number of individuals, who exhibit normal cognition on psychometric tests but whose brains show widespread postmortem AD pathology, are classified as 'asymptomatic' or 'preclinical' AD (PCAD). In this study, we evaluated changes in protein phosphorylation states in the inferior parietal lobule of subjects with AD, MCI, PCAD, and control brain using a 2-D PAGE proteomics approach in conjunction with Pro-Q Diamond phosphoprotein staining. Statistically significant changes in phosphorylation levels were found in 19 proteins involved in energy metabolism, neuronal plasticity, signal transduction, and oxidative stress response. Changes in the disease state phosphoproteome may provide insights into underlying mechanisms for the preservation of memory with expansive AD pathology in PCAD and the progressive memory loss in amnestic MCI that escalates to the dementia and the characteristic pathology of AD brain.

%B J Alzheimers Dis %V 49 %P 45-62 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444780?dopt=Abstract %R 10.3233/JAD-150417 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Quantitative Proteomics Reveals the Mechanism of Oxygen Treatment on Lenses of Alzheimer's Disease Model Mice. %A Wang, Hao %A Wang, Ying %A Hong, Xiaoyu %A Li, Shuiming %A Wang, Yong %X

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease with well-characterized pathological features. Yet the underlying mechanisms have not been resolved and an effective therapeutic approach is lacking. Cerebral hypoxia is considered a risk factor of AD.

OBJECTIVE: We tested whether oxygen supplementation can relieve AD symptoms and how it affects the expression levels of proteins in the lens.

METHODS: Triple transgenic AD model (3xTg-AD) mice were divided into oxygen treated (OT) and control (Ctrl) groups. Their cognitive performances were tested in a Morris water maze (MWM) paradigm. Then, their eye lens tissues were subjected to quantitative proteomics analysis by the iTRAQ (isobaric tags for relative and absolute quantification) method. The up- and downregulated proteins were classified according to a Gene Ontology (GO) database in PANTHER. Behavioral and proteomic data were compared between the groups.

RESULTS: Mice in the OT group had better learning and memorizing performance compared with the Ctrl group in MWM test. Lenses from the OT group had 205 differentially regulated proteins, relative to lenses from the Ctrl group, including proteins that are involved in the clearance of amyloid β-protein.

CONCLUSION: The results of this study indicate that oxygen treatment can improve cognitive function in AD model mice and alters protein expression in a manner consistent with improved redox regulation.

%B J Alzheimers Dis %V 54 %P 275-86 %8 2016 Aug 10 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567828?dopt=Abstract %R 10.3233/JAD-160263 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Redefining Amnestic Mild Cognitive Impairment as an Early Form of Alzheimer's Disease Based on Assessment of Memory Systems. %A Bolívar, Juan Carlos Cejudo %A Saladie, Domènec Gil %X

BACKGROUND: It has been suggested that mild cognitive impairment (MCI) can be used to identify patients at risk of developing clinical stages of Alzheimer's disease (AD).

OBJECTIVE: The aim of this study was to describe the characteristics of amnesic syndrome of dementia of the Alzheimer's type (DAT) as a continuous degenerative process from normality to amnesic syndrome and provide a classification of the degrees of amnesia.

METHODS: Of 3,800 new incidental cases at the Memory Clinic, 747 were classified as non-demented patients. A 96-month follow-up study was conducted. We described and compared longitudinal outcomes from normality to amnesic syndrome based on immediate memory, verbal learning, free recall, and recognition using the memory scale from the Basic Neuropsychological Battery, version D (BNB-D) and created a new classification of memory impairment.

RESULTS: Based on differences observed in this longitudinal study, we classified patients in four memory stages: M1, Normal episodic memory; M2, mild impairment in learning and/or free recall; M3, clear impairment in learning and/or free recall; and M4, complete amnesic syndrome. With this new amnesia classification, we studied the chronological progression of all patients diagnosed without dementia from baseline to DAT conversion using the Kaplan-Meier estimator of survival probability (Log Rank/Mantel Cox comparison. χ2  = 171.84, p = 0.001).

CONCLUSION: This new classification of memory impairment can help increase the prediction certainty of conversion from amnestic MCI to AD and improve research on AD biomarkers and their relationship with memory as the principal manifestation of AD.

%B J Alzheimers Dis %V 53 %P 705-12 %8 2016 May 04 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163821?dopt=Abstract %R 10.3233/JAD-160117 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reduction of Amyloid-β Plasma Levels by Hemodialysis: An Anti-Amyloid Treatment Strategy? %A Tholen, Susanne %A Schmaderer, Christoph %A Chmielewski, Stefan %A Förstl, Hans %A Heemann, Uwe %A Baumann, Marcus %A Steubl, Dominik %A Grimmer, Timo %K Adult %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Cognition Disorders %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Renal Dialysis %X

BACKGROUND: Cognitive impairment in hemodialysis patients is common, but the underlying pathogenesis remains unclear. Alzheimer's disease is the most common cause of dementia in the general elderly population. Histopathological hallmarks are, among others, senile plaques, which consist of amyloid-β (Aβ).

OBJECTIVE: To measure plasma levels of Aβ42 and Aβ40 during hemodialysis and to examine potential associations with cognitive performance in cognitively impaired hemodialysis patients.

METHODS: Plasma samples of 26 hemodialysis patients were collected shortly before, after 50% of dialysis time, and at the end of a dialysis session. Aβ42 and Aβ40 levels were measured by a high-sensitivity ELISA for human amyloid-β. Cognition was tested under standardized conditions using the Montreal Cognitive Assessment (MoCA) as proposed previously.

RESULTS: Clearance rates of both peptides during one dialysis session were 22% and 35% for Aβ42 and Aβ40, respectively. Aβ42 but not Aβ40 baseline levels were significantly associated with MoCA test results (r = 0.654, p = 0.001).

CONCLUSION: In cognitively impaired hemodialysis patients plasma Aβ42 levels were associated with cognitive performance and both Aβ42 and Aβ40 plasma levels could be effectively reduced by dialysis. By inducing peripheral Aβ sink, hemodialysis may be considered as an anti-amyloid treatment strategy.

%B J Alzheimers Dis %V 50 %P 791-6 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682683?dopt=Abstract %R 10.3233/JAD-150662 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reduction of Blood Amyloid-β Oligomers in Alzheimer's Disease Transgenic Mice by c-Abl Kinase Inhibition. %A Estrada, Lisbell D %A Chamorro, David %A Yañez, María José %A Gonzalez, Marcelo %A Leal, Nancy %A von Bernhardi, Rommy %A Dulcey, Andrés E %A Marugan, Juan %A Ferrer, Marc %A Soto, Claudio %A Zanlungo, Silvana %A Inestrosa, Nibaldo C %A Alvarez, Alejandra R %X

One of the pathological hallmarks of Alzheimer's disease (AD) is the presence of amyloid plaques, which are deposits of misfolded and aggregated amyloid-beta peptide (Aβ). The role of the c-Abl tyrosine kinase in Aβ-mediated neurodegeneration has been previously reported. Here, we investigated the therapeutic potential of inhibiting c-Abl using imatinib. We developed a novel method, based on a technique used to detect prions (PMCA), to measure minute amounts of misfolded-Aβ in the blood of AD transgenic mice. We found that imatinib reduces Aβ-oligomers in plasma, which correlates with a reduction of AD brain features such as plaques and oligomers accumulation, neuroinflammation, and cognitive deficits. Cells exposed to imatinib and c-Abl KO mice display decreased levels of β-CTF fragments, suggesting that an altered processing of the amyloid-beta protein precursor is the most probable mechanism behind imatinib effects. Our findings support the role of c-Abl in Aβ accumulation and AD, and propose AD-PMCA as a new tool to evaluate AD progression and screening for drug candidates.

%B J Alzheimers Dis %V 54 %P 1193-1205 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567806?dopt=Abstract %R 10.3233/JAD-151087 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reelin in Alzheimer's Disease, Increased Levels but Impaired Signaling: When More is Less. %A Cuchillo-Ibañez, Inmaculada %A Balmaceda, Valeria %A Mata-Balaguer, Trinidad %A Lopez-Font, Inmaculada %A Sáez-Valero, Javier %X

In the continuing search for proteins that play a role in Alzheimer's disease (AD) and that are related to the pathological hallmarks, those that influence cognitive function and that constitute potential therapeutic targets deserve special interest. Reelin is a signaling protein that is involved in a cascade of cytoplasmic events that control tau phosphorylation and that regulate synaptic neurotransmission, plasticity, and memory. Both Reelin expression and glycosylation are modulated by amyloid-β (Aβ), suggesting that the activity of Reelin could be affected in AD and hence, its possible influence on this pathology should be taken into consideration. The levels of Reelin in the brain of AD patients appear to be altered and interestingly, disrupted Reelin signaling is associated with increased tau phosphorylation as well as with amyloid-β protein precursor processing. We discuss here the somewhat contradictory data regarding Reelin levels in AD and we evaluate the processing of the Reelin receptor, ApoER2, and other downstream events, such as the phosphorylation of the intracellular adapter Dab1. Together with brain Reelin levels, these changes may represent a relevant read-out of Reelin signaling in the human brain.

%B J Alzheimers Dis %V 52 %P 403-16 %8 2016 Mar 26 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031488?dopt=Abstract %R 10.3233/JAD-151193 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Region-Specific Vulnerability to Oxidative Stress, Neuroinflammation, and Tau Hyperphosphorylation in Experimental Diabetes Mellitus Mice. %A Elahi, Montasir %A Hasan, Zafrul %A Motoi, Yumiko %A Matsumoto, Shin-Ei %A Ishiguro, Koichi %A Hattori, Nobutaka %K Adaptor Proteins, Signal Transducing %K Animals %K Antibiotics, Antineoplastic %K Brain %K Calcium-Binding Proteins %K Calcium-Calmodulin-Dependent Protein Kinase Type 2 %K Cell Proliferation %K Diabetes Mellitus, Experimental %K Disease Models, Animal %K Encephalitis %K Female %K Humans %K Lipid Peroxidation %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microfilament Proteins %K Neuroglia %K Oxidative Stress %K Reactive Oxygen Species %K Streptozocin %K tau Proteins %X

Recent epidemiological evidence suggests that diabetes mellitus (DM) is a risk factor for Alzheimer's disease (AD). One of the pathological hallmarks of AD is hyperphosphorylated tau protein, which forms neurofibrillary tangles. Oxidative stress and the activation of inflammatory pathways are features that are associated with both DM and AD. However, the brain region specificity of AD-related neurodegeneration, which mainly occurs in the hippocampus while the cerebellum is relatively unaffected, has not yet been clarified. Therefore, we used experimental DM mice (caused by an intraperitoneal injection of streptozotocin [STZ]) to determine whether these neurodegeneration-associated mechanisms were associated with region-specific selective vulnerability or tau phosphorylation. The hippocampus, midbrain, and cerebellum of aged (14 to 18 months old) non-transgenic (NTg) and transgenic mice overexpressing wild-type human tau (Tg601 mice) were evaluated after a treatment with STZ. The STZ injection increased reactive oxygen species, lipid peroxidation markers such as 4-hydroxynonenal and malondialdehyde in the hippocampus, but not in the midbrain or cerebellum. The STZ treatment also increased the number of Iba-1-positive and CD68-positive microglial cells, astrocytes, and IL-1β, IL-6, IL-10, and IL-18 levels in the hippocampus, but not in the midbrain or cerebellum. Tau hyperphosphorylation was also enhanced in the hippocampus, but not in the midbrain or cerebellum. When the effects of STZ were compared between Tg601 and NTg mice, microglial proliferation and elevations in IL-6 and phosphorylated tau were higher in Tg601 mice. These results suggest that neuroinflammation and oxidative stress in STZ-treated mice are associated with tau hyperphosphorylation, which may contribute to selective neurodegeneration in human AD.

%B J Alzheimers Dis %V 51 %P 1209-24 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923011?dopt=Abstract %R 10.3233/JAD-150820 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Regular Benzodiazepine and Z-Substance Use and Risk of Dementia: An Analysis of German Claims Data. %A Gomm, Willy %A von Holt, Klaus %A Thomé, Friederike %A Broich, Karl %A Maier, Wolfgang %A Weckbecker, Klaus %A Fink, Anne %A Doblhammer, Gabriele %A Haenisch, Britta %X

BACKGROUND: While acute detrimental effects of benzodiazepine (BDZ), and BDZ and related z-substance (BDZR) use on cognition and memory are known, the association of BDZR use and risk of dementia in the elderly is controversially discussed. Previous studies on cohort or claims data mostly show an increased risk for dementia with the use of BDZs or BDZRs. For Germany, analyses on large population-based data sets are missing.

OBJECTIVE: To evaluate the association between regular BDZR use and incident any dementia in a large German claims data set.

METHODS: Using longitudinal German public health insurance data from 2004 to 2011 we analyzed the association between regular BDZR use (versus no BDZR use) and incident dementia in a case-control design. We examined patient samples aged≥60 years that were free of dementia at baseline. To address potential protopathic bias we introduced a lag time between BDZR prescription and dementia diagnosis. Odds ratios were calculated applying conditional logistic regression, adjusted for potential confounding factors such as comorbidities and polypharmacy.

RESULTS: The regular use of BDZRs was associated with a significant increased risk of incident dementia for patients aged≥60 years (adjusted odds ratio [OR] 1.21, 95% confidence interval [CI] 1.13-1.29). The association was slightly stronger for long-acting substances than for short-acting ones. A trend for increased risk for dementia with higher exposure was observed.

CONCLUSION: The restricted use of BDZRs may contribute to dementia prevention in the elderly.

%B J Alzheimers Dis %V 54 %P 801-8 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567804?dopt=Abstract %R 10.3233/JAD-151006 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Relative Alterations in Blood-Based Levels of Sestrin in Alzheimer's Disease and Mild Cognitive Impairment Patients. %A Rai, Nitish %A Kumar, Rahul %A Desai, Gaurav Rajesh %A Venugopalan, G %A Shekhar, Shashank %A Chatterjee, Prasun %A Tripathi, Manjari %A Upadhyay, Ashish Datt %A Dwivedi, Sadanand %A Dey, Aparajit B %A Dey, Sharmistha %X

Sestrins (sesn) are highly conserved proteins that play an important neuroprotective role, in part as a consequence of their antioxidative capacity, which prevents reactive oxygen species formation. In this study, we evaluated the concentrations of sesn1 and sesn2 in the serum of 41 Alzheimer's disease (AD) patients, 27 mild cognitive impairment (MCI), and 60 elderly controls, by surface plasmon resonance, which was validated by using western blot. Moreover, the mRNA level of sestrins in all the study groups was determined by real time polymerase chain reaction. The results showed significant overexpression of serum sesn2 protein and mRNA levels in the AD group compared to MCI and elderly control groups. A difference in serum sesn2 concentration between MCI and the control group was also evident. ROC analysis showed highly sensitive, selective cutoff values for sens2 in the differentiation of AD, MCI, and controls. No significant difference in sesn1 level was observed among the study groups. This study highlights the important role of sesn2 in the progression of the AD, indicating its potential utility as a protein marker in this devastating disease.

%B J Alzheimers Dis %V 54 %P 1147-1155 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567861?dopt=Abstract %R 10.3233/JAD-160479 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reliability and Validity of a Novel Internet-Based Battery to Assess Mood and Cognitive Function in the Elderly. %A Myers, Candice A %A Keller, Jeffrey N %A Allen, H Raymond %A Brouillette, Robert M %A Foil, Heather %A Davis, Allison B %A Greenway, Frank L %A Johnson, William D %A Martin, Corby K %X

Dementia is a chronic condition in the elderly and depression is often a concurrent symptom. As populations continue to age, accessible and useful tools to screen for cognitive function and its associated symptoms in elderly populations are needed. The aim of this study was to test the reliability and validity of a new internet-based assessment battery for screening mood and cognitive function in an elderly population. Specifically, the Helping Hand Technology (HHT) assessments for depression (HHT-D) and global cognitive function (HHT-G) were evaluated in a sample of 57 elderly participants (22 male, 35 female) aged 59-85 years. The study sample was categorized into three groups: 1) dementia (n = 8; Mini-Mental State Exam (MMSE) score 10-24), 2) mild cognitive impairment (n = 24; MMSE score 25-28), and 3) control (n = 25; MMSE score 29-30). Test-retest reliability (Pearson correlation coefficient, r) and internal consistency reliability (Cronbach's alpha, α) of the HHT-D and HHT-G were assessed. Validity of the HHT-D and HHT-G was tested via comparison (Pearson r) to commonly used pencil-and-paper based assessments: HHT-D versus the Geriatric Depression Scale (GDS) and HHT-G versus the MMSE. Good test-retest (r = 0.80; p < 0.0001) and acceptable internal consistency reliability (α= 0.73) of the HHT-D were established. Moderate support for the validity of the HHT-D was obtained (r = 0.60 between the HHT-D and GDS; p < 0.0001). Results indicated good test-retest (r = 0.87; p < 0.0001) and acceptable internal consistency reliability (α= 0.70) of the HHT-G. Validity of the HHT-G was supported (r = 0.71 between the HHT-G and MMSE; p < 0.0001). In summary, the HHT-D and HHT-G were found to be reliable and valid computerized assessments to screen for depression and cognitive status, respectively, in an elderly sample.

%B J Alzheimers Dis %V 54 %P 1359-1364 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589529?dopt=Abstract %R 10.3233/JAD-160441 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reproductive history and risk of cognitive impairment in elderly women: a cross-sectional study in eastern China. %A Li, Fu-Dong %A He, Fan %A Chen, Ting-Rui %A Xiao, Yuan-Yuan %A Lin, Shang-Tong %A Shen, Wei %A Wang, Xin-Yi %A Zhai, Yu-Jia %A Shang, Xiao-Peng %A Lin, Jun-Fen %K Aged %K Aged, 80 and over %K China %K Cognition %K Cognition Disorders %K Contraceptives, Oral %K Cross-Sectional Studies %K Estrogens %K Female %K Humans %K Intrauterine Devices %K Logistic Models %K Middle Aged %K Neuropsychological Tests %K Odds Ratio %K Postmenopause %K Psychiatric Status Rating Scales %K Reproductive History %X

BACKGROUND: Epidemiological studies suggest that proxies of higher lifetime estrogen exposure are associated with better cognitive function in postmenopausal women, but this has not been found consistently.

OBJECTIVE: To determine whether reproductive history, an important modifier of estrogen exposure across the lifetime, is associated with risk of cognitive impairment in postmenopausal women.

METHODS: We analyzed the baseline data from Zhejiang Major Public Health Surveillance Program (ZPHS) including 4,796 postmenopausal women. Cognitive impairment was assessed through the application of Mini-Mental State Examination questionnaire. Logistic regression models, controlled for an extensive range of potential confounders, were generated to examine the associations between women's reproductive history and risk of cognitive impairment in their later life.

RESULTS: The length of reproductive period was inversely associated with risk of cognitive impairment (p = 0.001). Odds ratio (OR) of cognitive impairment were 1.316 (95% CI 1.095∼1.582) for women with 5 or more times of full-term pregnancies, compared with those with 1∼4 times of full-term pregnancies. Women without incomplete pregnancy had a significant higher risk of cognitive impairment (OR = 1.194, 95% CI 1.000∼1.429), compared with the reference (1∼2 times of incomplete pregnancies). Oral contraceptive use (OR = 0.489, 95% CI 0.263∼0.910) and intrauterine device (IUD) use (OR = 0.684, 95% CI 0.575∼0.815) were associated with significantly reduced risk of cognitive impairment.

CONCLUSION: Our results indicated that shorter reproductive period, higher number of full-term pregnancies and no incomplete pregnancy history were associated with an increased risk of cognitive impairment. In contrast, oral contraceptive and IUD use corresponded to reduced risk of cognitive impairment.

%B J Alzheimers Dis %V 49 %P 139-47 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444784?dopt=Abstract %R 10.3233/JAD-150444 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Resting-State Cardiac Workload is Related to Both Increased Neocortical Aggregation of Amyloid-β and Relative Impairments in Spatial Working Memory in Pre-Clinical Alzheimer's Disease. %A Santos, Cláudia Yang %A Lim, Yen Ying %A Wu, Wen-Chih %A Machan, Jason Timothy %A Polynice, Shahena %A Schindler, Rachel %A Maruff, Paul %A Snyder, Peter Jeffrey %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Blood Pressure %K Disease Progression %K Female %K Heart Rate %K Humans %K Male %K Maze Learning %K Memory Disorders %K Middle Aged %K Neocortex %K Neuropsychological Tests %K Positron-Emission Tomography %K Protein Aggregation, Pathological %K Workload %X

We sought to determine whether there is any association between a cardiac workload marker, rate pressure product (RPP), working memory, and cortical amyloid-β (Aβ) burden in 63 cognitively normal midlife adults (Mage = 62.8 years; range = 55 to 75 years) at risk for Alzheimer's disease (AD). The results show a small-to-moderate relationship between increasing cardiac workload (at rest) and neocortical amyloidosis in individuals at the preclinical stage of AD. Moreover, increasing RPP was linearly related to increasing relative impairments on a spatial working memory task (R2 = 0.30), but only for those individuals with neuroimaging evidence suggestive of preclinical AD. These results support a relationship between the aggregation of Aβ protein plaques in the neocortex, increased cognitive impairment, and more inefficient myocardial oxygen use in the absence of significant metabolic demands.

%B J Alzheimers Dis %V 50 %P 127-31 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639961?dopt=Abstract %R 10.3233/JAD-150576 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Retinal oximetry imaging in Alzheimer's disease. %A Einarsdottir, Anna Bryndis %A Hardarson, Sveinn Hakon %A Kristjansdottir, Jona Valgerdur %A Bragason, David Thor %A Snaedal, Jon %A Stefánsson, Einar %K Aged %K Alzheimer Disease %K Case-Control Studies %K Female %K Hemoglobins %K Humans %K Male %K Middle Aged %K Oximetry %K Oxygen %K Oxygen Consumption %K Regional Blood Flow %K Retina %K Retinal Vessels %X

BACKGROUND: Structural and physiological abnormalities have been reported in the retina in Alzheimer's disease (AD). Retinal oximetry detects changes in retinal oxygen metabolism in many eye diseases, where structural changes are seen.

OBJECTIVE: To compare oxygen saturation in retinal blood vessels in patients with AD and a healthy cohort.

METHODS: Oxygen saturation of hemoglobin was measured in retinal blood vessels, using imaging with spectrophotometric noninvasive retinal oximeter. 18 individuals with mild to moderate dementia of the Alzheimer-type (stage 3-5 according to the Global Deterioration Scale) and 18 healthy subjects underwent retinal oximetry in a case control study.

RESULTS: Retinal oxygen saturation in arterioles and venules in patients with moderate AD was significantly elevated compared to healthy individuals. Retinal arterioles have 94.2 ± 5.4% oxygen saturation in moderate AD compared with 90.5 ± 3.1% in healthy subjects (mean ± SD, n = 10, p = 0.028). Retinal venules were 51.9 ± 6.0% saturated in moderate AD compared with 49.7 ± 7.0% in healthy subjects (mean ± SD, n = 10, p = 0.02).

CONCLUSION: This is the first study of retinal oxygen metabolism in any central nervous system disease. It discovers abnormalities in retinal oxygen metabolism in AD. The findings are similar to those seen in age-related macular degeneration and diabetic retinopathy. Noninvasive retinal oximetry may offer new insights into pathophysiology of AD. Further studies are needed to confirm and expand these findings.

%B J Alzheimers Dis %V 49 %P 79-83 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444785?dopt=Abstract %R 10.3233/JAD-150457 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reversal of ApoE4-Driven Brain Pathology by Vascular Endothelial Growth Factor Treatment. %A Salomon-Zimri, Shiran %A Glat, Micaela Johanna %A Barhum, Yael %A Luz, Ishai %A Boehm-Cagan, Anat %A Liraz, Ori %A Ben-Zur, Tali %A Offen, Daniel %A Michaelson, Daniel M %X

Apolipoprotein E4 (ApoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with increased neurodegeneration and vascular impairments. Vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, has recently been shown to play a crucial role in the nervous system. The objective of this research is to examine the role of VEGF in mediating the apoE4-driven pathologies. We show that hippocampal VEGF levels are lower in apoE4 targeted replacement mice compared to the corresponding apoE3 mice. This effect was accompanied by a specific decrease in both VEGF receptor-2 and HIF1-α. We next set to examine whether upregulation of VEGF can reverse apoE4-driven pathologies, namely the accumulation of hyperphosphorylated tau (AT8) and Aβ42, and reduced levels of the pre-synaptic marker, VGluT1, and of the ApoE receptor, ApoER2. This was first performed utilizing intra-hippocampal injection of VEGF-expressing-lentivirus (LV-VEGF). This revealed that LV-VEGF treatment reversed the apoE4-driven cognitive deficits and synaptic pathologies. The levels of Aβ42 and AT8, however, were increased in apoE3 mice, masking any potential effects of this treatment on the apoE4 mice. Follow-up experiments utilizing VEGF-expressing adeno-associated-virus (AAV-VEGF), which expresses VEGF specifically under the GFAP astrocytic promoter, prevented this effects on apoE3 mice, and reversed the apoE4-related increase in Aβ42 and AT8. Taken together, these results suggest that apoE4-driven pathologies are mediated by a VEGF-dependent pathway, resulting in cognitive impairments and brain pathology. These animal model findings suggest that the VEGF system is a promising target for the treatment of apoE4 carriers in AD.

%B J Alzheimers Dis %V 53 %P 1443-58 %8 2016 Jun 30 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372644?dopt=Abstract %R 10.3233/JAD-160182 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reversal of LTP-Like Cortical Plasticity in Alzheimer's Disease Patients with Tau-Related Faster Clinical Progression. %A Koch, Giacomo %A Di Lorenzo, Francesco %A Del Olmo, Miguel Fernandez %A Bonní, Sonia %A Ponzo, Viviana %A Caltagirone, Carlo %A Bozzali, Marco %A Martorana, Alessandro %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognition %K Disease Progression %K Evoked Potentials, Motor %K Female %K Humans %K Male %K Motor Cortex %K Neuronal Plasticity %K Neuropsychological Tests %K Phosphorylation %K tau Proteins %K Transcranial Magnetic Stimulation %X

Cerebrospinal fluid (CSF) concentrations of amyloid-β (Aβ), total tau (t-tau), and phosphorylated tau proteins are associated with different clinical progression in Alzheimer's disease (AD). We enrolled forty newly diagnosed AD patients, who underwent lumbar puncture, and carried out a K-means cluster analysis based on CSF biomarkers levels, resulting in two AD patient groups: Cluster 1 showed relatively high levels of Aβ and low levels of tau; Cluster 2 showed relatively low levels of Aβ and high levels of tau. Cortical plasticity was tested using the intermittent and continuous theta burst stimulation (iTBS and cTBS) protocols evoking respectively long-term potentiation (LTP) and depression (LTD). Cholinergic transmission was tested by the short-latency afferent inhibition protocol. Neurophysiological evaluation showed that the two AD groups differed in terms of cortical plasticity: after iTBS, Cluster 2 patients showed a remarkable reversal of LTP toward LTD that was not observed in Cluster 1. LTD and central cholinergic transmission did not differ between groups. Patients were assessed longitudinally with Mini-Mental State Examination at 6, 12, and 18 month follow-ups. Cluster 2 AD had a faster cognitive decline already evident at the 12 month follow-up. High tau CSF levels were associated with LTD-like cortical plasticity and faster clinical progression. These results suggest that more aggressive tau pathology is associated with prominent LTD-like mechanisms of cortical plasticity and faster cognitive decline.

%B J Alzheimers Dis %V 50 %P 605-16 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757193?dopt=Abstract %R 10.3233/JAD-150813 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reversible Mild Cognitive Impairment: The Role of Comorbidities at Baseline Evaluation. %A Grande, Giulia %A Cucumo, Valentina %A Cova, Ilaria %A Ghiretti, Roberta %A Maggiore, Laura %A Lacorte, Eleonora %A Galimberti, Daniela %A Scarpini, Elio %A Clerici, Francesca %A Pomati, Simone %A Vanacore, Nicola %A Mariani, Claudio %K Analysis of Variance %K Cognitive Dysfunction %K Cohort Studies %K Comorbidity %K Female %K Humans %K Male %K Memory %K Mental Status Schedule %K Neuropsychological Tests %K Reference Values %K Verbal Learning %X

The prognostic value of mild cognitive impairment (MCI) is being questioned, with some MCI subjects reverting to normal cognition (NC). The reversion rate varies mostly depending on the study design, the setting, and both MCI and NC definitions. Previous studies have focused on the profile of subjects who revert to NC, but the role of comorbidities has not been entirely investigated. We aimed to evaluate the proportion of MCI subjects who revert to NC in a memory clinic context, focusing on the role of comorbidities. Between 2004 and 2013, 374 MCI subjects were recruited. During a mean time of 32 ± 25.5 months, 21 subjects (5.6%) reverted to NC. Subjects who reverted to NC were younger (p = 0.0001), more educated (p = 0.0001), had a better global cognition (p = 0.0001), as assessed by the Mini-Mental State Examination (MMSE) and suffered from more comorbidities (p = 0.002), as assessed by Cumulative Illness Rating Scale (CIRS) than those who developed dementia. The Cox Regression Model, constructed to adjust for the confounders, showed that the higher were the MMSE (HR = 1.83, CI 95%: 1.07-3.11) and the CIRS score (HR = 1.3, CI 95% 0.88-1.92) at baseline, the higher was the probability of returning to NC than developing dementia, though the last association was not significant. Subjects who reverted to NC were more frequently affected by respiratory (p = 0.002), urologic (p = 0.012), and psychiatric (p = 0.012) diseases. The cognitive performance of subjects with medical comorbidities could benefit from preventive strategies aimed at treating the underlying diseases.

%B J Alzheimers Dis %V 51 %P 57-67 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836169?dopt=Abstract %R 10.3233/JAD-150786 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Review of the Evidence that Transcranial Electromagnetic Treatment will be a Safe and Effective Therapeutic Against Alzheimer's Disease. %A Arendash, Gary W %X

We have demonstrated in multiple studies that daily, long-term electromagnetic field (EMF) treatment in the ultra-high frequency range not only protects Alzheimer's disease (AD) transgenic mice from cognitive impairment, but also reverses such impairment in aged AD mice. Moreover, these beneficial cognitive effects appear to be through direct actions on the AD process. Based on a large array of pre-clinical data, we have initiated a pilot clinical trial to determine the safety and efficacy of EMF treatment to mild-moderate AD subjects. Since it is important to establish the safety of this new neuromodulatory approach, the main purpose of this review is to provide a comprehensive assessment of evidence supporting the safety of EMFs, particularly through transcranial electromagnetic treatment (TEMT). In addition to our own pre-clinical studies, a rich variety of both animal and cell culture studies performed by others have underscored the anticipated safety of TEMT in clinical AD trials. Moreover, numerous clinical studies have determined that short- or long-term human exposure to EMFs similar to those to be provided clinically by TEMT do not have deleterious effects on general health, cognitive function, or a variety of physiologic measures-to the contrary, beneficial effects on brain function/activity have been reported. Importantly, such EMF exposure has not been shown to increase the risk of any type of cancer in human epidemiologic studies, as well as animal and cell culture studies. In view of all the above, clinical trials of safety/efficacy with TEMT to AD subjects are clearly warranted and now in progress.

%B J Alzheimers Dis %V 53 %P 753-71 %8 2016 May 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258417?dopt=Abstract %R 10.3233/JAD-160165 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings. %A Baiardi, Simone %A Capellari, Sabina %A Ladogana, Anna %A Strumia, Silvia %A Santangelo, Mario %A Pocchiari, Maurizio %A Parchi, Piero %K Aged %K Aged, 80 and over %K Brain %K Creutzfeldt-Jakob Syndrome %K Female %K Genotype %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Phenotype %K Prions %X

The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of "probable" CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2).

%B J Alzheimers Dis %V 50 %P 465-76 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682685?dopt=Abstract %R 10.3233/JAD-150668 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Risk Assessment of Alzheimer's Disease using the Information Diffusion Model from Structural Magnetic Resonance Imaging. %A Beheshti, Iman %A Olya, Hossain G T %A Demirel, Hasan %X

BACKGROUND: Recently, automatic risk assessment methods have been a target for the detection of Alzheimer's disease (AD) risk.

OBJECTIVE: This study aims to develop an automatic computer-aided AD diagnosis technique for risk assessment of AD using information diffusion theory.

METHODS: Information diffusion is a fuzzy mathematics logic of set-value that is used for risk assessment of natural phenomena, which attaches fuzziness (uncertainty) and incompleteness. Data were obtained from voxel-based morphometry analysis of structural magnetic resonance imaging.

RESULTS AND CONCLUSION: The information diffusion model results revealed that the risk of AD increases with a reduction of the normalized gray matter ratio (p > 0.5, normalized gray matter ratio <40%). The information diffusion model results were evaluated by calculation of the correlation of two traditional risk assessments of AD, the Mini-Mental State Examination and the Clinical Dementia Rating. The correlation results revealed that the information diffusion model findings were in line with Mini-Mental State Examination and Clinical Dementia Rating results. Application of information diffusion model contributes to the computerization of risk assessment of AD, which has a practical implication for the early detection of AD.

%B J Alzheimers Dis %V 52 %P 1335-42 %8 2016 Apr 05 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060960?dopt=Abstract %R 10.3233/JAD-151176 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Risk of dementia in patients with celiac disease: a population-based cohort study. %A Lebwohl, Benjamin %A Luchsinger, Jose A %A Freedberg, Daniel E %A Green, Peter H R %A Ludvigsson, Jonas F %K Aged %K Celiac Disease %K Cohort Studies %K Databases, Factual %K Dementia %K Female %K Humans %K Incidence %K Logistic Models %K Male %K Middle Aged %K Proportional Hazards Models %K Risk Factors %K Sweden %X

BACKGROUND: Patients with celiac disease (CD) frequently report cognitive symptoms when they are exposed to gluten, and cognitive deficits have been quantified in patients with newly diagnosed CD.

OBJECTIVE: To determine whether patients with CD have an increased risk of dementia.

METHODS: Using a population-based database of older adults (age ≥50 years) with histologically proven CD (duodenal/jejunal villous atrophy) from all 28 pathology departments in Sweden, we compared the incidence of a subsequent dementia diagnosis to those of age- and gender-matched controls.

RESULTS: Among patients with CD (n = 8,846) and controls (n = 43,474), the median age was 63 years and 56% were female. During a median follow-up time of 8.4 years, dementia was diagnosed in 4.3% of CD patients and 4.4% of controls (HR 1.07; 95% CI 0.95-1.20). Although there was an increased risk of dementia in the first year following a diagnosis of CD (HR 1.73; 95% CI 1.15-2.61), this risk was not present in the whole observation period. Among those subjects with a dementia subtype specified, the increased risk was restricted to vascular dementia (HR 1.28; 95% CI 1.00-1.64) and was not present for Alzheimer's dementia (HR 1.12; 95% CI 0.91-1.37).

CONCLUSIONS: Patients with CD are not at increased risk for dementia overall, though subgroup analysis suggests that they may be at increased risk for vascular dementia.

%B J Alzheimers Dis %V 49 %P 179-85 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444775?dopt=Abstract %R 10.3233/JAD-150388 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Role of Alzheimer's and Cerebrovascular Pathology in Mediating the Effects of Age, Race, and Apolipoprotein E Genotype on Dementia Severity in Pathologically-Confirmed Alzheimer's Disease. %A Gavett, Brandon E %A John, Samantha E %A Gurnani, Ashita S %A Bussell, Cara A %A Saurman, Jessica L %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Apolipoproteins E %K Cerebrovascular Disorders %K Continental Population Groups %K Dementia %K Educational Status %K Female %K Genotype %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Models, Theoretical %X

BACKGROUND: Dementia severity can be modeled as the construct δ, representing the "cognitive correlates of functional status."

OBJECTIVE: We recently validated a model for estimating δ in the National Alzheimer's Coordinating Center's Uniform Data Set; however, the association of δ with neuropathology remains untested.

METHODS: We used data from 727 decedents evaluated at Alzheimer's Disease (AD) Centers nationwide. Participants spoke English, had no genetic abnormalities, and were pathologically diagnosed with AD as a primary or contributing etiology. Clinical data from participants' last visit prior to death were used to estimate dementia severity (δ).

RESULTS: A structural equation model using age, education, race, and apolipoprotein E (APOE) genotype (number of ɛ2 and ɛ4 alleles) as predictors and latent AD pathology and cerebrovascular disease (CVD) pathology as mediators fit the data well (RMSEA = 0.031; CFI = 0.957). AD pathology mediated the effects of age and APOE genotype on dementia severity. An older age at death and more ɛ2 alleles were associated with less AD pathology and, in turn, with less severe dementia. In contrast, more ɛ4 alleles were associated with more pathology and more severe dementia. Although age and race contributed to differences in CVD pathology, CVD pathology was not related to dementia severity in this sample of decedents with pathologically-confirmed AD.

CONCLUSIONS: Using δ as an estimate of dementia severity fits well within a structural model in which AD pathology directly affects dementia severity and mediates the relationship between age and APOE genotype on dementia severity.

%B J Alzheimers Dis %V 49 %P 531-45 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444761?dopt=Abstract %R 10.3233/JAD-150252 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Role of Capillaries in the Lesser Ailments of Old Age and in Alzheimer's Disease and Vascular Dementia: The Potential of Pro-Therapeutic Angiogenesis. %A Ambrose, Charles T %X

Apart from chronic diseases (arthritis, diabetes, etc.), old age is generally characterized by three lesser ailments: muscle weakness, minor memory lapses, and cold intolerance. This trio of complaints may have a common, underlying cause, namely, the age-associated reduced microcirculation in muscles, brain, skin, and elsewhere in the body. The Angiogenesis Hypothesis proposes that old age is in part a deficiency disease due to the decline in angiogenic (AG) factors, resulting in a reduced capillary density (CD) throughout the body. Over fifty published papers document waning levels of AG factors and/or decreased CD in various organ systems of aged animals and people, including those with Alzheimer's disease. The deficiency of AG factors is analogous to that of certain hormones (e.g., testosterone) whose blood levels also decline with age. In theory, therapeutic angiogenesis employing recombinant AG factors is a tenable treatment for the lesser ailments of old age and may improve the later years of human life. An optimal administration route may be intranasal.

%B J Alzheimers Dis %V 54 %P 31-43 %8 2016 Jul 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392865?dopt=Abstract %R 10.3233/JAD-160303 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Role of Cerebrospinal Fluid Biomarkers in the Evolution of Diagnostic Criteria in Alzheimer's Disease: Shortcomings in Prodromal Diagnosis. %A Szalárdy, Levente %A Zádori, Dénes %A Klivenyi, Peter %A Vecsei, Laszlo %X

The available evidence indicates a high performance of core cerebrospinal fluid (CSF) biomarkers in differentiating between Alzheimer's disease (AD) and other dementias, and suggests that their characteristic alterations can be detected even at the prodromal stage of AD. On this basis, the ability of core CSF biomarkers to identify prodromal AD patients from pre-dementia of all causes can be postulated, a concept that is reflected in recent revisions of AD research criteria and a consensus statement. Following an overview on the role of biomarkers in the evolution of diagnostic criteria of AD in recent decades, this paper provides a critical review of the widely applied CSF biomarker study designs and evaluating approaches that address the ability of core CSF biomarkers to diagnose prodromal AD, with special focus on their potential limitations in terms of clinical interpretation and utility. The findings together raise the question of whether we are indeed able to establish a CSF biomarker-based diagnosis of AD at the prodromal stage.

%B J Alzheimers Dis %V 53 %P 373-92 %8 2016 May 07 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163812?dopt=Abstract %R 10.3233/JAD-160037 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Role of Cerebrovascular Disease in Amyloid Deposition. %A Noh, Young %A Seo, Sang Won %A Jeon, Seun %A Lee, Jong Min %A Kim, Jae Seung %A Lee, Jae-Hong %A Kim, Jung-Hyun %A Kim, Geon Ha %A Ye, Byoung Seok %A Cho, Hanna %A Kim, Hee Jin %A Yoon, Cindy W %A Choe, Yearn Seong %A Lee, Kyung-Han %A Weiner, Michael W %A Na, Duk L %X

BACKGROUND: Some patients clinically diagnosed with subcortical vascular cognitive impairment (SVCI) have co-morbidity with AD pathology.

OBJECTIVE: We investigated topographical differences in amyloid burden between SVCI and Alzheimer's disease type cognitive impairment (ADCI) using [11C] Pittsburgh compound B (PiB) positron emission tomography (PET). The purpose of this study was to investigate the role of cerebrovascular disease (CVD) in amyloid deposition.

METHODS: We recruited 44 patients with SVCI and 44 patients with ADCI (amnestic mild cognitive impairment or Alzheimer's disease) with absent or minimal white matter hyperintensities, all with PiB-positive PET scans [PiB+]. As controls, we included 13 participants with normal cognition and PiB-negative scans. We divided the SVCI and ADCI patients into three groups according to global PiB retention ratio of SVCI, and then compared the tertiles in terms of the distribution of PiB retention using statistical parametric mapping analyses. Lobar to global PiB retention ratio and asymmetry indices were also compared between SVCI and ADCI groupsResults: Compared to PiB+ ADCI patients, PiB+ SVCI patients exhibited: 1) increased left-right asymmetry, and increased anterior-posterior difference; and 2) increased PiB retention in the parietal cortex, the occipital cortex and the precuneus-posterior cingulate cortex. In contrast, ADCI patients showed increased PiB retention in the striatum. When stratified by level of PiB retention, each group showed different characteristics.

CONCLUSION: Our results showed that the distribution of amyloid deposition differed between patients with PiB+ SVCI and ADCI. These suggest that CVD contribute to and alter the known progression pattern in amyloid deposition in Alzheimer's disease.

%B J Alzheimers Dis %V 54 %P 1015-1026 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567803?dopt=Abstract %R 10.3233/JAD-150832 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Role of Ethnicity in Alzheimer's Disease: Findings From The C-PATH Online Data Repository. %A Chen, Huei-Yang %A Panegyres, Peter K %K African Americans %K Age Factors %K Aged %K Alaska Natives %K Alzheimer Disease %K Apolipoproteins E %K Asian Continental Ancestry Group %K Clinical Trials as Topic %K Comorbidity %K Databases, Factual %K European Continental Ancestry Group %K Female %K Hispanic Americans %K Humans %K Indians, North American %K Internet %K Logistic Models %K Male %K Oceanic Ancestry Group %K Risk %K Sex Factors %X

BACKGROUND: Ethnic minorities seem to be at an increased risk of Alzheimer's disease (AD). However, little is known about ethnic differences and the risks of early onset AD (EOAD).

OBJECTIVE: Cognitive function changes over time and odds of EOAD by ethnicity were analyzed by the mixed model and the logistic regression.

METHODS: Information on demographics, self-reported co-morbidities, cognitive functions (MMSE and ADAS-COG), and ApoE genotypes were collected for 6,500 subjects with AD obtained from the placebo arm of clinical trials; this data was examined by ethnicities: Caucasian, Asian, African American, Hispanic, and other minorities--including Native Alaskans, Americans, and Hawaiians.

RESULTS: Of the total subjects, Caucasians accounted for 89.0% , followed by 4.7% Asians, 2.7% African Americans, 2.4% Hispanics, and 1.2% Native Americans, Alaskans, and Hawaiians. Age, gender, EOAD status, co-morbidities, family history of AD, and ApoE genotypes were significantly different by ethnicity. ApoE ɛ2 allele is possibly overrepresented in the Native Americans, Africans, Hawaiians, and African Americans. A significant interaction with time, ethnicity, and cognitive performance was found, indicating more cognitive deterioration in other minorities than Caucasians for mini-mental state (p <  0.01). After adjusting for co-morbidities and gender, the odds of EOAD among African Americans (OR: 1.6, 95% CI: 1.1-2.4) and Native Alaskans, Americans, and Hispanics (OR: 2.1, 95% CI: 1.2-3.5) were significantly higher, compared with Caucasians.

CONCLUSIONS: Ethnicity may impact AD through age of onset, co-morbidities, family history, ApoE gene status, and cognitive change over time. The greater odds of EOAD among African Americans, Alaskans, and Hawaiians suggest that some ethnicities may be at risk of AD at a younger age.

%B J Alzheimers Dis %V 51 %P 515-23 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890783?dopt=Abstract %R 10.3233/JAD-151089 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Role of Physical Fitness in the Neurocognitive Performance of Task Switching in Older Persons with Mild Cognitive Impairment. %A Tsai, Chia-Liang %A Pai, Ming-Chyi %A Ukropec, Jozef %A Ukropcová, Barbara %X

Although elderly people with amnestic mild cognitive impairment (aMCI) have been found to show impaired behavioral performance in task switching, no research has yet explored the electrophysiological mechanisms and the potential correlation between physical fitness and neurocognitive (i.e., behavioral and electrophysiological) performance in aMCI. The present study was thus aimed to examine whether there are differences in electrophysiological (i.e., event-related potential) performance between aMCI participants and controls when performing a task-switching paradigm, and to investigate the role of physical fitness in the relationship between neurocognitive performance and aMCI. Sixty participants were classified into aMCI (n = 30) and control (n = 30) groups, and performed a task-switching paradigm with concomitant electrophysiological recording, as well as underwent senior functional physical fitness tests. The aMCI group showed comparable scores on most parts of the physical fitness tests, but reduced lower body flexibility and VO2max as compared to the control group. When performing the task-switching paradigm, the aMCI group showed slower reaction times in the heterogeneous condition and larger global switching costs, although no significant difference was observed in accuracy rates between the two groups. In addition, the aMCI group showed significantly prolonged P3 latencies in the homogeneous and heterogeneous conditions, and a smaller P3 amplitude only in the heterogeneous condition. The level of cardiorespiratory fitness was significantly correlated with P3 amplitude in the aMCI group, particularly in the heterogeneous condition of the task-switching paradigm. These results show that the aMCI group exhibited abnormalities in their neurocognitive performance when performing the task-switching paradigm and such a deficit was likely associated with reduced cardiorespiratory fitness, which was shown to be the important predictor of neurocognitive performance.

%B J Alzheimers Dis %V 53 %P 143-59 %8 2016 Apr 23 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128369?dopt=Abstract %R 10.3233/JAD-151093 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Safety and Efficacy of Medical Cannabis Oil for Behavioral and Psychological Symptoms of Dementia: An-Open Label, Add-On, Pilot Study. %A Shelef, Assaf %A Barak, Yoram %A Berger, Uri %A Paleacu, Diana %A Tadger, Shelly %A Plopsky, Igor %A Baruch, Yehuda %K Aged %K Aged, 80 and over %K Antipsychotic Agents %K Behavioral Symptoms %K Cognition Disorders %K Dementia %K Female %K Humans %K Male %K Medical Marijuana %K Neuropsychological Tests %K Outcome Assessment (Health Care) %K Physical Examination %K Pilot Projects %K Prospective Studies %K Psychiatric Status Rating Scales %X

BACKGROUND: Tetrahydrocannabinol (THC) is a potential treatment for Alzheimer's disease (AD).

OBJECTIVE: To measure efficacy and safety of medical cannabis oil (MCO) containing THC as an add-on to pharmacotherapy, in relieving behavioral and psychological symptoms of dementia (BPSD).

METHODS: Eleven AD patients were recruited to an open label, 4 weeks, prospective trial.

RESULTS: Ten patients completed the trial. Significant reduction in CGI severity score (6.5 to 5.7; p <  0.01) and NPI score were recorded (44.4 to 12.8; p <  0.01). NPI domains of significant decrease were: Delusions, agitation/aggression, irritability, apathy, sleep and caregiver distress.

CONCLUSION: Adding MCO to AD patients' pharmacotherapy is safe and a promising treatment option.

%B J Alzheimers Dis %V 51 %P 15-9 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757043?dopt=Abstract %R 10.3233/JAD-150915 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Safety and Tolerability of R(+) Pramipexole in Mild-to-Moderate Alzheimer's Disease. %A Bennett, James %A Burns, Jeffrey %A Welch, Paul %A Bothwell, Rebecca %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Benzothiazoles %K Biomarkers %K Brain %K Female %K Glucose %K Humans %K Male %K Neuropsychological Tests %K Nootropic Agents %K Peptide Fragments %K Positron-Emission Tomography %K Severity of Illness Index %K tau Proteins %K Treatment Outcome %X

Alzheimer's disease (AD) is an aging-related, degenerative brain disease of adults. Most (∼95%) of AD occurs sporadically and is associated with early-appearing deficits in brain regional glucose uptake, changes in cerebrospinal fluid (CSF) AD-related proteins, regional brain atrophy, and oxidative stress damage. We treated mild-moderate AD individuals with R(+)-pramipexole-dihydrochloride (R(+)PPX), a neuroprotective, lipophilic-cation, free-radical scavenger that accumulates into brain and mitochondria. 19 subjects took R(+)PPX twice a day in increasing daily doses up to 300 mg/day under a physician-sponsor IND (60,948, JPB), IRB-approved protocol and quarterly external safety committee monitoring. 15 persons finished and contributed baseline and post-treatment serum, lumbar spinal fluid, brain 18F-2DG PET scans, and ADAS-Cog scores. ADAS-Cog scores did not change (n = 1), improved (n = 2), declined 1-3 points (n = 5), or declined 4-13 points (n = 8) over 6 months of R(+)PPX treatment. Serum PPX levels were not related to changes in ADAS-Cog scores. Fasting AM serum PPX levels at 6 months varied considerably across subjects and correlated strongly with CSF [PPX] (r = 0.97, p <  0.0001). CSF [PPX] was not related to CSF [Aβ(42)], [Tau], or [P-Tau]. Regional 18F-2DG measures of brain glucose uptake demonstrated a 3-6% decline during R(+)PPX treatment. 56 mild-moderate adverse events occurred, 26 probably/definitely related to R(+)PPX use, with 4 withdrawals. R(+)PPX was generally well-tolerated and entered brain extracellular space linearly. Further studies of R(+)PPX in AD should include a detailed pharmacokinetic study of peak and trough serum [PPX] variations among subjects prior to planning any larger studies that would be needed to determine efficacy in altering disease progression.

%B J Alzheimers Dis %V 49 %P 1179-87 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682692?dopt=Abstract %R 10.3233/JAD-150788 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Salidroside, a Bioactive Compound of Rhodiola Rosea, Ameliorates Memory and Emotional Behavior in Adult Mice. %A Palmeri, Agostino %A Mammana, Leonardo %A Tropea, Maria Rosaria %A Gulisano, Walter %A Puzzo, Daniela %K Animals %K Anti-Anxiety Agents %K Antidepressive Agents %K Anxiety Disorders %K Conditioning (Psychology) %K Depressive Disorder %K Disease Models, Animal %K Drug Evaluation, Preclinical %K Exploratory Behavior %K Fear %K Female %K Freezing Reaction, Cataleptic %K Glucosides %K Male %K Maze Learning %K Memory %K Mice, Inbred C57BL %K Motor Activity %K Nootropic Agents %K Phenols %K Phytotherapy %K Plant Extracts %K Rhodiola %X

Rhodiola Rosea (R. Rosea) is a plant used in traditional popular medicine to enhance cognition and physical performance. R. Rosea medicinal properties have been related to its capability to act as an adaptogen, i.e., a substance able to increase the organism's resistance to a variety of chemical, biological, and physical stressors in a non-specific way. These adaptogen properties have been mainly attributed to the glycoside salidroside, one of the bioactive compounds present in the standardized extracts of R. Rosea. Here, we aimed to investigate whether a single dose of salidroside is able to affect memory and emotional behavior in wild type adult mice. We performed fear conditioning to assess cued and contextual memory, elevated plus maze and open field to evaluate anxiety, and tail suspension test to evaluate depression. Our results showed that a single i.p. administration of salidroside was able to enhance fear memory and exerted an anxiolytic and antidepressant effect. These data confirmed the adaptogenic effect of R. Rosea bioactive compounds in animal models and suggest that salidroside might represent an interesting pharmacological tool to ameliorate cognition and counteract mood disorders.

%B J Alzheimers Dis %V 52 %P 65-75 %8 2016 02 26 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967223?dopt=Abstract %R 10.3233/JAD-151159 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Savvy Caregiver Program: A Probe Multicenter Randomized Controlled Pilot Trial in Caregivers of Patients Affected by Alzheimer's Disease. %A Sepe-Monti, Micaela %A Vanacore, Nicola %A Bartorelli, Luisa %A Tognetti, Alessandra %A Giubilei, Franco %X

Alzheimer's disease (AD) is a major cause of disability in the elderly, leading to a considerable burden on caregivers and high costs to society. Psycho-education programs such as the Savvy Caregiver Program (SCP) are reported to be a successful means of reducing caregivers' distress through various intervention strategies. The aim of the present study was to assess the efficacy of the SCP in reducing the burden and psychological symptoms in caregivers of AD patients and to analyze the coping strategies adopted by the caregivers. The study was designed as a multicenter, randomized, controlled, pilot clinical trial. One hundred and sixty-four caregivers of patients with probable AD were randomized. The SCP was structured in six, weekly, two-hour sessions. All the clinical scales were administered before treatment, two weeks and six months after treatment. Caregivers in the SCP group displayed better coping strategies adopted to positive attitudes, and they tended to be less anxious and less depressed than those in the control group. However, caregiver burden levels were not reduced in SCP caregivers. The patients of SCP caregivers received a lower number of new prescriptions of neuroleptics during the 6 months of follow-up than the patients of control caregivers and apathy was the neuropsychiatric symptom that improved most as a result of the SCP. The results of this study suggest that the SCP may improve coping strategies of caregivers of people affected by AD, influencing their psychological symptoms and those of their patients.

%B J Alzheimers Dis %V 54 %P 1235-1246 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567824?dopt=Abstract %R 10.3233/JAD-160235 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Screening for Mild Cognitive Impairment: Comparison of "MCI Specific" Screening Instruments. %A O'Caoimh, Rónán %A Timmons, Suzanne %A Molloy, D William %K Aged %K Aged, 80 and over %K Area Under Curve %K Cognitive Dysfunction %K Dementia %K Diagnosis, Differential %K Female %K Humans %K Male %K Neuropsychological Tests %K Perception %K ROC Curve %K Sensitivity and Specificity %K Time Factors %X

BACKGROUND: Sensitive and specific instruments are required to screen for cognitive impairment (CI) in busy clinical practice. The Montreal Cognitive Assessment (MoCA) is widely validated but few studies compare it to tests designed specifically to detect mild cognitive impairment (MCI).

OBJECTIVE: Comparison of two "MCI specific" screens: the Quick Mild Cognitive Impairment screen (Qmci) and MoCA.

METHODS: Patients with subjective memory complaints (SMC; n = 73), MCI (n = 103), or dementia (n = 274), were referred to a university hospital memory clinic and underwent comprehensive assessment. Caregivers, without cognitive symptoms, were recruited as normal controls (n = 101).

RESULTS: The Qmci was more accurate than the MoCA in differentiating MCI from controls, area under the curve (AUC) of 0.90 versus 0.80, p = 0.009. The Qmci had greater (AUC 0.81), albeit non-significant, accuracy than the MoCA (AUC 0.73) in separating MCI from SMC, p = 0.09. At its recommended cut-off (<62/100), the Qmci had a sensitivity of 90% and specificity of 87% for CI (MCI/dementia). Raising the cut-off to <65 optimized sensitivity (94%), reducing specificity (80%). At <26/30 the MoCA had better sensitivity (96%) but poor specificity (58%). A MoCA cut-off of <24 provided the optimal balance. Median Qmci administration time was 4.5 (±1.3) minutes compared with 9.5 (±2.8) for the MoCA.

CONCLUSIONS: Although both tests distinguish MCI from dementia, the Qmci is particularly accurate in separating MCI from normal cognition and has shorter administration times, suggesting it is more useful in busy hospital clinics. This study reaffirms the high sensitivity of the MoCA but suggests a lower cut-off (<24) in this setting.

%B J Alzheimers Dis %V 51 %P 619-29 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890758?dopt=Abstract %R 10.3233/JAD-150881 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Searching for Primary Predictors of Conversion from Mild Cognitive Impairment to Alzheimer's Disease: A Multivariate Follow-Up Study. %A López, María Eugenia %A Turrero, Agustín %A Cuesta, Pablo %A López-Sanz, David %A Bruña, Ricardo %A Marcos, Alberto %A Gil, Pedro %A Yus, Miguel %A Barabash, Ana %A Cabranes, José Antonio %A Maestú, Fernando %A Fernández, Alberto %X

Recent proposals of diagnostic criteria within the healthy aging-Alzheimer's disease (AD) continuum stressed the role of biomarker information. More importantly, such information might be critical to predict those mild cognitive impairment (MCI) patients at a higher risk of conversion to AD. Usually, follow-up studies utilize a reduced number of potential markers although the conversion phenomenon may be deemed as multifactorial in essence. In addition, not only biological but also cognitive markers may play an important role. Considering this background, we investigated the role of cognitive reserve, cognitive performance in neuropsychological testing, hippocampal volumes, APOE genotype, and magnetoencephalography power sources to predict the conversion to AD in a sample of 33 MCI patients. MCIs were followed up during a 2-year period and divided into two subgroups according to their outcome: The "stable" MCI group (sMCI, 21 subjects) and the "progressive" MCI group (pMCI, 12 subjects). Baseline multifactorial information was submitted to a hierarchical logistic regression analysis to build a predictive model of conversion to AD. Results indicated that the combination of left hippocampal volume, occipital cortex theta power, and clock drawing copy subtest scores predicted conversion to AD with a 100% of sensitivity and 94.7% of specificity. According to these results it might be suggested that anatomical, cognitive, and neurophysiological markers may be considered as "first order" predictors of progression to AD, while APOE or cognitive reserve proxies might play a more secondary role.

%B J Alzheimers Dis %V 52 %P 133-43 %8 2016 03 05 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060953?dopt=Abstract %R 10.3233/JAD-151034 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Self-Consciousness in Patients with Behavioral Variant Frontotemporal Dementia. %A Arroyo-Anlló, Eva M %A Bouston, Adèle Turpin %A Fargeau, Marie-Noëlle %A Orgaz Baz, Begõna %A Gil, Roger %K Aged %K Brain %K Educational Status %K Female %K Frontotemporal Dementia %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Positron-Emission Tomography %K Psychological Tests %K Self Concept %X

Self-consciousness (SC) is multifaceted and considered to be the consciousness of one's own mental states. The medial prefrontal cortex may play a critical role in SC. The main aim of this paper was to examine SC in patients with behavioral variant frontotemporal dementia, who are characterized more by changes in personal, social, and emotional conduct and loss of insight than by cognitive disturbances. Control and patient groups of 21 subjects each, matched by age, educational level, gender, and nationality were assessed using a SC questionnaire. It measures several aspects: Personal identity, Anosognosia, Affective state, Body representation, Prospective memory, Introspection, and Moral judgments. The most disturbed ones in patients were Anosognosia, Affective state, and Moral judgments, and the least disturbed aspects were awareness of identity and of body representation. No significant correlations were found between the SC score and any clinical or demographical characteristics. The core deficiency of SC in patients was related to behavioral SC aspects, which are more dependent on orbito-frontal functioning.

%B J Alzheimers Dis %V 49 %P 1021-9 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599058?dopt=Abstract %R 10.3233/JAD-150821 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Self-Perceived Quality of Life Among Patients with Alzheimer's Disease: Two Longitudinal Models of Analysis. %A Conde-Sala, Josep L %A Turró-Garriga, Oriol %A Portellano-Ortiz, Cristina %A Viñas-Diez, Vanesa %A Gascón-Bayarri, Jordi %A Reñé-Ramírez, Ramón %X

The objective was to analyze the factors that influence self-perceived quality of life (QoL) in patients with Alzheimer's disease (AD), contrasting two different longitudinal models. A total of 127 patients were followed up over 24 months. The instruments applied were: Quality of Life in Alzheimer's Disease scale (QoL-AD), Geriatric Depression Scale-15, Anosognosia Questionnaire-Dementia, Disability Assessment in Dementia, Neuropsychiatric Inventory, and the Mini-Mental State Examination. Two models for grouping patients were tested: 1) Baseline score on the QoL-AD (QoL-Baseline), and 2) Difference in QoL-AD score between baseline and follow-up (QoL-Change). Generalized estimating equations were used to analyze longitudinal data, and multinomial regression analyses were performed. Over the follow-up period the QoL-Baseline model showed greater variability between groups (Wald χ2 = 172.3, p < 0.001) than did the QoL-Change model (Wald χ2  = 1.7, p = 0.427). In the QoL-Baseline model the predictive factors were greater depression (odds ratio [OR] = 1.20; 95% CI: 1.00- 1.45) and lower functional ability (OR = 0.92; 95% CI: 0.85- 0.99) for the Low QoL group (< 33 QoL-AD), and less depression (OR = 0.68; 95% CI: 0.52- 0.88), more anosognosia (OR = 1.07; 95% CI: 1.01- 1.13), and fewer neuropsychiatric symptoms (OR = 0.95; 95% CI: 0.91- 0.99) for the High-QoL group (>37 QoL-AD). The model based on baseline scores (QoL-Baseline) was better than the QoL-Change model in terms of identifying trajectories and predictors of QoL in AD.

%B J Alzheimers Dis %V 52 %P 999-1012 %8 2016 Apr 12 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079721?dopt=Abstract %R 10.3233/JAD-160040 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Self-Reported Change in Quality of Life with Retirement and Later Cognitive Decline: Prospective Data from the Nurses' Health Study. %A Vercambre, Marie-Noël %A Okereke, Olivia I %A Kawachi, Ichiro %A Grodstein, Francine %A Kang, Jae H %X

To investigate whether a positive transition into retirement may be associated with later cognitive aging, we included a subset of 4,926 Nurses' Health Study participants who retired from work at ages 60-69, then provided a subjective assessment of the change in overall quality of life (QOL) with retirement. Subsequently (range: 1 month to 4.7 years later), when all were aged 70+ years, they completed a baseline telephone cognitive battery evaluating global cognition, episodic memory, and executive function. They had up to three follow-up cognitive assessments. Controlling for various occupational factors before retirement and socioeconomic, lifestyle, and health-related factors as of the baseline cognitive assessment, we used generalized linear models for repeated measures to estimate mean differences in rates of cognitive decline across categories of QOL transition at retirement: "worse", "same", or "better". Over a median 6 years of follow-up, the global cognitive score change was -0.123 on average. Compared with women who reported no change in QOL at retirement (31%), women who reported improvement (61%) showed a significantly slower rate of cognitive decline (difference = +0.011 95% CI = 0.004, 0.019). This mean difference was equivalent to that observed between women who were 2 years apart in age. No significant differences in cognitive decline rates were observed for the women who reported worsened QOL (8%). Secondary analyses to address possible reverse causation showed robust associations. A positive transition into retirement was associated with better maintenance of cognitive function over time in aging women. These findings need to be replicated in other populations.

%B J Alzheimers Dis %V 52 %P 887-98 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060944?dopt=Abstract %R 10.3233/JAD-150867 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Self-Reported Traumatic Brain Injury and Mild Cognitive Impairment: Increased Risk and Earlier Age of Diagnosis. %A LoBue, Christian %A Denney, David %A Hynan, Linda S %A Rossetti, Heidi C %A Lacritz, Laura H %A Hart, John %A Womack, Kyle B %A Woon, Fu L %A Cullum, C Munro %K Age of Onset %K Aged %K Apolipoproteins E %K Brain Injuries, Traumatic %K Cognitive Dysfunction %K Cohort Studies %K Databases, Factual %K Depression %K Educational Status %K Female %K Humans %K Logistic Models %K Male %K Risk Factors %K Self Report %K United States %X

This study examined whether history of traumatic brain injury (TBI) is associated with increased risk and earlier onset of mild cognitive impairment (MCI). Subjects with MCI (n = 3,187) and normal cognition (n = 3,244) were obtained from the National Alzheimer's Coordinating Center database. TBI was categorized based on lifetime reported TBI with loss of consciousness (LOC) without chronic deficit. Logistic regression was used to examine TBI history as a predictor of MCI, adjusted for demographics, apolipoprotein E-ɛ4 (ApoE4), a composite vascular risk score, and history of psychiatric factors. ANCOVA was used to examine whether age at MCI diagnosis and estimated age of onset differed between those with (TBI+) and without (TBI-) a history of TBI. TBI history was a significant predictor (p <  0.01) and associated with increased odds of MCI diagnosis in unadjusted (OR = 1.25; 95% CI = 1.05-1.49) and adjusted models, accounting for age, education, ApoE4, and a composite vascular score (OR = 1.32; 95% CI = 1.10-1.58). This association, however, was largely attenuated (OR = 1.14; 95% CI = 0.94-1.37; p = 0.18) after adjustment for reported history of depression. MCI was diagnosed a mean of 2.3 years earlier (p <  0.001) in the TBI+ group, and although TBI+ subjects had an estimated mean of decline 1.7 years earlier, clinician-estimated age of onset failed to differ (p = 0.13) when gender and psychiatric factors were controlled. This is the first report of a possible role for TBI as a risk factor in MCI, but its association may be related to other factors such as gender and depression and requires further investigation.

%B J Alzheimers Dis %V 51 %P 727-36 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890760?dopt=Abstract %R 10.3233/JAD-150895 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Sensitivity of Neuropsychological Tests to Identify Cognitive Decline in Highly Educated Elderly Individuals: 12 Months Follow up. %A Elkana, Odelia %A Eisikovits, Osnat Reichman %A Oren, Noga %A Betzale, Vered %A Giladi, Nir %A Ash, Elissa L %K Aged %K Aged, 80 and over %K Aging %K Brain %K Cognition Disorders %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Sensitivity and Specificity %K Statistics as Topic %X

Highly educated individuals have a lower risk of developing dementia and Alzheimer's disease (AD). A common assumption is that their "cognitive reserve" protects them from cognitive decline and postpones the clinical manifestation of dementia. These highly educated individuals usually obtain normal scores on cognitive screening tests, although at the same time they can experience subjective cognitive decline and difficulty in multiple cognitive domains. Although comprehensive neuropsychological evaluations usually identify subtle changes in cognition, they demand extensive resources and thus are expensive and difficult to obtain. Therefore, lack of sensitivity of screening tests on the one hand, along with difficulty to acquire a comprehensive neuropsychological evaluation on the other hand, impede identification of cognitive decline at its earliest stages in this special population. Accordingly, this study aims to identify which neuropsychological tests have the highest sensitivity to detect the earliest stages of cognitive decline among highly educated elderly [n = 27, ages 66-80 (mean = 72.6 SD = 4.54), mean education level = 17.14 (SD = 3.21 range: 12-24 years)]. Baseline scores and scores at one-year follow up were obtained. We also conducted MRI scans to characterize the relation between brain volume and cognitive performance. Results show significant reductions in RVALT, Semantic verbal Fluency, ROCF copy, and MoCA scores whereas PF, TMT, ROCF delay, digit span, and knowledge tests were not significant. The study stresses the importance of using sensitive neuropsychological tests to examine this special population and the need to create norms that combine an individual's education with age.

%B J Alzheimers Dis %V 49 %P 607-16 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484925?dopt=Abstract %R 10.3233/JAD-150562 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Serotonin 2A Receptor Inverse Agonist as a Treatment for Parkinson's Disease Psychosis: A Systematic Review and Meta-analysis of Serotonin 2A Receptor Negative Modulators. %A Yasue, Ichiro %A Matsunaga, Shinji %A Kishi, Taro %A Fujita, Kiyoshi %A Iwata, Nakao %K Antiparkinson Agents %K Humans %K Parkinson Disease %K Randomized Controlled Trials as Topic %K Receptor, Serotonin, 5-HT2A %K Serotonin 5-HT2 Receptor Agonists %X

BACKGROUND: There is uncertainty about the efficacy and tolerability of serotonin 2A (5-HT2A) receptor negative modulators for Parkinson's disease psychosis (PDP).

OBJECTIVE: This is the first meta-analysis of randomized placebo-controlled trials (RCTs) testing negative modulators of the 5-HT2A receptor as a treatment for PDP.

METHODS: The primary outcome was the Scale for Assessment of Positive Symptoms (SAPS)-hallucinations (H) and -delusions (D) scores (SAPS-H+D). Other outcome measures were SAPS-H, SAPS-D, the Unified Parkinson's Disease Rating Scale Part II and III (UPDRS-II+III), discontinuation rates, and individual adverse events.

RESULTS: Four RCTs were identified that met inclusion criteria, all assessing the 5-HT2A inverse agonist pimavanserin (including 417 drug-treated and 263 placebo-treated PDP patients). Pimavanserin significantly decreased SAPS-H+D scores compared to placebo [weighted mean differences (WMD) = -2.26, 95% confidence interval (95% CI) = -3.86 to -0.67, p = 0.005, I2 = 30% , N = 4 studies, n = 502 patients]. Moreover, pimavanserin was superior to placebo for reducing SAPS-H (WMD = -2.15, 95% CI = -3.45 to -0.86, p = 0.001, I2 = 0% , N = 2, n = 237) and SAPS-D scores (WMD = -1.32, 95% CI = -2.32 to -0.32, p = 0.010, I2 = 0% , N = 2, n = 237). Pimavanserin was associated with less orthostatic hypotension than placebo (risk ratio = 0.33, 95% CI = 0.15-0.75, p = 0.008, I2 = 0% , number needed to harm = 17, p = 0.01, N = 3, n = 476). There were no significant differences in rates of all-cause discontinuation, adverse events, and death, UPDRS-II+III scores, and incidences of individual adverse events (other than orthostatic hypotension) between pimavanserin and placebo groups.

CONCLUSIONS: Pooled RCT results suggest that pimavanserin is beneficial for the treatment of PDP and is well tolerated. We did not identify other negative modulators of the 5-HT2A receptor for the treatment of PDP.

%B J Alzheimers Dis %V 50 %P 733-40 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757194?dopt=Abstract %R 10.3233/JAD-150818 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Serum Adiponectin Levels, Neuroimaging, and Cognition in the Mayo Clinic Study of Aging. %A Wennberg, Alexandra M V %A Gustafson, Deborah %A Hagen, Clinton E %A Roberts, Rosebud O %A Knopman, David %A Jack, Clifford %A Petersen, Ronald C %A Mielke, Michelle M %X

BACKGROUND: Adiponectin, a protein involved in inflammatory pathways, may impact the development and progression of Alzheimer's disease (AD). Adiponectin levels have been associated with mild cognitive impairment (MCI) and AD; however, its association with Alzheimer-associated neuroimaging and cognitive outcomes is unknown.

OBJECTIVE: Determine the cross-sectional association between plasma adiponectin and neuroimaging and cognitive outcomes in an older population-based sample.

METHODS: Multivariable adjusted regression models were used to investigate the association between plasma adiponectin and hippocampal volume (HVa), PiB-PET, FDG PET, cortical thickness, MCI diagnosis, and neuropsychological test performance. Analyses included 535 non-demented participants aged 70 and older enrolled in the Mayo Clinic Study of Aging.

RESULTS: Women had higher adiponectin than men (12,631 ng/mL versus 8,908 ng/mL, p < 0.001). Among women, higher adiponectin was associated with smaller HVa (B = -0.595; 95% CI -1.19, -0.005), poorer performance in language (B = -0.676; 95% CI -1.23, -0.121), and global cognition (B = -0.459; 95% CI -0.915, -0.002), and greater odds of a MCI diagnosis (OR = 6.23; 95% CI 1.20, 32.43). In analyses stratified by sex and elevated amyloid (PiB-PET SUVR >1.4), among women with elevated amyloid, higher adiponectin was associated with smaller HVa (B = -0.723; 95% CI -1.43, -0.014), poorer performance in memory (B = -1.02; 95% CI -1.73, -0.312), language (B = -0.896; 95% CI -1.58, -0.212), global cognition (B = -0.650; 95% CI -1.18, -0.116), and greater odds of MCI (OR = 19.34; 95% CI 2.72, 137.34).

CONCLUSION: Higher plasma adiponectin was associated with neuroimaging and cognitive outcomes among women. Longitudinal analyses are necessary to determine whether higher adiponectin predicts neurodegeneration and cognitive decline.

%B J Alzheimers Dis %V 53 %P 573-81 %8 2016 May 04 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163809?dopt=Abstract %R 10.3233/JAD-151201 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Serum Uric Acid and Its Association with Longitudinal Cognitive Change Among Urban Adults. %A Beydoun, May A %A Canas, Jose-Atilio %A Dore, Gregory A %A Beydoun, Hind A %A Rostant, Ola S %A Fanelli-Kuczmarski, Marie T %A Evans, Michele K %A Zonderman, Alan B %X

Uric acid, a waste metabolite among humans, was linked to various cognitive outcomes. We describe sex and age-group specific associations of baseline serum uric acid (SUAbase) and significant change in SUA (ΔSUA: 1 versus 0 = decrease versus no change; 2 versus 0 = increase versus no change) with longitudinal annual rate of cognitive change among a large sample of urban adults. Data from the Healthy Aging in Neighborhoods of Diversity across the Life Span study, 2004-2009 (visit 1) and 2009-2013 (visit 2) were used. Of 3,720 adults selected at baseline (age range: 30-64 y), complete data were available for N = 1,487-1,602 with a mean repeat of 1.5-1.7 visits/participant. Cognitive test domains spanned attention, processing speed, learning/memory, executive function, visuo-spatial/visuo-construction ability, language/verbal, and global cognitive function. SUA was measured at both visits. Multiple mixed-effects regression analyses were conducted. In the total population, a higher SUAbase was associated with a faster annual rate of decline on a measure of visual memory/visuo-construction ability (the Benton Visual Retention Test) by γ= 0.07 with a standard error of 0.02, p < 0.001. Among older men, a significant increase in SUA was associated with slower decline on a test of attention/processing speed, namely Trailmaking test, Part A, measured in seconds to completion (γ= -6.91 ± 1.73, p < 0.001). In sum, a higher SUAbase was associated with faster cognitive decline over-time in a visual memory/visuo-construction ability test. ΔSUA had particular beneficial effects of an increasing ΔSUA on the domain of attention/processing speed among older men. More longitudinal studies are needed to examine cognitive domain-specific effects of over-time change in SUA within sex and age groups.

%B J Alzheimers Dis %V 52 %P 1415-30 %8 2016 Apr 21 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104899?dopt=Abstract %R 10.3233/JAD-160028 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Severe Brain Metabolic Decreases Associated with REM Sleep Behavior Disorder in Dementia with Lewy Bodies. %A Iaccarino, Leonardo %A Marelli, Sara %A Iannaccone, Sandro %A Magnani, Giuseppe %A Ferini-Strambi, Luigi %A Perani, Daniela %X

BACKGROUND/OBJECTIVE: To evaluate the prevalence of REM sleep behavior disorder (RBD) in a sample of Dementia with Lewy Bodies (DLB) and Alzheimer's Disease (AD) patients and compare the patterns of brain glucose metabolism in DLB patients with or without the sleep disturbances.

METHODS: In this retrospective study, the presence of probable RBD was ascertained for 27 clinically diagnosed DLB patients and 11 AD patients by a self-administered RBD Single-Question Screen (RBD1Q), followed by a sleep structured interview by experts in sleep disorders blinded to clinical information. For 18F-FDG-PET metabolic comparisons, we considered an additional 13 DLB patients with negative history for sleep disturbance. We performed DLB within-group comparisons covarying for age and disease duration.

RESULTS: The RBD1Q questionnaire identified 20 out of 27 DLB RBD+ and 7 out of 27 DLB RBD-. None of the AD patients was positive to RBD1Q test. 18F-FDG-PET hypometabolism at the single- and group-level tested by means of an optimized SPM approach revealed the typical DLB metabolic pattern. Each DLB patient showed a predominant occipital hypometabolism. The SPM voxel-based comparisons revealed significant brain metabolic differences, namely a more severe metabolic decrease in DLB RBD+ in the dorsolateral and medial frontal regions, left precuneus, bilateral superior parietal lobule and rolandic operculum, and amygdala.

DISCUSSION: We found a high prevalence of RBD in DLB and none in AD, as identified by the RBD1Q questionnaire, indicating its utility in clinical practice. DLB patients with or without RBD show different hypometabolism patterns that might reflect differences in underlying pathology.

%B J Alzheimers Dis %V 52 %P 989-97 %8 2016 Apr 05 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060952?dopt=Abstract %R 10.3233/JAD-151000 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Shared Genetic Etiology between Type 2 Diabetes and Alzheimer's Disease Identified by Bioinformatics Analysis. %A Gao, Lei %A Cui, Zhen %A Shen, Liang %A Ji, Hong-Fang %K Alzheimer Disease %K Apolipoprotein C-I %K Computational Biology %K Databases, Factual %K Diabetes Mellitus, Type 2 %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Lipid Metabolism %K Male %K Polymorphism, Single Nucleotide %X

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two major health issues, and increasing evidence in recent years supports the close connection between these two diseases. The present study aimed to explore the shared genetic etiology underlying T2D and AD based on the available genome wide association studies (GWAS) data collected through August 2014. We performed bioinformatics analyses based on GWAS data of T2D and AD on single nucleotide polymorphisms (SNPs), gene, and pathway levels, respectively. Six SNPs (rs111789331, rs12721046, rs12721051, rs4420638, rs56131196, and rs66626994) were identified for the first time to be shared genetic factors between T2D and AD. Further functional enrichment analysis found lipid metabolism related pathways to be common between these two disorders. The findings may have important implications for future mechanistic and interventional studies for T2D and AD.

%B J Alzheimers Dis %V 50 %P 13-7 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639962?dopt=Abstract %R 10.3233/JAD-150580 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Shared Genetic Risk Factors for Late-Life Depression and Alzheimer's Disease. %A Ye, Qing %A Bai, Feng %A Zhang, Zhijun %K Age of Onset %K Alzheimer Disease %K Animals %K Depressive Disorder %K Genetic Predisposition to Disease %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %X

BACKGROUND: Considerable evidence has been reported for the comorbidity between late-life depression (LLD) and Alzheimer's disease (AD), both of which are very common in the general elderly population and represent a large burden on the health of the elderly. The pathophysiological mechanisms underlying the link between LLD and AD are poorly understood. Because both LLD and AD can be heritable and are influenced by multiple risk genes, shared genetic risk factors between LLD and AD may exist.

OBJECTIVE: The objective is to review the existing evidence for genetic risk factors that are common to LLD and AD and to outline the biological substrates proposed to mediate this association.

METHODS: A literature review was performed.

RESULTS: Genetic polymorphisms of brain-derived neurotrophic factor, apolipoprotein E, interleukin 1-beta, and methylenetetrahydrofolate reductase have been demonstrated to confer increased risk to both LLD and AD by studies examining either LLD or AD patients. These results contribute to the understanding of pathophysiological mechanisms that are common to both of these disorders, including deficits in nerve growth factors, inflammatory changes, and dysregulation mechanisms involving lipoprotein and folate. Other conflicting results have also been reviewed, and few studies have investigated the effects of the described polymorphisms on both LLD and AD.

CONCLUSION: The findings suggest that common genetic pathways may underlie LLD and AD comorbidity. Studies to evaluate the genetic relationship between LLD and AD may provide insights into the molecular mechanisms that trigger disease progression as the population ages.

%B J Alzheimers Dis %V 52 %P 1-15 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060956?dopt=Abstract %R 10.3233/JAD-151129 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Shear-Induced Amyloid Formation in the Brain: I. Potential Vascular and Parenchymal Processes. %A Trumbore, Conrad N %X

Shear distortion of amyloid-beta (Aβ) solutions accelerates amyloid cascade reactions that may yield different toxic oligomers than those formed in quiescent solutions. Recent experiments indicate that cerebrospinal fluid (CSF) and interstitial fluid (ISF) containing Aβ flow through narrow brain perivascular pathways and brain parenchyma. This paper suggests that such flow causes shear distortion of Aβ molecules involving conformation changes that may be one of the initiating events in the etiology of Alzheimer's disease. Aβ shearing can occur in or around brain arteries and arterioles and is suggested as the origin of cerebral amyloid angiopathy deposits in cerebrovascular walls. Comparatively low flow rates of ISF within the narrow extracellular spaces (ECS) of the brain parenchyma are suggested as a possible initiating factor in both the formation of neurotoxic Aβ42 oligomers and amyloid fibrils. Aβ42 in slow-flowing ISF can gain significant shear energy at or near the walls of tortuous brain ECS flow paths, promoting the formation of a shear-distorted, excited state hydrophobic Aβ42* conformation. This Aβ42* molecule could possibly be involved in one of two paths, one involving rapid adsorption to a brain membrane surface, ultimately forming neurotoxic oligomers on membranes, and the other ultimately forming plaque within the ECS flow pathways. Rising Aβ concentrations combined with shear at or near critical brain membranes are proposed as contributing factors to Alzheimer's disease neurotoxicity. These hypotheses may be applicable in other neurodegenerative diseases, including tauopathies and alpha-synucleinopathies, in which shear-distorted proteins also may form in the brain ECS.

%B J Alzheimers Dis %V 54 %P 457-70 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567812?dopt=Abstract %R 10.3233/JAD-160027 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Short-Term Effects of Rhythmic Sensory Stimulation in Alzheimer's Disease: An Exploratory Pilot Study. %A Clements-Cortes, Amy %A Ahonen, Heidi %A Evans, Michael %A Freedman, Morris %A Bartel, Lee %X

This study assessed the effect of stimulating the somatosensory system of Alzheimer's disease (AD) patients at three stages of their illness with 40 Hz sound. In this AB cross-over study design, 18 participants (6 mild, 6 moderate, 6 severe) each participated in 13 sessions: one intake and 12 treatment. Treatment A consisted of 40 Hz sound stimulation and Treatment B consisted of visual stimulation using DVDs, each provided twice a week over 6 weeks for a total of 6 times per treatment. Outcome measures included: St. Louis University Mental Status Test (SLUMS), Observed Emotion Rating Scale, and behavioral observation by the researcher. Data were submitted to regression analysis for the series of 6 SLUMS scores in treatment A and 6 scores in B with comparison by group. The slopes for the full sample and subgroups in the 40 Hz treatment were all significant beyond alpha = 0.05, while those for the DVD were not. A thematic analysis of qualitative observations supported the statistical findings. 40 Hz treatment appeared to have the strongest impact on persons with mild and moderate AD. Results are promising in terms of a potential new treatment for persons with AD, and further research is needed.

%B J Alzheimers Dis %V 52 %P 651-60 %8 2016 Mar 25 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031491?dopt=Abstract %R 10.3233/JAD-160081 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Sideritis spp. Extracts Enhance Memory and Learning in Alzheimer's β-Amyloidosis Mouse Models and Aged C57Bl/6 Mice. %A Hofrichter, Jacqueline %A Krohn, Markus %A Schumacher, Toni %A Lange, Cathleen %A Feistel, Bjöorn %A Walbroel, Bernd %A Pahnke, Jens %X

Nowadays, Alzheimer's disease is the most prevalent epiphenomenon of the aging population. Although soluble amyloid-β (Aβ) species (monomers, oligomers) are recognized triggers of the disease, no therapeutic approach is able to stop it. Herbal medicines are used to treat different diseases in many regions of the world. On the Balkan Peninsula, at the eastern Mediterranean Sea, and adjacent regions, Sideritis species are used as traditional medicine to prevent age-related problems in elderly. To evaluate this traditional knowledge in controlled experiments, we tested extracts of two commonly used Sideritis species, Sideritis euboea and Sideritis scardica, with regard to their effects on cognition in APP-transgenic and aged, non-transgenic C57Bl/6 mice. Additionally, histomorphological and biochemical changes associated with Aβ deposition and treatment were assessed. We found that daily oral treatment with Sideritis spp. extracts highly enhanced cognition in aged, non-transgenic as well as in APP-transgenic mice, an effect that was even more pronounced when extracts of both species were applied in combination. The treatment strongly reduced Aβ42 load in APP-transgenic mice, accompanied by increased phagocytic activity of microglia, and increased expression of the α-secretase ADAM10. Moreover, the treatment was able to fully rescue neuronal loss of APP-transgenic mice to normal levels as seen in non-transgenic controls. Having the traditional knowledge in mind, our results imply that treatment with Sideritis spp. extracts might be a potent, well-tolerated option for treating symptoms of cognitive impairment in elderly and with regard to Alzheimer's disease by affecting its most prominent hallmarks: Aβ pathology and cognitive decline.

%B J Alzheimers Dis %V 53 %P 967-80 %8 2016 May 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258424?dopt=Abstract %R 10.3233/JAD-160301 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Sirtuin 2 Inhibition Improves Cognitive Performance and Acts on Amyloid-β Protein Precursor Processing in Two Alzheimer's Disease Mouse Models. %A Biella, Gloria %A Fusco, Federica %A Nardo, Emanuele %A Bernocchi, Ottavia %A Colombo, Alessio %A Lichtenthaler, Stefan F %A Forloni, Gianluigi %A Albani, Diego %X

The neuropathological hallmarks of Alzheimer's disease (AD) are extracellular plaques built up by the accumulation of the amyloid-β protein precursor (AβPP)-derived peptide β (Aβ), and intracellular tangles of hyperphosphorylated tau protein. Sirtuin 2 (SIRT2) is a member of the sirtuin family, featuring conserved enzymes with deacetylase activity and involved in several cell molecular pathways. We investigated the importance of SIRT2 inhibition in AD. We inhibited SIRT2 by small molecules (AGK-2, AK-7) and examined AβPP metabolism in H4-SW neuroglioma cells overexpressing AβPP and two AD transgenic mouse models (3xTg-AD and APP23). The in vitro studies suggested that the inhibition of SIRT2 reduced Aβ production; in vivo data showed an improvement of cognitive performance in the novel object recognition test, and an effect on AβPP proteolytic processing leading to a reduction of soluble β-AβPP and an increase of soluble α-AβPP protein. In 3xTg-AD mice, we noticed that total tau protein level rose. Overall, our pre-clinical data support a role for SIRT2 inhibition in the improvement of cognitive performance and the modulation of molecular mechanisms relevant for AD, thus deserving attention as possible therapeutic strategy.

%B J Alzheimers Dis %V 53 %P 1193-207 %8 2016 Jun 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372638?dopt=Abstract %R 10.3233/JAD-151135 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Six-Month Cognitive-Motor and Aerobic Exercise Program Improves Executive Function in Persons with an Objective Cognitive Impairment: A Pilot Investigation Using the Antisaccade Task. %A Heath, Matthew %A Weiler, Jeffrey %A Gregory, Michael A %A Gill, Dawn P %A Petrella, Robert J %X

Persons with an objective cognitive impairment (OCI) are at increased risk for progression to Alzheimer's disease and related dementias. The present pilot project sought to examine whether participation in a long-term exercise program involving cognitive-motor (CM) dual-task gait training and aerobic exercise training improves executive function in persons with an OCI. To accomplish our objective, individuals with an OCI (n = 12) as determined by a Montreal Cognitive Assessment (MoCA) score of less than 26 and older adults (n = 11) deemed to be cognitively healthy (i.e., control group: MoCA score ≥26) completed a six-month moderate-to-high intensity (65-85% maximum heart rate) treadmill-based CM and aerobic exercise training program wherein pre- and post-intervention executive control was examined via the antisaccade task. Notably, antisaccades require a goal-directed eye-movement mirror-symmetrical to a target and represent an ideal tool for the study of executive deficits because of its hands- and language-free nature. As well, the cortical networks mediating antisaccades represent regions associated with neuropathology in cognitive decline and dementia (e.g., dorsolateral prefrontal cortex). Results showed that antisaccade reaction times for the OCI group reliably decreased by 30 ms from pre- to post-intervention, whereas the control group did not produce a reliable pre- to post-intervention change in reaction time (i.e., 6 ms). Thus, we propose that in persons with OCI long-term CM and aerobic training improves the efficiency and effectiveness of the executive mechanisms mediating high-level oculomotor control.

%B J Alzheimers Dis %V 54 %P 923-931 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567829?dopt=Abstract %R 10.3233/JAD-160288 %0 Journal Article %J J Alzheimers Dis %D 2016 %T So Close Yet So Far: Executive Contribution to Memory Processing in Behavioral Variant Frontotemporal Dementia. %A Bertoux, Maxime %A Ramanan, Siddharth %A Slachevsky, Andrea %A Wong, Stephanie %A Henriquez, Fernando %A Musa, Gada %A Delgado, Carolina %A Flanagan, Emma %A Bottlaender, Michel %A Sarazin, Marie %A Hornberger, Michael %A Dubois, Bruno %X

BACKGROUND: Memory impairment in behavioral variant frontotemporal dementia (bvFTD) is traditionally considered to be mild and attributed to prefrontal cortex dysfunction. Recent studies, however, indicated that some patients can present with a memory impairment of the hippocampal type, showing storage and consolidation deficits in addition to the more executive/prefrontal related encoding and strategic difficulties.

OBJECTIVE: This study aimed to study the relationship between executive functions (EF) and memory processes in bvFTD via a data-driven approach.

METHOD: Participants consisted of 71 bvFTD (among which 60.6% had a lumbar puncture showing non-Alzheimer biomarker profile) and 60 controls (among which 45% had amyloid imaging showing a normal profile). EF were assessed by the Frontal Assessment Battery, semantic/lexical verbal fluency tests, and forward/backward digit spans. Patients were split into amnestic (n = 33) and non-amnestic (n = 38) subgroups based on normative data (total recall score) from the Free and Cued Selective Reminding Test (FCSRT). Relationships between FCSRT subscores and EF measures were explored through hierarchical clustering analysis, partial correlation analysis with an EF component, and automated linear modeling.

RESULTS: Convergent findings across the statistical approaches show that, overall, memory performance was independent from EF in bvFTD whereas the relationship was stronger in controls. Indeed, in bvFTD, memory performance did not cluster with EF, was not correlated with the EF component, and was only partially (4% - 12.7%) predicted by EF.

DISCUSSION: These findings show that executive dysfunctions cannot solely explain the memory deficits occurring in bvFTD. Indeed, some patients present with a genuine amnesia affecting storage and consolidation abilities, which are independent from executive dysfunctions. On the clinical level, this study highlights the importance of revising the neuropsychological diagnosis criteria for bvFTD.

%B J Alzheimers Dis %V 54 %P 1005-1014 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567869?dopt=Abstract %R 10.3233/JAD-160522 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Social Cognition Deficits: The Key to Discriminate Behavioral Variant Frontotemporal Dementia from Alzheimer's Disease Regardless of Amnesia? %A Bertoux, Maxime %A de Souza, Leonardo Cruz %A O'Callaghan, Claire %A Greve, Andrea %A Sarazin, Marie %A Dubois, Bruno %A Hornberger, Michael %K Aged %K Alzheimer Disease %K Amnesia %K Cognition %K Diagnosis, Differential %K Emotions %K Female %K Frontotemporal Dementia %K Humans %K Male %K Memory, Episodic %K Neuropsychological Tests %K Social Perception %X

Relative sparing of episodic memory is a diagnostic criterion of behavioral variant frontotemporal dementia (bvFTD). However, increasing evidence suggests that bvFTD patients can show episodic memory deficits at a similar level as Alzheimer's disease (AD). Social cognition tasks have been proposed to distinguish bvFTD, but no study to date has explored the utility of such tasks for the diagnosis of amnestic bvFTD. Here, we contrasted social cognition performance of amnestic and non-amnestic bvFTD from AD, with a subgroup having confirmed in vivo pathology markers. Ninety-six participants (38 bvFTD and 28 AD patients as well as 30 controls) performed the short Social-cognition and Emotional Assessment (mini-SEA). BvFTD patients were divided into amnestic versus non-amnestic presentation using the validated Free and Cued Selective Reminding Test (FCSRT) assessing episodic memory. As expected, the accuracy of the FCSRT to distinguish the overall bvFTD group from AD was low (69.7% ) with ∼50% of bvFTD patients being amnestic. By contrast, the diagnostic accuracy of the mini-SEA was high (87.9% ). When bvFTD patients were split on the level of amnesia, mini-SEA diagnostic accuracy remained high (85.1% ) for amnestic bvFTD versus AD and increased to very high (93.9% ) for non-amnestic bvFTD versus AD. Social cognition deficits can distinguish bvFTD and AD regardless of amnesia to a high degree and provide a simple way to distinguish both diseases at presentation. These findings have clear implications for the diagnostic criteria of bvFTD. They suggest that the emphasis should be on social cognition deficits with episodic memory deficits not being a helpful diagnostic criterion in bvFTD.

%B J Alzheimers Dis %V 49 %P 1065-74 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26756325?dopt=Abstract %R 10.3233/JAD-150686 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Societal Cost of Dementia in Singapore: Results from the WiSE Study. %A Abdin, Edimansyah %A Subramaniam, Mythily %A Achilla, Evanthia %A Chong, Siow Ann %A Vaingankar, Janhavi Ajit %A Picco, Louisa %A Sambasivam, Rajeswari %A Pang, Shirlene %A Chua, Boon Yiang %A Ng, Li Ling %A Chua, Hong Choon %A Heng, Derrick %A Prince, Martin %A McCrone, Paul %K Adult %K Aged, 80 and over %K Cost of Illness %K Dementia %K Female %K Humans %K Linear Models %K Male %K Middle Aged %K Singapore %X

BACKGROUND: There is currently limited evidence on the economic burden that dementia exerts on multi-ethnic Asian populations.

OBJECTIVE: The present study aimed to estimate the economic cost of dementia in Singapore.

METHODS: We used data from the Well-being of the Singapore Elderly study, a nationally representative survey of the older Singapore Resident population aged 60 years and above. Generalized linear modeling was used to estimate factors associated with costs.

RESULTS: The total cost of dementia in 2013 was estimated at S$532 million (95% CI, S$361 million to S$701 million) while the annual cost per person was estimated at S$10,245 per year (95% CI, S$6,954 to S$12,495). Apart from dementia, higher total societal cost were also significantly associated with older age, Indian ethnicity, and those who were diagnosed with heart problems, stroke, diabetes or depression, whereas being divorced/separated, lower education, and those who were diagnosed with hypertension were significantly associated with lower total societal cost.

CONCLUSION: The study provides a rich body of information on healthcare utilization and cost of dementia, which is essential for future planning of services for the elderly population.

%B J Alzheimers Dis %V 51 %P 439-49 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890766?dopt=Abstract %R 10.3233/JAD-150930 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Soluble Amyloid-β42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor. %A Hascup, Kevin N %A Hascup, Erin R %X

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and hippocampal atrophy. Soluble amyloid-β (Aβ)42 and plaque accumulation is implicated as the neurotoxic species in this disorder; however, at physiological concentrations (pM-nM), Aβ42 contributes to neurogenesis, long-term potentiation, and neuromodulation. Because Aβ42 binds the α7 nicotinic acetylcholine receptors (α7nAChRs) located presynaptically on glutamatergic terminals, involved with hippocampal dependent learning and memory, we examined the effects of the human, monomeric isoform of Aβ42 on glutamate release in the dentate gyrus (DG), CA3, and CA1, of isoflurane anesthetized, 6-9 month old male C57BL/6J mice. We utilized an enzyme-based microelectrode array selective for L-glutamate measures with fast temporal (4 Hz), low spatial resolution (50×100μm) and minimal damage to the surrounding parenchyma (50-100μm). Local application of Aβ42 (0.01, 0.1, 1.0, and 10.0μM; ∼150 nl; 1-2 Seconds) elicited robust, reproducible glutamate signals in all hippocampal subfields studied. Local application of 0.1 and 1.0μM Aβ42 significantly increased the average maximal amplitude of glutamate release compared to saline in the DG and CA1. 10.0μM Aβ42 significantly elevated glutamate release in the DG and CA3, but not in the CA1. Glutamate release was completely attenuated with coapplication of 10.0μM α-Bungarotoxin, the potent α7nAChR antagonist. Coapplication of 10.0μM tetrodotoxin, indicates Aβ42 - induced glutamate release originates from neuronal rather than glial sources. This study demonstrates that the human, monomeric Aβ42 isoform evokes glutamate release through the α7nAChR and varies across hippocampal subfields.

%B J Alzheimers Dis %V 53 %P 337-47 %8 2016 May 03 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163813?dopt=Abstract %R 10.3233/JAD-160041 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Spatial Memory Impairment is Associated with Intraneural Amyloid-β Immunoreactivity and Dysfunctional Arc Expression in the Hippocampal-CA3 Region of a Transgenic Mouse Model of Alzheimer's Disease. %A Morin, Jean-Pascal %A Cerón-Solano, Giovanni %A Velázquez-Campos, Giovanna %A Pacheco-López, Gustavo %A Bermúdez-Rattoni, Federico %A Díaz-Cintra, Sofía %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Benzeneacetamides %K CA3 Region, Hippocampal %K Cytoskeletal Proteins %K Disease Models, Animal %K Gene Expression Regulation %K Humans %K Maze Learning %K Memory Disorders %K Mice %K Mice, Transgenic %K Mutation %K Nerve Tissue Proteins %K Neurons %K Presenilin-1 %K Pyridines %K tau Proteins %X

Dysfunction of synaptic communication in cortical and hippocampal networks has been suggested as one of the neuropathological hallmarks of the early stages of Alzheimer's disease (AD). Also, several lines of evidence have linked disrupted levels of activity-regulated cytoskeletal associated protein (Arc), an immediate early gene product that plays a central role in synaptic plasticity, with AD "synaptopathy". The mapping of Arc expression patterns in brain networks has been extensively used as a marker of memory-relevant neuronal activity history. Here we evaluated basal and behavior-induced Arc expression in hippocampal networks of the 3xTg-AD mouse model of AD. The basal percentage of Arc-expressing cells in 10-month-old 3xTg-AD mice was higher than wild type in CA3 (4.88% versus 1.77% , respectively) but similar in CA1 (1.75% versus 2.75% ). Noteworthy, this difference was not observed at 3 months of age. Furthermore, although a Morris water maze test probe induced a steep (∼4-fold) increment in the percentage of Arc+ cells in the CA3 region of the 10-month-old wild-type group, no such increment was observed in age-matched 3xTg-AD, whereas the amount of Arc+ cells in CA1 increased in both groups. Further, we detected that CA3 neurons with amyloid-β were much more likely to express Arc protein under basal conditions. We propose that in 3xTg-AD mice, intraneuronal amyloid-β expression in CA3 could increase unspecific neuronal activation and subsequent Arc protein expression, which might impair further memory-stabilizing processes.

%B J Alzheimers Dis %V 51 %P 69-79 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836189?dopt=Abstract %R 10.3233/JAD-150975 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Spatial Navigation in Preclinical Alzheimer's Disease. %A Allison, Samantha L %A Fagan, Anne M %A Morris, John C %A Head, Denise %K Aged %K Alzheimer Disease %K Biomarkers %K Educational Status %K Female %K Humans %K Learning %K Male %K Neuropsychological Tests %K Prodromal Symptoms %K Psychomotor Performance %K ROC Curve %K Spatial Navigation %K tau Proteins %K User-Computer Interface %X

Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer's disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: Clinically normal without preclinical AD (n = 42), clinically normal with preclinical AD (n = 13), and early-stage symptomatic AD (n = 16) groups. Preclinical AD was defined based on cerebrospinal fluid Aβ42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD.

%B J Alzheimers Dis %V 52 %P 77-90 %8 2016 02 09 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967209?dopt=Abstract %R 10.3233/JAD-150855 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Specific Binding of Cu(II) Ions to Amyloid-Beta Peptides Bound to Aggregation-Inhibiting Molecules or SDS Micelles Creates Complexes that Generate Radical Oxygen Species. %A Tiiman, Ann %A Luo, Jinghui %A Wallin, Cecilia %A Olsson, Lisa %A Lindgren, Joel %A Jarvet, Jϋri %A Per, Roos %A Sholts, Sabrina B %A Rahimipour, Shai %A Abrahams, Jan Pieter %A Karlström, Amelie Eriksson %A Gräslund, Astrid %A Wärmländer, Sebastian K T S %X

Aggregation of the amyloid-beta (Aβ) peptide into insoluble plaques is a major factor in Alzheimer's disease (AD) pathology. Another major factor in AD is arguably metal ions, as metal dyshomeostasis is observed in AD patients, metal ions modulate Aβ aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo, Aβ is found in various cellular locations including membranes. So far, Cu(II)/Aβ interactions and ROS generation have not been investigated in a membrane environment. Here, we study Cu(II) and Zn(II) interactions with Aβ bound to SDS micelles or to engineered aggregation-inhibiting molecules (the cyclic peptide CP-2 and the ZAβ3(12-58)Y18L Affibody molecule). In all studied systems the Aβ N-terminal segment was found to be unbound, unstructured, and free to bind metal ions. In SDS micelles, Aβ was found to bind Cu(II) and Zn(II) with the same ligands and the same KD as in aqueous solution. ROS was generated in all Cu(II)/Aβ complexes. These results indicate that binding of Aβ to membranes, drugs, and other entities that do not interact with the Aβ N-terminal part, appears not to compromise the N-terminal segment's ability to bind metal ions, nor impede the capacity of N-terminally bound Cu(II) to generate ROS.

%B J Alzheimers Dis %V 54 %P 971-982 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567855?dopt=Abstract %R 10.3233/JAD-160427 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Specific Features of Subjective Cognitive Decline Predict Faster Conversion to Mild Cognitive Impairment. %A Fernández-Blázquez, Miguel A %A Ávila-Villanueva, Marina %A Maestú, Fernando %A Medina, Miguel %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Cognitive Dysfunction %K Disease Progression %K Female %K Follow-Up Studies %K Genotyping Techniques %K Humans %K Kaplan-Meier Estimate %K Male %K Neuropsychological Tests %K Perception %K Prodromal Symptoms %K Prognosis %K Prospective Studies %K Time Factors %X

BACKGROUND: Alzheimer's disease (AD) is a silent disorder that needs the earliest possible intervention in order to reduce its high economic and social impact. It has been recently suggested that subjective cognitive decline (SCD) appears at preclinical stages many years before the onset of AD. Therefore, SCD could become an ideal target for early therapeutic intervention.

OBJECTIVE: The goal of this study was to evaluate the clinical significance of SCD on the conversion from a cognitively healthy stage to a mild cognitive impairment (MCI) in one-year follow-up.

METHODS: A total of 608 cognitively intact individuals from the Vallecas Project's cohort, a community-based prospective study to identify early markers of AD, were enrolled in this study. Participants were classified in three groups: i) No Complaints (NCg), ii) Subjects with complaints in one or more cognitive domains (SCDg), and iii) Subjects who, besides complaints, fulfilled the features of SCD Plus proposed by the International Working Group of SCD (SCD-Pg).

RESULTS: Individuals were followed up for a mean of 13.1 months (range 10.7-22.4). During this time, 41 volunteers developed MCI (6.7% of total sample). The conversion rate for SCD-Pg (18.9%) was significantly higher than SCDg (5.6%) and NCg (4.9%).

CONCLUSION: Specific features associated with SCD may help to identify individuals at high risk of fast conversion to MCI. These results highlight the importance of a close follow-up of subjects with SCD-P and include them in early intervention programs because of their increased risk for the development of MCI.

%B J Alzheimers Dis %V 52 %P 271-81 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060949?dopt=Abstract %R 10.3233/JAD-150956 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Specific Triazine Herbicides Induce Amyloid-β42 Production. %A Portelius, Erik %A Durieu, Emilie %A Bodin, Marion %A Cam, Morgane %A Pannee, Josef %A Leuxe, Charlotte %A Mabondzo, Aloϊse %A Oumata, Nassima %A Galons, Hervé %A Lee, Jung Yeol %A Chang, Young-Tae %A Stϋber, Kathrin %A Koch, Philipp %A Fontaine, Gaëlle %A Potier, Marie-Claude %A Manousopoulou, Antigoni %A Garbis, Spiros D %A Covaci, Adrian %A Van Dam, Debby %A De Deyn, Peter %A Karg, Frank %A Flajolet, Marc %A Omori, Chiori %A Hata, Saori %A Suzuki, Toshiharu %A Blennow, Kaj %A Zetterberg, Henrik %A Meijer, Laurent %X

Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by secretases leads to extracellular release of amyloid-β (Aβ) peptides. Increased production of Aβ42 over Aβ40 and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark. Identifying products of the 'human chemical exposome' (HCE) able to induce Aβ42 production may be a key to understanding some of the initiating causes of AD and to generate non-genetic, chemically-induced AD animal models. A cell model was used to screen HCE libraries for Aβ42 inducers. Out of 3500+ compounds, six triazine herbicides were found that induced a β- and γ-secretases-dependent, 2-10 fold increase in the production of extracellular Aβ42 in various cell lines, primary neuronal cells, and neurons differentiated from human-induced pluripotent stem cells (iPSCs). Immunoprecipitation/mass spectrometry analyses show enhanced production of Aβ peptides cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and lower, a characteristic of AD. Neurons derived from iPSCs obtained from a familial AD (FAD) patient (AβPP K724N) produced more Aβ42 versus Aβ40 than neurons derived from healthy controls iPSCs (AβPP WT). Triazines enhanced Aβ42 production in both control and AD iPSCs-derived neurons. Triazines also shifted the cleavage pattern of alcadeinα, another γ-secretase substrate, suggesting a direct effect of triazines on γ-secretase activity. In conclusion, several widely used triazines enhance the production of toxic, aggregation prone Aβ42/Aβ43 amyloids, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD.

%B J Alzheimers Dis %V 54 %P 1593-1605 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589520?dopt=Abstract %R 10.3233/JAD-160310 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Stability of Progranulin Under Pre-Analytical Conditions in Serum and Cerebrospinal Fluid. %A Willemse, Eline A J %A Durieux-Lu, Sisi %A van der Flier, Wiesje M %A Pijnenburg, Yolande A L %A de Jonge, Robert %A Teunissen, Charlotte E %X

Progranulin (PGRN) levels in blood and cerebrospinal fluid (CSF) are increasingly studied as potential markers for neurodegenerative disorders. We aimed to 1) characterize two commercially available PGRN ELISAs on several assay validation parameters, 2) assess the stability of PGRN in serum and CSF under pre-analytical conditions, and 3) compare stability in the two assays. Intra- and inter-assay variation, inter-lot variation, linearity, lower limit of detection, and kit correlations were assessed for the Adipogen and R&D PGRN ELISA kits. Blood and serum samples were experimentally exposed to ≤9 freeze/thaw cycles, delayed processing for ≤24 h at room temperature and 4°C, and to temperature stability tests for ≤3 weeks at -20°C, 4°C, room temperature, and 37°C. Both commercial PGRN ELISA kits showed acceptable ranges for intra- and inter-assay variation, where the R&D kit performed more accurate than the Adipogen kit, especially for inter-assay variation (intra-assay serum: 6.7 and 8.3%, respectively; inter-assay serum: 9.2 and 21.0%; intra-assay CSF: 3.6 and 12.0%; inter-assay CSF: 16.0 and 44.5%). Absolute serum PGRN concentrations were 1.9-fold higher in Adipogen than R&D (p < 0.001) and strongly correlated between both kits (ρ= 0.86, p < 0.0001) and CSF PGRN levels were on the borderline of detection in both kits. PGRN was typically stable under all pre-analytical conditions addressed, although two weeks at 37°C resulted in decreased PGRN concentrations in CSF, only when using the Adipogen kit. These results support further examination of PGRN as a potential marker in neurodegenerative diseases, since PGRN is stable in serum and CSF and can be measured using ELISA kits from several providers.

%B J Alzheimers Dis %V 53 %P 107-16 %8 2016 Apr 21 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104901?dopt=Abstract %R 10.3233/JAD-160061 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Staging Alzheimer's Disease Risk by Sequencing Brain Function and Structure, Cerebrospinal Fluid, and Cognition Biomarkers. %A Chen, Guangyu %A Shu, Hao %A Chen, Gang %A Ward, B Douglas %A Antuono, Piero G %A Zhang, Zhijun %A Li, Shi-Jiang %X

This study aims to develop a composite biomarker that can accurately measure the sequential biological stages of Alzheimer's disease (AD) on an individual level. We selected 144 subjects from the Alzheimer's Disease Neuroimaging Initiative 2 datasets. Ten biomarkers, from brain function and structure, cerebrospinal fluid, and cognitive performance, were integrated using the event-based probabilistic model to estimate their optimal temporal sequence (Soptimal). We identified the numerical order of the Soptimal as the characterizing Alzheimer's disease risk events (CARE) index to measure disease stage. The results show that, in the Soptimal, hippocampal and posterior cingulate cortex network biomarkers occur first, followed by aberrant cerebrospinal fluid amyloid-β and p-tau levels, then cognitive deficit, and finally regional gray matter loss and fusiform network abnormality. The CARE index significantly correlates with disease severity and exhibits high reliability. Our findings demonstrate that use of the CARE index would advance AD stage measurement across the whole AD continuum and facilitate personalized treatment of AD.

%B J Alzheimers Dis %V 54 %P 983-993 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567874?dopt=Abstract %R 10.3233/JAD-160537 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Standardized Uptake Value Ratio-Independent Evaluation of Brain Amyloidosis. %A Chincarini, Andrea %A Sensi, Francesco %A Rei, Luca %A Bossert, Irene %A Morbelli, Silvia %A Guerra, Ugo Paolo %A Frisoni, Giovanni %A Padovani, Alessandro %A Nobili, Flavio %X

The assessment of in vivo18F images targeting amyloid deposition is currently carried on by visual rating with an optional quantification based on standardized uptake value ratio (SUVr) measurements. We target the difficulties of image reading and possible shortcomings of the SUVr methods by validating a new semi-quantitative approach named ELBA. ELBA involves a minimal image preprocessing and does not rely on small, specific regions of interest (ROIs). It evaluates the whole brain and delivers a geometrical/intensity score to be used for ranking and dichotomic assessment. The method was applied to adniimages 18F-florbetapir images from the ADNI database. Five expert readers provided visual assessment in blind and open sessions. The longitudinal trend and the comparison to SUVr measurements were also evaluated. ELBA performed with area under the roc curve (AUC) = 0.997 versus the visual assessment. The score was significantly correlated to the SUVr values (r = 0.86, p < 10-4). The longitudinal analysis estimated a test/retest error of ≃2.3%. Cohort and longitudinal analysis suggests that the ELBA method accurately ranks the brain amyloid burden. The expert readers confirmed its relevance in aiding the visual assessment in a significant number (85) of difficult cases. Despite the good performance, poor and uneven image quality constitutes the major limitation.

%B J Alzheimers Dis %V 54 %P 1437-1457 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662288?dopt=Abstract %R 10.3233/JAD-160232 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Stem Cell Therapy for Alzheimer's Disease: A Review of Recent Clinical Trials. %A Kang, Jae Myeong %A Yeon, Byeong Kil %A Cho, Seong-Jin %A Suh, Yoo-Hun %X

Stem cell therapy has been noted to be a disease-modifying treatment for Alzheimer's disease (AD). After the failure to develop new drugs for AD, the number of studies on stem cells, such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs), has increased from the early 2000 s. Issues pertaining to stem cells have been investigated in many animal studies in terms of stem cell origin, differentiation potency, method of culture, tumor formation, injection route, and mobility. Since 2010, mainly in East Asia, researchers began clinical trials investigating the use of stem cells for AD. Two phase I trials on moderate AD have been completed; though they revealed no severe acute or long-term side effects, no significant clinical efficacy was observed. Several studies, which involve more sophisticated study designs using different injection routes, well-established scales, and biomarkers such as amyloid positron emission tomography, are planned for mild to moderate AD patients. Here, we review the concept of stem cell therapy for AD and the progress of recent clinical trials.

%B J Alzheimers Dis %V 54 %P 879-889 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567851?dopt=Abstract %R 10.3233/JAD-160406 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Stimulating the Activity of Amyloid-Beta Degrading Enzymes: A Novel Approach for the Therapeutic Manipulation of Amyloid-Beta Levels. %A Kuruppu, Sanjaya %A Rajapakse, Niwanthi W %A Spicer, Alexander J %A Parkington, Helena C %A Smith, A Ian %X

Alzheimer's disease is a debilitating neurological disease placing significant burden on health care budgets around the world. It is widely believed that accumulation of amyloid-beta (Aβ) in the brain is a key event that initiates neurodegeneration, thus the clearance of Aβ from brain could be a key therapeutic strategy. Aβ exists in an equilibrium in healthy individuals, and recent research would suggest that dysfunction in the clearance pathways is the driving force behind its accumulation. One mechanism of clearance is proteolytic degradation by enzymes, and increasing the expression of these enzymes in animal models of Alzheimer's disease has indeed shown promising results. This approach could be challenging to translate into the clinic given the likely need for genetic manipulation. We hypothesize that stimulating the activity of these enzymes (as opposed to increasing expression) through pharmacological agents will enhance degradation or at least prevent amyloid deposition, and is therefore another potentially novel avenue to manipulate Aβ levels for therapeutic purposes. We discuss the recent research supporting this hypothesis as well as possible drawbacks to this approach.

%B J Alzheimers Dis %V 54 %P 891-895 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567865?dopt=Abstract %R 10.3233/JAD-160492 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Strategies for improving memory: a randomized trial of memory groups for older people, including those with mild cognitive impairment. %A Kinsella, Glynda J %A Ames, David %A Storey, Elsdon %A Ong, Ben %A Pike, Kerryn E %A Saling, Michael M %A Clare, Linda %A Mullaly, Elizabeth %A Rand, Elizabeth %K Aged %K Aged, 80 and over %K Aging %K Cognitive Dysfunction %K Cross-Over Studies %K Female %K Humans %K Male %K Memory, Episodic %K Neuropsychological Tests %K Self Report %X

BACKGROUND: Governments are promoting the importance of maintaining cognitive health into older age to minimize risk of cognitive decline and dementia. Older people with amnestic mild cognitive impairment (aMCI) are particularly vulnerable to memory challenges in daily activities and are seeking ways to maintain independent living.

OBJECTIVE: To evaluate the effectiveness of memory groups for improving memory strategies and memory ability of older people, especially those with aMCI.

METHODS: 113 healthy older adults (HOA) and 106 adults with aMCI were randomized to a six-week memory group or a waitlist control condition. Outcome was evaluated through knowledge and use of memory strategies, memory ability (self-report and neuropsychological tests), and wellbeing. Assessments included a six-month follow-up.

RESULTS: Using intention to treat analyses, there were intervention effects for HOA and aMCI groups in strategy knowledge (HOA: η2= 0.20; aMCI: η2= 0.06), strategy use (HOA: η2= 0.18; aMCI: η2= 0.08), and wellbeing (HOA: η2= 0.11; aMCI: η2= 0.05). There were also intervention effects in the HOA group, but not the aMCI group, in self-reported memory ability (η2= 0.06) and prospective memory tests (η2= 0.02). By six-month follow-up, gains were found on most HOA outcomes. In the aMCI group gains were found in strategy use, and by this stage, gains in prospective memory were also found.

CONCLUSION: Memory groups can engage older people in techniques for maintaining cognitive health and improve memory performance, but more modest benefits are seen for older adults with aMCI.

%B J Alzheimers Dis %V 49 %P 31-43 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444773?dopt=Abstract %R 10.3233/JAD-150378 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Stratification by Genetic and Demographic Characteristics Improves Diagnostic Accuracy of Cerebrospinal Fluid Biomarkers in Rapidly Progressive Dementia. %A Karch, André %A Llorens, Franc %A Schmitz, Matthias %A Arora, Amandeep Singh %A Zafar, Saima %A Lange, Peter %A Schmidt, Christian %A Zerr, Inga %X

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are routinely used for the differential diagnosis of rapidly progressive dementia, but are also affected by patients' characteristics.

OBJECTIVE: To assess if stratification by age, sex, and genetic risk factors improves the accuracy of cerebrospinal fluid (CSF) biomarkers in patients with rapidly progressive dementia.

METHODS: 1,538 individuals with sporadic Creutzfeldt-Jakob disease (CJD), 173 with classic Alzheimer's disease (cAD), 37 with rapidly progressive Alzheimer's disease (rpAD), and 589 without signs of dementia were included in this retrospective diagnostic study. The effect of age, sex, PRNP codon 129, and APOE genotype on CSF levels of tau, p-tau, Aβ1-42, and Aβ1-40 values measured at time of diagnostic work-up was assessed.

RESULTS: Tau was a better marker for the differentiation of CJD and rpAD in older (AUC:0.97; 95% CI:0.96-1.00) than in younger (AUC:0.91; 95% CI:0.87-0.94) patients as tau levels increased with age in CJD patients, but not in rpAD patients. PRNP codon 129 and APOE genotype had complex effects on biomarkers in all diseases, making stratification by genotype a powerful tool. In females (AUC:0.78; 95% CI:0.65-0.91) and patients older than 70 (AUC:0.78; 95% CI:0.62-0.93), tau was able to differentiate with moderate accuracy between cAD and rpAD patients.

CONCLUSION: Implementation of stratum-specific reference ranges improves the diagnostic accuracy of CSF biomarkers for the differential diagnosis of rapidly progressive dementia. Diagnostic criteria developed for this setting have to take this into account.

%B J Alzheimers Dis %V 54 %P 1385-1393 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589519?dopt=Abstract %R 10.3233/JAD-160267 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Streptozotocin Induces Mild Cognitive Impairment at Appropriate Doses in Mice as Determined by Long-Term Potentiation and the Morris Water Maze. %A Li, Dong %A Huang, Yan %A Cheng, Bin %A Su, Jie %A Zhou, Wen-Xia %A Zhang, Yong-Xiang %X

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and effective therapeutic drugs in the clinic are still lacking. Ideally, AD progression could be stopped at an early stage, such as at the mild cognitive impairment (MCI) stage. MCI refers to the clinical condition between normal aging and dementia. Patients with MCI experience memory loss but do not meet the criteria for the diagnosis of clinically probable AD. However, few MCI animal models have been established. Here, we used in vivo long-term potentiation (LTP) recording and the Morris water maze (MWM) to evaluate the effects of intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. We found a relationship between cognitive behavior and LTP in vivo and determined the appropriate doses of STZ for a putative MCI animal model. Animals that received≥150μg of STZ exhibited cognitive impairment in the MWM test, and few changes in behavior tests were observed in animals receiving less than 150μg of STZ. In vivo LTP recordings revealed that the induction of LTP decreased significantly in STZ-treated animals, even at the lowest dose (25μg/mouse), in a dose-dependent manner. Pathology analysis revealed STZ-induced neuron loss in a dose-dependent manner, both in the cortex and in the hippocampus, as evidenced by a significantly decreased neuronal number in the cohort treated with 75μg of STZ/mouse. Our study indicated that a low dose (25μg/mouse) of STZ impaired neural plasticity; at a higher dose of 75μg/mouse STZ, further LTP deficits were noted along with induced neuronal loss in both the cortex and the hippocampus, which could be considered a possible MCI or pre-MCI animal model; and finally, at 150μg/mouse STZ, dementia was induced, feasibly indicating a state of AD.

%B J Alzheimers Dis %V 54 %P 89-98 %8 2016 Jul 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472873?dopt=Abstract %R 10.3233/JAD-150979 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Stroke, Vascular Dementia, and Alzheimer's Disease: Molecular Links. %A Vijayan, Murali %A Reddy, P Hemachandra %X

Stroke is a brain disease that occurs when blood flow stops, resulting in reduced oxygen supply to neurons. Stroke occurs at any time and at any age, but increases after the age of 55. It is the second leading cause of death and the third leading cause of disability-adjusted, life-years. The pathophysiology of ischemic stroke is complex and recent molecular, cellular, and animal models and postmortem brain studies have revealed that multiple cellular changes have been implicated, including oxidative stress/mitochondrial dysfunction, inflammatory responses, micro RNA alterations, and marked changes in brain proteins. These cellular changes provide new information for developing therapeutic strategies for ischemic stroke treatment. Research also revealed that stroke increases with a number of modifiable factors and most strokes can be prevented and/or controlled through pharmacological or surgical interventions and lifestyle changes. Ischemic stroke is the major risk factor for vascular dementia and Alzheimer's disease. This review summarizes the latest research findings on stroke, including causal factors and molecular links between stroke and vascular disease/Alzheimer's disease.

%B J Alzheimers Dis %V 54 %P 427-43 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567871?dopt=Abstract %R 10.3233/JAD-160527 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Strong Impact of Chronic Cerebral Hypoperfusion on Neurovascular Unit, Cerebrovascular Remodeling, and Neurovascular Trophic Coupling in Alzheimer's Disease Model Mouse. %A Shang, Jingwei %A Yamashita, Toru %A Zhai, Yun %A Nakano, Yumiko %A Morihara, Ryuta %A Fukui, Yusuke %A Hishikawa, Nozomi %A Ohta, Yasuyuki %A Abe, Koji %X

Although chronic cerebral hypoperfusion (CCH) may affect Alzheimer's disease (AD) pathogenesis, the mechanism remains elusive. In the present study, we investigated the role of CCH on an AD mouse model in neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of galantamine. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral hypoperfusion. CCH exacerbated neuronal loss and decrease of α7 subunit of nicotinic acetylcholine receptors (α7-nAChRs) expression in hippocampus and thalamus at 12 months. Meanwhile, CCH greatly induced advanced glycation end products expression, and blood-brain barrier leakage through observing IgG and MMP9 expressions. Furthermore, a significant number of dramatic enlarged cerebral vessels with remodeling, BDNF/TrkB decreased in neurovascular trophic coupling. The present study demonstrated that CCH strongly enhanced primary AD pathology including neurodegeneration, neurovascular unit disruption, cerebrovascular remodeling and neurovascular trophic coupling damage in AD mice, and that galantamine treatment greatly ameliorated such neuropathologic abnormalities.

%B J Alzheimers Dis %V 52 %P 113-26 %8 2016 03 05 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060955?dopt=Abstract %R 10.3233/JAD-151126 %0 Journal Article %J J Alzheimers Dis %D 2016 %T STX, a Novel Membrane Estrogen Receptor Ligand, Protects Against Amyloid-β Toxicity. %A Gray, Nora E %A Zweig, Jonathan A %A Kawamoto, Colleen %A Quinn, Joseph F %A Copenhaver, Philip F %K Acrylamides %K Adenosine Triphosphate %K Amyloid beta-Peptides %K Animals %K Cell Death %K Cell Line, Tumor %K Drug Evaluation, Preclinical %K Estrogen Receptor Modulators %K Genes, Mitochondrial %K Hippocampus %K Humans %K Mice, Transgenic %K Mitochondria %K Neurons %K Neuroprotective Agents %X

Because STX is a selective ligand for membrane estrogen receptors, it may be able to confer the beneficial effects of estrogen without eliciting the deleterious side effects associated with activation of the nuclear estrogen receptors. This study evaluates the neuroprotective properties of STX in the context of amyloid-β (Aβ) exposure. MC65 and SH-SY5Y neuroblastoma cell lines, as well as primary hippocampal neurons from wild type (WT) and Tg2576 mice, were used to investigate the ability of STX to attenuate cell death, mitochondrial dysfunction, dendritic simplification, and synaptic loss induced by Aβ. STX prevented Aβ-induced cell death in both neuroblastoma cell lines; it also normalized the decrease in ATP and mitochondrial gene expression caused by Aβ in these cells. Notably, STX also increased ATP content and mitochondrial gene expression in control neuroblastoma cells (in the absence of Aβ). Likewise in primary neurons, STX increased ATP levels and mitochondrial gene expression in both genotypes. In addition, STX treatment enhanced dendritic arborization and spine densities in WT neurons and prevented the diminished outgrowth of dendrites caused by Aβ exposure in Tg2576 neurons. These data suggest that STX can act as an effective neuroprotective agent in the context of Aβ toxicity, improving mitochondrial function as well as dendritic growth and synaptic differentiation. In addition, since STX also improved these endpoints in the absence of Aβ, this compound may have broader therapeutic value beyond Alzheimer's disease.

%B J Alzheimers Dis %V 51 %P 391-403 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890746?dopt=Abstract %R 10.3233/JAD-150756 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Subjective Memory Complaints in APOEɛ4 Carriers are Associated with High Amyloid-β Burden. %A Zwan, Marissa D %A Villemagne, Victor L %A Doré, Vincent %A Buckley, Rachel %A Bourgeat, Pierrick %A Veljanoski, Robyn %A Salvado, Olivier %A Williams, Rob %A Margison, Laura %A Rembach, Alan %A Macaulay, S Lance %A Martins, Ralph %A Ames, David %A van der Flier, Wiesje M %A Ellis, Kathryn A %A Scheltens, Philip %A Masters, Colin L %A Rowe, Christopher C %K Aged %K Aging %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoprotein E4 %K Benzothiazoles %K Brain %K Cognition Disorders %K Female %K Genotyping Techniques %K Heterozygote %K Humans %K Logistic Models %K Male %K Neuropsychological Tests %K Positron-Emission Tomography %K Radiopharmaceuticals %K Thiazoles %X

BACKGROUND: APOEɛ4 genotype and aging have been identified as risk factors for Alzheimer's disease (AD). In addition, subjective memory complaints (SMC) might be a first clinical expression of the effect of AD pathology on cognitive functioning.

OBJECTIVE: To assess whether APOEɛ4 genotype, age, SMC, and episodic memory are risk factors for high amyloid-β (Aβ) burden in cognitively normal elderly.

METHODS: 307 cognitively normal participants (72.7 ± 6.8 years, 53% female, 55% SMC) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent amyloid PET and APOE genotyping. Logistic regression analyses were performed to determine the association of APOEɛ4 genotype, age, SMC, and episodic memory with Aβ pathology.

RESULTS: Odds of high Aβ burden were greater at an older age (OR = 3.21; 95% CI = 1.68-6.14), when SMC were present (OR = 1.90; 95% CI = 1.03-3.48), and for APOEɛ4 carriers (OR = 7.49; 95% CI = 3.96-14.15), while episodic memory was not associated with odds of high Aβ burden. Stratified analyses showed that odds of SMC for high Aβ burden were increased in specifically APOEɛ4 carriers (OR = 4.58, 95% CI = 1.83-11.49) and younger participants (OR = 3.73, 95% CI = 1.39-10.01).

CONCLUSION: Aging, APOEɛ4 genotype, and SMC were associated with high Aβ burden. SMC were especially indicative of high Aβ burden in younger participants and in APOEɛ4 carriers. These findings suggest that selection based on the presence of SMC, APOEɛ4 genotype and age may help identify healthy elderly participants with high Aβ burden eligible for secondary prevention trials.

%B J Alzheimers Dis %V 49 %P 1115-22 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639956?dopt=Abstract %R 10.3233/JAD-150446 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Synergistic Roles of the Chronic Prenatal and Offspring Stress Exposures in Impairing Offspring Learning and Memory. %A Tang, Wei %A Cheng, Juan %A Wang, Zheng-Yu %A Chen, Ke-Yang %A Han, Zhen-Min %A Wang, Qi-Hong %A Yao, Yu-You %X

In Alzheimer's disease (AD), extensive experimental studies have demonstrated a negative impact of chronic stress during various stages of life (including prenatal phase) on some aspects of AD pathology. Nevertheless, presently, few studies have been involved in the learning and memory impairments, as well as neuropathology elicited by the chronic prenatal stress (CPS) and the chronic offspring stress (COS) exposures simultaneously, particularly for the adult male APPswe/PS1dE9 murine offspring. Therefore, the aim of the present study was to investigate the influence of CPS on learning and memory impairments induced by COS in 6-month-old male APPswe/PS1dE9 offspring mice and the related mechanism. Our study firstly demonstrates that 14-day exposure to CPS could exacerbate the learning and memory impairments, as well as neuropathological damages in the CA3 regions of the hippocampus and cortex neurons, which is induced by the 28-day exposure to COS in 6-month-old male APPswe/PS1dE9 offspring mice. In addition, CPS could potentiate the production of AβPP, Aβ42, and corticosterone in 6-month-old male APPswe/PS1dE9 offspring that also suffer COS. In conclusion, our novel findings strongly implicate the synergistic roles of the CPS and COS exposures in impairing offspring learning and memory. Moreover, CPS potentiating the production of Aβ42 might be mediated by glucocorticoids through increasing the expression of APP and BACE1 gene.

%B J Alzheimers Dis %V 53 %P 221-36 %8 2016 Apr 23 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128656?dopt=Abstract %R 10.3233/JAD-160011 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Systematic Review and Meta-Analysis of On-Road Simulator and Cognitive Driving Assessment in Alzheimer's Disease and Mild Cognitive Impairment. %A Hird, Megan A %A Egeto, Peter %A Fischer, Corinne E %A Naglie, Gary %A Schweizer, Tom A %X

BACKGROUND: Many individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) are at an increased risk of driving impairment. There is a need for tools with sufficient validity to help clinicians assess driving ability.

OBJECTIVE: Provide a systematic review and meta-analysis of the primary driving assessment methods (on-road, cognitive, driving simulation assessments) in patients with MCI and AD.

METHODS: We investigated (1) the predictive utility of cognitive tests and domains, and (2) the areas and degree of driving impairment in patients with MCI and AD. Effect sizes were derived and analyzed in a random effects model.

RESULTS: Thirty-two articles (including 1,293 AD patients, 92 MCI patients, 2,040 healthy older controls) met inclusion criteria. Driving outcomes included: On-road test scores, pass/fail classifications, errors; caregiver reports; real world crash involvement; and driving simulator collisions/risky behavior. Executive function (ES [95% CI]; 0.61 [0.41, 0.81]), attention (0.55 [0.33, 0.77]), visuospatial function (0.50 [0.34, 0.65]), and global cognition (0.61 [0.39, 0.83]) emerged as significant predictors of driving performance. Trail Making Test Part B (TMT-B, 0.61 [0.28, 0.94]), TMT-A (0.65 [0.08, 1.21]), and Maze test (0.88 [0.60, 1.15]) emerged as the best single predictors of driving performance. Patients with very mild AD (CDR = 0.5) mild AD (CDR = 1) were more likely to fail an on-road test than healthy control drivers (CDR = 0), with failure rates of 13.6%, 33.3% and 1.6%, respectively.

CONCLUSION: The driving ability of patients with MCI and AD appears to be related to degree of cognitive impairment. Across studies, there are inconsistent cognitive predictors and reported driving outcomes in MCI and AD patients. Future large-scale studies should investigate the driving performance and associated neural networks of subgroups of AD (very mild, mild, moderate) and MCI (amnestic, non-amnestic, single-domain, multiple-domain).

%B J Alzheimers Dis %V 53 %P 713-29 %8 2016 May 11 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27176076?dopt=Abstract %R 10.3233/JAD-160276 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Systematic Review and Meta-Analysis of the Association between Helicobacterpylori Infection and Dementia. %A Shindler-Itskovitch, Tali %A Ravona-Springer, Ramit %A Leibovitz, Arthur %A Muhsen, Khitam %X

BACKGROUND: A positive association between Helicobacter pylori infection and dementia has been reported, yet findings are inconsistent.

OBJECTIVE: To examine the association between H. pylori infection and dementia.

METHODS: A literature search was performed using the databases OVID-Medline, Institute of Scientific Information Web of Science, and EMBASE. The meta-analysis was conducted using the random effects model. The primary analysis included studies in which the exposure variable was presence of H. pylori infection (yes versus no) and the outcome was incident dementia (yes versus no), which was pre-selected as the end-result of gradual cognitive decline overtime. Publication bias was explored using funnel plot and the Egger regression intercept.

RESULTS: A total of 260 records were identified; 13 addressed cognition and/or dementia in relation to H. pylori infection, of which only seven were included in the meta-analysis. The primary analysis showed a significant positive association between H. pylori infection and dementia; pooled odds ratio 1.71 (95% CI 1.17-2.49) (pv = 0.01). No significant evidence of publication bias was found.

CONCLUSIONS: H. pylori may play a role in the etiology of dementia. Identification of the biological mechanisms of such association is needed, as well as assessment of the impact of H. pylori therapy on the risk and progression of dementia.

%B J Alzheimers Dis %V 52 %P 1431-42 %8 2016 Apr 15 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079725?dopt=Abstract %R 10.3233/JAD-160132 %0 Journal Article %J J Alzheimers Dis %D 2016 %T T3D-959: A Multi-Faceted Disease Remedial Drug Candidate for the Treatment of Alzheimer's Disease. %A Tong, Ming %A Deochand, Chetram %A Didsbury, John %A de la Monte, Suzanne M %K Alzheimer Disease %K Analysis of Variance %K Animals %K Animals, Newborn %K Antibiotics, Antineoplastic %K Antipsychotic Agents %K Blood Glucose %K Body Weight %K Brain %K Choline O-Acetyltransferase %K Disease Models, Animal %K Dose-Response Relationship, Drug %K Glial Fibrillary Acidic Protein %K Glucosephosphate Dehydrogenase %K In Vitro Techniques %K Maze Learning %K Myelin Basic Protein %K Neurotoxicity Syndromes %K Organ Culture Techniques %K PPAR delta %K PPAR gamma %K Rats %K Rats, Long-Evans %K Spatial Learning %K Streptozocin %X

BACKGROUND: T3D-959, a dual PPAR-δ/PPAR γ nuclear receptor agonist and former diabetes drug candidate, has been repositioned as an Alzheimer's disease (AD)-modifying therapy.

OBJECTIVE: This study examines the effectiveness and mechanisms of T3D-959's therapeutic effects using in vivo and ex vivo rat models of sporadic AD.

METHODS: A sporadic AD model was generated by intracerebral (i.c.) administration of streptozotocin (STZ). Control and i.c. STZ treated rats were gavaged with saline or T3D-959 (0.3 to 3.0 mg/kg/day) for 28 days. Spatial learning and memory were evaluated using the Morris water maze test. Frontal lobe slice cultures generated 24 hours after i.c. STZ or vehicle were used to study early effects of T3D-959 (0.5-1.0 μM) on viability and molecular markers of AD.

RESULTS: T3D-959 significantly improved spatial learning and memory in i.c STZ-treated rats. Mechanistically, T3D-959 significantly improved culture viability and brain morphology, reduced levels of oxidative stress and Aβ, and normalized expression of phospho-tau, choline acetyltransferase, and myelin-associated glycoprotein. Protective effects occurred even at the lowest tested dose of T3D-959.

CONCLUSIONS: Pre-clinical proof of concept has been demonstrated that T3D-959 can improve multiple pathologies of AD resulting in significant improvements in cognitive function and molecular and biochemical indices of neurodegeneration. These results support the theses that (1) effective disease modification in AD can be achieved by targeting relevant nuclear receptors, and (2) treating AD as a metabolic disease has the potential to be disease remedial. A Phase 2a trial of T3D-959 in mild-to-moderate AD patients has been initiated (ClinicalTrials.gov identifier NCT02560753).

%B J Alzheimers Dis %V 51 %P 123-38 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836193?dopt=Abstract %R 10.3233/JAD-151013 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Targretin Improves Cognitive and Biological Markers in a Patient with Alzheimer's Disease. %A Pierrot, Nathalie %A Lhommel, Renaud %A Quenon, Lisa %A Hanseeuw, Bernard %A Dricot, Laurence %A Sindic, Christian %A Maloteaux, Jean-Marie %A Octavea, Jean-Noël %A Ivanoiu, Adrian %K Aged %K Alzheimer Disease %K Amyloidogenic Proteins %K Biomarkers %K Cognition Disorders %K Humans %K Male %K Mental Recall %K Neuropsychological Tests %K Receptors, Retinoic Acid %K tau Proteins %K Tetrahydronaphthalenes %X

We present the effects of Targretin® (bexarotene) on cognition and biomarkers in a patient with mild Alzheimer's disease (AD). Targretin® is a Retinoic X Receptor (RXR) agonist shown to improve synaptic and cognitive functions in animal models of AD by increasing neuronal cholesterol efflux. After 6 months of treatment with Targretin® 300 mg/day, memory improved by about 40% and the tau protein in the cerebrospinal fluid decreased by about 20% . No significant side effects were noticed. This observation in a single patient indicates that Targretin® may improve memory performance and biological markers at an early stage of AD.

%B J Alzheimers Dis %V 49 %P 271-6 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444777?dopt=Abstract %R 10.3233/JAD-150405 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Tau Accumulation in Primary Motor Cortex of Variant Alzheimer's Disease with Spastic Paraparesis. %A Lyoo, Chul Hyoung %A Cho, Hanna %A Choi, Jae Yong %A Hwang, Mi Song %A Hong, Sang Kyoon %A Kim, Yun Joong %A Ryu, Young Hoon %A Lee, Myung Sik %K Adult %K Aged %K Alzheimer Disease %K Aniline Compounds %K Brain Mapping %K Carbolines %K Female %K Humans %K Male %K Motor Cortex %K Mutation, Missense %K Paraparesis, Spastic %K Positron-Emission Tomography %K Presenilin-1 %K Radiopharmaceuticals %K Stilbenes %K tau Proteins %X

We studied topographic distribution of tau and amyloid-β in a patient with variant Alzheimer's disease with spastic paraparesis (VarAD) by comparing AD patients. The proband developed progressive memory impairment, dysarthria, and spastic paraparesis at age 23. Heterozygous missense mutation (L166P) was found in exon 6 of presenilin-1 gene. The proband showed prominently increased amyloid binding in striatum and cerebellum and asymmetrical tau binding in the primary sensorimotor cortex contralateral to the side more affected by spasticity. We suspect that upper motor neuron dysfunctions may be attributed to excessive abnormal tau accumulation rather than amyloid-β in the primary motor cortex.

%B J Alzheimers Dis %V 51 %P 671-5 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890779?dopt=Abstract %R 10.3233/JAD-151052 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Tau in Late-Life Depression: A Systematic Review and Meta-Analysis. %A Brown, Eric E %A Iwata, Yusuke %A Chung, Jun Ku %A Gerretsen, Philip %A Graff-Guerrero, Ariel %X

A lifetime history of major depressive disorder (MDD) increases the risk of developing Alzheimer's disease, of which neurofibrillary tangles due to abnormal tau proteins are a hallmark. We systematically reviewed the literature on tau in MDD and identified 49 relevant articles spanning a number of modalities, including cerebrospinal fluid (CSF) analysis, positron emission tomography, and clinicopathological correlation. We compared CSF total and phosphorylated tau proteins in MDD and controls using a meta-analytic approach. We found no difference in total or phosphorylated tau in MDD. We also found no difference in a comparison of a subgroup excluding studies with significant age differences. Positron emission tomography studies lacked specificity. Clinicopathological studies failed to associate neurofibrillary tangles with MDD. The available data on tau in MDD is limited. The involvement of tau in a subset of MDD cannot be ruled out and requires prospective exploration.

%B J Alzheimers Dis %V 54 %P 615-33 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497481?dopt=Abstract %R 10.3233/JAD-160401 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A TgCRND8 Mouse Model of Alzheimer's Disease Exhibits Sexual Dimorphisms in Behavioral Indices of Cognitive Reserve. %A Granger, Matthew W %A Franko, Bettina %A Taylor, Matthew W %A Messier, Claude %A George-Hyslop, Peter St %A Bennett, Steffany A L %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Brain %K Cognitive Reserve %K Cyclic Nucleotide Phosphodiesterases, Type 6 %K Disease Models, Animal %K Female %K Humans %K Male %K Maze Learning %K Mice, Inbred C3H %K Mice, Inbred C57BL %K Mice, Transgenic %K Plaque, Amyloid %K Psychomotor Performance %K Sex Characteristics %K Spatial Memory %K Spatial Navigation %K Survival Analysis %X

Cognitive decline is sexually dimorphic in Alzheimer's disease (AD). Men show higher incidences of amnestic mild cognitive impairment yet women disproportionally phenoconvert to AD. It is hypothesized that men maintain greater cognitive reserve than women under comparable amyloid-β (Aβ) challenge. One behavioral aspect of cognitive reserve in mice is the capacity to cope with Aβ-associated stereotypies by switching to increasingly effective navigational search strategies in the Morris water maze. To explore inherent sex differences in this paradigm, however, we require an AβPP mouse model wherein behavioral flexibility is impaired earlier in females than males despite equivalent Aβ load. Here, we show that when F1 C57Bl/6×C3H/HeJ TgCRND8 mice are placed on C57Bl/6 background, N5 Tg males and females exhibit equivalent Aβ pathologies at 2, 4, 6, and 8 months of age yet females display learning and memory deficits earlier than males. We further show that this N5 line does not carry the autosomal recessive pde6brd1 mutation that impairs visual acuity and that the estrous cycle is not disrupted on this genetic background. At 5.5 months of age, Tg males, but not females, compensate for Aβ-associated stereotypic behaviors (i.e., hyperactive tight circling) by alternating navigational search strategies and adopting increasingly productive spatial search strategies. Females fail to overcome Aβ-associated stereotypies and do not efficiently switch from systematic to spatial learning strategies. Together, these data identify a novel AβPP mouse model that can be used for preclinical testing of interventions targeting sexual dimorphisms in behavioral indices of cognitive reserve.

%B J Alzheimers Dis %V 51 %P 757-73 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890738?dopt=Abstract %R 10.3233/JAD-150587 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Theoretical Analysis of the Synergy of Amyloid and Tau in Alzheimer's Disease. %A Han, Pengcheng %A Shi, Jiong %X

Amyloid plaques and Tau protein neurofibrillary tangles are considered the two most important pathogenic factors in Alzheimer's disease. The prevailing amyloid cascade hypothesis suggests that amyloid-β (Aβ) elevation induces downstream Tau hyperphosphorylation and aggregation, synaptic dysfunction, and neuronal loss that ultimately results in cognitive impairment. Alternatively, the dual-pathway hypothesis suggests that Aβ and abnormal Tau are two independent factors that exert synergistic effects on synaptic dysfunction and neuronal loss. We hypothesize that the intrinsic interaction of Aβ and Tau would better predict cognitive impairment. Herein, we propose an Aβ-Tau interactive model based on a review of the medical literature, mathematic modeling, and analysis of our clinicopathological data.

%B J Alzheimers Dis %V 52 %P 1461-70 %8 2016 Apr 19 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104897?dopt=Abstract %R 10.3233/JAD-151206 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Three-Dimensional Eigenbrain for the Detection of Subjects and Brain Regions Related with Alzheimer's Disease. %A Zhang, Yudong %A Wang, Shuihua %A Phillips, Preetha %A Yang, Jiquan %A Yuan, Ti-Fei %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Datasets as Topic %K Early Diagnosis %K Female %K Humans %K Image Interpretation, Computer-Assisted %K Imaging, Three-Dimensional %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Sensitivity and Specificity %K Young Adult %X

BACKGROUND: Considering that Alzheimer's disease (AD) is untreatable, early diagnosis of AD from the healthy elderly controls (HC) is pivotal. However, computer-aided diagnosis (CAD) systems were not widely used due to its poor performance.

OBJECTIVE: Inspired from the eigenface approach for face recognition problems, we proposed an eigenbrain to detect AD brains. Eigenface is only for 2D image processing and is not suitable for volumetric image processing since faces are usually obtained as 2D images.

METHODS: We extended the eigenbrain to 3D. This 3D eigenbrain (3D-EB) inherits the fundamental strategies in either eigenface or 2D eigenbrain (2D-EB). All the 3D brains were transferred to a feature space, which encoded the variation among known 3D brain images. The feature space was named as the 3D-EB, and defined as eigenvectors on the set of 3D brains. We compared four different classifiers: feed-forward neural network, support vector machine (SVM) with linear kernel, polynomial (Pol) kernel, and radial basis function kernel.

RESULTS: The 50x10-fold stratified cross validation experiments showed that the proposed 3D-EB is better than the 2D-EB. SVM with Pol kernel performed the best among all classifiers. Our "3D-EB + Pol-SVM" achieved an accuracy of 92.81% ± 1.99% , a sensitivity of 92.07% ± 2.48% , a specificity of 93.02% ± 2.22% , and a precision of 79.03% ± 2.37% . Based on the most important 3D-EB U1, we detected 34 brain regions related with AD. The results corresponded to recent literature.

CONCLUSIONS: We validated the effectiveness of the proposed 3D-EB by detecting subjects and brain regions related to AD.

%B J Alzheimers Dis %V 50 %P 1163-79 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836190?dopt=Abstract %R 10.3233/JAD-150988 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Thyroid-Stimulating Hormone and Mild Cognitive Impairment: Results of the Heinz Nixdorf Recall Study. %A Winkler, Angela %A Weimar, Christian %A Jöckel, Karl-Heinz %A Erbel, Raimund %A Dragano, Nico %A Broecker-Preuss, Martina %A Moebus, Susanne %A Führer-Sakel, Dagmar %A Dlugaj, Martha %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Follow-Up Studies %K Humans %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Risk Factors %K Sex Characteristics %K Statistics, Nonparametric %K Thyrotropin %X

BACKGROUND: Although some studies reported on the association of serum thyroid-stimulating hormone (TSH) concentration and cognition, only one population-based study investigated the association of TSH concentration and mild cognitive impairment (MCI).

OBJECTIVE: To investigate the gender-specific association of low- and high-normal TSH concentrations with MCI in euthyroid participants.

METHODS: Analysis sample 1 included 2,563 euthyroid participants (aged 50-80 years) from the second examination of the population-based Heinz Nixdorf Recall study. Gender-specific TSH quintiles (Q1 low, Q2-Q4 middle, Q5 high TSH concentration) were determined and group comparisons of age- and education-adjusted mean scores were performed for all cognitive subtests. Analysis sample 2 included 378 participants with MCI and 931 cognitively normal participants. MCI was diagnosed according to previously published MCI criteria. Multivariate logistic regression models were performed using TSH quintiles (Q2-Q4 as reference) to assess the association of low- and high-normal TSH concentration with MCI. Models were performed unadjusted and adjusted for sociodemographic and cardiovascular risk factors.

RESULTS: Group comparisons showed significant differences only in the immediate recall of the verbal memory task in women. Only women showed a strong association of high-normal TSH concentration with MCI (unadjusted: odds ratio 2.09, 95% confidence interval 1.29-3.37, full adjusted: 1.86, 1.06-3.27). There was no association with low-normal TSH concentration in women and no association of either low- or high-normal TSH concentration with MCI in men.

CONCLUSIONS: These results suggest that women with high-normal TSH concentration might be at higher risk of cognitive decline. This needs to be confirmed in the longitudinal analysis.

%B J Alzheimers Dis %V 49 %P 797-807 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519440?dopt=Abstract %R 10.3233/JAD-150561 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Time Orientation and 10 Years Risk of Dementia in Elderly Adults: The Three-City Study. %A Dumurgier, Julien %A Dartigues, Jean-François %A Gabelle, Audrey %A Paquet, Claire %A Prevot, Magali %A Hugon, Jacques %A Tzourio, Christophe %X

Time disorientation is commonly observed in dementia, however very little is known about the pathological significance of minor time errors in community-dwelling population. Our objective was to investigate the relationship between time orientation and risk of dementia in a population of older adults. Analyses relies on 8611 dementia-free subjects from the Three-City Study, France. Participants were followed up for 10 years for incident dementia. Time orientation was assessed by asking for the date, the day of the week, the month, the season and the year. At baseline, 905 subjects made at least one error in time orientation. During 57,073 person-years of follow-up, 827 participants developed dementia. After controlling for age, gender and education level, subjects with one error in time had a greater risk of dementia (hazard ratio [HR] 1.44 [1.18-1.77]), while those with at least 2 errors had a more than three-fold increased risk (HR 3.10 [1.98-4.83]). This association was particularly marked for the diagnosis of probable Alzheimer's disease. Time disorientation was associated with an increased risk of dementia in a large population of cognitively normal older people followed during up to 10 years and should not be underestimated in clinical setting.

%B J Alzheimers Dis %V 53 %P 1411-8 %8 2016 Jul 01 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392864?dopt=Abstract %R 10.3233/JAD-160295 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Time trends in antipsychotic drug use in patients with dementia: a nationwide study. %A Nørgaard, Ane %A Jensen-Dahm, Christina %A Gasse, Christiane %A Hansen, Hanne Vibe %A Waldemar, Gunhild %K Aged %K Aged, 80 and over %K Anti-Anxiety Agents %K Antidepressive Agents %K Antipsychotic Agents %K Dementia %K Denmark %K Drug Prescriptions %K Female %K Homes for the Aged %K Humans %K Hypnotics and Sedatives %K Longitudinal Studies %K Male %K Multivariate Analysis %K Nursing Homes %K Registries %X

BACKGROUND: Antipsychotics are often used to treat neuropsychiatric symptoms in dementia, but the evidence for effect is limited. Antipsychotics have been associated with increased risk of adverse events and mortality in patients with dementia, leading to safety regulations worldwide.

OBJECTIVE: To investigate time trends in use of antipsychotics and other psychotropic drugs in dementia care.

METHODS: The study included longitudinal data on all Danish residents ≥65 years. The study population was defined on January 1 of each year from 2000-2012. Data included prescriptions, discharge diagnoses, and somatic and psychiatric comorbidities. Multivariate time trend analyses of psychotropic drug use in patients with dementia within 4-year age bands were performed.

RESULTS: Overall, among patients with dementia the prevalence of antipsychotic drug use decreased from 31.3% in 2000 to 20.4% in 2012. The decreasing use of antipsychotics was accompanied by decreasing use of anxiolytics and hypnotics/sedatives, but an increase in the use of antidepressants from 43.3% in 2000 to 53.8% in 2012. These changes were significant across almost all age groups. Treatment intensity among patients using antipsychotics increased as the annual median number of defined daily doses (DDD) increased from 33.3 to 42.0 DDD.

CONCLUSIONS: The changing patterns of psychotropic drug use may be caused by warnings against use of antipsychotics. Further research is needed to explore the implications for patient safety.

%B J Alzheimers Dis %V 49 %P 211-20 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444790?dopt=Abstract %R 10.3233/JAD-150481 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Timely Diagnosis for Alzheimer's Disease: A Literature Review on Benefits and Challenges. %A Dubois, Bruno %A Padovani, Alessandro %A Scheltens, Philip %A Rossi, Andrea %A Dell'Agnello, Grazia %K Alzheimer Disease %K Databases, Bibliographic %K Humans %K Time Factors %X

BACKGROUND: Timely diagnosis of Alzheimer's disease (AD) refers to a diagnosis at the stage when patients come to the attention of clinicians because of concerns about changes in cognition, behavior, or functioning and can be still free of dementia and functionally independent.

OBJECTIVES: To comprehensively review existing scientific evidence on the benefits and potential challenges of making a timely diagnosis of AD.

METHODS: Relevant studies were identified by searching electronic databases (Medline, Embase) and bibliographies for studies published in English between 1 January 2000 and 2 June 2014 on the consequences of a timely diagnosis of AD.

RESULTS: Nine studies were identified that investigated the consequences of diagnosing AD at the initial stages; none were specifically focused on prodromal AD. A timely diagnosis potentially offers the opportunities of early intervention, implementation of coordinated care plans, better management of symptoms, patient safety, cost savings, and postponement of institutionalization. Barriers to making a timely diagnosis include stigma, suicide risk, lack of training, diagnostic uncertainty, shortage of specialized diagnostic services, and the reluctance of healthcare providers to make a diagnosis when no effective disease-modifying options are available.

CONCLUSIONS: Despite its potential benefits, few published studies have explored the advantages or risks of a timely diagnosis of AD. In light of the cultural shift toward diagnosis at the initial stage of the disease continuum, when the patient does not yet have dementia, more investigations are needed to evaluate the benefits and address the barriers that may impede making a timely AD diagnosis.

%B J Alzheimers Dis %V 49 %P 617-31 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484931?dopt=Abstract %R 10.3233/JAD-150692 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration. %A Deochand, Chetram %A Tong, Ming %A Agarwal, Amit R %A Cadenas, Enrique %A de la Monte, Suzanne M %K Animals %K Brain %K Insulin %K Male %K Mice %K Nerve Degeneration %K Neurons %K Phosphorylation %K Receptor, IGF Type 1 %K Signal Transduction %K Somatomedins %K Tobacco Smoke Pollution %X

BACKGROUND: Human studies suggest tobacco smoking is a risk factor for cognitive impairment and neurodegeneration, including Alzheimer's disease (AD). However, experimental data linking tobacco smoke exposures to underlying mediators of neurodegeneration, including impairments in brain insulin and insulin-like growth factor (IGF) signaling in AD are lacking.

OBJECTIVE: This study tests the hypothesis that cigarette smoke (CS) exposures can impair brain insulin/IGF signaling and alter expression of AD-associated proteins.

METHODS: Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 or 8 weeks (CS4, CS8), or CS8 followed by 2 weeks recovery (CS8+R). Gene expression was measured by qRT-PCR analysis and proteins were measured by multiplex bead-based or direct binding duplex ELISAs.

RESULTS: CS exposure effects on insulin/IGF and insulin receptor substrate (IRS) proteins and phosphorylated proteins were striking compared with the mRNA. The main consequences of CS4 or CS8 exposures were to significantly reduce insulin R, IGF-1R, IRS-1, and tyrosine phosphorylated insulin R and IGF-1R proteins. Paradoxically, these effects were even greater in the CS8+R group. In addition, relative levels of S312-IRS-1, which inhibits downstream signaling, were increased in the CS4, CS8, and CS8+R groups. Correspondingly, CS and CS8+R exposures inhibited expression of proteins and phosphoproteins required for signaling through Akt, PRAS40, and/or p70S6K, increased AβPP-Aβ, and reduced ASPH protein, which is a target of insulin/IGF-1 signaling.

CONCLUSION: Secondhand CS exposures caused molecular and biochemical abnormalities in brain that overlap with the findings in AD, and many of these effects were sustained or worsened despite short-term CS withdrawal.

%B J Alzheimers Dis %V 50 %P 373-86 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682684?dopt=Abstract %R 10.3233/JAD-150664 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Tobacco Smoke-Induced Brain White Matter Myelin Dysfunction: Potential Co-Factor Role of Smoking in Neurodegeneration. %A Yu, Rosa %A Deochand, Chetram %A Krotow, Alexander %A Leão, Raiane %A Tong, Ming %A Agarwal, Amit R %A Cadenas, Enrique %A de la Monte, Suzanne M %K 2',3'-Cyclic-Nucleotide Phosphodiesterases %K AC133 Antigen %K Animals %K Antigens, CD %K Brain %K Disease Models, Animal %K Galactosylceramides %K Gene Expression Regulation %K Glycoproteins %K Leukoencephalopathies %K Male %K Mice %K Nerve Degeneration %K Nerve Tissue Proteins %K Neuroglia %K Neurons %K Oligodendroglia %K Papain %K Peptides %K Smoking %K Tobacco %K Transcription Factors %X

BACKGROUND: Meta-analysis studies showed that smokers have increased risk for developing Alzheimer's disease (AD) compared with non-smokers, and neuroimaging studies revealed that smoking damages white matter structural integrity.

OBJECTIVE: The present study characterizes the effects of side-stream (second hand) cigarette smoke (CS) exposures on the expression of genes that regulate oligodendrocyte myelin-synthesis, maturation, and maintenance and neuroglial functions.

METHODS: Adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). The frontal lobes were used for histology and qRT-PCR analysis.

RESULTS: Luxol fast blue, Hematoxylin and Eosin stained histological sections revealed CS-associated reductions in myelin staining intensity and narrowing of the corpus callosum. CS exposures broadly decreased mRNA levels of immature and mature oligodendrocyte myelin-associated, neuroglial, and oligodendrocyte-related transcription factors. These effects were more prominent in the CS8 compared with CS4 group, suggesting that molecular abnormalities linked to white matter atrophy and myelin loss worsen with duration of CS exposure. Recovery normalized or upregulated less than 25% of the suppressed genes; in most cases, inhibition of gene expression was either sustained or exacerbated.

CONCLUSION: CS exposures broadly inhibit expression of genes needed for myelin synthesis and maintenance. These adverse effects often were not reversed by short-term CS withdrawal. The results support the hypothesis that smoking contributes to white matter degeneration, and therefore could be a key risk factor for a number of neurodegenerative diseases, including AD.

%B J Alzheimers Dis %V 50 %P 133-48 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639972?dopt=Abstract %R 10.3233/JAD-150751 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Topographical APOE ɛ4 Genotype Influence on Cerebral Metabolism in the Continuum of Alzheimer's Disease: Amyloid Burden Adjusted Analysis. %A Seo, Eun Hyun %A Kim, Sang Hoon %A Park, Sang Hag %A Kang, Seong-Ho %A Choo, Il Han %X

BACKGROUND: APOE ɛ4 contributes to Alzheimer's disease (AD) pathogenesis by amyloid-beta (Aβ)-dependent and Aβ-independent processes.

OBJECTIVE: We investigated the APOE ɛ4 influence on regional cerebral glucose metabolism (rCMglc) in the continuum of AD after Aβ adjustment.

METHODS: We included 318 cognitively normal (CN) elderly, 498 mild cognitive impairment (MCI), and 178 AD from the Alzheimer's Disease Neuroimaging Initiative database. They had [18F] florbetapir positron emission tomography (PET) and [18F] fluorodeoxyglucose (FDG)-PET conducted within 3 months of a clinical and cognitive assessment visit and APOE genotype. At first, the rCMglc differences between APOE ɛ4 carriers (ɛ4+) and non-carriers (ɛ4-) were estimated on a voxel-based analysis using a 'two-sample t-test' design. In the second analysis, Aβ was added as covariate.

RESULTS: In CN, ɛ4+ showed reduced rCMglc compared to ɛ4-in the bilateral frontal, temporal, and the left parietal regions. In MCI, ɛ4+ showed reduced rCMglc compared to ɛ4- in the bilateral posterior parietal, temporal, and left frontal regions. In AD, ɛ4+ showed reduced rCMglc in the left hippocampus, right insular, and right temporal gyrus. However, after Aβ adjustment, the significant differences in the temporal regions were absent in CN and MCI, and none of the areas detected as significant in the first analysis were statistically significant in AD.

CONCLUSIONS: Our study demonstrated that Aβ-independent APOE ɛ4 influence on rCMglc is limited to the parietal and frontal, but not temporal lobes. These results suggest that APOE ɛ4 may predispose for regional vulnerability according to Aβ-independent and Aβ-dependent processes.

%B J Alzheimers Dis %V 54 %P 559-68 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567846?dopt=Abstract %R 10.3233/JAD-160395 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Topographical Information-Based High-Order Functional Connectivity and Its Application in Abnormality Detection for Mild Cognitive Impairment. %A Zhang, Han %A Chen, Xiaobo %A Shi, Feng %A Li, Gang %A Kim, Minjeong %A Giannakopoulos, Panteleimon %A Haller, Sven %A Shen, Dinggang %X

Temporal synchronization-based functional connectivity (FC) has long been used by the neuroscience community. However, topographical FC information may provide additional information to characterize the advanced relationship between two brain regions. Accordingly, we proposed a novel method, namely high-order functional connectivity (HOFC), to capture this second-level relationship using inter-regional resemblance of the FC topographical profiles. Specifically, HOFC first calculates an FC profile for each brain region, notably between the given brain region and other brain regions. Based on these FC profiles, a second layer of correlations is computed between all pairs of brain regions (i.e., correlation's correlation). On this basis, we generated an HOFC network, where "high-order" network properties were computed. We found that HOFC was discordant with the traditional FC in several links, indicating additional information being revealed by the new metrics. We applied HOFC to identify biomarkers for early detection of Alzheimer's disease by comparing 77 mild cognitive impairment patients with 89 healthy individuals (control group). Sensitivity in detection of group difference was consistently improved by ∼25% using HOFC compared to using FC. An HOFC network analysis also provided complementary information to an FC network analysis. For example, HOFC between olfactory and orbitofrontal cortices was found significantly reduced in patients, besides extensive alterations in HOFC network properties. In conclusion, our results showed promise in using HOFC to comprehensively map the human brain connectome.

%B J Alzheimers Dis %V 54 %P 1095-1112 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567817?dopt=Abstract %R 10.3233/JAD-160092 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Towards a Pathway Inventory of the Human Brain for Modeling Disease Mechanisms Underlying Neurodegeneration. %A Iyappan, Anandhi %A Gündel, Michaela %A Shahid, Mohammad %A Wang, Jiali %A Li, Hui %A Mevissen, Heinz-Theodor %A Müller, Bernd %A Fluck, Juliane %A Jirsa, Viktor %A Domide, Lia %A Younesi, Erfan %A Hofmann-Apitius, Martin %X

Molecular signaling pathways have been long used to demonstrate interactions among upstream causal molecules and downstream biological effects. They show the signal flow between cell compartments, the majority of which are represented as cartoons. These are often drawn manually by scanning through the literature, which is time-consuming, static, and non-interoperable. Moreover, these pathways are often devoid of context (condition and tissue) and biased toward certain disease conditions. Mining the scientific literature creates new possibilities to retrieve pathway information at higher contextual resolution and specificity. To address this challenge, we have created a pathway terminology system by combining signaling pathways and biological events to ensure a broad coverage of the entire pathway knowledge domain. This terminology was applied to mining biomedical papers and patents about neurodegenerative diseases with focus on Alzheimer's disease. We demonstrate the power of our approach by mapping literature-derived signaling pathways onto their corresponding anatomical regions in the human brain under healthy and Alzheimer's disease states. We demonstrate how this knowledge resource can be used to identify a putative mechanism explaining the mode-of-action of the approved drug Rasagiline, and show how this resource can be used for fingerprinting patents to support the discovery of pathway knowledge for Alzheimer's disease. Finally, we propose that based on next-generation cause-and-effect pathway models, a dedicated inventory of computer-processable pathway models specific to neurodegenerative diseases can be established, which hopefully accelerates context-specific enrichment analysis of experimental data with higher resolution and richer annotations.

%B J Alzheimers Dis %V 52 %P 1343-60 %8 2016 Apr 12 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079715?dopt=Abstract %R 10.3233/JAD-151178 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Tract-Specific Correlates of Neuropsychological Deficits in Patients with Subcortical Vascular Cognitive Impairment. %A Jung, Na-Yeon %A Han, Cheol E %A Kim, Hee Jin %A Yoo, Sang Wook %A Kim, Hee-Jong %A Kim, Eun-Joo %A Na, Duk L %A Lockhart, Samuel N %A Jagust, William J %A Seong, Joon-Kyung %A Seo, Sang Won %K Aged %K Brain %K Cerebrovascular Disorders %K Cognitive Dysfunction %K Diffusion Magnetic Resonance Imaging %K Diffusion Tensor Imaging %K Female %K Gray Matter %K Humans %K Male %K Neural Pathways %K Neuropsychological Tests %K White Matter %X

The white matter tract-specific correlates of neuropsychological deficits are not fully established in patients with subcortical vascular cognitive impairment (SVCI), where white matter tract damage may be a critical factor in cognitive impairment. The purpose of this study is to investigate the tract-specific correlates of neuropsychological deficits in SVCI patients using tract-specific statistical analysis (TSSA). We prospectively recruited 114 SVCI patients, and 55 age-, gender-, and education-matched individuals with normal cognition (NC). All participants underwent diffusion weighted imaging and neuropsychological testing. We classified tractography results into fourteen major fiber tracts and analyzed group comparison and correlation with cognitive impairments. Relative to NC subjects, SVCI patients showed decreased fractional anisotropy values in bilateral anterior-thalamic radiation, cingulum, superior-longitudinal fasciculus, uncinate fasciculus, corticospinal tract, and left inferior-longitudinal fasciculus. Focal disruptions in specific tracts were associated with specific cognitive impairments. Our findings suggest that disconnection of specific white matter tracts, especially those neighboring and providing connections between gray matter regions important to certain cognitive functions, may contribute to specific cognitive impairments in SVCI.

%B J Alzheimers Dis %V 50 %P 1125-35 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836179?dopt=Abstract %R 10.3233/JAD-150841 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Transcriptional Analysis of Blood Lymphocytes and Skin Fibroblasts, Keratinocytes, and Endothelial Cells as a Potential Biomarker for Alzheimer's Disease. %A Mukhamedyarov, Marat A %A Rizvanov, Albert A %A Yakupov, Eduard Z %A Zefirov, Andrey L %A Kiyasov, Andrey P %A Reis, Helton J %A Teixeira, Antônio L %A Vieira, Luciene B %A Lima, Luciana M %A Salafutdinov, Ilnur I %A Petukhova, Elena O %A Khaiboullina, Svetlana F %A Schlauch, Karen A %A Lombardi, Vincent C %A Palotás, András %X

Alzheimer's disease (AD) is a devastating and progressive form of dementia that is typically associated with a build-up of amyloid-β plaques and hyperphosphorylated and misfolded tau protein in the brain. Presently, there is no single test that confirms AD; therefore, a definitive diagnosis is only made after a comprehensive medical evaluation, which includes medical history, cognitive tests, and a neurological examination and/or brain imaging. Additionally, the protracted prodromal phase of the disease makes selection of control subjects for clinical trials challenging. In this study we have utilized a gene-expression array to screen blood and skin punch biopsy (fibroblasts, keratinocytes, and endothelial cells) for transcriptional differences that may lead to a greater understanding of AD as well as identify potential biomarkers. Our analysis identified 129 differentially expressed genes from blood of dementia cases when compared to healthy individuals, and four differentially expressed punch biopsy genes between AD subjects and controls. Additionally, we identified a set of genes in both tissue compartments that showed transcriptional variation in AD but were largely stable in controls. The translational products of these variable genes are involved in the maintenance of the Golgi structure, regulation of lipid metabolism, DNA repair, and chromatin remodeling. Our analysis potentially identifies specific genes in both tissue compartments that may ultimately lead to useful biomarkers and may provide new insight into the pathophysiology of AD.

%B J Alzheimers Dis %V 54 %P 1373-1383 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589530?dopt=Abstract %R 10.3233/JAD-160457 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Transferring cut-off values between assays for cerebrospinal fluid Alzheimer's disease biomarkers. %A García Barrado, Leandro %A Coart, Els %A Vanderstichele, Hugo M J %A Burzykowski, Tomasz %K Alzheimer Disease %K Amyloid beta-Peptides %K Bayes Theorem %K Biomarkers %K Cognitive Dysfunction %K Datasets as Topic %K Humans %K Linear Models %K Multivariate Analysis %K Peptide Fragments %K tau Proteins %X

Current technologies quantifying cerebrospinal fluid biomarkers to identify subjects with Alzheimer's disease pathology report different concentrations in function of technology and suffer from between-laboratory variability. Hence, lab- and technology-specific cut-off values are required. It is common practice to establish cut-off values on small datasets and, in the absence of well-characterized samples, to transfer the cut-offs to another assay format using 'side-by-side' testing of samples with both assays. We evaluated the uncertainty in cut-off estimation and the performance of two methods of cut-off transfer by using two clinical datasets and simulated data. The cut-off for the new assay was transferred by applying the commonly-used linear regression approach and a new Bayesian method, which consists of using prior information about the current assay for estimation of the biomarker's distributions for the new assay. Simulations show that cut-offs established with current sample sizes are insufficiently precise and also show the effect of increasing sample sizes on the cut-offs' precision. The Bayesian method results in unbiased and less variable cut-offs with substantially narrower 95% confidence intervals compared to the linear-regression transfer. For the BIODEM datasets, the transferred cut-offs for INNO-BIA Aβ1-42 are 167.5 pg/mL (95% credible interval [156.1, 178.0] and 172.8 pg/mL (95% CI [147.6, 179.6]) with Bayesian and linear regression methods, respectively. For the EUROIMMUN assay, the estimated cut-offs are 402.8 pg/mL (95% credible interval [348.0, 473.9]) and 364.4 pg/mL (95% CI [269.7, 426.8]). Sample sizes and statistical methods used to establish and transfer cut-off values have to be carefully considered to guarantee optimal diagnostic performance of biomarkers.

%B J Alzheimers Dis %V 49 %P 187-99 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484919?dopt=Abstract %R 10.3233/JAD-150511 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Transthyretin Suppresses Amyloid-β Secretion by Interfering with Processing of the Amyloid-β Protein Precursor. %A Li, Xinyi %A Song, Yuanli %A Sanders, Charles R %A Buxbaum, Joel N %X

In Alzheimer's disease (AD), most hippocampal and cortical neurons show increased staining with anti-transthyretin (TTR) antibodies. Genetically programmed overexpression of wild type human TTR suppressed the neuropathologic and behavioral abnormalities in APP23 AD model mice and TTR-Aβ complexes have been isolated from some human AD brains and those of APP23 transgenic mice. In the present study, in vitro NMR analysis showed interaction between the hydrophobic thyroxine binding pocket of TTR and the cytoplasmic loop of the C99 fragment released by β-secretase cleavage of AβPP, with Kd = 86±9 μM. In cultured cells expressing both proteins, the interaction reduced phosphorylation of C99 (at T668) and suppressed its cleavage by γ-secretase, significantly decreasing Aβ secretion. Coupled with its previously demonstrated capacity to inhibit Aβ aggregation (with the resultant cytotoxicity in tissue culture) and its regulation by HSF1, these findings indicate that TTR can behave as a stress responsive multimodal suppressor of AD pathogenesis.

%B J Alzheimers Dis %V 52 %P 1263-75 %8 2016 Apr 08 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079720?dopt=Abstract %R 10.3233/JAD-160033 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Two Phase 2 Multiple Ascending-Dose Studies of Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer's Disease. %A Pasquier, Florence %A Sadowsky, Carl %A Holstein, Ann %A Leterme, Ghislaine Le Prince %A Peng, Yahong %A Jackson, Nicholas %A Fox, Nick C %A Ketter, Nzeera %A Liu, Enchi %A Ryan, J Michael %K Adjuvants, Immunologic %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Antipsychotic Agents %K Dose-Response Relationship, Drug %K Female %K Follow-Up Studies %K Humans %K Interferon-gamma %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Recombinant Fusion Proteins %K Saponins %K Single-Blind Method %K Treatment Outcome %X

Vanutide cridificar (ACC-001), an immunotherapeutic vaccine, is a potentially disease-modifying therapy that aims to reduce brain amyloid-β (Aβ) plaques in patients with Alzheimer's disease (AD). ACC-001 was evaluated in two phase 2a, multicenter, randomized, third party-unblinded, placebo-controlled, multiple ascending-dose studies of ACC-001 (3μg, 10μg, 30μg) with and without QS-21 adjuvant that enrolled patients with mild-to-moderate AD (n = 245). Patients were treated with up to five doses of study vaccine or placebo and followed for safety and tolerability (primary objective) and anti-Aβ IgG immunogenicity (secondary objective) up to 12 months after the last vaccination. Exploratory assessments included cognitive/functional measures, brain magnetic resonance imaging (MRI) volumetry, and pharmacodynamic markers in plasma and cerebrospinal fluid (CSF). The most frequent treatment-emergent adverse events (≥10%) were local injection reactions and headache. Amyloid-related imaging abnormalities with vasogenic edema occurred in two (0.8%) patients (ACC-001 30μg + QS-21; ACC-001 10μg). ACC-001 + QS-21 elicited consistently higher peak and sustained anti-Aβ IgG titers compared with ACC-001 alone. Plasma Aβx-40 was significantly higher in all ACC-001 + QS-21 groups versus placebo (weeks 16-56), with no evidence of dose response. Exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers did not show differences or trends between treatment groups and placebo. ACC-001 with or without QS-21 adjuvant has an acceptable safety profile in patients with mild-to-moderate AD.

%B J Alzheimers Dis %V 51 %P 1131-43 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967206?dopt=Abstract %R 10.3233/JAD-150376 %0 Journal Article %J J Alzheimers Dis %D 2016 %T UCH-L1 Inhibition Decreases the Microtubule-Binding Function of Tau Protein. %A Xie, Min %A Han, Yun %A Yu, Quntao %A Wang, Xia %A Wang, Shaohui %A Liao, Xiaomei %K Animals %K Cell Line, Tumor %K Dose-Response Relationship, Drug %K HEK293 Cells %K Humans %K Immunoprecipitation %K Indoles %K Mice %K Microtubules %K Neuroblastoma %K Oximes %K Protein Binding %K Proteolysis %K RNA, Small Interfering %K tau Proteins %K Ubiquitin Thiolesterase %K Ubiquitination %X

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is critical for protein degradation and free ubiquitin recycling. In Alzheimer's disease brains, UCH-L1 is negatively related to neurofibrillary tangles whose major component is hyperphosphorylated tau protein, but the direct action of UCH-L1 on tau has not been reported. In the current study, mouse neuroblastoma Neuro2a (N2a) cells were treated by the different concentrations of UCH-L1 inhibitor LDN (2.5, 5 and 10 μM) to inhibit the hydrolase activity of UCH-L1. In addition, we also used UCH-L1 siRNA to treat the HEK293/tau441 cells to decrease the expression of UCH-L1. After LDN and UCH-L1 siRNA treatment, we used immunofluorescence, immunoprecipitation, and tau-microtubule binding assay to measure the microtubule-binding ability and post-translational modifications of tau protein. All the results presented that both inhibition of the activity and expression of UCH-L1 induced the decreased microtubule-binding ability and increased phosphorylation of tau protein. Abnormal aggregation and ubiquitination of tau protein was also observed after UCH-L1 inhibition. The above results suggested that aggregation of tau protein might be devoted to the abnormal post-translational modifications of tau protein. Our study first indicates that dysfunction of UCH-L1 most likely affected normal biological function of tau protein through decreasing degradation of ubiquitinated and hyperphosphorylated tau.

%B J Alzheimers Dis %V 49 %P 353-63 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444754?dopt=Abstract %R 10.3233/JAD-150032 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia. %A Dermody, Nadene %A Wong, Stephanie %A Ahmed, Rebekah %A Piguet, Olivier %A Hodges, John R %A Irish, Muireann %X

Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer's disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information.

%B J Alzheimers Dis %V 53 %P 801-16 %8 2016 May 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258418?dopt=Abstract %R 10.3233/JAD-160175 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Unmet Needs of Community-Dwelling Primary Care Patients with Dementia in Germany: Prevalence and Correlates. %A Eichler, Tilly %A Thyrian, Jochen René %A Hertel, Johannes %A Richter, Steffen %A Wucherer, Diana %A Michalowsky, Bernhard %A Teipel, Stefan %A Kilimann, Ingo %A Dreier, Adina %A Hoffmann, Wolfgang %K Aged, 80 and over %K Caregivers %K Cross-Sectional Studies %K Dementia %K Depression %K Female %K Germany %K Health Services Needs and Demand %K Humans %K Male %K Needs Assessment %K Prevalence %X

BACKGROUND: To provide an optimal care for persons with dementia (PWD), their individual unmet needs have to be identified and comprehensively addressed.

OBJECTIVES: Present analyses aim to describe the number and types of unmet needs of German primary care patients screened positive for dementia and factors associated with the number of unmet needs.

METHODS: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is a general practitioner-based, cluster-randomized controlled intervention trial. Analyses are based on the baseline data of 227 PWD (≥70 years, living at home) of the intervention group who had screened positive for dementia (DemTect<9) and received a standardized computer-assisted needs assessment.

RESULTS: PWD had on average 8.77±5.04 unmet needs (Range = 0-31). More than 90% of the PWD had three or more unmet needs. Unmet needs were identified across all predefined 26 subcategories. The majority of unmet needs occurred in the domains "nursing treatment and care" (38%), "social counseling and legal support" (20%), and "pharmacological treatment and care" (15%). More impairment in the activities of daily living was the only factor that was significantly associated with a higher number of unmet needs, independent of age, gender, living situation, presence of an informal caregiver, cognitive impairment, and depression.

CONCLUSIONS: Present results demonstrate that community-dwelling PWD had a broad range of varying unmet needs. These findings emphasize the importance of a comprehensive needs assessment that allows the identification of individual needs as the basis for a tailored intervention- such as Dementia Care Management- that can address these needs.

%B J Alzheimers Dis %V 51 %P 847-55 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890767?dopt=Abstract %R 10.3233/JAD-150935 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Unraveling Alzheimer's: Making Sense of the Relationship between Diabetes and Alzheimer's Disease1. %A Schilling, Melissa A %K Alzheimer Disease %K Amyloid beta-Peptides %K Amylose %K Diabetes Mellitus %K Humans %K Insulin %K Insulysin %X

Numerous studies have documented a strong association between diabetes and Alzheimer's disease (AD). The nature of the relationship, however, has remained a puzzle, in part because of seemingly incongruent findings. For example, some studies have concluded that insulin deficiency is primarily at fault, suggesting that intranasal insulin or inhibiting the insulin-degrading enzyme (IDE) could be beneficial. Other research has concluded that hyperinsulinemia is to blame, which implies that intranasal insulin or the inhibition of IDE would exacerbate the disease. Such antithetical conclusions pose a serious obstacle to making progress on treatments. However, careful integration of multiple strands of research, with attention to the methods used in different studies, makes it possible to disentangle the research on AD. This integration suggests that there is an important relationship between insulin, IDE, and AD that yields multiple pathways to AD depending on the where deficiency or excess in the cycle occurs. I review evidence for each of these pathways here. The results suggest that avoiding excess insulin, and supporting robust IDE levels, could be important ways of preventing and lessening the impact of AD. I also describe what further tests need to be conducted to verify the arguments made in the paper, and their implications for treating AD.

%B J Alzheimers Dis %V 51 %P 961-77 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967215?dopt=Abstract %R 10.3233/JAD-150980 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Unstable Body Mass Index and Progression to Probable Alzheimer's Disease Dementia in Patients with Amnestic Mild Cognitive Impairment. %A Ye, Byoung Seok %A Jang, Eun Young %A Kim, Seong Yoon %A Kim, Eun-Joo %A Park, Sun Ah %A Lee, Yunhwan %A Hong, Chang Hyung %A Choi, Seong Hye %A Yoon, Bora %A Yoon, Soo Jin %A Na, Hae Ri %A Lee, Jae-Hong %A Jeong, Jee H %A Kim, Hee Jin %A Na, Duk L %A Seo, Sang Won %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Body Mass Index %K Body Weight %K Cognitive Dysfunction %K Dementia %K Disease Progression %K Female %K Humans %K Kaplan-Meier Estimate %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Registries %X

BACKGROUND AND OBJECTIVE: We investigated the influence of body mass index (BMI) status at baseline and changes in BMI over a follow-up period on the development of dementia in amnestic mild cognitive impairment (aMCI) patients.

METHODS: The longitudinal data of 747 aMCI patients were used to investigate the relationships among baseline BMI status, subsequent changes in BMI (median follow-up duration: 1.6 years, interquartile range: 1.0-2.3 years), and risk of progression to probable Alzheimer's disease dementia (pADD). The aMCI patients were classified into underweight, normal weight, overweight, and obese subgroups, and further categorized into increased BMI, stable BMI, and decreased BMI subgroups during follow-up using a 4% mean annual change in BMI cut-off value.

RESULTS: Compared to the normal weight group, the underweight group had a higher risk of pADD (hazard ratio [HR]: 1.89, 95% confidence interval [CI]: 1.07-3.37) while the obese group had a lower risk (HR: 0.70, 95% CI: 0.49-0.999). After controllingfor baseline BMI status, the decreased BMI (HR: 2.29, 95% CI: 1.41-3.72) and increased BMI (HR: 3.96, 95% CI: 2.62-6.00) groups were at increased risk of progression to pADD.

CONCLUSIONS: Our findings suggested that underweight at baseline was associated with a higher risk of progression to pADD, while obesity at baseline predicted a lower risk. Furthermore, significant changes in BMI during the follow-up period reflected an increased risk of progression to pADD, regardless of BMI status at baseline.

%B J Alzheimers Dis %V 49 %P 483-91 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484923?dopt=Abstract %R 10.3233/JAD-150556 %0 Journal Article %J J Alzheimers Dis %D 2016 %T An Update on Type 2 Diabetes Mellitus as a Risk Factor for Dementia. %A Li, Wei %A Huang, Edgar %X

With the rapidly expanding evidence on brain structural and functional changes in type 2 diabetes mellitus (T2DM) patients, there is an increasing need to update our understanding on how T2DM associates with dementia as well as the underlying pathophysiological mechanisms. A literature search of T2DM and dementia or cognition impairments was carried out in electronic databases Medline, EMBASE, and Google Scholar. In this review, the chosen evidence was limited to human subject studies only, and data on either type 1 diabetes mellitus (T1DM) or non-classified diabetes were excluded. T2DM is a risk factor for both vascular dementia (VaD) and Alzheimer's disease (AD), although AD pathological marker studies have not provided sufficient evidence. T2DM interacts additively or synergistically with many factors, including old age, hypertension, total cholesterol, and APOEɛ4 carrier status for impaired cognition functions seen in patients with T2DM. In addition, comorbid T2DM can worsen the clinical presentations of patients with either AD or VaD. In summary, T2DM increases the risk for AD through different mechanisms for VaD although some mechanisms may overlap. Tau-related neurofibrillary tangles instead of amyloid-β plaques are more likely to be the pathological biomarkers for T2DM-related dementia. Degeneration of neurons in the brain, impaired regional blood supply/metabolism, and genetic predisposition are all involved in T2DM-associated dementia or cognitive impairments.

%B J Alzheimers Dis %V 53 %P 393-402 %8 2016 May 03 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163819?dopt=Abstract %R 10.3233/JAD-160114 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Upregulation of Connexin 43 Expression Via C-Jun N-Terminal Kinase Signaling in Prion Disease. %A Lee, Geon-Hwi %A Jang, Byungki %A Choi, Hong-Seok %A Kim, Hee-Jun %A Park, Jeong-Ho %A Jeon, Yong-Chul %A Carp, Richard I %A Kim, Yong-Sun %A Choi, Eun-Kyoung %K Animals %K Brain %K Cell Membrane %K Cells, Cultured %K Connexin 43 %K Disease Models, Animal %K JNK Mitogen-Activated Protein Kinases %K MAP Kinase Signaling System %K Mesocricetus %K Mice, Inbred C57BL %K Mice, Knockout %K PrPSc Proteins %K RNA, Messenger %K Scrapie %K Up-Regulation %X

Prion infection leads to neuronal cell death, glial cell activation, and the accumulation of misfolded prion proteins. However, the altered cellular environments in animals with prion diseases are poorly understood. In the central nervous system, cells connect the cytoplasm of adjacent cells via connexin (Cx)-assembled gap junction channels to allow the direct exchange of small molecules, including ions, neurotransmitters, and signaling molecules, which regulate the activities of the connected cells. Here, we investigate the role of Cx43 in the pathogenesis of prion diseases. Upregulated Cx43 expression, which was dependent on c-Jun N-Terminal Kinase (JNK)/c-Jun signaling cascades, was found in prion-affected brain tissues and hippocampal neuronal cells. Scrapie infection-induced Cx43 formed aggregated plaques within the cytoplasmic compartments at the cell-cell interfaces. The ethidium bromide (EtBr) uptake assay and scrape-loading dye transfer assay demonstrated that increased Cx43 has functional consequences for the activity of Cx43 hemichannels. Interestingly, blockade of PrPSc accumulation reduced Cx43 expression through the inhibition of JNK signaling, indicating that PrPSc accumulation may be directly involved in JNK activation-mediated Cx43 upregulation. Overall, our findings describe a scrapie infection-mediated novel regulatory signaling pathway of Cx43 expression and may suggest a role for Cx43 in the pathogenesis of prion diseases.

%B J Alzheimers Dis %V 49 %P 1005-19 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599051?dopt=Abstract %R 10.3233/JAD-150283 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Usefulness of an Integrated Analysis of Different Memory Tasks to Predict the Progression from Mild Cognitive Impairment to Alzheimer's Disease: The Episodic Memory Score (EMS). %A Marra, Camillo %A Gainotti, Guido %A Fadda, Lucia %A Perri, Roberta %A Lacidogna, Giordano %A Scaricamazza, Eugenia %A Piccininni, Chiara %A Quaranta, Davide %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Memory, Episodic %K Mental Recall %K Neuropsychological Tests %K ROC Curve %X

Taking into the account both the severity and the consistency of performances obtained on memory tests by patients with amnestic mild cognitive impairment (aMCI) could improve the power to predict their progression to Alzheimer's disease. For this purpose, we constructed the Episodic Memory Score (EMS), which is obtained by subdividing in tertiles performances obtained at baseline in verbal (RAVLT) and visual episodic memory (Rey-Osterrieth Figure-delayed recall) and giving a score ranging from 1 (worst result) to 3 (best result) to results falling within each tertile. The EMS was computed for each patient by summing the tertile score obtained on each memory task, so that the total score ranged from 4 (worst performance) to 12 (best performance). The aMCI sample consisted of 198 subjects who completed the two-year follow-up, at the end of which 55 subjects had converted to dementia. The mean EMS score obtained by aMCI converters was significantly lower than that of aMCI-stable patients. In detecting conversion to dementia, the comparison between EMS and individual memory scores obtained at baseline was made by computing ROC curves, and estimating the respective area under the curve (AUC). The EMS had a larger AUC than the individual memory scores. At baseline aMCI converters performed worse than non-converters not only on memory tasks, but also on executive functions tasks. However, in a multiple variables logistic regression analysis in which all scores showing statistically significant differences between aMCI-converters and aMCI-stable were entered, the EMS was the only reliable predictor of progression from aMCI to dementia.

%B J Alzheimers Dis %V 50 %P 61-70 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639965?dopt=Abstract %R 10.3233/JAD-150613 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Utilization of Retinal Nerve Fiber Layer Thickness to Predict Cognitive Deterioration. %A Shi, Zhongyong %A Zhu, Yingbo %A Wang, Meijuan %A Wu, Yujie %A Cao, Jing %A Li, Chunbo %A Xie, Zhongcong %A Shen, Yuan %K Aged %K Cognition Disorders %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Nerve Fibers %K Neuropsychological Tests %K Predictive Value of Tests %K Retina %K ROC Curve %K Statistics, Nonparametric %K Tomography, Optical Coherence %X

Our previous studies have shown that longitudinal reduction in retinal nerve fiber layer (RNFL) thickness is associated with cognitive deterioration. However, whether the combination of longitudinal reduction in RNFL thickness with baseline episodic memory performance can better predict cognitive deterioration remains unknown. Therefore, we set out to re-analyze the data obtained from our previous studies with 78 elderly adults (mean age 74.4 ± 3.83 years, 48.7% male) in the community over a 25-month period. The participants were categorized as either stable participants whose cognitive status did not change (n = 60) or converted participants whose cognitive status deteriorated (n = 18). A logistic regression analysis was applied to determine a conversion score for predicting the cognitive deterioration in the participants. We found that the area under the receiver operating characteristic curve (AUC) for the multivariable model was 0.854 (95% CI 0.762-0.947) using baseline story recall as a predictor, but the AUC increased to 0.915 (95% CI 0.849-0.981) with the addition of the longitudinal reduction of RNFL thickness in the inferior quadrant. The conversion score was significantly higher for the converted participants than the stable participants (0.59 ± 0.30 versus 0.12 ± 0.19, p <  0.001). Finally, the optimal cutoff value of the conversion score (0.134) was determined by the analysis of receiver operating characteristic curve, and this conversion score generated a sensitivity of 0.944 and a specificity of 0.767 in predicting the cognitive deterioration. These findings have established a system to perform a larger scale study to further test whether the longitudinal reduction in RNFL thickness could serve as a biomarker of Alzheimer's disease.

%B J Alzheimers Dis %V 49 %P 399-405 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484909?dopt=Abstract %R 10.3233/JAD-150438 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Validation of a Commercial Chemiluminescence Immunoassay for the Simultaneous Measurement of Three Different Amyloid-β Peptides in Human Cerebrospinal Fluid and Application to a Clinical Cohort. %A Klafki, Hans-W %A Hafermann, Henning %A Bauer, Chris %A Haussmann, Ute %A Kraus, Inga %A Schuchhardt, Johannes %A Muck, Stephan %A Scherbaum, Norbert %A Wiltfang, Jens %X

A comprehensive assay validation campaign of a commercially available chemiluminescence multiplex immunoassay for the simultaneous measurement of the amyloid-β peptides Aβ38, Aβ40, and Aβ42 in human cerebrospinal fluid (CSF) is presented. The assay quality parameters we addressed included impact of sample dilution, parallelism, lower limits of detection, lower limits of quantification, intra- and inter-assay repeatability, analytical spike recoveries, and between laboratory reproducibility of the measurements. The assay performed well in our hands and fulfilled a number of predefined acceptance criteria. The CSF levels of Aβ40 and Aβ42 determined in a clinical cohort (n = 203) were statistically significantly correlated with available ELISA data of Aβ1-40 (n = 158) and Aβ1-42 (n = 179) from a different laboratory. However, Bland-Altman method comparison indicated systematic differences between the assays. The data presented here furthermore indicate that the CSF concentration of Aβ40 can surrogate total CSF Aβ and support the hypothesis that the Aβ42/Aβ40 ratio outperforms CSF Aβ42 alone as a biomarker for Alzheimer's disease due to a normalization to total Aβ levels.

%B J Alzheimers Dis %V 54 %P 691-705 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567847?dopt=Abstract %R 10.3233/JAD-160398 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Validation of Immunoassay-Based Tools for the Comprehensive Quantification of Aβ40 and Aβ42 Peptides in Plasma. %A Pérez-Grijalba, Virginia %A Fandos, Noelia %A Canudas, Jesús %A Insua, Daniel %A Casabona, Diego %A Lacosta, Ana M %A Montañés, María %A Pesini, Pedro %A Sarasa, Manuel %X

Recent advances in neuroimaging and cerebrospinal fluid (CSF) biomarker assays have provided evidence of a long preclinical stage of Alzheimer's disease (AD). This period is being increasingly targeted for secondary prevention trials of new therapies. In this context, the interest of a noninvasive, cost-effective amyloid-β (Aβ) blood-based test does not need to be overstated. Nevertheless, a thorough validation of these bioanalytical methods should be performed as a prerequisite for confident interpretation of clinical results. The aim of this study was to validate ELISA sandwich colorimetric ABtest40 and ABtest42 for the quantification of Aβ40 and Aβ42 in human plasma. The validation parameters assessed included precision, accuracy, sensitivity, specificity, recovery, and dilution linearity. ABtest40 and ABtest42 proved to be specific for their target peptide using Aβ peptides with sequence similar to the target. Mean relative error in the quantification was found to be below 7.5% for both assays, with high intra-assay, inter-assay, and inter-batch precision (CV <9.0% on average). Sensitivity was assessed by determination of the limit of quantification fulfilling precision and accuracy criteria; it was established at 7.60 pg/ml and 3.60 pg/ml for ABtest40 and ABtest42, respectively. Plasma dilution linearity was demonstrated in PBS; however, dilution in a proprietary formulated buffer significantly increased the recovery of both Aβ40 and Aβ42 masked by matrix interactions, allowing a more comprehensive assessment of the free and total peptide levels in the plasma. In conclusion, both assays were successfully validated as tools for the quantification Aβ40 and Aβ42 in plasma.

%B J Alzheimers Dis %V 54 %P 751-62 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567833?dopt=Abstract %R 10.3233/JAD-160325 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Validation of microRNAs in Cerebrospinal Fluid as Biomarkers for Different Forms of Dementia in a Multicenter Study. %A Müller, Mareike %A Kuiperij, H Bea %A Versleijen, Alexandra A M %A Chiasserini, Davide %A Farotti, Lucia %A Baschieri, Francesca %A Parnetti, Lucilla %A Struyfs, Hanne %A De Roeck, Naomi %A Luyckx, Jill %A Engelborghs, Sebastiaan %A Claassen, Jurgen A %A Verbeek, Marcel M %X

MicroRNAs (miRNAs) regulate translational inhibition of proteins, but are also detected in body fluids, including cerebrospinal fluid (CSF), where they may serve as disease-specific biomarkers. Previously, we showed differential expression of miR-146a, miR-29a, and miR-125b in the CSF of Alzheimer's disease (AD) patients versus controls. In this study, we aim to confirm these findings by using larger, independent sample cohorts of AD patients and controls from three different centers. Furthermore, we aim to identify confounding factors that possibly arise using such a multicenter approach. The study was extended by including patients diagnosed with mild cognitive impairment due to AD, frontotemporal dementia and dementia with Lewy bodies. Previous results of decreased miR-146a levels in AD patients compared to controls were confirmed in one center. When samples from all three centers were combined, several confounding factors were identified. After controlling for these factors, we did not identify differences in miRNA levels between the different groups. However, we provide suggestions to circumvent various pitfalls when measuring miRNAs in CSF to improve future studies.

%B J Alzheimers Dis %V 52 %P 1321-33 %8 2016 Apr 16 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104900?dopt=Abstract %R 10.3233/JAD-160038 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Validation of the Spanish version of the Baylor Profound Mental Status Examination. %A Salmerón, Sergio %A Huedo, Isabel %A López-Utiel, Melisa %A Soler-Moratalla, Isabel %A Flores-Ruano, Teresa %A Fernández-Sánchez, Miguel %A Noguerón, Alicia %A Doody, Rachelle S %A Abizanda, Pedro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition %K Cognition Disorders %K Female %K Humans %K Language %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Reproducibility of Results %K Severity of Illness Index %K Spain %X

BACKGROUND: There are no short valid instruments to evaluate cognitive status in severe Alzheimer's disease (AD) patients in the Spanish language.

OBJECTIVE: To validate the Spanish version of the Baylor Profound Mental Status Examination (BPMSE-Sp).

METHODS: The Baylor Profound Mental Status Examination (BPMSE) was translated to Spanish and back translated. Validation was conducted in 100 patients with severe probable AD with a Mini-Mental State Examination (MMSE) <12. We assessed internal consistency (Cronbach's alpha), concurrent validity (Pearson's correlations) with the MMSE, Severe Impairment Battery (SIB), Neuropsychiatric Inventory Short Form (NPI-Q) and the Functional Assessment Staging and reliability.

RESULTS: The mean age of patients was 84.9; 74% were female; 64% were institutionalized. The mean MMSE was 5.6; the mean BPMSE-Sp was 13.6; the mean BPMSE-Sp behavior was 1.2; the mean SIB was 42.2; and the mean NPI-Q was 4.7. BPMSE-Sp presented good internal consistency (Cronbach α= 0.84). There were significant correlations between the BPMSE-Sp and MMSE (r = 0.86, p <  0.001), and between the BPMSE-Sp and SIB (r = 0.92, p <  0.001). Inter-rater and test-retest reliability were in both cases excellent, ranging between 0.96 and 0.99 (p <  0.001). BPMSE-Sp had fewer floor and ceiling effects than the MMSE.

CONCLUSIONS: The BPMSE-Sp is a valid tool for use in daily practice and research in the evaluation of cognitive function of patients with severe AD.

%B J Alzheimers Dis %V 49 %P 73-8 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444781?dopt=Abstract %R 10.3233/JAD-150422 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Validation of the Total Cerebrovascular Disease Burden Scale in a Community Sample. %A Xu, Xin %A Hilal, Saima %A Collinson, Simon L %A Chan, Qun Lin %A Yi Chong, Eddie Jun %A Ikram, Mohammad Kamran %A Venketasubramanian, Narayanaswamy %A Cheng, Ching-Yu %A Wong, Tien Yin %A Chen, Christopher Li-Hsian %X

BACKGROUND: A total cerebrovascular disease (CeVD) burden scale was previously constructed and an inverse association of CeVD burden and cognition was found. However, the generalizability of the CeVD scale has not been examined.

OBJECTIVE: The objective was to validate the previously constructed total CeVD burden scale by establishing its association with cognitive function and dementia diagnosis in a community sample.

METHODS: Eligible participants were assessed on an extensive neuropsychological battery and underwent MRI scans. The total CeVD scale, comprising markers of both small- and large-vessel diseases, was derived according to previously described criteria. Association of total CeVD burden with global and domain-based cognitive performance and dementia diagnostic utility of the scale was established.

RESULTS: A total of 863 participants were included in the analysis. A stepwise association of CeVD burden score with global and domain-specific cognitive function was found. Per score increase on the total CeVD burden scale was associated with 3.6 (95% CI = 2.1-6.4) times higher odds of dementia compared to dementia-free.

DISCUSSION: The total CeVD burden scale is associated with cognition and dementia in a community sample. Longitudinal studies are required to establish the predictive ability of this scale.

%B J Alzheimers Dis %V 52 %P 1021-8 %8 2016 Apr 12 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079726?dopt=Abstract %R 10.3233/JAD-160139 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Validation Study of Vascular Cognitive Impairment Genetics Meta-Analysis Findings in an Independent Collaborative Cohort. %A Skrobot, Olivia Anna %A McKnight, Amy Jayne %A Passmore, Peter Anthony %A Seripa, Davide %A Mecocci, Patrizia %A Panza, Francesco %A Kalaria, Rajesh %A Wilcock, Gordon %A Munafò, Marcus %A Erkinjuntti, Timo %A Karhunen, Pekka %A Pessi, Tanja %A Martiskainen, Mika %A Love, Seth %A Kehoe, Patrick Gavin %X

Vascular cognitive impairment (VCI), including its severe form, vascular dementia (VaD), is the second most common form of dementia. The genetic etiology of sporadic VCI remains largely unknown. We previously conducted a systematic review and meta-analysis of all published genetic association studies of sporadic VCI prior to 6 July 2012, which demonstrated that APOE (ɛ4, ɛ2) and MTHFR (rs1801133) variants were associated with susceptibility for VCI. De novo genotyping was conducted in a new independent relatively large collaborative European cohort of VaD (nmax = 549) and elderly non-demented samples (nmax = 552). Where available, genotype data derived from Illumina's 610-quad array for 1210 GERAD1 control samples were also included in analyses of genes examined. Associations were tested using the Cochran-Armitage trend test: MTHFR rs1801133 (OR = 1.36, 95% CI 1.16-1.58, p = <0.0001), APOE rs7412 (OR = 0.62, 95% CI 0.42-0.90, p = 0.01), and APOE rs429358 (OR = 1.59, 95% CI 1.17-2.16, p = 0.003). Association was also observed with APOE epsilon alleles; ɛ4 (OR = 1.85, 95% CI 1.35-2.52, p = <0.0001) and ɛ2 (OR = 0.67, 95% CI 0.46-0.98, p = 0.03). Logistic regression and Bonferroni correction in a subgroup of the cohort adjusted for gender, age, and population maintained the association of APOE rs429358 and ɛ4 allele.

%B J Alzheimers Dis %V 53 %P 981-9 %8 2016 Jun 15 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27314523?dopt=Abstract %R 10.3233/JAD-150862 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview. %A Jefferson, Angela L %A Gifford, Katherine A %A Acosta, Lealani Mae Y %A Bell, Susan P %A Donahue, Manus J %A Davis, L Taylor %A Gottlieb, JoAnn %A Gupta, Deepak K %A Hohman, Timothy J %A Lane, Elizabeth M %A Libon, David J %A Mendes, Lisa A %A Niswender, Kevin %A Pechman, Kimberly R %A Rane, Swati %A Ruberg, Frederick L %A Su, Yan Ru %A Zetterberg, Henrik %A Liu, Dandan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Blood Pressure Monitoring, Ambulatory %K Brain %K Case-Control Studies %K Cerebral Angiography %K Cognitive Dysfunction %K Echocardiography %K Epidemiologic Research Design %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Research Design %X

BACKGROUND: Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities.

OBJECTIVE: To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics.

METHODS: From September 2012 to November 2014, 335 participants age 60- 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection.

RESULTS: As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values < 0.001), were more likely to be APOEɛ4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants.

CONCLUSION: Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.

%B J Alzheimers Dis %V 52 %P 539-59 %8 2016 03 08 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967211?dopt=Abstract %R 10.3233/JAD-150914 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vascular Contributions in Alzheimer's Disease-Related Neuropathological Changes: First Autopsy Evidence from a South Asian Aging Population. %A Wijesinghe, Printha %A Shankar, S K %A Yasha, T C %A Gorrie, Catherine %A Amaratunga, Dhammika %A Hulathduwa, Sanjayah %A Kumara, K Sunil %A Samarasinghe, Kamani %A Suh, Yoo-Hun %A Steinbusch, Harry W M %A De Silva, K Ranil D %X

BACKGROUND: Evidence from various consortia on vascular contributions has been inconsistent in determining the etiology of sporadic Alzheimer's disease (AD).

OBJECTIVE: To investigate vascular risk factors and cerebrovascular pathologies associated in manifestation of AD-related neuropathological changes of an elderly population.

METHODS: Postmortem brain samples from 76 elderly subjects (≥50 years) were used to study genetic polymorphisms, intracranial atherosclerosis of the circle of Willis (IASCW), and microscopic infarcts in deep white matters. From this cohort, 50 brains (≥60 years) were subjected to neuropathological diagnosis using immunohistopathological techniques.

RESULTS: Besides the association with age, the apolipoprotein E ɛ4 allele was significantly and strongly associated with Thal amyloid-β phases ≥1 [odds ratio (OR) = 6.76, 95% confidence interval (CI) 1.37-33.45] and inversely with Braak neurofibrillary tangle (NFT) stages ≥III (0.02, 0.0-0.47). Illiterates showed a significant positive association for Braak NFT stages ≥IV (14.62, 1.21-176.73) and a significant negative association for microscopic infarcts (0.15, 0.03-0.71) in deep white matters. With respect to cerebrovascular pathologies, cerebral small vessel lesions (white matter hyperintensities and cerebral amyloid angiopathy) showed a higher degree of associations among them and with AD-related neuropathological changes (p < 0.05) compared to large vessel pathology (IASCW), which showed a significant association only with Braak NFT stages ≥I (p = 0.050).

CONCLUSION: These findings suggest that besides age, education, and genetic factors, other vascular risk factors were not associated with AD-related neuropathological changes and urge prompt actions be taken against cerebral small vessel diseases since evidence for effective prevention is still lacking.

%B J Alzheimers Dis %V 54 %P 1607-1618 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589527?dopt=Abstract %R 10.3233/JAD-160425 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vascular Health Indices and Cognitive Domain Function: Singapore Longitudinal Ageing Studies. %A Lim, Shir Lynn %A Gao, Qi %A Nyunt, Ma Shwe Zin %A Gong, Lingli %A Lunaria, Josephine B %A Lim, May Li %A Ling, Audrey %A Lam, Carolyn Su-Ping %A Richards, Arthur Mark %A Ling, Lieng Hsi %A Ng, Tze Pin %K Aged %K Blood Flow Velocity %K Blood Pressure %K Cardiovascular Diseases %K Carotid Intima-Media Thickness %K Cognitive Aging %K Female %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Singapore %K Vascular Stiffness %X

BACKGROUND: Few studies have comprehensively evaluated the relationship between vascular disease and cognition of older adults without cardiac disease.

OBJECTIVE: We explored the associations of structural atherosclerosis, vascular stiffness, and reactivity with global, memory, attention, language, visuospatial ability, and executive function in community-dwelling, non-demented older Asians without cardiac diseases.

METHODS: Cognition was assessed by Mini-Mental State Examination (MMSE) (n = 308) and detailed neuropsychological tests (n = 155). Vascular measures included carotid intima-media thickness; aortic stiffness [carotid-femoral pulse wave velocity (CFPWV), aortic augmentation index (AI), and aortic pulse pressure (PP)]; carotid stiffness [elasticity modulus (Ep), beta index (β), arterial compliance (AC), carotid AI]; and endothelial function [reactive hyperemia index (RHI)]. Multivariable analyses controlled for potential confounding by demographics, apolipoprotein E genotype and cardiovascular risk factors.

RESULTS: The participants' mean age was 63.0 ± 6.1 years. Inverse associations with MMSE were found for AC (β= 0.128, p = 0.019), Ep (β= -0.151, p = 0.008), β index (β= -0.122, p = 0.029), carotid stiffness z-score (β= -0.154, p = 0.007); with executive function for CFPWV (β= -0.209, p = 0.026), AC (β= 0.214, p = 0.005), Ep (β= -0.160, p = 0.050), β index (β= -0.165, p = 0.041), and both aortic (β= -0.229, p = 0.010) and carotid (β= -0.208, p = 0.010) stiffness z-scores; with verbal memory for AI (β= -0.229, p = 0.004) and aortic (β= -0.263, p = 0.004) stiffness z-score; with language for AI (β= -0.155, p = 0.025), aortic stiffness z-score (β= -0.196, p = 0.011). RHI positively correlated with visuospatial ability (β= 0.195, p = 0.013) and executive function (β= 0.151, p = 0.045).

CONCLUSION: The results support a link between systemic vascular health and neurocognitive function in older Asian adults. Subclinical noninvasive measures of arterial stiffness and reactivity may identify individuals vulnerable to cognitive impairment.

%B J Alzheimers Dis %V 50 %P 27-40 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639958?dopt=Abstract %R 10.3233/JAD-150516 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vascular Risk Factors and Cognition in Parkinson's Disease. %A Pilotto, Andrea %A Turrone, Rosanna %A Liepelt-Scarfone, Inga %A Bianchi, Marta %A Poli, Loris %A Borroni, Barbara %A Alberici, Antonella %A Premi, Enrico %A Formenti, Anna %A Bigni, Barbara %A Cosseddu, Maura %A Cottini, Elisabetta %A Berg, Daniela %A Padovani, Alessandro %K Age of Onset %K Aged %K Attention %K Disability Evaluation %K Educational Status %K Executive Function %K Female %K Humans %K Male %K Motor Activity %K Neuropsychological Tests %K Parkinson Disease %K Prevalence %K Risk Factors %K Sex Factors %K Time Factors %K Vascular Diseases %X

Vascular risk factors have been associated with cognitive deficits and incident dementia in the general population, but their role on cognitive dysfunction in Parkinson's disease (PD) is still unclear. The present study addresses the single and cumulative effect of vascular risk factors on cognition in PD patients, taking clinical confounders into account. Standardized neuropsychological assessment was performed in 238 consecutive PD patients. We evaluated the association of single and cumulative vascular risk factors (smoking, diabetes, hypercholesterolemia, hypertension, and heart disease), with the diagnosis of PD normal cognition (PDNC, n = 94), mild cognitive impairment (PD-MCI, n = 111), and dementia (PDD, n = 33). The association between single neuropsychological tests and vascular risk factors was evaluated with covariance analyses adjusted for age at onset, educational levels, gender, disease duration, and motor performance. Age, educational levels, disease duration, and motor function were significantly different between PDNC, PD-MCI, and PDD. Heart disease was the only vascular factor significantly more prevalent in PDD compared with PDNC in adjusted analyses. Performance of tests assessing executive and attention functions were significantly worse in patients with hypertension, heart disease, and/or diabetes (p <  0.05). Heart disease is associated with dementia in PD, suggesting a potential window of intervention. Vascular risk factors act especially on attention and executive functions in PD. Vascular risk stratification may be useful in order to identify PD patients with a greater risk of developing dementia. These findings need to be verified in longitudinal studies.

%B J Alzheimers Dis %V 51 %P 563-70 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890741?dopt=Abstract %R 10.3233/JAD-150610 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Ventilatory Response to Hypercapnia Predicts Dementia with Lewy Bodies in Late-Onset Major Depressive Disorder. %A Takahashi, Sho %A Mizukami, Katsuyoshi %A Arai, Tetsuaki %A Ogawa, Ryoko %A Kikuchi, Norihiro %A Hattori, Satoshi %A Darby, David %A Asada, Takashi %K 3-Iodobenzylguanidine %K Aged %K Aged, 80 and over %K Depressive Disorder, Major %K Follow-Up Studies %K Heart Rate %K Humans %K Hypercapnia %K Hypotension, Orthostatic %K Kaplan-Meier Estimate %K Lewy Body Disease %K Middle Aged %K Partial Pressure %K Psychiatric Status Rating Scales %K Retrospective Studies %K Ventilators, Mechanical %X

BACKGROUND: Studies have shown that developing major depressive disorder (MDD) at 50 years of age or older can predict dementia. Depression is particularly common in dementia with Lewy bodies (DLB), and occasionally occurs before the onset of extrapyramidal symptoms. Moreover, systemic autonomic dysfunction, including an abnormal ventilatory response to hypercapnia (VRH), is common in patients with DLB.

OBJECTIVE: Here, we aimed to determine whether the VRH is useful for distinguishing depression that is predictive of DLB from other types of MDD.

METHODS: Participants were 35 consecutive patients with first onset MDD at 50 years or older with bradykinesia. After diagnosing the clinical subtype of MDD according to DSM-IV criteria, each subject underwent a battery of psychological tests, autonomic examinations including VRH, brain magnetic resonance imaging, and 123I-meta-iodobenzylguanidine scintigraphy.

RESULTS: Longitudinal follow-up showed that all 18 patients with abnormal VRH results developed DLB, whereas none of the 17 patients with normal VRH results converted to DLB within the study period (sensitivity: 100% , specificity: 100%). Additionally, over half of the DLB converters showed abnormalities on other autonomic examinations. For converters, the most common MDD subtype had psychotic and melancholic features simultaneously. The frequency of hypersensitivity to psychotropics was higher in converters than it was in non-converters.

CONCLUSION: In the present study, patients with abnormal VRH results were very likely to develop DLB. Thus, for patients with late-onset MDD accompanied by bradykinesia, the VRH in combination with the clinical subtype of MDD or hypersensitivity to psychotropics may be useful for diagnosing prodromal DLB.

%B J Alzheimers Dis %V 50 %P 751-8 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757183?dopt=Abstract %R 10.3233/JAD-150507 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vitamin D and Memory Decline: Two Population-Based Prospective Studies. %A Kuźma, Elżbieta %A Soni, Maya %A Littlejohns, Thomas J %A Ranson, Janice M %A van Schoor, Natasja M %A Deeg, Dorly J H %A Comijs, Hannie %A Chaves, Paulo H M %A Kestenbaum, Bryan R %A Kuller, Lewis H %A Lopez, Oscar L %A Becker, James T %A Langa, Kenneth M %A Henley, William E %A Lang, Iain A %A Ukoumunne, Obioha C %A Llewellyn, David J %K Humans %K Memory Disorders %K Netherlands %K Prospective Studies %K United States %K Vitamin D %K Vitamin D Deficiency %X

BACKGROUND: Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown.

OBJECTIVE: To investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline.

METHODS: We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Rey's Auditory Verbal Learning Test (in the LASA) were used to assess visual and verbal memory, respectively.

RESULTS: In the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95% CI: -0.06 to 0.01) and -0.10 SD (95% CI: -0.19 to -0.02) per year respectively in visual memory compared to those sufficient (p = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95% CI: -0.01 to 0.02) and -0.01 SD (95% CI: -0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p = 0.34).

CONCLUSIONS: Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes.

%B J Alzheimers Dis %V 50 %P 1099-108 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836174?dopt=Abstract %R 10.3233/JAD-150811 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vitamin D, Cognition and Alzheimer's Disease: The Therapeutic Benefit is in the D-Tails. %A Landel, Véréna %A Annweiler, Cedric %A Millet, Pascal %A Morello, Maria %A Féron, François %X

Since its discovery during the epidemic of rickets in the early 1920s, the physiological effects of vitamin D on calcium/phosphorus homeostasis have been thoroughly studied. Along with the understanding of its actions on skeletal diseases and advances in cellular and molecular biology, this misnamed vitamin has gained attention as a potential player in a growing number of physiological processes and a variety of diseases. During the last 25 years, vitamin D has emerged as a serious candidate in nervous system development and function and a therapeutic tool in a number of neurological pathologies. More recently, experimental and pre-clinical data suggest a link between vitamin D status and cognitive function. Human studies strongly support a correlation between low levels of circulating 25-hydroxyvitamin D (25(OH)D) and cognitive impairment or dementia in aging populations. In parallel, animal studies show that supplementation with vitamin D is protective against biological processes associated with Alzheimer's disease (AD) and enhances learning and memory performance in various animal models of aging and AD. These experimental observations support multiple mechanisms by which vitamin D can act against neurodegenerative processes. However, clinical interventional studies are disappointing and fail to associate increased 25(OH)D levels with improved cognitive outcomes. This review collects the current available data from both animal and human studies and discusses the considerations that future studies examining the effects of vitamin D status on neurocognitive function might consider.

%B J Alzheimers Dis %V 53 %P 419-44 %8 2016 May 11 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27176073?dopt=Abstract %R 10.3233/JAD-150943 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vitamin D Supplementation Appears to Increase Plasma Aβ40 in Vitamin D Insufficient Older Adults: A Pilot Randomized Controlled Trial. %A Miller, Brendan J %A Whisner, Corrie M %A Johnston, Carol S %X

Low plasma amyloid-β (Aβ) is linked to Alzheimer's disease. Since vitamin D cleared brain Aβ in vitro, this 8-week trial examined whether vitamin D increased plasma Aβ40. Vitamin D insufficient adults (6/18 M/F; 64.3 ± 10.9 y) were randomized to placebo or vitamin (50,000 IU/week) treatments. The vitamin group experienced greater plasma Aβ40 change than controls, +14.9 ± 12.0 and +12.8 ± 12.8 pg/mL (p = 0.045; effect size, 0.228). Change in Aβ40 for older participants (≥60 y) was +18.3 ± 33.6 and -3.2 ± 44.5 pg/mL for vitamin (n = 4) and placebo (n = 4) groups (effect size, 0.295). Thus, vitamin D may increase plasma Aβ, particularly in older adults, suggesting decreased brain Aβ.

%B J Alzheimers Dis %V 52 %P 843-7 %8 2016 Mar 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031473?dopt=Abstract %R 10.3233/JAD-150901 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Volumetric and shape analysis of the thalamus and striatum in amnestic mild cognitive impairment. %A Leh, Sandra E %A Kälin, Andrea M %A Schroeder, Clemens %A Park, Min Tae M %A Chakravarty, M Mallar %A Freund, Patrick %A Gietl, Anton F %A Riese, Florian %A Kollias, Spyros %A Hock, Christoph %A Michels, Lars %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Corpus Striatum %K Female %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %K Thalamus %X

Alterations in brain structures, including progressive neurodegeneration, are a hallmark in patients with Alzheimer's disease (AD). However, pathological mechanisms, such as the accumulation of amyloid and the proliferation of tau, are thought to begin years, even decades, before the initial clinical manifestations of AD. In this study, we compare the brain anatomy of amnestic mild cognitive impairment patients (aMCI, n = 16) to healthy subjects (CS, n = 22) using cortical thickness, subcortical volume, and shape analysis, which we believe to be complimentary to volumetric measures. We were able to replicate "classical" cortical thickness alterations in aMCI in the hippocampus, amygdala, putamen, insula, and inferior temporal regions. Additionally, aMCI showed significant thalamic and striatal shape differences. We observed higher global amyloid deposition in aMCI, a significant correlation between striatal displacement and global amyloid, and an inverse correlation between executive function and right-hemispheric thalamic displacement. In contrast, no volumetric differences were detected in thalamic, striatal, and hippocampal regions. Our results provide new evidence for early subcortical neuroanatomical changes in patients with aMCI, which are linked to cognitive abilities and amyloid deposition. Hence, shape analysis may aid in the identification of structural biomarkers for identifying individuals at highest risk of conversion to AD.

%B J Alzheimers Dis %V 49 %P 237-49 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444755?dopt=Abstract %R 10.3233/JAD-150080 %0 Journal Article %J J Alzheimers Dis %D 2016 %T What are the Most Frequently Impaired Markers of Neurodegeneration in ADNI Subjects? %A Andriuta, Daniela %A Moullart, Véronique %A Schraen, Susanna %A Devendeville, Agnes %A Meyer, Marc-Etienne %A Godefroy, Olivier %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Brain %K Cognitive Dysfunction %K Databases, Factual %K Female %K Fluorodeoxyglucose F18 %K Humans %K Male %K Peptide Fragments %K Phosphorylation %K Positron-Emission Tomography %K Radiopharmaceuticals %K tau Proteins %X

The aim of this study was to examine the relationship between cerebrospinal fluid (CSF) levels of biomarkers for Alzheimer's disease (AD) (Aβ1-42, t-tau, and p-tau) and 18Fluorodeoxyglucose positron emission tomography (FDG-PET) hypometabolism in subjects from the Alzheimer's Disease Neuroimaging Initiative, and specifically to determine which index of neurodegeneration was most frequently affected. The secondary objective was to determine the most frequently hypometabolic region in patients with a CSF AD signature (abnormal Aβ1-42 and abnormal p-tau). We included the 372 subjects (85 normal subjects, 212 patients with mild cognitive impairment, and 75 patients with AD) with a CSF biomarker dosage (Aβ1-42, t-tau, and p-tau) and brain FDG-PET. The relationship between FDG-PET metabolism (in five regions of interest (ROI) known to be damaged in AD) and CSF t-tau and p-tau levels was studied as a function of CSF Aβ1-42 status. FDG-PET hypometabolism and CSF t-tau and p-tau levels were correlated only in patients with an abnormal CSF Aβ1-42 level (t-tau: R2 = 0.044, p = 0.001; p-tau: R2 = 0.02, p = 0.03). In the latter patients, CSF p-tau was the most frequently (p = 0.0001) abnormal neurodegeneration marker (p-tau: 92.8%; FDG-PET: 56.5%; CSF t-tau: 59.1%). Within the five ROI of FDG PET, the angular gyrus metabolism (R2 = 0.149; p = 0.0001) was selected as the most tightly associated with CSF AD signature. The relation between CSF markers of neurodegeneration (p-tau and t-tau) and brain hypometabolism (in FDG-PET) is conditioned by presence of amyloid abnormality. This finding supports the current physiopathological model of AD. P-tau is the most frequently impaired biomarker. Using FDG PET angular gyrus hypometabolism is the most sensitive to CSF-biomarker-defined AD.

%B J Alzheimers Dis %V 51 %P 793-800 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923012?dopt=Abstract %R 10.3233/JAD-150829 %0 Journal Article %J J Alzheimers Dis %D 2016 %T White Matter Abnormalities Track Disease Progression in PSEN1 Autosomal Dominant Alzheimer's Disease. %A Sánchez-Valle, Raquel %A Monté, Gemma C %A Sala-Llonch, Roser %A Bosch, Beatriz %A Fortea, Juan %A Lladó, Albert %A Antonell, Anna %A Balasa, Mircea %A Bargalló, Nuria %A Molinuevo, José Luis %K Adult %K Aging %K Alzheimer Disease %K Brain %K Cohort Studies %K Diffusion Tensor Imaging %K Disease Progression %K Family %K Female %K Heterozygote %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Mutation %K Neuropsychological Tests %K Organ Size %K Presenilin-1 %K White Matter %X

PSEN1 mutations are the most frequent cause of autosomal dominant Alzheimer's disease (ADAD), and show nearly full penetrance. There is presently increasing interest in the study of biomarkers that track disease progression in order to test therapeutic interventions in ADAD. We used white mater (WM) volumetric characteristics and diffusion tensor imaging (DTI) metrics to investigate correlations with the normalized time to expected symptoms onset (relative age ratio) and group differences in a cohort of 36 subjects from PSEN1 ADAD families: 22 mutation carriers, 10 symptomatic (SMC) and 12 asymptomatic (AMC), and 14 non-carriers (NC). Subjects underwent a 3T MRI. WM morphometric data and DTI metrics were analyzed. We found that PSEN1 MC showed significant negative correlation between fractional anisotropy (FA) and the relative age ratio in the genus and body of corpus callosum and corona radiate (p <  0.05 Family-wise error correction (FWE) at cluster level) and positive correlation with mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD) in the splenium of corpus callosum. SMC presented WM volume loss, reduced FA and increased MD, AxD, and RD in the anterior and posterior corona radiate, corpus callosum (p <  0.05 FWE) compared with NC. No significant differences were observed between AMC and NC in WM volume or DTI measures. These findings suggest that the integrity of the WM deteriorates linearly in PSEN1 ADAD from the early phases of the disease; thus DTI metrics might be useful to monitor the disease progression. However, the lack of significant alterations at the preclinical stages suggests that these indexes might not be good candidates for early markers of the disease.

%B J Alzheimers Dis %V 51 %P 827-35 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923015?dopt=Abstract %R 10.3233/JAD-150899 %0 Journal Article %J J Alzheimers Dis %D 2016 %T White Matter and Hippocampal Volume Predict the Risk of Dementia in Patients with Cerebral Small Vessel Disease: The RUN DMC Study. %A van Uden, Ingeborg W M %A van der Holst, Helena M %A Tuladhar, Anil M %A van Norden, Anouk G W %A de Laat, Karlijn F %A Rutten-Jacobs, Loes C A %A Norris, David G %A Claassen, Jurgen A H R %A van Dijk, Ewoud J %A Kessels, Roy P C %A de Leeuw, Frank-Erik %K Aged %K Cerebral Small Vessel Diseases %K Cohort Studies %K Dementia %K Diffusion Tensor Imaging %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Statistics, Nonparametric %K White Matter %X

BACKGROUND: The relationship between cerebral small vessel disease (SVD) and dementia has been studied without considering white matter (WM) volume, the microstructural integrity of the WM surrounding the SVD, and grey matter (GM).

OBJECTIVE: We prospectively investigated the relationship between these structures and the risk of dementia, and formed a prediction model to investigate which characteristics (macro- or microstructural) explained most of the variance.

METHODS: The RUN DMC study is a prospective cohort study among 503 non-demented participants with an age between 50 and 85 years at baseline, with baseline assessment in 2006 and follow-up assessment in 2012. Two were lost to follow-up (yielding a 99.6% response-rate). Cox regression analysis was used, to calculate hazard ratios for dementia, of baseline MRI characteristics. Tract-Based Spatial Statistics (TBSS) analysis was used to assess the added value of microstructural integrity of the WM.

RESULTS: Mean age at baseline was 65.6 years (SD 8.8) and 56.8% was male. 43 participants developed dementia (8.6%), resulting in a 5.5-year cumulative risk of 11.1% (95% CI 7.7-14.6). Low WM and hippocampal volume are significant predictors for dementia. WM, WM hyperintensities, and hippocampal volume explained most of the variance. TBSS analyses showed no additional value of diffusion parameters.

CONCLUSIONS: WM and hippocampal volume were the main predictors for the development of incident dementia at 5-year follow-up in elderly with SVD. There was no additional diagnostic value of the diffusion tensor imaging parameters on top of the macrostructural characteristics.

%B J Alzheimers Dis %V 49 %P 863-73 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26529206?dopt=Abstract %R 10.3233/JAD-150573 %0 Journal Article %J J Alzheimers Dis %D 2016 %T White Matter Changes are Associated with Ventricular Expansion in Aging, Mild Cognitive Impairment, and Alzheimer's Disease. %A Coutu, Jean-Philippe %A Goldblatt, Alison %A Rosas, H Diana %A Salat, David H %K Aged %K Aging %K Alzheimer Disease %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Factor Analysis, Statistical %K Female %K Hippocampus %K Humans %K Imaging, Three-Dimensional %K Male %K Mental Status Schedule %K Neuropsychological Tests %K White Matter %X

White matter lesions are highly prevalent in individuals with Alzheimer's disease (AD). Although these lesions are presumed to be of vascular origin and linked to small vessel disease in older adults, little information exists about their relationship to markers of classical AD neurodegeneration. Thus, we examined the link between these white matter changes (WMC) segmented on T1-weighted MRI and imaging markers presumed to be altered due to primary AD neurodegenerative processes. Tissue microstructure of WMC was quantified using diffusion tensor imaging and the relationship of WMC properties and volume to neuroimaging markers was examined in 219 cognitively healthy older adults and individuals with mild cognitive impairment and AD using data from the Alzheimer's Disease Neuroimaging Initiative. No significant group differences in WMC properties were found. However, there were strong associations between diffusivity of WMC and ventricular volume, volume of WMC and total WM volume. In comparison, group differences in parahippocampal white matter microstructure were found for all diffusion metrics and were largely explained by hippocampal volume. Factor analysis on neuroimaging markers suggested two independent sets of covarying degenerative changes, with potentially age- and vascular-mediated tissue damage contributing to one factor and classical neurodegenerative changes associated with AD contributing to a second factor. These data demonstrate two potentially distinct classes of degenerative change in AD, with one factor strongly linked to aging, ventricular expansion, and both volume and tissue properties of white matter lesions, while the other factor related to classical patterns of cortical and hippocampal neurodegeneration in AD.

%B J Alzheimers Dis %V 49 %P 329-42 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444767?dopt=Abstract %R 10.3233/JAD-150306 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Within-Individual Variability: An Index for Subtle Change in Neurocognition in Mild Cognitive Impairment. %A Roalf, David R %A Quarmley, Megan %A Mechanic-Hamilton, Dawn %A Wolk, David A %A Arnold, Steven E %A Moberg, Paul J %X

BACKGROUND: The transition from mild cognitive impairment (MCI) to Alzheimer's disease is characterized by a decline in cognitive performance in many domains. Cognitive performance profiles in MCI are heterogeneous, however, and additional insights into markers of incipient dementia are needed. Typically, studies focus on average or mean performance, but ignore consistency of performance across domains. WIV (within-individual variability) provides an index of this consistency and is a potential marker of cognitive decline.

OBJECTIVE: To use neurocognitive data from the Alzheimer's Disease Neuroimaging Initiative cohort to measure neurocognitive variability.

METHODS: The utility of WIV was measured, in addition to global neurocognitive performance (GNP), for identifying AD and MCI. In addition, the association between changes in neurocognitive variability and diagnostic transition over 12 months was measured.

RESULTS: As expected, variability was higher in AD and MCI as compared to healthy controls; GNP was lower in both groups as compared to healthy subjects. Global neurocognitive performance alone best distinguished those with dementia from healthy older adults. Yet, for individuals with MCI, including variability along with GNP improved diagnostic classification. Variability was higher at baseline in individuals transitioning from MCI to AD over a 12-month period.

CONCLUSION: We conclude that variability offers complementary information about neurocognitive performance in dementia, particularly in individuals with MCI, and may provide beneficial information about disease transition.

%B J Alzheimers Dis %V 54 %P 325-35 %8 2016 Aug 10 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567827?dopt=Abstract %R 10.3233/JAD-160259 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Yokukansan in the Treatment of Behavioral and Psychological Symptoms of Dementia: An Updated Meta-Analysis of Randomized Controlled Trials. %A Matsunaga, Shinji %A Kishi, Taro %A Iwata, Nakao %X

BACKGROUND: Previous clinical studies found that yokukansan has a therapeutic effect on behavioral and psychological symptoms of dementia (BPSD) in dementia patients.

OBJECTIVE: To perform an updated meta-analysis of randomized controlled trials (RCTs) testing yokukansan for patients with BPSD.

METHODS: Primary efficacy and safety endpoints were BPSD total scores and all-cause discontinuation, respectively. Secondary outcomes were BPSD subscales, cognitive function scores [Mini-mental state examination (MMSE)], activities of daily living (ADL) scores, discontinuation due to adverse events (AEs), and incidences of AEs.

RESULTS: Five RCTs with 381 patients with BPSD were included. Compared with controls [placebo+usual care (UC)], yokukansan significantly decreased BPSD total scores [standardized mean difference (SMD) = -0.32, 95% confidence interval (CI) = -0.53 to -0.11, p = 0.003, I2 = 0%, N = 5 studies, n = 361]. Yokukansan was more efficacious in reducing BPSD subscale scores (delusions: SMD = -0.51, 95% CI = -0.98 to -0.04, hallucinations: SMD = -0.54, 95% CI = -0.96 to -0.12, agitation/aggression: SMD = -0.37, 95% CI = -0.60 to -0.15) than placebo+UC. However, yokukansan was not superior to placebo+UC for BPSD total as well as any subscales scores only in Alzheimer's disease patients. Compared with UC, yokukansan treatment improved ADL scores (SMD = -0.32, 95% CI = -0.62 to -0.01). MMSE scores did not differ between the yokukansan and placebo+UC treatment groups. No significant differences were found in all-cause discontinuation, discontinuation due to AEs, and incidences of AEs between yokukansan and placebo+UC treatments.

CONCLUSIONS: Our results suggest that yokukansan is beneficial for the treatment of patients with BPSD and is well-tolerated; it was not beneficial for BPSD total and any subscale scores only in Alzheimer's disease patients.

%B J Alzheimers Dis %V 54 %P 635-43 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497482?dopt=Abstract %R 10.3233/JAD-160418 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Zebrafish Equivalent of Alzheimer's Disease-Associated PRESENILIN Isoform PS2V Regulates Inflammatory and Other Responses to Hypoxic Stress. %A Ebrahimie, Esmaeil %A Moussavi Nik, Seyyed Hani %A Newman, Morgan %A Van Der Hoek, Mark %A Lardelli, Michael %X

Dominant mutations in the PRESENILIN genes PSEN1 and PSEN2 cause familial Alzheimer's disease (fAD) that usually shows onset before 65 years of age. In contrast, genetic variation at the PSEN1 and PSEN2 loci does not appear to contribute to risk for the sporadic, late onset form of the disease (sAD), leading to doubts that these genes play a role in the majority of AD cases. However, a truncated isoform of PSEN2, PS2V, is upregulated in sAD brains and is induced by hypoxia and high cholesterol intake. PS2V can increase γ-secretase activity and suppress the unfolded protein response (UPR), but detailed analysis of its function has been hindered by lack of a suitable, genetically manipulable animal model since mice and rats lack this PRESENILIN isoform. We recently showed that zebrafish possess an isoform, PS1IV, that is cognate to human PS2V. Using an antisense morpholino oligonucleotide, we can block specifically the induction of PS1IV that normally occurs under hypoxia. Here, we exploit this ability to identify gene regulatory networks that are modulated by PS1IV. When PS1IV is absent under hypoxia-like conditions, we observe changes in expression of genes controlling inflammation (particularly sAD-associated IL1B and CCR5), vascular development, the UPR, protein synthesis, calcium homeostasis, catecholamine biosynthesis, TOR signaling, and cell proliferation. Our results imply an important role for PS2V in sAD as a component of a pathological mechanism that includes hypoxia/oxidative stress and support investigation of the role of PS2V in other diseases, including schizophrenia, when these are implicated in the pathology.

%B J Alzheimers Dis %V 52 %P 581-608 %8 2016 Mar 31 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031468?dopt=Abstract %R 10.3233/JAD-150678 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Zinc-Mediated Binding of Nucleic Acids to Amyloid-β Aggregates: Role of Histidine Residues. %A Khmeleva, Svetlana A %A Radko, Sergey P %A Kozin, Sergey A %A Kiseleva, Yana Y %A Mezentsev, Yuri V %A Mitkevich, Vladimir A %A Kurbatov, Leonid K %A Ivanov, Alexis S %A Makarov, Alexander A %X

Amyloid-β peptide (Aβ) plays a central role in Alzheimer's disease (AD) pathogenesis. Besides extracellular Aβ, intraneuronal Aβ (iAβ) has been suggested to contribute to AD onset and development. Based on reported in vitro Aβ-DNA interactions and nuclear localization of iAβ, the interference of iAβ with the normal DNA expression has recently been proposed as a plausible pathway by which Aβ can exert neurotoxicity. Employing the sedimentation assay, thioflavin T fluorescence, and dynamic light scattering we have studied effects of zinc ions on binding of RNA and single- and double-stranded DNA molecules to Aβ42 aggregates. It has been found that zinc ions significantly enhance the binding of RNA and DNA molecules to pre-formed β-sheet rich Aβ42 aggregates. Another type of Aβ42 aggregates, the zinc-induced amorphous aggregates, was demonstrated to also bind all types of nucleic acids tested. To evaluate the role of the Aβ metal-binding domain's histidine residues in Aβ-nucleic acid interactions mediated by zinc, Aβ16 mutants with substitutions H6R and H6A-H13A and rat Aβ16 lacking histidine residue 13 were used. The zinc-induced interaction of Aβ16 with DNA was shown to critically depend on histidine residues 6 and 13. However, the inclusion of H6R mutation in Aβ42 peptide did not affect DNA binding to Aβ42 aggregates. Since oxidative and/or nitrosative stresses implicated in AD pathogenesis are known to release zinc ions from metallothioneins in cytoplasm and cell nuclei, our findings suggest that intracellular zinc can be an important player in iAβ-nucleic acid interactions.

%B J Alzheimers Dis %V 54 %P 809-19 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567853?dopt=Abstract %R 10.3233/JAD-160415 %0 Journal Article %J J Alzheimers Dis %D 2016 %T δ Scores are Exportable Across Cultural and Linguistic Boundaries. %A Royall, Donald R %A Palmer, Raymond F %A Matsuoka, Teruyuki %A Kato, Yuka %A Taniguchi, Shogo %A Ogawa, Mayu %A Fujimoto, Hiroshi %A Okamura, Aiko %A Shibata, Keisuke %A Nakamura, Kaeko %A Nakaaki, Shutaro %A Koumi, Hiroyuki %A Mimura, Masaru %A Fukui, Kenji %A Narumoto, Jin %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Cognitive Dysfunction %K Cohort Studies %K Culture %K Executive Function %K Female %K Humans %K Linguistics %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Psychometrics %K Reproducibility of Results %K ROC Curve %K Texas %X

The latent variable "δ", can accurately diagnose dementia. Its generalizability across populations is unknown. We constructed a δ homolog ("dT2J") in data collected by the Texas Alzheimer's Research and Care Consortium (TARCC). From this, we calculated a composite d-score "d". We then tested d's generalizability across random subsets of TARCC participants and to a convenience sample of elderly Japanese persons with normal cognition (NC), mild cognitive impairment (MCI), and dementia (AD) (n = 176). dT2J was indicated by Instrumental Activities of Daily Living and psychometric measures. Embedded in this battery were the Mini-Mental Status Examination (MMSE) and an executive clock-drawing task (CLOX). Only MMSE and CLOX were available in both TARCC and the Japanese cohort. Therefore, a second composite variable, "T2J", was constructed solely from the factor loadings of CLOX and MMSE on d. The diagnostic accuracy of T2J was estimated in the validation sample, the remainder of the TARCC cohort, and in the Japanese sample. The areas under the receiver operating curve (AUC; ROC) for T2J were compared in each sample, and against d in TARCC. The AUCs for T2J were statistically indiscriminable within TARCC, and in Japanese persons. In Japanese persons, AUCs for T2J were 0.97 for the discrimination between AD versus NC, 0.86 for AD versus MCI, and 0.79 for NC versus MCI. The AUCs for T2J in Japanese persons were higher than any individual psychometric measure in that sample. Valid d-score composites can be abstracted from a subset of δ's indicators. Moreover, those composites are exportable across cultural and linguistic boundaries.

%B J Alzheimers Dis %V 49 %P 561-70 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444764?dopt=Abstract %R 10.3233/JAD-150261 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Acute Exposure of the Mediobasal Hypothalamus to Amyloid-β25-35 Perturbs Hepatic Glucose Metabolism. %A Arrieta-Cruz, Isabel %A Knight, Colette M %A Gutiérrez-Juérez, Roger %X

Patients with Alzheimer's disease (AD) have a higher risk for developing insulin resistance and diabetes. Amyloid plaques, a hallmark of AD, are composed of amyloid-β (Aβ). Because the mediobasal hypothalamus controls hepatic glucose production, we examined the hypothesis that its exposure to Aβ perturbs the regulation of glucose metabolism. The infusion of Aβ25-35, but not its scrambled counterpart, into the mediobasal hypothalamus of young rats, increased circulating glucose as a consequence of enhanced hepatic glucose production during pancreatic clamp studies. These findings suggest a link between AD and alterations of glucose metabolism.

%B J Alzheimers Dis %8 2015 Apr 13 %G eng %R 10.3233/JAD-131865 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Adipose Tissue Distribution in Patients with Alzheimer's Disease: A Whole Body MRI Case-Control Study. %A Diehl-Wiesenecker, Eva %A von Armin, Christine A F %A Dupuis, Luc %A Müller, Hans-Peter %A Ludolph, Albert C %A Kassubek, Jan %X

BACKGROUND: Total and central adiposity have been associated with increased risk of Alzheimer's disease (AD). Visceral and subcutaneous adipose tissues have different metabolic characteristics and could therefore be differentially associated with AD.

OBJECTIVE: To compare regional fat distribution determined by magnetic resonance imaging (MRI) in AD patients and healthy controls and investigate associations with stage of the disease and chemical markers. The investigation was performed in a prospective case-control study.

METHODS: We examined thirty patients with mild to moderate AD by whole-body MRI (1.5 T) and clinical questionnaires in comparison to thirty cognitively healthy age- and gender-matched study participants. Volumes of total, subcutaneous, and visceral body fat tissue were determined by an unbiased automatic analysis algorithm. Levels of leptin, ghrelin, and adiponectin were determined in serum, amyloid-β (Aβ)1-42 and tau protein levels in cerebrospinal fluid (CSF).

RESULTS: Male AD patients displayed significantly more total fat tissue than male controls. This difference was not observed in women. We observed a trend toward higher volume of visceral fat tissue in all patients (p = 0.13). Severity of disease was not associated with fat distribution in our study. Increased leptin levels correlated with lower CSF Aβ 1-42 in female, but not in male, AD patients.

CONCLUSIONS: Fat volume is increased in male, but not in female AD patients. Negative correlation of leptin levels and CSF Aβ 1-42 in females might be one co-factor for the increased AD risk of females. Further studies are required to confirm this gender difference in fat volume during AD and evaluate its pathophysiological importance.

%B J Alzheimers Dis %8 2015 Sep 16 %G eng %R 10.3233/JAD-150426 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. %A Li, Qiao-Xin %A Villemagne, Victor L %A Doecke, James D %A Rembach, Alan %A Sarros, Shannon %A Varghese, Shiji %A McGlade, Amelia %A Laughton, Katrina M %A Pertile, Kelly K %A Fowler, Christopher J %A Rumble, Rebecca L %A Trounson, Brett O %A Taddei, Kevin %A Rainey-Smith, Stephanie R %A Laws, Simon M %A Robertson, Joanne S %A Evered, Lisbeth A %A Silbert, Brendan %A Ellis, Kathryn A %A Rowe, Christopher C %A Macaulay, S Lance %A Darby, David %A Martins, Ralph N %A Ames, David %A Masters, Colin L %A Collins, Steven %X

BACKGROUND: The cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42, total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD).

OBJECTIVE: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands.

METHODS: Aβ pathology was determined by PET imaging, utilizing 11C-Pittsburgh Compound B, 18F-flutemetamol, or 18F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ1-42 >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology.

RESULTS: CSF Aβ1-42 was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ1-42 provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ1-42 to predict MCI/AD, reached ≥92% sensitivity and specificity.

CONCLUSIONS: CSF Aβ1-42 levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.

%B J Alzheimers Dis %V 48 %P 175-87 %8 2015 Aug 28 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401938?dopt=Abstract %R 10.3233/JAD-150247 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Amyloid-β and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus. %A Herukka, Sanna-Kaisa %A Rummukainen, Jaana %A Ihalainen, Jouni %A von Und Zu Fraunberg, Mikael %A Koivisto, Anne M %A Nerg, Ossi %A Puli, Lakshman K %A Seppälä, Toni T %A Zetterberg, Henrik %A Pyykkö, Okko T %A Helisalmi, Seppo %A Tanila, Heikki %A Alafuzoff, Irina %A Hiltunen, Mikko %A Rinne, Jaakko %A Soininen, Hilkka %A Jääskeläinen, Juha E %A Leinonen, Ville %X

Background: Amyloid-β (Aβ1-42), total tau (T-tau), and phosphorylated tau (P-tau181) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer's disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble Aβ decreases with increasing age and advanced Aβ pathology as seen similarly in CSF. Objective: To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF). Methods: Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF. Results: ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. Aβ1-42 and P-tau181 remained stable during the experiment (n = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while Aβ1-42 levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r = 0.70, p = 0.017) and P-tau181 (r = 0.64, p = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF Aβ1-42 levels than those six without amyloid pathology. Conclusions: This is the first study to report ISF Aβ and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease.

%B J Alzheimers Dis %8 2015 Feb 26 %G eng %R 10.3233/JAD-142862 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Analysis of the Inhibitory Elements in the p5 Peptide Fragment of the CDK5 Activator, p35, CDKR1 Protein. %A Binukumar, B K %A Shukla, Varsha %A Amin, Niranjana D %A Bhaskar, Manju %A Skuntz, Suzanne %A Steiner, Joseph %A Winkler, Dirk %A Pelech, Steven L %A Pant, Harish C %X

Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles, it is well documented that cyclin-dependent kinase 5 (CDK5), a critical neuronal protein kinase in nervous system development, function, and survival, when deregulated and hyperactivated induces Alzheimer's disease (AD) and amyotrophic lateral sclerosis and Parkinson's disease-like phenotypes in mice. In a recent study, we demonstrated that p5, a small, truncated fragment of 24 amino acid residues derived from the CDK5 activator protein 35 (NCK5A, p35), selectively inhibited deregulated CDK5 hyperactivity and ameliorated AD phenotypes in model mice. In this study, we identified the most inhibitory elements in the p5 peptide fragment. Each amino acid residue in p5 was systematically replaced with its homologous residues that may still be able to functionally substitute. The effects of these p5 peptide analogs were studied on the phosphotransferase activities of CDK5/p35, CDK5/p25, ERK1, and GSK3β. The mimetic p5 peptide (A/V substitution at the C-terminus of the peptide) in the sequence, KNAFYERALSIINLMTSKMVQINV (p5-MT) was the most effective inhibitor of CDK5 kinase activity of 79 tested mimetic peptides including the original p5 peptide, KEAFWDRCLSVINLMSSKMLQINA (p5-WT). Replacement of the residues in C-terminus end of the peptide affected CDK5 phosphotransferase activity most significantly. These peptides were strong inhibitors of CDK5, but not the related proline-directed kinases, ERK1 and GSK3β.

%B J Alzheimers Dis %8 2015 Oct 8 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/26444778?dopt=Abstract %R 10.3233/JAD-150412 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Ankle-Brachial Index but Neither Intima Media Thickness Nor Coronary Artery Calcification is Associated With Mild Cognitive Impairment. %A Weimar, Christian %A Winkler, Angela %A Dlugaj, Martha %A Lehmann, Nils %A Hennig, Frauke %A Bauer, Marcus %A Kröger, Knut %A Kälsch, Hagen %A Mahabadi, Amir-Abass %A Dragano, Nico %A Moebus, Susanne %A Hoffmann, Barbara %A Jöckel, Karl-Heinz %A Erbel, Raimund %X

BACKGROUND: Several studies have reported an association of atherosclerosis with mild cognitive impairment (MCI) and dementia independent of cardiovascular risk factors.

OBJECTIVE: To compare the cross-sectional association of the ankle-brachial index (ABI), intima media thickness (IMT), and coronary artery calcification (CAC) with MCI and its subtypes, amnestic MCI (aMCI) and non-amnestic MCI (naMCI) in the population-based Heinz Nixdorf Recall cohort study.

METHODS: 4,086 participants performed a validated brief cognitive assessment at the first follow-up examination (2006-2008). MCI was diagnosed according to previously published criteria. Prevalence ratio (PR) regression models adjusted for age, gender, education, cardiovascular risk factors, and APOE genotype were used to compare the association of the ABI, the CAC-Agatston score and the IMT with MCI and its subtypes.

RESULTS: We identified 490 participants with MCI (mean age 66.1 ± 7.8, 46.9 % male, aMCI n = 249, naMCI n = 241) and 1,242 cognitively normal participants. A decreasing ABI (per 0.1) was significantly associated with a higher MCI prevalence in fully adjusted models (PR 1.06; 95% confidence interval (CI) 1.01-1.11), whereas an increasing CAC (log(CAC+1)) or IMT (per 0.1 mm) were not associated after adjustment. A decreasing ABI was also significantly associated with naMCI in fully adjusted models (PR 1.12; CI 1.03-1.21) but not with aMCI.

CONCLUSIONS: Our data show that the degree of generalized atherosclerosis as measured by the ABI is associated with MCI and with naMCI in a population-based cohort.

%B J Alzheimers Dis %V 47 %P 433-42 %8 2015 Jul 24 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401565?dopt=Abstract %R 10.3233/JAD-150218 %0 Journal Article %J J Alzheimers Dis %D 2015 %T APOE Affects the Volume and Shape of the Amygdala and the Hippocampus in Mild Cognitive Impairment and Alzheimer's Disease: Age Matters. %A Tang, Xiaoying %A Holland, Dominic %A Dale, Anders M %A Miller, Michael I %X

This paper examines how age intervenes in the effects of APOE ɛ4 allele on the volume and shape morphometrics of the hippocampus and the amygdala in mild cognitive impairment (MCI) and Alzheimer's disease. We evaluate the structural morphological differences between ɛ4 carriers and non-carriers in two age-dependent subgroups; younger than 75 years (Young-Old) and older than 80 years (Very-Old). While we show that the four structures of interest atrophy significantly in the ɛ4 carriers, relative to the non-carriers, of the Young-Old group, this effect is not observed in their Very-Old counterparts. The structures in the right hemisphere are found to be more affected by the APOE genotype than those in the left hemisphere and we identify the relevant regions in which significant atrophy occurs to be parts of the basolateral, centromedial, and lateral nucleus subregions of the amygdala and the CA1 and subiculum subregions of the hippocampus. We also observe that the APOE genotype only affects MCI patients that deteriorated to dementia within 3 years while leaving their "non-converting" counterparts unaffected.

%B J Alzheimers Dis %V 47 %P 645-60 %8 2015 Aug 3 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401700?dopt=Abstract %R 10.3233/JAD-150262 %0 Journal Article %J J Alzheimers Dis %D 2015 %T The APOE Gene is Differentially Methylated in Alzheimer's Disease. %A Foraker, Jessica %A Millard, Steven P %A Leong, Lesley %A Thomson, Zachary %A Chen, Sunny %A Keene, C Dirk %A Bekris, Lynn M %A Yu, Chang-En %X

The ɛ4 allele of the human apolipoprotein E gene (APOE) is a well-proven genetic risk factor for the late onset form of Alzheimer's disease (AD). However, the biological mechanisms through which the ɛ4 allele contributes to disease pathophysiology are incompletely understood. The three common alleles of APOE, ɛ2, ɛ3 and ɛ4, are defined by two single nucleotide polymorphisms (SNPs) that reside in the coding region of exon 4, which overlaps with a well-defined CpG island (CGI). Both SNPs change not only the protein codon but also the quantity of CpG dinucleotides, primary sites for DNA methylation. Thus, we hypothesize that the presence of an ɛ4 allele changes the DNA methylation landscape of the APOE CGI and that such epigenetic alteration contributes to AD susceptibility. To explore the relationship between APOE genotype, AD risk, and DNA methylation of the APOE CGI, we applied bisulfite pyrosequencing and evaluated methylation profiles of postmortem brain from 15 AD and 10 control subjects. We observed a tissue-specific decrease in DNA methylation with AD and identified two AD-specific differentially methylated regions (DMRs), which were also associated with APOE genotype. We further demonstrated that one DMR was completely un-methylated in a sub-population of genomes, possibly due to a subset of brain cells carrying deviated APOE methylation profiles. These data suggest that the APOE CGI is differentially methylated in AD brain in a tissue- and APOE-genotype-specific manner. Such epigenetic alteration might contribute to neural cell dysfunction in AD brain.

%B J Alzheimers Dis %8 2015 Sep 4 %G eng %R 10.3233/JAD-143060 %0 Journal Article %J J Alzheimers Dis %D 2015 %T AβPP-Transgenic 2576 Mice Mimic Cell Type-Specific Aspects of Acetyl-CoA-Linked Metabolic Deficits in Alzheimer's Disease. %A Bielarczyk, Hanna %A Jankowska-Kulawy, Agnieszka %A Hofling, Corinna %A Ronowska, Anna %A Gul-Hinc, Sylwia %A Rossner, Steffen %A Schliebs, Reinhard %A Pawelczyk, Tadeusz %A Szutowicz, Andrzej %X

The pyruvate-derived acetyl-CoA is a principal direct precursor substrate for bulk energy synthesis in the brain. Deficits of pyruvate dehydrogenase in the neocortex are common features of Alzheimer's disease and other age-related encephalopathies in humans. Therefore, amyloid-β overload in brains of diverse transgenic Alzheimer's disease model animals was investigated as one of neurotoxic compounds responsible for pyruvate dehydrogenase inhibition yielding deficits of cholinergic neurotransmission and cognitive functions. Brains of aged, 14-16-month-old Tg2576 mice contained 0.6 μmol/kg levels of amyloid-β 1-42. Activities of pyruvate dehydrogenase complex, choline acetyltransferase, and several enzymes of acetyl-CoA and energy metabolism were found to be unchanged in both forebrain mitochondria and synaptosomes of Tg2576 mice, indicating preservation of structural integrity at least cholinergic neuronal cells. However, in transgenic brain synaptosomes, pyruvate utilization, mitochondrial levels, and cytoplasmic acetyl-CoA levels, as well as acetylcholine content and its quantal release, were all found to be decreased by 25-40% . On the contrary, activation of pyruvate utilization was detected and no alterations in acetyl-CoA content and citrate or α-ketoglutarate accumulation were observed in transgenic whole brain mitochondria. These data indicate that amyloid-β evoked deficits in acetyl-CoA are confined to mitochondrial and cytoplasmic compartments of Tg2576 nerve terminals, becoming early primary signals paving path for further stages of neurodegeneration. On the other hand, acetyl-CoA synthesis in mitochondrial compartments of glial cells seems to be activated despite amyloid-β accumulated in transgenic brains.

%B J Alzheimers Dis %8 2015 Sep 19 %G eng %R 10.3233/JAD-150327 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Blood Protein Markers of Neocortical Amyloid-β Burden: A Candidate Study Using SOMAscan Technology. %A Voyle, Nicola %A Baker, David %A Burnham, Samantha C %A Covin, Antonia %A Zhang, Zhanpan %A Sangurdekar, Dipen P %A Tan Hehir, Cristina A %A Bazenet, Chantal %A Lovestone, Simon %A Kiddle, Steven %A Dobson, Richard J B %X

BACKGROUND: Four previously reported studies have tested for association of blood proteins with neocortical amyloid-β burden (NAB). If shown to be robust, these proteins could have utility as a blood test for enrichment in clinical trials of Alzheimer's disease (AD) therapeutics.

OBJECTIVE: This study aimed to investigate whether previously identified blood proteins also show evidence for association with NAB in serum samples from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL). The study considers candidate proteins seen in cohorts other than AIBL and candidates previously discovered in the AIBL cohort.

METHODS: Our study used the SOMAscan platform for protein quantification in blood serum. Linear and logistic regressions were used to model continuous NAB and dichotomized NAB respectively using single proteins as a predictor. Multiple protein models were built using stepwise regression techniques and support vectors machines. Age and APOE ε4 carriage were used as covariates for all analysis.

RESULTS: Of the 41 proteins previously reported, 15 AIBL candidates and 20 non-AIBL candidates were available for testing. Of these candidates, pancreatic polypeptide (PPY) and IgM showed a significant association with NAB. Notably, IgM was found to associate with continuous NAB across cognitively normal control subjects.

CONCLUSIONS: We have further demonstrated the association of PPY and IgM with NAB, despite technical differences between studies. There are several reasons for a lack of significance for the other candidates including platform differences and the use of serum rather than plasma samples. To investigate the possibility of technical differences causing lack of further replication, further studies are required.

%B J Alzheimers Dis %8 2015 Apr 16 %G eng %R 10.3233/JAD-150020 %0 Journal Article %J J Alzheimers Dis %D 2015 %T A Blood-Based, 7-Metabolite Signature for the Early Diagnosis of Alzheimer's Disease. %A Olazarán, Javier %A Gil-de-Gómez, Luis %A Rodríguez-Martín, Andrés %A Valentí-Soler, Meritxell %A Frades-Payo, Belén %A Marín-Muñoz, Juan %A Antúnez, Carmen %A Frank-García, Ana %A Jiménez, Carmen Acedo %A Gracia, Lorenzo Morlén %A Torregrossa, Roberto Petidier %A Guisasola, María Concepción %A Bermejo-Pareja, Félix %A Sánchez-Ferro, Álvaro %A Pérez-Martínez, David A %A Palomo, Sagrario Manzano %A Farquhar, Ruth %A Rábano, Alberto %A Calero, Miguel %X

Accurate blood-based biomarkers of Alzheimer's disease (AD) could constitute simple, inexpensive, and non-invasive tools for the early diagnosis and treatment of this devastating neurodegenerative disease. We sought to develop a robust AD biomarker panel by identifying alterations in plasma metabolites that persist throughout the continuum of AD pathophysiology. Using a multicenter, cross-sectional study design, we based our analysis on metabolites whose levels were altered both in AD patients and in patients with amnestic mild cognitive impairment (aMCI), the earliest identifiable stage of AD. UPLC coupled to mass spectrometry was used to independently compare the levels of 495 plasma metabolites in aMCI (n = 58) and AD (n = 100) patients with those of normal cognition controls (NC, n = 93). Metabolite alterations common to both aMCI and AD patients were used to generate a logistic regression model that accurately distinguished AD from NC patients. The final panel consisted of seven metabolites: three amino acids (glutamic acid, alanine, and aspartic acid), one non-esterified fatty acid (22:6n-3, DHA), one bile acid (deoxycholic acid), one phosphatidylethanolamine [PE(36:4)], and one sphingomyelin [SM(39:1)]. Detailed analysis ruled out the influence of potential confounding variables, including comorbidities and treatments, on each of the seven biomarkers. The final model accurately distinguished AD from NC patients (AUC, 0.918). Importantly, the model also distinguished aMCI from NC patients (AUC, 0.826), indicating its potential diagnostic utility in early disease stages. These findings describe a sensitive biomarker panel that may facilitate the specific detection of early-stage AD through the analysis of plasma samples.

%B J Alzheimers Dis %8 2015 Feb 3 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/25649659?dopt=Abstract %R 10.3233/JAD-142925 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Body Mass Index and Mortality Rate in Korean Patients with Alzheimer's Disease. %A Jang, Hyemin %A Kim, Jong Hun %A Choi, Seong Hye %A Lee, Yunhwan %A Hong, Chang Hyung %A Jeong, Jee Hyang %A Han, Hyun Jeong %A Moon, So Young %A Park, Kyung Won %A Han, Seol-Hee %A Park, Kee Hyung %A Kim, Hee Jin %A Na, Duk L %A Seo, Sang Won %X

Background: A relationship between body weight, cognitive impairment, and the onset of Alzheimer's disease (AD) was recently reported. However, to our knowledge, no studies have investigated the relationship between body weight and mortality in Asian AD patients. Objective: We evaluated the relationship between body mass index (BMI) and mortality rate in Korean AD cohorts. Methods: Participants were consecutively included from two Korean representative registries: 579 AD patients from Samsung Medical Center and 1911 AD patients from the Clinical Research Center for Dementia of South Korea study. We combined these two AD cohorts to evaluate the association between BMI and mortality. BMI was used to categorize the participants into underweight, normal-weight, overweight, and obesity subgroups. All deaths were confirmed through the nationwide mortality database of Statistics Korea. Results: 53 of 181 (29.3%), 208 of 1,127 (18.5%), 88 of 626 (14.1%), and 115 of 556 (20.7%) patients died in the underweight, normal-weight, overweight, and obese subgroups during 43.7 months of follow-up. The time-dependent cox proportional hazards model showed that, relative to the normal-weight subgroup, the underweight group had higher mortality (HR 1.82 (95% CI, 1.07-3.09)) while overweight group had lower mortality rate (HR 0.60 (95% CI, 0.38-0.95)) The effects of underweight and overweight were prominent in younger and older elderly group, respectively. However, there were no interactive effects of dementia severity or gender and BMI on survival rate. Conclusion: Relative to AD patients of normal weight, those who were underweight had an increased mortality rate, and overweight predicted decreased mortality in AD patients. Furthermore, our findings may help facilitate mortality stratification in AD patients by using baseline BMI.

%B J Alzheimers Dis %8 2015 Mar 3 %G eng %R 10.3233/JAD-142790 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Buccal Cell Cytokeratin 14 Correlates with Multiple Blood Biomarkers of Alzheimer's Disease Risk. %A Leifert, Wayne R %A Nguyen, Tori %A Rembach, Alan %A Martins, Ralph %A Rainey-Smith, Stephanie %A Masters, Colin L %A Ames, David %A Rowe, Christopher C %A Macaulay, S Lance %A François, Maxime %A Fenech, Michael F %X

Mild cognitive impairment (MCI) may reflect early stages of neurodegenerative disorders such as Alzheimer's disease (AD). Our hypothesis was that cytokeratin 14 (CK14) expression could be used with blood-based biomarkers such as homocysteine, vitamin B12, and folate to identify individuals with MCI or AD from the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging. Buccal cells from 54 individuals were analyzed by a newly developed method that is rapid, automated, and quantitative for buccal cell CK14 expression levels. CK14 was negatively correlated with plasma Mg2 + and LDL, while positively correlated with vitamin B12, red cell hematocrit/volume, and basophils in the MCI group and positively correlated with insulin and vitamin B12 in the AD group. The combined biomarker panel (CK14 expression, plasma vitamin B12, and homocysteine) was significantly lower in the MCI (p = 0.003) and AD (p = 0.0001) groups compared with controls. Receiver-operating characteristic curves yielded area under the curve (AUC) values of 0.829 for the MCI (p = 0.002) group and 0.856 for the AD (p = 0.0003) group. These complex associations of multiple related parameters highlight the differences between the MCI and AD cohorts and possibly an underlying metabolic pathology associated with the development of early memory impairment. The changes in buccal cell CK14 expression observed in this pilot study supports previous results suggesting the peripheral biomarkers and metabolic changes are not restricted to brain pathology alone in MCI and AD and could prove useful as a potential biomarker in identifying individuals with an increased risk of developing MCI and eventually AD.

%B J Alzheimers Dis %V 48 %P 443-52 %8 2015 Sep 9 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26402008?dopt=Abstract %R 10.3233/JAD-150330 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Clinical Benefits for Older Alzheimer's Disease Patients: Okayama Late Dementia Study (OLDS). %A Matsuzono, Kosuke %A Yamashita, Toru %A Ohta, Yasuyuki %A Hishikawa, Nozomi %A Sato, Kota %A Kono, Syoichiro %A Deguchi, Kentaro %A Nakano, Yumiko %A Abe, Koji %X

BACKGROUND/OBJECTIVE: There are few reports on the effects of anti-Alzheimer's disease (AD) drugs on older AD patients, and possible differences based on gender in a real world setting.

METHODS: "Okayama Late Dementia Study (OLDS)" is a retrospective clinical cohort study focusing on older AD patients (n = 373; age≥75 years) treated with monotherapy donepezil (n = 55), galantamine (n = 222), rivastigmine (n = 63), or memantine (n = 33). The patients were evaluated as an entire group and separated by gender, using seven batteries for dementia assessment at baseline and at 3, 6, and 12 months of drug therapy.

RESULTS: All four drugs preserved cognitive and affective functions until 12 months, except for Frontal Assessment Battery (FAB) with memantine ( *p <  0.05 versus baseline). Donepezil monotherapy significantly improved Hasegawa Dementia Rating Scale-Revised (HDS-R) at 3 months ( *p <  0.05), and memantine (3 and 6 months,  *p <  0.05) and rivastigmine (3 months,  **p <  0.01) improved Abe's Behavior and Psychological Symptom of Dementia Score (ABS), respectively. Activities of daily living (ADL) became significantly worse with galantamine at 12 months ( *p <  0.05). Male Mini-Mental State Examination scores became worse at 12 months with donepezil ( *p <  0.05), as did female Geriatric Depression Scale scores at 6 months ( *p <  0.05). Male HDS-R and ABS scores were preserved in the galantamine group until 12 months. Female ABS scores with memantine improved at 6 months ( *p <  0.05), while male ADL scores became worse with rivastigmine at 12 months ( *p <  0.05).

CONCLUSION: OLDS revealed that anti-AD drugs were effective even for older AD patients, and the clinical benefits of each drug showed a small difference with regard to gender.

%B J Alzheimers Dis %V 46 %P 687-93 %8 2015 Jun 25 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26402513?dopt=Abstract %R 10.3233/JAD-150175 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Cognitive Effects of Soy Isoflavones in Patients with Alzheimer's Disease. %A Gleason, Carey E %A Fischer, Barbara L %A Dowling, N Maritza %A Setchell, Kenneth D R %A Atwood, Craig S %A Carlsson, Cynthia M %A Asthana, Sanjay %X

BACKGROUND: In a previous trial, treatment with soy isoflavones was associated with improved nonverbal memory, construction abilities, verbal fluency, and speeded dexterity compared to treatment with placebo in cognitively healthy older adults.

OBJECTIVE: The current trial aimed to examine the potential cognitive benefits of soy isoflavones in patients with Alzheimer's disease.

METHODS: Sixty-five men and women over the age of 60 were treated with 100 mg/day soy isoflavones, or matching placebo capsules for six months. APOE genotype was determined for all participants. Cognitive outcomes and plasma isoflavone levels were measured at baseline, and at two additional time points: three and six months after baseline.

RESULTS: Of the sixty-five participants enrolled, thirty-four (52.3% ) were women, and 31 (47.7% ) were APOEɛ4 positive. Average age was 76.3 (SD = 7.2) years. Fifty-nine (90.8% ) subjects completed all study visits. Plasma isoflavone levels increased in subjects treated with soy isoflavones compared to baseline and to placebo, although intersubject variability in plasma levels was large. No significant differences in treatment effects for cognition emerged between treatment groups or genders. Exploratory analyses of associations between changes in cognition and plasma isoflavone levels revealed an association between equol levels, and speeded dexterity and verbal fluency.

CONCLUSIONS: Six months of 100 mg/day treatment with soy isoflavones did not benefit cognition in older men and women with Alzheimer's disease. However, our results suggest the need to examine the role of isoflavone metabolism, i.e., the ability to effectively metabolize soy isoflavones by converting daidzen to equol when attempting to fully clarify the cognitive effects of isoflavones.

%B J Alzheimers Dis %V 47 %P 1009-19 %8 2015 Aug 11 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401779?dopt=Abstract %R 10.3233/JAD-142958 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Cognitive Function and Its Relationship with Macular Pigment Optical Density and Serum Concentrations of its Constituent Carotenoids. %A Kelly, David %A Coen, Robert F %A Akuffo, Kwadwo Owusu %A Beatty, Stephen %A Dennison, Jessica %A Moran, Rachel %A Stack, Jim %A Howard, Alan N %A Mulcahy, Riona %A Nolan, John M %X

BACKGROUND: Macular pigment (MP) levels correlate with brain concentrations of lutein (L) and zeaxanthin (Z), and have also been shown to correlate with cognitive performance in the young and elderly.

OBJECTIVE: To investigate the relationship between MP, serum concentrations of L and Z, and cognitive function in subjects free of retinal disease with low MP (Group 1, n = 105) and in subjects with AMD (Group 2, n = 121).

METHODS: MP was measured using customized heterochromatic flicker photometry and dual-wavelength autofluorescence; cognitive function was assessed using a battery of validated cognition tests; serum L and Z concentrations were determined by HPLC.

RESULTS: Significant correlations were evident between MP and various measures of cognitive function in both groups (r = -0.273 to 0.261, p≤0.05, for all). Both serum L and Z concentrations correlated significantly (r = 0.187, p≤0.05 and r = 0.197, p≤0.05, respectively) with semantic (animal) fluency cognitive scores in Group 2 (the AMD study group), while serum L concentrations also correlated significantly with Verbal Recognition Memory learning slope scores in the AMD study group (r = 0.200, p = 0.031). Most of the correlations with MP, but not serum L or Z, remained significant after controlling for age, gender, diet, and education level.

CONCLUSION: MP offers potential as a non-invasive clinical biomarker of cognitive health, and appears more successful in this role than serum concentrations of L or Z.

%B J Alzheimers Dis %V 48 %P 261-77 %8 2015 Aug 28 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401946?dopt=Abstract %R 10.3233/JAD-150199 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Cognitive Impairment Precedes and Predicts Functional Impairment in Mild Alzheimer's Disease. %A Liu-Seifert, Hong %A Siemers, Eric %A Price, Karen %A Han, Baoguang %A Selzler, Katherine J %A Henley, David %A Sundell, Karen %A Aisen, Paul %A Cummings, Jeffrey %A Raskin, Joel %A Mohs, Richard %X

BACKGROUND: The temporal relationship of cognitive deficit and functional impairment in Alzheimer's disease (AD) is not well characterized. Recent analyses suggest cognitive decline predicts subsequent functional decline throughout AD progression.

OBJECTIVE: To better understand the relationship between cognitive and functional decline in mild AD using autoregressive cross-lagged (ARCL) panel analyses in several clinical trials.

METHODS: Data included placebo patients with mild AD pooled from two multicenter, double-blind, Phase 3 solanezumab (EXPEDITION/2) or semagacestat (IDENTITY/2) studies, and from AD patients participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive and functional outcomes were assessed using AD Assessment Scale-Cognitive subscale (ADAS-Cog), AD Cooperative Study-Activities of Daily Living instrumental subscale (ADCS-iADL), or Functional Activities Questionnaire (FAQ), respectively. ARCL panel analyses evaluated relationships between cognitive and functional impairment over time.

RESULTS: In EXPEDITION, ARCL panel analyses demonstrated cognitive scores significantly predicted future functional impairment at 5 of 6 time points, while functional scores predicted subsequent cognitive scores in only 1 of 6 time points. Data from IDENTITY and ADNI programs yielded consistent results whereby cognition predicted subsequent function, but not vice-versa.

CONCLUSIONS: Analyses from three databases indicated cognitive decline precedes and predicts subsequent functional decline in mild AD dementia, consistent with previously proposed hypotheses, and corroborate recent publications using similar methodologies. Cognitive impairment may be used as a predictor of future functional impairment in mild AD dementia and can be considered a critical target for prevention strategies to limit future functional decline in the dementia process.

%B J Alzheimers Dis %V 47 %P 205-14 %8 2015 Jul 9 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26402769?dopt=Abstract %R 10.3233/JAD-142508 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Comorbid Depression and Diabetes as a Risk for Mild Cognitive Impairment and Alzheimer's Disease in Elderly Mexican Americans. %A Johnson, Leigh A %A Gamboa, Adriana %A Vintimilla, Raul %A Cheatwood, Austin J %A Grant, Alyann %A Trivedi, Ashesh %A Edwards, Melissa %A Hall, James R %A O'Bryant, Sid E %X

BACKGROUND: The links between diabetes, depression, and Alzheimer's disease (AD) has been established, but they are still poorly understood. However, little research has examined the effect that comorbidity of depression and diabetes has on cognitive impairment in an ethnically diverse sample.

OBJECTIVE: The purpose of this study was to investigate the relationship between comorbid diabetes and depression on cognitive dysfunction; and examine the relationship in an ethnically diverse population.

METHODS AND RESULTS: Analyses of data from 2,436 participants (914 men and 1,522 women) of three separate cohorts: HABLE, FRONTIER, and TARCC. In the HABLE cohort, comorbidity (odds ratio [OR] = 3.008; 95% CI = 1.358-6.667), age (OR = 1.138; 95% CI = 1.093-1.185), and education (OR = 0.915; 95% CI = 0.852-0.982) increased the risk of mild cognitive impairment (MCI) diagnosis among elderly Mexican American. In the TARCC cohort, results showed an increase risk of MCI in both non-Hispanic whites (OR = 18.795; 95% CI = 2.229-158.485) and Mexican Americans (OR = 8.417; 95% CI = 2.967-23.878). Finally, results in the FRONTIER cohort showed that in elderly Mexican Americans, comorbidity (OR = 2.754; 95% CI = 1.084-6.995) and age (OR = 1.069; 95% CI = 1.023-1.118) significantly increased risk of MCI. In non-Hispanic whites, comorbidity did not significantly increase risk of MCI.

CONCLUSIONS: Among elderly Mexican Americans, comorbid depression and diabetes significantly increased risk for MCI and AD across cohorts. Effects of comorbid diabetes and depression on MCI were inconclusive. Our results support the link between comorbid diabetes and depression and risk for cognitive decline among Mexican Americans. This finding is of critical importance as the Hispanic population is at higher risk of developing AD.

%B J Alzheimers Dis %V 47 %P 129-36 %8 2015 Jul 9 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26402761?dopt=Abstract %R 10.3233/JAD-142907 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Comprehensive Gene- and Pathway-Based Analysis of Depressive Symptoms in Older Adults. %A Nho, Kwangsik %A Ramanan, Vijay K %A Horgusluoglu, Emrin %A Kim, Sungeun %A Inlow, Mark H %A Risacher, Shannon L %A McDonald, Brenna C %A Farlow, Martin R %A Foroud, Tatiana M %A Gao, Sujuan %A Callahan, Christopher M %A Hendrie, Hugh C %A Niculescu, Alexander B %A Saykin, Andrew J %X

Depressive symptoms are common in older adults and are particularly prevalent in those with or at elevated risk for dementia. Although the heritability of depression is estimated to be substantial, single nucleotide polymorphism-based genome-wide association studies of depressive symptoms have had limited success. In this study, we PERFORMED genome-wide gene- and pathway-based analyses of depressive symptom burden. Study participants included non-Hispanic Caucasian subjects (n = 6,884) from three independent cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Health and Retirement Study (HRS), and the Indiana Memory and Aging Study (IMAS). Gene-based meta-analysis identified genome-wide significant associations (ANGPT4 and FAM110A, q-value = 0.026; GRM7-AS3 and LRFN5, q-value = 0.042). Pathway analysis revealed enrichment of association in 105 pathways, including multiple pathways related to ERK/MAPK signaling, GSK3 signaling in bipolar disorder, cell development, and immune activation and inflammation. GRM7, ANGPT4, and LRFN5 have been previously implicated in psychiatric disorders, including the GRM7 region displaying association with major depressive disorder. The ERK/MAPK signaling pathway is a known target of antidepressant drugs and has important roles in neuronal plasticity, and GSK3 signaling has been previously implicated in Alzheimer's disease and as a promising therapeutic target for depression. Our results warrant further investigation in independent and larger cohorts and add to the growing understanding of the genetics and pathobiology of depressive symptoms in aging and neurodegenerative disorders. In particular, the genes and pathways demonstrating association with depressive symptoms may be potential therapeutic targets for these symptoms in older adults.

%B J Alzheimers Dis %8 2015 Feb 17 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/25690665?dopt=Abstract %R 10.3233/JAD-148009 %0 Journal Article %J J Alzheimers Dis %D 2015 %T The Continuing Failure of Bexarotene in Alzheimer's Disease Mice. %A Balducci, Claudia %A Paladini, Alessandra %A Micotti, Edoardo %A Tolomeo, Daniele %A La Vitola, Pietro %A Grigoli, Emanuele %A Richardson, Jill C %A Forloni, Gianluigi %X

Alzheimer's disease (AD) is the most common form of dementia characterized by synaptic dysfunction, memory loss, neuroinflammation, and neuronal cell death. Amyloid-β (Aβ), recognized as the main culprit of AD, aggregates and accumulates in the extracellular compartment as neuritic plaques, after deregulation of its production or clearance. Apolipoprotein E (ApoE) plays a major role in Aβ clearance and its expression is transcriptionally regulated by the liver X receptor and retinoid X receptors (RXRs) system. Bexarotene (BEXA), an RXR agonist, that increases ApoE expression and microglia phagocytosis and has been proposed as a promising therapy for AD, resolving both the amyloid pathology and memory loss. Despite the first compelling report, however, multiple failures have been documented, raising concern about whether BEXA could in fact become a novel disease-modifying strategy for AD. To help clarify this, we investigated the effect of BEXA in vivo at multiple levels in TASTPM transgenic mice. Seven-day oral administration of BEXA to these mice did not achieve any significant memory improvement, plaque reduction, or enhancement of microglial cell activation. No differences were found when specifically investigating the microglial phagocytic state in vivo. In addition, a brain structural analysis with magnetic resonance did not detect any BEXA-mediated change in the volume reduction of the main affected brain areas in our mice. These results suggest that BEXA has no beneficial effect on the multi-factorial pathologic phenotype of AD mice.

%B J Alzheimers Dis %8 2015 Mar 16 %G eng %R 10.3233/JAD-150029 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Correcting for the Absence of a Gold Standard Improves Diagnostic Accuracy of Biomarkers in Alzheimer's Disease. %A Coart, Els %A Barrado, Leandro García %A Duits, Flora H %A Scheltens, Philip %A van der Flier, Wiesje M %A Teunissen, Charlotte E %A van der Vies, Saskia M %A Burzykowski, Tomasz %X

BACKGROUND: Studies investigating the diagnostic accuracy of biomarkers for Alzheimer's disease (AD) are typically performed using the clinical diagnosis or amyloid-β positron emission tomography as the reference test. However, neither can be considered a gold standard or a perfect reference test for AD. Not accounting for errors in the reference test is known to cause bias in the diagnostic accuracy of biomarkers.

OBJECTIVE: To determine the diagnostic accuracy of AD biomarkers while taking the imperfectness of the reference test into account.

METHODS: To determine the diagnostic accuracy of AD biomarkers and taking the imperfectness of the reference test into account, we have developed a Bayesian method. This method establishes the biomarkers' true value in predicting the AD-pathology status by combining the reference test and the biomarker data with available information on the reliability of the reference test. The new methodology was applied to two clinical datasets to establish the joint accuracy of three cerebrospinal fluid biomarkers (amyloid-β1-42, Total tau, and P-tau181) by including the clinical diagnosis as imperfect reference test into the analysis.

RESULTS: The area under the receiver-operating-characteristics curve to discriminate between AD and controls, increases from 0.949 (with 95% credible interval [0.935,0.960]) to 0.990 ([0.985,0.995]) and from 0.870 ([0.817,0.912]) to 0.975 ([0.943,0.990]) for the cohorts, respectively.

CONCLUSIONS: Use of the Bayesian methodology enables an improved estimate of the exact diagnostic value of AD biomarkers and overcomes the lack of a gold standard for AD. Using the new method will increase the diagnostic confidence for early stages of AD.

%B J Alzheimers Dis %8 2015 Apr 13 %G eng %R 10.3233/JAD-142886 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Cortical Transcriptional Profiles in APOE4 Carriers with Alzheimer's Disease: Patterns of Protection and Degeneration. %A Conejero-Goldberg, Concepcion %A Hyde, Thomas M %A Chen, Shufen %A Herman, Mary M %A Kleinman, Joel E %A Davies, Peter %A Goldberg, Terry E %X

Transcriptional profiling of postmortem Alzheimer's disease (AD) brain tissue has yielded important insights into disease. We recently described a novel approach to understand transcriptional changes in AD designed to identify both neurosusceptibility and intrinsic neuroprotective factors in young non-AD E4 carriers. Here we extend our work to APOE4-related AD itself. In temporal cortex (BA 21), a region known to be vulnerable to AD pathology, we identified over 1,400 transcripts that differed between APOE4 controls and APOE4 carriers diagnosed with AD. Results from somatosensory cortex (BA 1/2/3), a region relatively preserved in AD differed strikingly from temporal cortex in that differences were far fewer (37 versus 1,492). We also conducted another set of contrasts involving APOE3 AD cases and APOE4 AD cases to better understand what transcriptional differences were dependent on genotype, but independent of disease status. When analyzing interregional differences, ten pathways differed between both brain areas in the APOE4 AD cases to APOE4 controls contrast and two pathways differed between both brain areas in the APOE4 cases to APOE3 controls contrast. Base excision repair pathway was found in common for both contrasts. In summary, our results indicate that many of the molecular changes identified in the brains of patients with AD reflect the non-specific consequences of neurodegeneration, rather than causative processes. Additionally, the molecular signatures specific to somatosensory cortex may make it uniquely resistant to AD pathology and thereby could provide important leads for treatment.

%B J Alzheimers Dis %8 2015 Sep 28 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/26444771?dopt=Abstract %R 10.3233/JAD-150345 %0 Journal Article %J J Alzheimers Dis %D 2015 %T A Critical Proton MR Spectroscopy Marker of Alzheimer's Disease Early Neurodegenerative Change: Low Hippocampal NAA/Cr Ratio Impacts APOE ɛ4 Mexico City Children and Their Parents. %A Calderón-Garcidueñas, Lilian %A Mora-Tiscareño, Antonieta %A Sánchez, Gastón Melo %A Rodríguez-Díaz, Joel %A Torres-Jardón, Ricardo %A Styner, Martin %A Mukherjee, Partha S %A Lin, Weili %A Jewells, Valerie %X

Severe air pollution exposures produce systemic, respiratory, myocardial, and brain inflammation and Alzheimer's disease (AD) hallmarks in clinically healthy children. We tested whether hippocampal metabolite ratios are associated with contrasting levels of air pollution, APOE, and body mass index (BMI) in paired healthy children and one parent sharing the same APOE alleles. We used 1H-MRS to interrogate bilateral hippocampal single-voxel in 57 children (12.45 ± 3.4 years) and their 48 parents (37.5 ± 6.78 years) from a low pollution city versus Mexico City (MC). NAA/Cr, Cho/Cr, and mI/Cr metabolite ratios were analyzed. The right hippocampus NAA/Cr ratio was significantly different between cohorts (p = 0.007). The NAA/Cr ratio in right hippocampus in controls versus APOE ɛ4 MC children and in left hippocampus in MC APOE ɛ4 parents versus their children was significantly different after adjusting for age, gender, and BMI (p = 0.027 and 0.01, respectively). The NAA/Cr ratio is considered reflective of neuronal density/functional integrity/loss of synapses/higher pTau burden, thus a significant decrease in hippocampal NAA/Cr ratios may constitute a spectral marker of early neurodegeneration in young urbanites. Decreases in NAA/Cr correlate well with cognitive function, behavioral symptoms, and dementia severity; thus, since the progression of AD starts decades before clinical diagnosis, our findings support the hypothesis that under chronic exposures to fine particulate matter and ozone above the standards, neurodegenerative processes start in childhood and APOE ɛ4 carriers are at higher risk. Gene and environmental factors are critical in the development of AD and the identification and neuroprotection of young urbanites at high risk must become a public health priority.

%B J Alzheimers Dis %8 2015 Sep 19 %G eng %R 10.3233/JAD-150415 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Depression and Suicidal Ideation During Two Psychosocial Treatments in Older Adults with Major Depression and Dementia. %A Kiosses, Dimitris N %A Rosenberg, Paul B %A McGovern, Amanda %A Fonzetti, Pasquale %A Zaydens, Hana %A Alexopoulos, George S %X

BACKGROUND: Depression is prevalent in dementia and contributes to poor outcomes for patients and their families. Antidepressants have limited efficacy in older adults with major depression and dementia, and psychosocial interventions are under-investigated.

OBJECTIVE: To examine the course, predictors and moderators of depression and suicidal ideation during 12 weeks of home-delivered Problem Adaptation Therapy (PATH) versus Supportive Therapy for Cognitively Impaired Older Adults (ST-CI) in 39 older adults with major depression and dementia.

METHODS: Thirty-nine older adults with major depression, mild or moderate dementia, and disability participated in a randomized controlled trial that compared the efficacy of PATH versus ST-CI. Depression and suicidal ideation were assessed with Cornell Scale for Depression in Dementia Total Score and Suicide Item.

RESULTS: PATH participants had significantly greater reduction in depression than ST-CI participants over 12 weeks of treatment. PATH participants with high social support had the greatest reduction in depression. Both treatments had comparable reduction in suicidal ideation.

CONCLUSION: PATH is more effective in reducing depression in older adults with major depression and dementia compared to ST-CI. These results are clinically significant as antidepressants have limited efficacy in this population. Home-delivered psychosocial treatments may reduce suicidal ideation in this population.

%B J Alzheimers Dis %V 48 %P 453-62 %8 2015 Sep 9 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26402009?dopt=Abstract %R 10.3233/JAD-150200 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Depressive Symptoms and Biomarkers of Alzheimer's Disease in Cognitively Normal Older Adults. %A Donovan, Nancy J %A Hsu, David C %A Dagley, Alexander S %A Schultz, Aaron P %A Amariglio, Rebecca E %A Mormino, Elizabeth C %A Okereke, Olivia I %A Rentz, Dorene M %A Johnson, Keith A %A Sperling, Reisa A %A Marshall, Gad A %X

Even low levels of depressive symptoms are associated with an increased risk of cognitive decline in older adults without overt cognitive impairment (CN). Our objective was to examine whether very low, "subthreshold symptoms of depression" are associated with Alzheimer's disease (AD) biomarkers of neurodegeneration in CN adults and whether these associations are specific to particular depressive symptoms. We analyzed data from 248 community-dwelling CN older adults, including measurements of cortical amyloid burden, neurodegeneration markers of hippocampal volume (HV) and cerebral 18F-fluorodeoxyglucose (FDG) metabolism in a composite of AD-related regions and the 30-item Geriatric Depression Scale (GDS). Participants with GDS >10 were excluded. General linear regression models evaluated the cross-sectional relations of GDS to HV or FDG in separate backward elimination models. Predictors included GDS total score, age, gender, premorbid intelligence, a binary amyloid variable and its interaction with GDS. Principal component analyses of GDS item scores revealed three factors (the Dysphoria, Apathy-Anhedonia, and Anxiety-Concentration Factors). In secondary analyses, GDS total score was replaced with the three factor scores in repeated models. Higher GDS score (p = 0.03) was significantly associated with lower HV and was marginally related (p = 0.06) to FDG hypometabolism. In secondary models, higher Dysphoria (p = 0.02) and Apathy-Anhedonia (p = 0.05) were related to lower HV while higher Apathy-Anhedonia (p = 0.003) was the sole factor related to FDG hypometabolism. Amyloid was not a significant predictor in any model. In conclusion, very low-level dysphoria, apathy and anhedonia may point to neurodegeneration in AD-related regions but this association appears to be independent of amyloid burden.

%B J Alzheimers Dis %8 2015 Feb 19 %G eng %R 10.3233/JAD-142940 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Diabetes is Associated with Worse Executive Function in Both Eastern and Western Populations: Shanghai Aging Study and Mayo Clinic Study of Aging. %A Zhao, Qianhua %A Roberts, Rosebud O %A Ding, Ding %A Cha, Ruth %A Guo, Qihao %A Meng, Haijiao %A Luo, Jianfeng %A Machulda, Mary M %A Shane Pankratz, V %A Wang, Bei %A Christianson, Teresa J H %A Aakre, Jeremiah A %A Knopman, David S %A Boeve, Bradley F %A Hong, Zhen %A Petersen, Ronald C %X

BACKGROUND AND OBJECTIVES: It remains unknown whether the association between diabetes mellitus (DM) and cognitive function differs in Eastern and Western populations. This study aimed to elucidate whether DM is associated with worse cognitive performance in both populations.

METHODS: The Shanghai Aging Study (SAS) and the Mayo Clinic Study of Aging (MCSA) are two population-based studies with similar design and methodology in Shanghai, China and Rochester, MN, USA. Non-demented participants underwent cognitive testing, and DM was assessed from the medical record. Separate analyses were performed in SAS and MCSA regarding the association between DM and cognitive performance.

RESULTS: A total of 3,348 Chinese participants in the SAS and 3,734 American subjects in the MCSA were included. Compared with MCSA subjects, SAS participants were younger, less educated, and had lower frequency of vascular disease, APOE ɛ4 carriers and obesity. Participants with DM (compared to non-DM participants) performed significantly worse on all the cognitive domains in both the SAS and MCSA. After adjustment for age, gender, education, and vascular covariates, DM was associated with worse performance in executive function (β=-0.15, p = 0.001 for SAS, and β=-0.10, p = 0.008 for MCSA) in the total sample and in the cognitively normal sub-sample. Furthermore, DM was associated with poor performance in visuospatial skills, language, and memory in the SAS, but not in the MCSA.

CONCLUSIONS: Diabetes is associated with cognitive dysfunction and, in particular, exerts a negative impact on executive function regardless of race, age, and prevalence of vascular risk factors.

%B J Alzheimers Dis %V 47 %P 167-76 %8 2015 Jul 9 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26402765?dopt=Abstract %R 10.3233/JAD-150073 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Differential Effects of Meal Challenges on Cognition, Metabolism, and Biomarkers for Apolipoprotein E ɛ4 Carriers and Adults with Mild Cognitive Impairment. %A Hanson, Angela J %A Bayer, Jennifer L %A Baker, Laura D %A Cholerton, Brenna %A VanFossen, Brian %A Trittschuh, Emily %A Rissman, Robert A %A Donohue, Michael C %A Moghadam, Setareh H %A Plymate, Stephen R %A Craft, Suzanne %X

BACKGROUND: High intake of saturated fat (SF) and glycemic index (GI) foods is a risk factor for sporadic Alzheimer's disease. Meal challenges may elucidate mechanisms that contribute to this risk, enabling development of targeted interventions.

OBJECTIVE: To assess cognitive and metabolic changes after a meal high in SF and GI calories (HIGH) versus a meal low in these macronutrients (LOW) in older adults with and without cognitive impairment, and with and without the apolipoprotein E4 risk factor.

METHODS: 46 adults with either cognitive impairment (CI) or normal cognition (NC) ingested a LOW (25% total fat, 7% SF, GI <55) and a HIGH meal (50% total fat, 25% SF, GI >70) in a blinded random fashion. Participants then underwent cognitive testing and blood sampling for metabolic and Alzheimer's disease biomarkers. Data were analyzed using repeated measures ANOVA and Spearman correlations.

RESULTS: E4-adults with NC demonstrated lower delayed memory scores after the HIGH compared to the LOW meal, whereas normal E4+ and CI E4- groups had higher scores after the HIGH meal (ANOVA p = 0.03). These findings were associated with meal-induced changes in glucose (p = 0.05), insulin (p = 0.004), triglycerides (p <  0.01), and plasma Aβ42 (p = 0.05).

CONCLUSIONS: These preliminary data suggest that cognitive performance of adults without CI may worsen following high SF and sugar meals, whereas adults with CI or those at risk for CI due to E4 status may benefit acutely from such meals. Furthermore, plasma Aβ was affected by meal type, suggesting a relationship between metabolic response and amyloid regulation.

%B J Alzheimers Dis %V 48 %P 205-18 %8 2015 Aug 28 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401941?dopt=Abstract %R 10.3233/JAD-150273 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Divalent Copper as a Major Triggering Agent in Alzheimer's Disease. %A Brewer, George J %X

Alzheimer's disease (AD) is at epidemic proportions in developed countries, with a steady increase in the early 1900 s, and then exploding over the last 50 years. This epidemiology points to something causative in the environment of developed countries. This paper will review the considerable evidence that that something could be inorganic copper ingestion. The epidemic parallels closely the spread of copper plumbing, with copper leached from the plumbing into drinking water being a main causal feature, aided by the increasingly common use of supplement pills containing copper. Inorganic copper is divalent copper, or copper-2, while we now know that organic copper, or copper in foods, is primarily monovalent copper, or copper-1. The intestinal transport system, Ctr1, absorbs copper-1 and the copper moves to the liver, where it is put into safe channels. Copper-2 is not absorbed by Ctr1, and some of it bypasses the liver and goes directly into the blood, where it appears to be exquisitely toxic to brain cognition. Thus, while aggregation of amyloid-β has been postulated to be the cause of AD under current dogma, the great increase in prevalence over the last century appears to be due to ingestion of copper-2, which may be causing the aggregation, and/or increasing the oxidant toxicity of the aggregates. An alternative hypothesis proposes that oxidant stress is the primary injuring agent, and under this hypothesis, copper-2 accumulation in the brain may be a causal factor of the oxidant injury. Thus, irrespective of which hypothesis is correct, AD can be classified, at least in part, as a copper-2 toxicity disease. It is relatively easy to avoid copper-2 ingestion, as discussed in this review. If most people begin avoiding copper-2 ingestion, perhaps the epidemic of this serious disease can be aborted.

%B J Alzheimers Dis %8 2015 Apr 8 %G eng %R 10.3233/JAD-143123 %0 Journal Article %J J Alzheimers Dis %D 2015 %T The Existence of Primary Age-Related Tauopathy Suggests that not all the Cases with Early Braak Stages of Neurofibrillary Pathology are Alzheimer's Disease. %A Giaccone, Giorgio %X

The distinction between Alzheimer's disease (AD) and Primary Age-Related Tauopathy (PART) is a hotly debated issue. As most lines of evidence support the tenet that tau pathology occurs downstream of amyloid-β deposition, it seems reasonable to consider PART as a separate disease process not necessarily related to Aβ and hence AD. Following this view, the early stages of neurofibrillary pathology may not always be the forerunner of diffuse neurofibrillary changes and AD. The ongoing debate further enhances the need for greater caution against any future predictions using tau cerebrospinal fluid and imaging biomarkers.

%B J Alzheimers Dis %8 2015 Sep 16 %G eng %R 10.3233/JAD-150435 %0 Journal Article %J J Alzheimers Dis %D 2015 %T The GLP-1 Receptor Agonist Liraglutide Improves Memory Function and Increases Hippocampal CA1 Neuronal Numbers in a Senescence-Accelerated Mouse Model of Alzheimer's Disease. %A Hansen, Henrik H %A Fabricius, Katrine %A Barkholt, Pernille %A Niehoff, Michael L %A Morley, John E %A Jelsing, Jacob %A Pyke, Charles %A Bjerre Knudsen, Lotte %A Farr, Susan A %A Vrang, Niels %X

Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor agonists, currently used in the management of type 2 diabetes, exhibit neurotrophic and neuroprotective effects in amyloid-β (Aβ) toxicity models of Alzheimer's disease (AD). We investigated the potential pro-cognitive and neuroprotective effects of the once-daily GLP-1 receptor agonist liraglutide in senescence-accelerated mouse prone 8 (SAMP8) mice, a model of age-related sporadic AD not dominated by Aβ plaques. Six-month-old SAMP8 mice received liraglutide (100 or 500 μg/kg/day, s.c.) or vehicle once daily for 4 months. Vehicle-dosed age-matched 50% back-crossed as well as untreated young (4-month-old) SAMP8 mice were used as control groups for normal memory function. Vehicle-dosed 10-month-old SAMP8 mice showed significant learning and memory retention deficits in an active-avoidance T-maze, as compared to both control groups. Also, 10-month-old SAMP8 mice displayed no immunohistological signatures of Aβ plaques or hyperphosphorylated tau, indicating the onset of cognitive deficits prior to deposition of amyloid plaques and neurofibrillary tangles in this AD model. Liraglutide significantly increased memory retention and total hippocampal CA1 pyramidal neuron numbers in SAMP8 mice, as compared to age-matched vehicle-dosed SAMP8 mice. In conclusion, liraglutide delayed or partially halted the progressive decline in memory function associated with hippocampal neuronal loss in a mouse model of pathological aging with characteristics of neurobehavioral and neuropathological impairments observed in early-stage sporadic AD.

%B J Alzheimers Dis %8 2015 Apr 13 %G eng %R 10.3233/JAD-143090 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Human ApoE Isoforms Differentially Modulate Glucose and Amyloid Metabolic Pathways in Female Brain: Evidence of the Mechanism of Neuroprotection by ApoE2 and Implications for Alzheimer's Disease Prevention and Early Intervention. %A Keeney, Jeriel Thomas-Richard %A Ibrahimi, Shaher %A Zhao, Liqin %X

Three major genetic isoforms of apolipoprotein E (ApoE), ApoE2, ApoE3, and ApoE4, exist in humans and lead to differences in susceptibility to Alzheimer's disease (AD). This study investigated the impact of human ApoE isoforms on brain metabolic pathways involved in glucose utilization and amyloid-β (Aβ) degradation, two major areas that are significantly perturbed in preclinical AD. Hippocampal RNA samples from middle-aged female mice with targeted human ApoE2, ApoE3, and ApoE4 gene replacement were comparatively analyzed with a qRT-PCR custom array for the expression of 85 genes involved in insulin/insulin-like growth factor (Igf) signaling. Consistent with its protective role against AD, ApoE2 brain exhibited the most metabolically robust profile among the three ApoE genotypes. When compared to ApoE2 brain, both ApoE3 and ApoE4 brains exhibited markedly reduced levels of Igf1, insulin receptor substrates (Irs), and facilitated glucose transporter 4 (Glut4), indicating reduced glucose uptake. Additionally, ApoE4 brain exhibited significantly decreased Pparg and insulin-degrading enzyme (Ide), indicating further compromised glucose metabolism and Aβ dysregulation associated with ApoE4. Protein analysis showed significantly decreased Igf1, Irs, and Glut4 in ApoE3 brain, and Igf1, Irs, Glut4, Pparg, and Ide in ApoE4 brain compared to ApoE2 brain. These data provide the first documented evidence that human ApoE isoforms differentially affect brain insulin/Igf signaling and downstream glucose and amyloid metabolic pathways, illustrating a potential mechanism for their differential risk in AD. A therapeutic strategy that enhances brain insulin/Igf1 signaling activity to a more robust ApoE2-like phenotype favoring both energy production and amyloid homeostasis holds promise for AD prevention and early intervention.

%B J Alzheimers Dis %V 48 %P 411-24 %8 2015 Sep 9 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26402005?dopt=Abstract %R 10.3233/JAD-150348 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Identification of Novel Tau Interactions with Endoplasmic Reticulum Proteins in Alzheimer's Disease Brain. %A Meier, Shelby %A Bell, Michelle %A Lyons, Danielle N %A Ingram, Alexandria %A Chen, Jing %A Gensel, John C %A Zhu, Haining %A Nelson, Peter T %A Abisambra, Jose F %X

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is pathologically characterized by the formation of extracellular amyloid plaques and intraneuronal tau tangles. We recently identified that tau associates with proteins known to participate in endoplasmic reticulum (ER)-associated degradation (ERAD); consequently, ERAD becomes dysfunctional and causes neurotoxicity. We hypothesized that tau associates with other ER proteins, and that this association could also lead to cellular dysfunction in AD. Portions of human AD and non-demented age matched control brains were fractionated to obtain microsomes, from which tau was co-immunoprecipitated. Samples from both conditions containing tau and its associated proteins were analyzed by mass spectrometry. In total, we identified 91 ER proteins that co-immunoprecipitated with tau; 15.4% were common between AD and control brains, and 42.9% only in the AD samples. The remainder, 41.8% of the proteins, was only seen in the control brain samples. We identified a variety of previously unreported interactions between tau and ER proteins. These proteins participate in over sixteen functional categories, the most abundant being involved in RNA translation. We then determined that association of tau with these ER proteins was different between the AD and control samples. We found that tau associated equally with the ribosomal protein L28 but more robustly with the ribosomal protein P0. These data suggest that the differential association between tau and ER proteins in disease could reveal the pathogenic processes by which tau induces cellular dysfunction.

%B J Alzheimers Dis %8 2015 Sep 3 %G eng %R 10.3233/JAD-150298 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Impairment of Age Estimation from Faces in Alzheimer's Disease. %A Moyse, Evelyne %A Bastin, Christine %A Salmon, Eric %A Brédart, Serge %X

A prerequisite for any function in social cognition is the perception and processing of social cues. Age estimation is a skill that is used in everyday life and is fundamental in social interactions. This study evaluated whether facial age estimation is impaired in patients with mild to moderate Alzheimer's disease (AD). The current age of faces is known to have an impact on age estimation, and therefore stimuli belonging to different age groups (young, middle-aged, and older adults' faces) were used. As expected, an impairment of age estimation from faces was observed in mild to moderate AD patients. However, the profile of impairment depended on the age of faces and stage of the disease. Mild AD patients presented difficulties mainly in assessing the age of middle-aged adults. In moderate disease stage, these difficulties also affected the age estimation of young adult faces. Interestingly, AD patients remained relatively good at estimating the age of older adults' faces, compared to healthy controls.

%B J Alzheimers Dis %8 2015 Jan 13 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/25589725?dopt=Abstract %R 10.3233/JAD-142253 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Long-Term Interrelationship between Brain Metabolism and Amyloid Deposition in Mild Cognitive Impairment. %A Kemppainen, Nina %A Joutsa, Juho %A Johansson, Jarkko %A Scheinin, Noora M %A Någren, Kjell %A Rokka, Johanna %A Parkkola, Riitta %A Rinne, Juha O %X

The aim of this longitudinal positron emission tomography (PET) study was to evaluate the interrelationship between brain metabolism and amyloid accumulation during the disease process from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Nine MCI patients, who converted to AD between two and five years, and nine healthy subjects underwent [11C]PIB and [18F]FDG PET scans at baseline and at 5 years. [11C]PIB uptake was clearly higher in MCI patients at baseline compared to controls and spread extensively to the cerebral cortex during the conversion to AD. [18F]FDG uptake was reduced especially in the temporal-parietal regions in MCI compared to controls at baseline, and widely over the cortex at the 5-year follow-up. The reduction in metabolism during the follow-up was significant in the posterior brain regions. In addition, brain amyloid load was positively associated with metabolism in posterior brain regions in MCI, but not after conversion to AD. The results suggest that there are interactions between brain amyloid accumulation and metabolism during the AD process, including a possible compensatory upregulation of posterior brain metabolism in the early phase.

%B J Alzheimers Dis %V 48 %P 123-33 %8 2015 Aug 28 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401934?dopt=Abstract %R 10.3233/JAD-150190 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Mapping the Progression of Atrophy in Early- and Late-Onset Alzheimer's Disease. %A Migliaccio, Raffaella %A Agosta, Federica %A Possin, Katherine L %A Canu, Elisa %A Filippi, Massimo %A Rabinovici, Gil D %A Rosen, Howard J %A Miller, Bruce L %A Gorno-Tempini, Maria Luisa %X

The term early-onset Alzheimer's disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter atrophy in EOAD patients compared to late-onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital, and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate.

%B J Alzheimers Dis %8 2015 Mar 3 %G eng %R 10.3233/JAD-142292 %0 Journal Article %J J Alzheimers Dis %D 2015 %T The Multi-Target Drug M30 Shows Pro-Cognitive and Anti-Inflammatory Effects in a Rat Model of Alzheimer's Disease. %A Pimentel, Luisa S %A Allard, Simon %A Do Carmo, Sonia %A Weinreb, Orly %A Danik, Marc %A Hanzel, Cecilia E %A Youdim, Moussa B %A Cuello, A Claudio %X

Current therapies for Alzheimer's disease (AD) offer partial symptomatic relief and do not modify disease progression. There is substantial evidence indicating a disease onset years before clinical diagnosis, at which point no effective therapy has been found. In this study, we investigated the efficacy of a new multi-target drug, M30, at relatively early stages of the AD-like amyloid pathology in a robust rat transgenic model. McGill-R-Thy1-APP transgenic rats develop the full AD-like amyloid pathology in a progressive fashion, and have a minimal genetic burden. McGill rats were given 5 mg/kg M30 or vehicle per os, every 2 days for 4 months, starting at a stage where the transgenic animals suffer detectable cognitive impairments. At the completion of the treatment, cognitive functions were assessed with Novel Object Location and Novel Object Recognition tests. The brains were then analyzed to assess amyloid-β (Aβ) burden and the levels of key inflammatory markers. Long-term treatment with M30 was associated with both the prevention and the reversal of transgene-related cognitive decline. The effects on cognition were accompanied by a shift of the Aβ-immunoreactive material toward an amyloid plaque aggregated molecular form, diminished molecular signs of CNS inflammation and a change in microglia morphology toward a surveying phenotype. This study is the first to demonstrate the therapeutic potential of M30 in a rat model of the AD amyloid pathology. It provides a rationale for further investigations with M30 and with potential multi-target approaches to delay, prevent or reverse the progression the AD pathology at early disease-stages.

%B J Alzheimers Dis %V 47 %P 373-83 %8 2015 Jul 24 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401560?dopt=Abstract %R 10.3233/JAD-143126 %0 Journal Article %J J Alzheimers Dis %D 2015 %T A Novel Plasma Based Biomarker of Alzheimer's Disease. %A Bradley-Whitman, Melissa A %A Abner, Erin %A Lynn, Bert C %A Lovell, Mark A %X

Specific biomarkers in a readily accessible biological fluid, such as blood, could aid in the identification, characterization, validation, and routine monitoring of Alzheimer's disease (AD) progression. In the current study, levels of the previously described novel cerebrospinal fluid aberrant protein complex composed of prostaglandin-D-synthase (PDS) and transthyretin (TTR) were quantified in plasma by a custom two-probe sandwich ELISA and compared to amyloid-β (Aβ)1-42 as a standard plasma biomarker of AD. Plasma was analyzed from 140 probable AD subjects, 135 subjects with mild cognitive impairment (MCI), 74 normal control subjects (NC) prior to MCI transition, 23 diseased control (DC) subjects with either frontotemporal dementia or dementia with Lewy bodies, and 182 normal control (NC) subjects who did not progress to MCI or dementia. Levels of Aβ 1-42 were significantly elevated in NC subjects prior to MCI conversion but significantly reduced in probable AD subjects compared to NC subjects. Similarly, levels of the PDS-TTR complex were significantly reduced in both MCI and probable AD subjects compared to NC subjects. Furthermore, levels of Aβ 1-42 and the PDS-TTR complex were not significantly different in DC subjects compared to NC subjects. MMSE scores were weakly but significantly correlated with plasma levels of the PDS-TTR complex and Aβ 1-42. Trail B scores were weakly but significantly correlated with plasma levels of Aβ 1-42. Comparison of receiver operating curves shows the PDS-TTR complex is comparable to Aβ 1-42 in both MCI and probable AD subjects.

%B J Alzheimers Dis %V 47 %P 761-71 %8 2015 Aug 3 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401710?dopt=Abstract %R 10.3233/JAD-150183 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Olfactory Dysfunction in ApoE ε4/4 Homozygotes with Alzheimer's Disease. %A Oleson, Stephanie %A Murphy, Claire %X

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory impairment and the presence of amyloid plaques and neurofibrillary tangles. The associated neuropathology originates in brain areas responsible for olfaction, which makes olfactory tasks potentially useful for assessing AD. The strongest genetic risk factor for AD is the apolipoprotein E (ApoE) ε4 allele that has been associated with increased cognitive and olfactory deficits. While individuals carrying one ε4 allele of the ApoE gene are at increased risk for AD relative to non-carriers, those with two copies of the ε4 allele demonstrate an even higher risk for developing AD. Furthermore, homozygous ApoE ε4/4 individuals diagnosed with AD are known to have heightened amyloid burden and a more rapid rate of cognitive decline relative to heterozygous ε3/4 ApoE carriers. All of these factors suggest there are differences in severity and progression of AD as a function of possessing one versus two ε4 alleles. The current study investigated olfactory functioning in homozygous ε4/4 older adults diagnosed with probable AD. Compared to demographically matched ε3/3 and ε3/4 individuals, ε4/4 individuals showed deficits in odor identification and remote odor memory as measured by odor familiarity ratings. The current findings suggest that these particular domains of olfactory functioning may be more impaired in AD ε4/4 homozygotes compared to ε3/4 heterozygotes and ε3/3 homozygotes. These deficits give insight into how the presence of two ε4 alleles may differentially affect the progression of AD and suggest the usefulness of odor tasks in detecting those at risk for AD.

%B J Alzheimers Dis %8 2015 Apr 13 %G eng %R 10.3233/JAD-150089 %0 Journal Article %J J Alzheimers Dis %D 2015 %T A Phase II Randomized Clinical Trial of a Nutritional Formulation for Cognition and Mood in Alzheimer's Disease. %A Remington, Ruth %A Bechtel, Cynthia %A Larsen, David %A Samar, Annemarie %A Doshanjh, Laura %A Fishman, Paul %A Luo, Yuan %A Smyers, Kathleen %A Page, Robert %A Morrell, Christopher %A Shea, Thomas B %X

Background: Increasing evidence points toward the efficacy of nutritional modifications in delaying cognitive decline and mood/behavioral difficulties in Alzheimer's disease (AD). Nutritional supplementation with individual agents has shown varied results suggesting the need for combinatorial intervention. Objective: We set out to determine whether nutritional intervention could positively impact cognitive performance and behavioral difficulties for individuals diagnosed with AD. Methods: A double-blind, multi-site, phase II study (ClinicalTrials.gov NCT01320527; Alzheimer's Association Trialmatch) was conducted in which 106 individuals with AD were randomized to a nutraceutical formulation (NF; folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or placebo for 3 or 6 months, followed by an open-label extension where participants received NF for 6 additional months. Results: The NF cohort improved versus the placebo cohort within 3 months (Clox-1 p = 0.0083, 95%CI [0.4481, 2.9343]; Dementia Rating Scale p = 0.0266, 95%CI [0.1722, 2.7171]). Caregivers reported non-significant improvements in Neuropsychiatric Inventory. Both cohorts improved or maintained baseline performance during open-label extensions. Activities of Daily Living did not change for either cohort. Conclusions: These findings extend phase I studies where NF maintained or improved cognitive performance and mood/behavior.

%B J Alzheimers Dis %8 2015 Jan 7 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/25589719?dopt=Abstract %R 10.3233/JAD-142499 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Reduced Benefit of Memory Elaboration in Older Adults with Subjective Memory Decline. %A Pike, Kerryn E %A Zeneli, Amina %A Ong, Ben %A Price, Sarah %A Kinsella, Glynda J %X

BACKGROUND: Cognitive interventions for neurodegenerative diseases, such as Alzheimer's disease (AD), are best targeted at the preclinical stages, and subjective memory decline (SMD) without objective memory impairment on standard tests in older adults may represent a very early preclinical stage. Elaborated encoding effectively enhances memory performance for healthy older adults (HOAs), but has not been examined in people with SMD.

OBJECTIVE: To examine elaborated encoding in people with SMD, compared with HOAs.

METHODS: Participants were 32 HOAs and 22 people with SMD, defined using the Memory Complaint Questionnaire. Participants completed a verbal paired associate learning (PAL) task with delayed recall under elaborated and non-elaborated encoding conditions, as well as the California Verbal Learning Test-II.

RESULTS: On the PAL learning trials, with age controlled, a significant interaction of group X encoding condition emerged, F(1, 51) =  6.47, MSE = 6.54, p = 0.014, ηp2 = 0.11. Simple main effects revealed no differences between groups in the non-elaborated condition, but in the elaborated condition HOAs recalled more pairs than SMD, although both groups benefited from elaboration. At delayed recall, HOA recalled more pairs than SMD, F(1, 51) =  4.59, p = 0.037, ηp2 = 0.08, and both groups benefited from elaboration, F(1, 52) =  19.25, p <  0.001, ηp2 = 0.27.

CONCLUSION: People with SMD benefit from elaborated encoding, although not to the same extent as HOAs. This objective difference in complex learning and memory suggests neural changes in SMD that may represent preclinical AD. Elaborated encoding is a promising technique to help maintain memory and decrease anxiety in this at-risk population.

%B J Alzheimers Dis %V 47 %P 705-13 %8 2015 Aug 3 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401705?dopt=Abstract %R 10.3233/JAD-150062 %0 Journal Article %J J Alzheimers Dis %D 2015 %T sAβPPα is a Potent Endogenous Inhibitor of BACE1. %A Peters-Libeu, Clare %A Campagna, Jesus %A Mitsumori, Michael %A Poksay, Karen S %A Spilman, Patricia %A Sabogal, Alex %A Bredesen, Dale E %A John, Varghese %X

Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by the enzyme BACE1 (BACE) is the initial step in production of amyloid-β peptide (Aβ), and as such has been a major target of Alzheimer's disease (AD) drug discovery efforts. Overproduction of Aβ results in neuronal cell death and accumulation of amyloid plaques in AD and in traumatic brain injury, and is also associated with stroke due to cerebral amyloid angiopathy. Herein we report for the first time that sAβPPα, the product of the cleavage of AβPP by α-secretase, is a potent endogenous direct inhibitor of the BACE enzyme, and that its inhibition is likely by an allosteric mechanism. Furthermore, using small-angle X-ray scattering, we show that sAβPPβ, which is identical to sAβPPα except for a 16-amino acid truncation at the carboxy terminus, adopts a completely different structure than sAβPPα and does not inhibit BACE. Our data thus reveal a novel mechanistic role played by sAβPPα in regulating overproduction of Aβ and restoring neuronal homeostasis and neuroprotection. Identification of sAβPPα as a direct BACE inhibitor may lead to design of new therapeutics targeting pathologies associated with overproduction of Aβ.

%B J Alzheimers Dis %V 47 %P 545-55 %8 2015 Aug 3 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401691?dopt=Abstract %R 10.3233/JAD-150282 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Subtle Cognitive Decline and Biomarker Staging in Preclinical Alzheimer's Disease. %A Edmonds, Emily C %A Delano-Wood, Lisa %A Galasko, Douglas R %A Salmon, David P %A Bondi, Mark W %X

The NIA-AA criteria for "preclinical" Alzheimer's disease (AD) propose a staging method in which AD biomarkers follow an invariable temporal sequence in accordance with the amyloid cascade hypothesis. However, recent findings do not align with the proposed temporal sequence and "subtle cognitive decline," which has not been definitively operationalized, may occur earlier than suggested in preclinical AD. We aimed to define "subtle cognitive decline" using sensitive and reliable neuropsychological tests, and to examine the number and sequence of biomarker abnormalities in the Alzheimer's Disease Neuroimaging Initiative (ADNI). 570 cognitively normal ADNI participants were classified based on NIA-AA criteria and separately based on the number of abnormal biomarkers/cognitive markers associated with preclinical AD that each individual possessed. Results revealed that neurodegeneration alone was 2.5 times more common than amyloidosis alone at baseline. For those who demonstrated only one abnormal biomarker at baseline and later progressed to mild cognitive impairment/AD, neurodegeneration alone was most common, followed by amyloidosis alone or subtle cognitive decline alone, which were equally common. Findings suggest that most individuals do not follow the temporal order proposed by NIA-AA criteria. We provide an operational definition of subtle cognitive decline that captures both cognitive and functional decline. Additionally, we offer a new approach for staging preclinical AD based on number of abnormal biomarkers, without regard to their temporal order of occurrence. This method of characterizing preclinical AD is more parsimonious than the NIA-AA staging system and does not presume that all patients follow a singular invariant expression of the disease.

%B J Alzheimers Dis %V 47 %P 231-42 %8 2015 Jul 9 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26402771?dopt=Abstract %R 10.3233/JAD-150128 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Tau and Amyloid-β Cerebrospinal Fluid Biomarkers have Differential Relationships with Cognition in Mild Cognitive Impairment. %A Malpas, Charles B %A Saling, Michael M %A Velakoulis, Dennis %A Desmond, Patricia %A O'Brien, Terence J %X

Alzheimer's disease (AD) is characterized by two primary pathologies: tau-related neurofibrillary tangles and the extracellular accumulation of amyloid-β (Aβ). The development of these pathologies is topologically distinct early in the disease, with Aβ beginning to accumulate as a diffuse, neocortical pathology, while tau-related pathology begins to form in mesial temporal regions. This study investigated the hypothesis that, by virtue of this distinction, there exist preferential associations between the primary pathologies and aspects of the cognitive phenotype. We investigated the relationship between cerebrospinal fluid (CSF) biomarkers for tau and Aβ pathologies with neurocognitive measures in 191 patients with mild cognitive impairment (MCI). Participants completed cognitive tests of new learning, information processing speed, and working memory. Separate regression models were computed and then followed up with mediation analyses to examine the predictive status of CSF biomarkers. The effect of Aβ on learning was mediated by phospho-tau (p = 0.008). In contrast, Aβ had a direct effect on information processing speed that was not mediated by phospho-tau (p = 0.59). No predictors were significant for working memory. This study provided evidence for a differential relationship of Aβ and phospho-tau pathologies on the neurocognitive phenotype of MCI. This supports the proposition that these primary AD pathologies maximally affect different aspects of cognition, and has potential implications for cognitive assessments and the use of biomarkers in disease-modifyingtherapeutic trials.

%B J Alzheimers Dis %V 47 %P 965-75 %8 2015 Aug 11 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401775?dopt=Abstract %R 10.3233/JAD-142643 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Tracking Discourse Complexity Preceding Alzheimer's Disease Diagnosis: A Case Study Comparing the Press Conferences of Presidents Ronald Reagan and George Herbert Walker Bush. %A Berisha, Visar %A Wang, Shuai %A LaCross, Amy %A Liss, Julie %X

Changes in some lexical features of language have been associated with the onset and progression of Alzheimer's disease. Here we describe a method to extract key features from discourse transcripts, which we evaluated on non-scripted news conferences from President Ronald Reagan, who was diagnosed with Alzheimer's disease in 1994, and President George Herbert Walker Bush, who has no known diagnosis of Alzheimer's disease. Key word counts previously associated with cognitive decline in Alzheimer's disease were extracted and regression analyses were conducted. President Reagan showed a significant reduction in the number of unique words over time and a significant increase in conversational fillers and non-specific nouns over time. There was no significant trend in these features for President Bush.

%B J Alzheimers Dis %8 2015 Jan 29 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/25633673?dopt=Abstract %R 10.3233/JAD-142763 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Variants in Antiviral Genes are Risk Factors for Cognitive Decline and Dementia. %A Licastro, Federico %A Raschi, Elena %A Carbone, Ilaria %A Porcellini, Elisa %X

A gene association study of factors regulating antiviral response such as interferon (IFN)-λ3, also known as IL-28B, mediator complex (Med) 23, and interferon regulatory factor (IRF) 7 with cognitive deterioration and Alzheimer's disease (AD) was performed. Differences in the TT genotype distribution of IL-28B single nucleotide polymorphism (SNP) between AD patients and controls were found. The GG genotype of Med23 gene appeared to influence the progression of the disease, being more frequent in the APOE ε4 negative elderly that developed AD during the five year follow-up. Leukocyte positivity for Epstein Barr virus (EBV) and human herpes virus (HHV)-6 DNA was analyzed. Med23 GG genotype correlated with the positivity to HHV-6 DNA. EBV and HHV-6 plasma IgG levels were also investigated and EBV IgG levels were increased in AD with the IRF7 GG genotype. A differential genetic background in genes regulating anti-virus responses was associated with an increased risk of cognitive decline and AD. EBV and HHV-6 appeared to be risk factors for AD in genetically susceptible elderly.

%B J Alzheimers Dis %8 2015 Apr 2 %G eng %R 10.3233/JAD-142718 %0 Journal Article %J Lancet Neurol %D 2014 %T Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. %A Dubois, Bruno %A Feldman, Howard H %A Jacova, Claudia %A Hampel, Harald %A Molinuevo, José Luis %A Blennow, Kaj %A DeKosky, Steven T %A Gauthier, Serge %A Selkoe, Dennis %A Bateman, Randall %A Cappa, Stefano %A Crutch, Sebastian %A Engelborghs, Sebastiaan %A Frisoni, Giovanni B %A Fox, Nick C %A Galasko, Douglas %A Habert, Marie-Odile %A Jicha, Gregory A %A Nordberg, Agneta %A Pasquier, Florence %A Rabinovici, Gil %A Robert, Philippe %A Rowe, Christopher %A Salloway, Stephen %A Sarazin, Marie %A Epelbaum, Stéphane %A de Souza, Leonardo C %A Vellas, Bruno %A Visser, Pieter J %A Schneider, Lon %A Stern, Yaakov %A Scheltens, Philip %A Cummings, Jeffrey L %K Alzheimer Disease %K Biomarkers %K Humans %K International Cooperation %K Phenotype %K Practice Guidelines as Topic %K Societies, Medical %X

In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.

%B Lancet Neurol %V 13 %P 614-29 %8 2014 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24849862?dopt=Abstract %R 10.1016/S1474-4422(14)70090-0 %0 Journal Article %J Nature %D 2014 %T C9orf72 nucleotide repeat structures initiate molecular cascades of disease. %A Haeusler, Aaron R %A Donnelly, Christopher J %A Periz, Goran %A Simko, Eric A J %A Shaw, Patrick G %A Kim, Min-Sik %A Maragakis, Nicholas J %A Troncoso, Juan C %A Pandey, Akhilesh %A Sattler, Rita %A Rothstein, Jeffrey D %A Wang, Jiou %K Amyotrophic Lateral Sclerosis %K B-Lymphocytes %K Base Sequence %K Cell Nucleolus %K DNA %K DNA Repeat Expansion %K Frontotemporal Dementia %K G-Quadruplexes %K HEK293 Cells %K Humans %K Models, Molecular %K Neurons %K Open Reading Frames %K Phosphoproteins %K Ribonucleoproteins %K RNA %K RNA-Binding Proteins %K Stress, Physiological %K Transcription, Genetic %X

A hexanucleotide repeat expansion (HRE), (GGGGCC)n, in C9orf72 is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA•DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.

%B Nature %V 507 %P 195-200 %8 2014 Mar 13 %G eng %N 7491 %1 http://www.ncbi.nlm.nih.gov/pubmed/24598541?dopt=Abstract %R 10.1038/nature13124 %0 Journal Article %J N Engl J Med %D 2014 %T Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. %A Doody, Rachelle S %A Thomas, Ronald G %A Farlow, Martin %A Iwatsubo, Takeshi %A Vellas, Bruno %A Joffe, Steven %A Kieburtz, Karl %A Raman, Rema %A Sun, Xiaoying %A Aisen, Paul S %A Siemers, Eric %A Liu-Seifert, Hong %A Mohs, Richard %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Antibodies, Monoclonal, Humanized %K Apolipoproteins E %K Biomarkers %K Cognition %K Double-Blind Method %K Female %K Humans %K Intention to Treat Analysis %K Male %K Neuropsychological Tests %K Severity of Illness Index %K tau Proteins %K Treatment Failure %X

BACKGROUND: Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain.

METHODS: In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease.

RESULTS: Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was -0.8 points for the ADAS-cog11 score (95% confidence interval [CI], -2.1 to 0.5; P=0.24) and -0.4 points for the ADCS-ADL score (95% CI, -2.3 to 1.4; P=0.64) in EXPEDITION 1 and -1.3 points (95% CI, -2.5 to 0.3; P=0.06) and 1.6 points (95% CI, -0.2 to 3.3; P=0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were -1.7 points in patients with mild Alzheimer's disease (95% CI, -3.5 to 0.1; P=0.06) and -1.5 in patients with moderate Alzheimer's disease (95% CI, -4.1 to 1.1; P=0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P=0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P=0.49).

CONCLUSIONS: Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 and NCT00904683.).

%B N Engl J Med %V 370 %P 311-21 %8 2014 Jan 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24450890?dopt=Abstract %R 10.1056/NEJMoa1312889 %0 Journal Article %J Nat Med %D 2014 %T Plasma phospholipids identify antecedent memory impairment in older adults. %A Mapstone, Mark %A Cheema, Amrita K %A Fiandaca, Massimo S %A Zhong, Xiaogang %A Mhyre, Timothy R %A MacArthur, Linda H %A Hall, William J %A Fisher, Susan G %A Peterson, Derick R %A Haley, James M %A Nazar, Michael D %A Rich, Steven A %A Berlau, Dan J %A Peltz, Carrie B %A Tan, Ming T %A Kawas, Claudia H %A Federoff, Howard J %K Aged %K Alzheimer Disease %K Asparagine %K Biomarkers %K Carnitine %K Cohort Studies %K Dipeptides %K Female %K Humans %K Longitudinal Studies %K Lysophosphatidylcholines %K Malates %K Male %K Memory Disorders %K Metabolome %K Mild Cognitive Impairment %K Neuropsychological Tests %K Phosphatidylcholines %K Phosphatidylinositols %K Phospholipids %K Proline %K Prospective Studies %K Sensitivity and Specificity %K Sphingomyelins %K Ursodeoxycholic Acid %X

Alzheimer's disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies. Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-β levels, structural and functional magnetic resonance imaging and the recent use of brain amyloid imaging or inflammaging, are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimer's disease with the required sensitivity and specificity. Herein, we describe our lipidomic approach to detecting preclinical Alzheimer's disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer's disease within a 2-3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimer's disease.

%B Nat Med %V 20 %P 415-8 %8 2014 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24608097?dopt=Abstract %R 10.1038/nm.3466 %0 Journal Article %J Nature %D 2014 %T REST and stress resistance in ageing and Alzheimer's disease. %A Lu, Tao %A Aron, Liviu %A Zullo, Joseph %A Pan, Ying %A Kim, Haeyoung %A Chen, Yiwen %A Yang, Tun-Hsiang %A Kim, Hyun-Min %A Drake, Derek %A Liu, X Shirley %A Bennett, David A %A Colaiácovo, Monica P %A Yankner, Bruce A %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Autophagy %K Brain %K Caenorhabditis elegans Proteins %K Cell Death %K Cell Nucleus %K Chromatin Immunoprecipitation %K Cognition %K DNA-Binding Proteins %K Down-Regulation %K Frontotemporal Dementia %K Gene Expression Regulation %K Humans %K Lewy Body Disease %K Longevity %K Mice %K Mild Cognitive Impairment %K Neurons %K Neuroprotective Agents %K Oxidative Stress %K Phagosomes %K Repressor Proteins %K Transcription Factors %K Up-Regulation %K Wnt Signaling Pathway %K Young Adult %X

Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

%B Nature %V 507 %P 448-54 %8 2014 Mar 27 %G eng %N 7493 %1 http://www.ncbi.nlm.nih.gov/pubmed/24670762?dopt=Abstract %R 10.1038/nature13163 %0 Journal Article %J J Am Geriatr Soc %D 2014 %T Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. %A Rebok, George W %A Ball, Karlene %A Guey, Lin T %A Jones, Richard N %A Kim, Hae-Young %A King, Jonathan W %A Marsiske, Michael %A Morris, John N %A Tennstedt, Sharon L %A Unverzagt, Frederick W %A Willis, Sherry L %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Aging %K Cognition Disorders %K Cognitive Therapy %K Female %K Follow-Up Studies %K Humans %K Independent Living %K Male %K Memory Disorders %K Mental Processes %K Single-Blind Method %K United States %X

OBJECTIVES: To determine the effects of cognitive training on cognitive abilities and everyday function over 10 years.

DESIGN: Ten-year follow-up of a randomized, controlled single-blind trial (Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE)) with three intervention groups and a no-contact control group.

SETTING: Six U.S. cities.

PARTICIPANTS: A volunteer sample of 2,832 persons (mean baseline age 73.6; 26% African American) living independently.

INTERVENTION: Ten training sessions for memory, reasoning, or speed of processing; four sessions of booster training 11 and 35 months after initial training.

MEASUREMENTS: Objectively measured cognitive abilities and self-reported and performance-based measures of everyday function.

RESULTS: Participants in each intervention group reported less difficulty with instrumental activities of daily living (IADLs) (memory: effect size = 0.48, 99% confidence interval (CI) = 0.12-0.84; reasoning: effect size = 0.38, 99% CI = 0.02-0.74; speed of processing: effect size = 0.36, 99% CI = 0.01-0.72). At a mean age of 82, approximately 60% of trained participants, versus 50% of controls (P < .05), were at or above their baseline level of self-reported IADL function at 10 years. The reasoning and speed-of-processing interventions maintained their effects on their targeted cognitive abilities at 10 years (reasoning: effect size = 0.23, 99% CI = 0.09-0.38; speed of processing: effect size = 0.66, 99% CI = 0.43-0.88). Memory training effects were no longer maintained for memory performance. Booster training produced additional and durable improvement for the reasoning intervention for reasoning performance (effect size = 0.21, 99% CI = 0.01-0.41) and the speed-of-processing intervention for speed-of-processing performance (effect size = 0.62, 99% CI = 0.31-0.93).

CONCLUSION: Each Advanced Cognitive Training for Independent and Vital Elderly cognitive intervention resulted in less decline in self-reported IADL compared with the control group. Reasoning and speed, but not memory, training resulted in improved targeted cognitive abilities for 10 years.

%B J Am Geriatr Soc %V 62 %P 16-24 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24417410?dopt=Abstract %R 10.1111/jgs.12607 %0 Journal Article %J Nature %D 2014 %T A three-dimensional human neural cell culture model of Alzheimer's disease. %A Choi, Se Hoon %A Kim, Young Hye %A Hebisch, Matthias %A Sliwinski, Christopher %A Lee, Seungkyu %A D'Avanzo, Carla %A Chen, Hechao %A Hooli, Basavaraj %A Asselin, Caroline %A Muffat, Julien %A Klee, Justin B %A Zhang, Can %A Wainger, Brian J %A Peitz, Michael %A Kovacs, Dora M %A Woolf, Clifford J %A Wagner, Steven L %A Tanzi, Rudolph E %A Kim, Doo Yeon %K Alzheimer Disease %K Amyloid beta-Peptides %K Cell Culture Techniques %K Cell Differentiation %K Drug Evaluation, Preclinical %K Extracellular Space %K Glycogen Synthase Kinase 3 %K Humans %K Microtubule-Associated Proteins %K Models, Biological %K Neural Stem Cells %K Neurites %K Phosphorylation %K Presenilin-1 %K Protein Aggregation, Pathological %K Reproducibility of Results %K tau Proteins %X

Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer's disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders.

%B Nature %V 515 %P 274-8 %8 2014 Nov 13 %G eng %N 7526 %1 http://www.ncbi.nlm.nih.gov/pubmed/25307057?dopt=Abstract %R 10.1038/nature13800 %0 Journal Article %J N Engl J Med %D 2014 %T Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. %A Salloway, Stephen %A Sperling, Reisa %A Fox, Nick C %A Blennow, Kaj %A Klunk, William %A Raskind, Murray %A Sabbagh, Marwan %A Honig, Lawrence S %A Porsteinsson, Anton P %A Ferris, Steven %A Reichert, Marcel %A Ketter, Nzeera %A Nejadnik, Bijan %A Guenzler, Volkmar %A Miloslavsky, Maja %A Wang, Daniel %A Lu, Yuan %A Lull, Julia %A Tudor, Iulia Cristina %A Liu, Enchi %A Grundman, Michael %A Yuen, Eric %A Black, Ronald %A Brashear, H Robert %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Antibodies, Monoclonal, Humanized %K Apolipoproteins E %K Biomarkers %K Brain %K Cognition %K Double-Blind Method %K Edema %K Female %K Humans %K Intention to Treat Analysis %K Male %K Middle Aged %K Neuropsychological Tests %K Phosphorylation %K Positron-Emission Tomography %K Severity of Illness Index %K tau Proteins %K Treatment Failure %X

BACKGROUND: Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease.

METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations.

RESULTS: There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers.

CONCLUSIONS: Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).

%B N Engl J Med %V 370 %P 322-33 %8 2014 Jan 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24450891?dopt=Abstract %R 10.1056/NEJMoa1304839 %0 Journal Article %J Nat Med %D 2014 %T Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. %A Villeda, Saul A %A Plambeck, Kristopher E %A Middeldorp, Jinte %A Castellano, Joseph M %A Mosher, Kira I %A Luo, Jian %A Smith, Lucas K %A Bieri, Gregor %A Lin, Karin %A Berdnik, Daniela %A Wabl, Rafael %A Udeochu, Joe %A Wheatley, Elizabeth G %A Zou, Bende %A Simmons, Danielle A %A Xie, Xinmin S %A Longo, Frank M %A Wyss-Coray, Tony %K Age Factors %K Aging %K Animals %K Blood Transfusion %K Blotting, Western %K Cell Line %K Cognition Disorders %K Cyclic AMP Response Element-Binding Protein %K DNA Primers %K Hippocampus %K Immunohistochemistry %K Mice %K Mice, Inbred C57BL %K Microarray Analysis %K Neuronal Plasticity %K Parabiosis %K Polymerase Chain Reaction %X

As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

%B Nat Med %V 20 %P 659-63 %8 2014 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24793238?dopt=Abstract %R 10.1038/nm.3569 %0 Journal Article %J Neuron %D 2013 %T Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. %A Griciuc, Ana %A Serrano-Pozo, Alberto %A Parrado, Antonio R %A Lesinski, Andrea N %A Asselin, Caroline N %A Mullin, Kristina %A Hooli, Basavaraj %A Choi, Se Hoon %A Hyman, Bradley T %A Tanzi, Rudolph E %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Case-Control Studies %K Disease Models, Animal %K Genetic Predisposition to Disease %K Humans %K Matched-Pair Analysis %K Mice %K Mice, Inbred C57BL %K Mice, Knockout %K Mice, Transgenic %K Microglia %K Polymorphism, Single Nucleotide %K Reference Values %K RNA, Messenger %K Sialic Acid Binding Ig-like Lectin 3 %X

The transmembrane protein CD33 is a sialic acid-binding immunoglobulin-like lectin that regulates innate immunity but has no known functions in the brain. We have previously shown that the CD33 gene is a risk factor for Alzheimer's disease (AD). Here, we observed increased expression of CD33 in microglial cells in AD brain. The minor allele of the CD33 SNP rs3865444, which confers protection against AD, was associated with reductions in both CD33 expression and insoluble amyloid beta 42 (Aβ42) levels in AD brain. Furthermore, the numbers of CD33-immunoreactive microglia were positively correlated with insoluble Aβ42 levels and plaque burden in AD brain. CD33 inhibited uptake and clearance of Aβ42 in microglial cell cultures. Finally, brain levels of insoluble Aβ42 as well as amyloid plaque burden were markedly reduced in APP(Swe)/PS1(ΔE9)/CD33(-/-) mice. Therefore, CD33 inactivation mitigates Aβ pathology and CD33 inhibition could represent a novel therapy for AD.

%B Neuron %V 78 %P 631-43 %8 2013 May 22 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23623698?dopt=Abstract %R 10.1016/j.neuron.2013.04.014 %0 Journal Article %J Ann Neurol %D 2013 %T Anti-amyloid β autoantibodies in cerebral amyloid angiopathy-related inflammation: implications for amyloid-modifying therapies. %A Piazza, Fabrizio %A Greenberg, Steven M %A Savoiardo, Mario %A Gardinetti, Margherita %A Chiapparini, Luisa %A Raicher, Irina %A Nitrini, Ricardo %A Sakaguchi, Hideya %A Brioschi, Monica %A Billo, Giuseppe %A Colombo, Antonio %A Lanzani, Francesca %A Piscosquito, Giuseppe %A Carriero, Maria Rita %A Giaccone, Giorgio %A Tagliavini, Fabrizio %A Ferrarese, Carlo %A DiFrancesco, Jacopo C %K Adult %K Aged %K Amyloid beta-Peptides %K Apolipoproteins E %K Autoantibodies %K Brain %K Case-Control Studies %K Cerebral Amyloid Angiopathy %K Female %K Humans %K Inflammation %K Male %K Middle Aged %K Peptide Fragments %K Phosphorylation %K Retrospective Studies %K Steroids %K tau Proteins %X

OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid β (Aβ) autoantibodies in the acute and remission phases of CAA-ri.

METHODS: We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aβ autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Aβ40, Aβ42, tau, P-181 tau, and APOE genotype were also investigated.

RESULTS: During the acute phase of CAA-ri, anti-Aβ autoantibodies were specifically increased and directly correlated with Aβ mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aβ and axonal degeneration markers decreased in parallel.

INTERPRETATION: Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Aβ, directly related to autoantibody concentration and soluble Aβ. The CSF dosage of anti-Aβ autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aβ autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA.

%B Ann Neurol %V 73 %P 449-58 %8 2013 Apr %G eng %N 4 %R 10.1002/ana.23857 %0 Journal Article %J Cell %D 2013 %T Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. %A Zhang, Bin %A Gaiteri, Chris %A Bodea, Liviu-Gabriel %A Wang, Zhi %A McElwee, Joshua %A Podtelezhnikov, Alexei A %A Zhang, Chunsheng %A Xie, Tao %A Tran, Linh %A Dobrin, Radu %A Fluder, Eugene %A Clurman, Bruce %A Melquist, Stacey %A Narayanan, Manikandan %A Suver, Christine %A Shah, Hardik %A Mahajan, Milind %A Gillis, Tammy %A Mysore, Jayalakshmi %A MacDonald, Marcy E %A Lamb, John R %A Bennett, David A %A Molony, Cliona %A Stone, David J %A Gudnason, Vilmundur %A Myers, Amanda J %A Schadt, Eric E %A Neumann, Harald %A Zhu, Jun %A Emilsson, Valur %K Adaptor Proteins, Signal Transducing %K Alzheimer Disease %K Animals %K Bayes Theorem %K Brain %K Gene Regulatory Networks %K Humans %K Membrane Proteins %K Mice %K Microglia %X

The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer's disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune- and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD.

%B Cell %V 153 %P 707-20 %8 2013 Apr 25 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23622250?dopt=Abstract %R 10.1016/j.cell.2013.03.030 %0 Journal Article %J Nat Genet %D 2013 %T Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. %A Lambert, J C %A Ibrahim-Verbaas, C A %A Harold, D %A Naj, A C %A Sims, R %A Bellenguez, C %A DeStafano, A L %A Bis, J C %A Beecham, G W %A Grenier-Boley, B %A Russo, G %A Thorton-Wells, T A %A Jones, N %A Smith, A V %A Chouraki, V %A Thomas, C %A Ikram, M A %A Zelenika, D %A Vardarajan, B N %A Kamatani, Y %A Lin, C F %A Gerrish, A %A Schmidt, H %A Kunkle, B %A Dunstan, M L %A Ruiz, A %A Bihoreau, M T %A Choi, S H %A Reitz, C %A Pasquier, F %A Cruchaga, C %A Craig, D %A Amin, N %A Berr, C %A Lopez, O L %A De Jager, P L %A Deramecourt, V %A Johnston, J A %A Evans, D %A Lovestone, S %A Letenneur, L %A Morón, F J %A Rubinsztein, D C %A Eiriksdottir, G %A Sleegers, K %A Goate, A M %A Fiévet, N %A Huentelman, M W %A Gill, M %A Brown, K %A Kamboh, M I %A Keller, L %A Barberger-Gateau, P %A McGuiness, B %A Larson, E B %A Green, R %A Myers, A J %A Dufouil, C %A Todd, S %A Wallon, D %A Love, S %A Rogaeva, E %A Gallacher, J %A St George-Hyslop, P %A Clarimon, J %A Lleo, A %A Bayer, A %A Tsuang, D W %A Yu, L %A Tsolaki, M %A Bossù, P %A Spalletta, G %A Proitsi, P %A Collinge, J %A Sorbi, S %A Sanchez-Garcia, F %A Fox, N C %A Hardy, J %A Deniz Naranjo, M C %A Bosco, P %A Clarke, R %A Brayne, C %A Galimberti, D %A Mancuso, M %A Matthews, F %A Moebus, S %A Mecocci, P %A Del Zompo, M %A Maier, W %A Hampel, H %A Pilotto, A %A Bullido, M %A Panza, F %A Caffarra, P %A Nacmias, B %A Gilbert, J R %A Mayhaus, M %A Lannefelt, L %A Hakonarson, H %A Pichler, S %A Carrasquillo, M M %A Ingelsson, M %A Beekly, D %A Alvarez, V %A Zou, F %A Valladares, O %A Younkin, S G %A Coto, E %A Hamilton-Nelson, K L %A Gu, W %A Razquin, C %A Pastor, P %A Mateo, I %A Owen, M J %A Faber, K M %A Jonsson, P V %A Combarros, O %A O'Donovan, M C %A Cantwell, L B %A Soininen, H %A Blacker, D %A Mead, S %A Mosley, T H %A Bennett, D A %A Harris, T B %A Fratiglioni, L %A Holmes, C %A de Bruijn, R F %A Passmore, P %A Montine, T J %A Bettens, K %A Rotter, J I %A Brice, A %A Morgan, K %A Foroud, T M %A Kukull, W A %A Hannequin, D %A Powell, J F %A Nalls, M A %A Ritchie, K %A Lunetta, K L %A Kauwe, J S %A Boerwinkle, E %A Riemenschneider, M %A Boada, M %A Hiltuenen, M %A Martin, E R %A Schmidt, R %A Rujescu, D %A Wang, L S %A Dartigues, J F %A Mayeux, R %A Tzourio, C %A Hofman, A %A Nöthen, M M %A Graff, C %A Psaty, B M %A Jones, L %A Haines, J L %A Holmans, P A %A Lathrop, M %A Pericak-Vance, M A %A Launer, L J %A Farrer, L A %A van Duijn, C M %A Van Broeckhoven, C %A Moskvina, V %A Seshadri, S %A Williams, J %A Schellenberg, G D %A Amouyel, P %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cohort Studies %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

%B Nat Genet %V 45 %P 1452-8 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24162737?dopt=Abstract %R 10.1038/ng.2802 %0 Journal Article %J Cell Stem Cell %D 2013 %T Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. %A Kondo, Takayuki %A Asai, Masashi %A Tsukita, Kayoko %A Kutoku, Yumiko %A Ohsawa, Yutaka %A Sunada, Yoshihide %A Imamura, Keiko %A Egawa, Naohiro %A Yahata, Naoki %A Okita, Keisuke %A Takahashi, Kazutoshi %A Asaka, Isao %A Aoi, Takashi %A Watanabe, Akira %A Watanabe, Kaori %A Kadoya, Chie %A Nakano, Rie %A Watanabe, Dai %A Maruyama, Kei %A Hori, Osamu %A Hibino, Satoshi %A Choshi, Tominari %A Nakahata, Tatsutoshi %A Hioki, Hiroyuki %A Kaneko, Takeshi %A Naitoh, Motoko %A Yoshikawa, Katsuhiro %A Yamawaki, Satoko %A Suzuki, Shigehiko %A Hata, Ryuji %A Ueno, Shu-Ichi %A Seki, Tsuneyoshi %A Kobayashi, Kazuhiro %A Toda, Tatsushi %A Murakami, Kazuma %A Irie, Kazuhiro %A Klein, William L %A Mori, Hiroshi %A Asada, Takashi %A Takahashi, Ryosuke %A Iwata, Nobuhisa %A Yamanaka, Shinya %A Inoue, Haruhisa %K Alzheimer Disease %K Amyloid beta-Peptides %K Cell Differentiation %K Cerebral Cortex %K Docosahexaenoic Acids %K Humans %K Induced Pluripotent Stem Cells %K Intracellular Space %K Models, Biological %K Mutant Proteins %K Neurons %K Oxidative Stress %K Phenotype %K Protein Structure, Quaternary %X

Oligomeric forms of amyloid-β peptide (Aβ) are thought to play a pivotal role in the pathogenesis of Alzheimer's disease (AD), but the mechanism involved is still unclear. Here, we generated induced pluripotent stem cells (iPSCs) from familial and sporadic AD patients and differentiated them into neural cells. Aβ oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693Δ mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated Aβ oligomers were not proteolytically resistant, and docosahexaenoic acid (DHA) treatment alleviated the stress responses in the AD neural cells. Differential manifestation of ER stress and DHA responsiveness may help explain variable clinical results obtained with the use of DHA treatment and suggests that DHA may in fact be effective for a subset of patients. It also illustrates how patient-specific iPSCs can be useful for analyzing AD pathogenesis and evaluating drugs.

%B Cell Stem Cell %V 12 %P 487-96 %8 2013 Apr 4 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23434393?dopt=Abstract %R 10.1016/j.stem.2013.01.009 %0 Journal Article %J Lancet Neurol %D 2013 %T Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. %A Jack, Clifford R %A Knopman, David S %A Jagust, William J %A Petersen, Ronald C %A Weiner, Michael W %A Aisen, Paul S %A Shaw, Leslie M %A Vemuri, Prashanthi %A Wiste, Heather J %A Weigand, Stephen D %A Lesnick, Timothy G %A Pankratz, Vernon S %A Donohue, Michael C %A Trojanowski, John Q %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognition Disorders %K Humans %K Models, Biological %K Nonlinear Dynamics %K tau Proteins %X

In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.

%B Lancet Neurol %V 12 %P 207-16 %8 2013 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23332364?dopt=Abstract %R 10.1016/S1474-4422(12)70291-0 %0 Journal Article %J N Engl J Med %D 2013 %T TREM2 variants in Alzheimer's disease. %A Guerreiro, Rita %A Wojtas, Aleksandra %A Bras, Jose %A Carrasquillo, Minerva %A Rogaeva, Ekaterina %A Majounie, Elisa %A Cruchaga, Carlos %A Sassi, Celeste %A Kauwe, John S K %A Younkin, Steven %A Hazrati, Lilinaz %A Collinge, John %A Pocock, Jennifer %A Lashley, Tammaryn %A Williams, Julie %A Lambert, Jean-Charles %A Amouyel, Philippe %A Goate, Alison %A Rademakers, Rosa %A Morgan, Kevin %A Powell, John %A St George-Hyslop, Peter %A Singleton, Andrew %A Hardy, John %K Aged %K Alzheimer Disease %K Animals %K Brain %K Exome %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Genotyping Techniques %K Heterozygote %K Humans %K Membrane Glycoproteins %K Mice %K Mice, Inbred A %K Mutation %K Receptors, Immunologic %K Risk Factors %K RNA, Messenger %K Sequence Analysis, DNA %X

BACKGROUND: Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.

METHODS: We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice.

RESULTS: We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease.

CONCLUSIONS: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).

%B N Engl J Med %V 368 %P 117-27 %8 2013 Jan 10 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23150934?dopt=Abstract %R 10.1056/NEJMoa1211851 %0 Journal Article %J Arch Gen Psychiatry %D 2012 %T Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. %A Buchhave, Peder %A Minthon, Lennart %A Zetterberg, Henrik %A Wallin, Asa K %A Blennow, Kaj %A Hansson, Oskar %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Female %K Follow-Up Studies %K Humans %K Male %K Mild Cognitive Impairment %K Peptide Fragments %K Predictive Value of Tests %K tau Proteins %K Time Factors %X

CONTEXT: Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease.

OBJECTIVES: To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and β-amyloid 1-42 (Aβ42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD.

DESIGN: A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years).

SETTING: Memory disorder clinic. Patients A total of 137 patients with MCI who underwent lumbar puncture at baseline. MAIN OUTCOME MEASURE Conversion to AD dementia.

RESULTS: During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF Aβ42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P < .001). Baseline CSF Aβ42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline Aβ42:P-tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%.

CONCLUSIONS: Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of Aβ42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aβ metabolism precedes tau-related pathology and neuronal degeneration.

%B Arch Gen Psychiatry %V 69 %P 98-106 %8 2012 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22213792?dopt=Abstract %R 10.1001/archgenpsychiatry.2011.155 %0 Journal Article %J Lancet Neurol %D 2012 %T Cognitive reserve in ageing and Alzheimer's disease. %A Stern, Yaakov %K Aging %K Alzheimer Disease %K Animals %K Cognitive Reserve %K Humans %X

The concept of cognitive reserve provides an explanation for differences between individuals in susceptibility to age-related brain changes or pathology related to Alzheimer's disease, whereby some people can tolerate more of these changes than others and maintain function. Epidemiological studies suggest that lifelong experiences, including educational and occupational attainment, and leisure activities in later life, can increase this reserve. For example, the risk of developing Alzheimer's disease is reduced in individuals with higher educational or occupational attainment. Reserve can conveniently be divided into two types: brain reserve, which refers to differences in the brain structure that may increase tolerance to pathology, and cognitive reserve, which refers to differences between individuals in how tasks are performed that might enable some people to be more resilient to brain changes than others. Greater understanding of the concept of cognitive reserve could lead to interventions to slow cognitive ageing or reduce the risk of dementia.

%B Lancet Neurol %V 11 %P 1006-12 %8 2012 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/23079557?dopt=Abstract %R 10.1016/S1474-4422(12)70191-6 %0 Journal Article %J J Clin Invest %D 2012 %T Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. %A Talbot, Konrad %A Wang, Hoau-Yan %A Kazi, Hala %A Han, Li-Ying %A Bakshi, Kalindi P %A Stucky, Andres %A Fuino, Robert L %A Kawaguchi, Krista R %A Samoyedny, Andrew J %A Wilson, Robert S %A Arvanitakis, Zoe %A Schneider, Julie A %A Wolf, Bryan A %A Bennett, David A %A Trojanowski, John Q %A Arnold, Steven E %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Brain %K Cerebellar Cortex %K Cognition Disorders %K Diabetes Complications %K Drug Resistance %K Female %K Glucose %K Hippocampus %K Humans %K Insulin %K Insulin Receptor Substrate Proteins %K Insulin Resistance %K Insulin-Like Growth Factor I %K Male %K Middle Aged %K Phosphorylation %K Phosphoserine %K Protein Processing, Post-Translational %K Recombinant Proteins %K Signal Transduction %X

While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.

%B J Clin Invest %V 122 %P 1316-38 %8 2012 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22476197?dopt=Abstract %R 10.1172/JCI59903 %0 Journal Article %J Nature %D 2012 %T An epigenetic blockade of cognitive functions in the neurodegenerating brain. %A Gräff, Johannes %A Rei, Damien %A Guan, Ji-Song %A Wang, Wen-Yuan %A Seo, Jinsoo %A Hennig, Krista M %A Nieland, Thomas J F %A Fass, Daniel M %A Kao, Patricia F %A Kahn, Martin %A Su, Susan C %A Samiei, Alireza %A Joseph, Nadine %A Haggarty, Stephen J %A Delalle, Ivana %A Tsai, Li-Huei %K Acetylation %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Disease Models, Animal %K Epigenesis, Genetic %K Gene Expression Regulation %K Gene Knockdown Techniques %K Hippocampus %K Histone Deacetylase 2 %K Histones %K Humans %K Hydrogen Peroxide %K Memory Disorders %K Mice %K Neurodegenerative Diseases %K Neuronal Plasticity %K Peptide Fragments %K Phosphorylation %K Promoter Regions, Genetic %K Receptors, Glucocorticoid %K RNA Polymerase II %X

Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer's-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer's disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.

%B Nature %V 483 %P 222-6 %8 2012 Mar 8 %G eng %N 7388 %1 http://www.ncbi.nlm.nih.gov/pubmed/22388814?dopt=Abstract %R 10.1038/nature10849 %0 Journal Article %J Arch Neurol %D 2012 %T Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. %A Head, Denise %A Bugg, Julie M %A Goate, Alison M %A Fagan, Anne M %A Mintun, Mark A %A Benzinger, Tammie %A Holtzman, David M %A Morris, John C %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoprotein E4 %K Brain %K Cognition %K Cohort Studies %K Exercise %K Female %K Genetic Association Studies %K Genotype %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Positron-Emission Tomography %K Regression Analysis %K Surveys and Questionnaires %K Thiazoles %X

OBJECTIVE: APOE ε4 status has been associated with greater cortical amyloid deposition, whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults.

DESIGN: APOE genotyping data and answers to a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB) positron emission tomography. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association.

SETTING: Knight Alzheimer's Disease Research Center at Washington University, St Louis, Missouri.

PARTICIPANTS: A total of 201 cognitively normal adults (135 of whom were women) aged 45 to 88 years were recruited from the Knight Alzheimer's Disease Research Center. Samples of CSF were collected from 165 participants. Amyloid imaging was performed for 163 participants.

RESULTS: APOE ε4 carriers evidenced higher [(11)C]PiB binding (P<.001) and lower CSF Aβ42 levels (P<.001) than did noncarriers. Our previous findings of higher [(11)C]PiB binding (P=.005) and lower CSF Aβ42 levels (P=.009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for [(11)C]PiB binding (P=.008) such that a more sedentary lifestyle was significantly associated with higher [(11)C]PiB binding for ε4 carriers (P=.013) but not for noncarriers (P=.20). All findings remained significant after controlling for age; sex; educational level; body mass index; the presence or history of hypertension, diabetes mellitus, heart problems, or depression; and the interval between assessments.

CONCLUSION: Collectively, these results suggest that cognitively normal sedentary APOE ε4-positive individuals may be at augmented risk for cerebral amyloid deposition.

%B Arch Neurol %V 69 %P 636-43 %8 2012 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/22232206?dopt=Abstract %R 10.1001/archneurol.2011.845 %0 Journal Article %J Nature %D 2012 %T A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. %A Jonsson, Thorlakur %A Atwal, Jasvinder K %A Steinberg, Stacy %A Snaedal, Jon %A Jonsson, Palmi V %A Bjornsson, Sigurbjorn %A Stefansson, Hreinn %A Sulem, Patrick %A Gudbjartsson, Daniel %A Maloney, Janice %A Hoyte, Kwame %A Gustafson, Amy %A Liu, Yichin %A Lu, Yanmei %A Bhangale, Tushar %A Graham, Robert R %A Huttenlocher, Johanna %A Bjornsdottir, Gyda %A Andreassen, Ole A %A Jönsson, Erik G %A Palotie, Aarno %A Behrens, Timothy W %A Magnusson, Olafur T %A Kong, Augustine %A Thorsteinsdottir, Unnur %A Watts, Ryan J %A Stefansson, Kari %K Aging %K Alleles %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Aspartic Acid Endopeptidases %K Cognition %K Cognition Disorders %K Genetic Predisposition to Disease %K HEK293 Cells %K Humans %K Mutation %K Plaque, Amyloid %X

The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.

%B Nature %V 488 %P 96-9 %8 2012 Aug 2 %G eng %N 7409 %1 http://www.ncbi.nlm.nih.gov/pubmed/22801501?dopt=Abstract %R 10.1038/nature11283 %0 Journal Article %J Alzheimers Dement %D 2012 %T National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. %A Hyman, Bradley T %A Phelps, Creighton H %A Beach, Thomas G %A Bigio, Eileen H %A Cairns, Nigel J %A Carrillo, Maria C %A Dickson, Dennis W %A Duyckaerts, Charles %A Frosch, Matthew P %A Masliah, Eliezer %A Mirra, Suzanne S %A Nelson, Peter T %A Schneider, Julie A %A Thal, Dietmar Rudolf %A Thies, Bill %A Trojanowski, John Q %A Vinters, Harry V %A Montine, Thomas J %K Alzheimer Disease %K Brain %K Consensus Development Conferences, NIH as Topic %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K Societies, Medical %K United States %X

A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.

%B Alzheimers Dement %V 8 %P 1-13 %8 2012 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22265587?dopt=Abstract %R 10.1016/j.jalz.2011.10.007 %0 Journal Article %J J Alzheimers Dis %D 2012 %T Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults. %A Calderón-Garcidueñas, Lilian %A Kavanaugh, Michael %A Block, Michelle %A D'Angiulli, Amedeo %A Delgado-Chávez, Ricardo %A Torres-Jardón, Ricardo %A González-Maciel, Angelica %A Reynoso-Robles, Rafael %A Osnaya, Norma %A Villarreal-Calderon, Rodolfo %A Guo, Ruixin %A Hua, Zhaowei %A Zhu, Hongtu %A Perry, George %A Diaz, Philippe %K Adolescent %K Adult %K Age Factors %K Air Pollution %K Child %K Child, Preschool %K Cohort Studies %K Down-Regulation %K Encephalitis %K Female %K Frontal Lobe %K Gene Regulatory Networks %K Humans %K Infant %K Male %K Mexico %K Phosphorylation %K Plaque, Amyloid %K Prions %K tau Proteins %K Young Adult %X

Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% had amyloid-β (Aβ) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aβ plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrP(C)) was seen in highly exposed subjects. The down-regulation of the PrP(C) is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrP(C) and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders.

%B J Alzheimers Dis %V 28 %P 93-107 %8 2012 %G eng %N 1 %R 10.3233/JAD-2011-110722 %0 Journal Article %J Ann Neurol %D 2012 %T An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease. %A Jack, Clifford R %A Knopman, David S %A Weigand, Stephen D %A Wiste, Heather J %A Vemuri, Prashanthi %A Lowe, Val %A Kantarci, Kejal %A Gunter, Jeffrey L %A Senjem, Matthew L %A Ivnik, Robert J %A Roberts, Rosebud O %A Rocca, Walter A %A Boeve, Bradley F %A Petersen, Ronald C %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Aniline Compounds %K Biomarkers %K Brain %K Cognition Disorders %K Disease Progression %K Female %K Fluorodeoxyglucose F18 %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K National Institute on Aging (U.S.) %K Neuropsychological Tests %K Positron-Emission Tomography %K Thiazoles %K United States %X

OBJECTIVE: A workgroup commissioned by the Alzheimer's Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer disease (AD). We performed a preliminary assessment of these guidelines.

METHODS: We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis, and (18) fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cutpoints. A group of 450 cognitively normal (CN) subjects from a population-based sample was used to develop cognitive cutpoints and to assess population frequencies of the different preclinical AD stages using different cutpoint criteria.

RESULTS: The new criteria subdivide the preclinical phase of AD into stages 1 to 3. To classify our CN subjects, 2 additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected non-AD pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cutpoints corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0, 16% stage 1, 12 % stage 2, 3% stage 3, and 23% SNAP.

INTERPRETATION: This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1-3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving only 3% unclassified. Future longitudinal validation of the criteria will be important.

%B Ann Neurol %V 71 %P 765-75 %8 2012 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22488240?dopt=Abstract %R 10.1002/ana.22628 %0 Journal Article %J Sci Transl Med %D 2012 %T A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. %A Iliff, Jeffrey J %A Wang, Minghuan %A Liao, Yonghong %A Plogg, Benjamin A %A Peng, Weiguo %A Gundersen, Georg A %A Benveniste, Helene %A Vates, G Edward %A Deane, Rashid %A Goldman, Steven A %A Nagelhus, Erlend A %A Nedergaard, Maiken %K Amyloid beta-Peptides %K Animals %K Aquaporin 4 %K Astrocytes %K Biological Transport %K Brain %K Cerebral Ventricles %K Cerebrospinal Fluid %K Extracellular Fluid %K Imaging, Three-Dimensional %K Male %K Mice %K Mice, Inbred C57BL %K Microscopy, Fluorescence, Multiphoton %K Water %X

Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.

%B Sci Transl Med %V 4 %P 147ra111 %8 2012 Aug 15 %G eng %N 147 %1 http://www.ncbi.nlm.nih.gov/pubmed/22896675?dopt=Abstract %R 10.1126/scitranslmed.3003748 %0 Journal Article %J Neuron %D 2012 %T Predicting regional neurodegeneration from the healthy brain functional connectome. %A Zhou, Juan %A Gennatas, Efstathios D %A Kramer, Joel H %A Miller, Bruce L %A Seeley, William W %K Aged %K Atrophy %K Brain %K Brain Mapping %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Nerve Net %K Neural Pathways %K Neurodegenerative Diseases %K Oxygen %K Reference Values %X

Neurodegenerative diseases target large-scale neural networks. Four competing mechanistic hypotheses have been proposed to explain network-based disease patterning: nodal stress, transneuronal spread, trophic failure, and shared vulnerability. Here, we used task-free fMRI to derive the healthy intrinsic connectivity patterns seeded by brain regions vulnerable to any of five distinct neurodegenerative diseases. These data enabled us to investigate how intrinsic connectivity in health predicts region-by-region vulnerability to disease. For each illness, specific regions emerged as critical network "epicenters" whose normal connectivity profiles most resembled the disease-associated atrophy pattern. Graph theoretical analyses in healthy subjects revealed that regions with higher total connectional flow and, more consistently, shorter functional paths to the epicenters, showed greater disease-related vulnerability. These findings best fit a transneuronal spread model of network-based vulnerability. Molecular pathological approaches may help clarify what makes each epicenter vulnerable to its targeting disease and how toxic protein species travel between networked brain structures.

%B Neuron %V 73 %P 1216-27 %8 2012 Mar 22 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22445348?dopt=Abstract %R 10.1016/j.neuron.2012.03.004 %0 Journal Article %J Neuron %D 2012 %T Propagation of tau pathology in a model of early Alzheimer's disease. %A de Calignon, Alix %A Polydoro, Manuela %A Suárez-Calvet, Marc %A William, Christopher %A Adamowicz, David H %A Kopeikina, Kathy J %A Pitstick, Rose %A Sahara, Naruhiko %A Ashe, Karen H %A Carlson, George A %A Spires-Jones, Tara L %A Hyman, Bradley T %K Age Factors %K Alzheimer Disease %K Animals %K Disease Models, Animal %K Disease Progression %K Entorhinal Cortex %K Epitopes %K Gene Expression Regulation %K Glial Fibrillary Acidic Protein %K Gliosis %K Hippocampus %K Humans %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Nerve Degeneration %K Neurofibrillary Tangles %K Neurons %K RNA, Messenger %K Serine %K tau Proteins %K Tauopathies %X

Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.

%B Neuron %V 73 %P 685-97 %8 2012 Feb 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22365544?dopt=Abstract %R 10.1016/j.neuron.2011.11.033 %0 Journal Article %J Neuron %D 2012 %T Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. %A Bakker, Arnold %A Krauss, Gregory L %A Albert, Marilyn S %A Speck, Caroline L %A Jones, Lauren R %A Stark, Craig E %A Yassa, Michael A %A Bassett, Susan S %A Shelton, Amy L %A Gallagher, Michela %K Aged %K Aged, 80 and over %K Amnesia %K Brain Mapping %K Case-Control Studies %K Choice Behavior %K Double-Blind Method %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Mild Cognitive Impairment %K Neuropsychological Tests %K Nootropic Agents %K Oxygen %K Photic Stimulation %K Piracetam %K Statistics as Topic %X

Elevated hippocampal activation is observed in conditions that confer risk for Alzheimer's disease, including amnestic mild cognitive impairment (aMCI). Studies in relevant animal models have indicated that overactivity in selective hippocampal circuits contributes to cognitive impairment. Here, we tested the effect of reducing hippocampal activation in aMCI. Under placebo treatment, hippocampal activation in the dentate gyrus/CA3 was elevated in aMCI patients compared to a healthy control group. By using a low dose of the antiepileptic levetiracetam hippocampal activation in aMCI was reduced to a level that did not differ from the control group. Compared to aMCI memory performance under placebo, performance in the scanning task was significantly improved under drug treatment. Contrary to the view that greater hippocampal activation might serve a beneficial function, these results support the view that increased hippocampal activation in aMCI is a dysfunctional condition and that targeting excess hippocampal activity has therapeutic potential.

%B Neuron %V 74 %P 467-74 %8 2012 May 10 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22578498?dopt=Abstract %R 10.1016/j.neuron.2012.03.023 %0 Journal Article %J Brain %D 2011 %T 18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease. %A Fodero-Tavoletti, Michelle T %A Okamura, Nobuyuki %A Furumoto, Shozo %A Mulligan, Rachel S %A Connor, Andrea R %A McLean, Catriona A %A Cao, Diana %A Rigopoulos, Angela %A Cartwright, Glenn A %A O'Keefe, Graeme %A Gong, Sylvia %A Adlard, Paul A %A Barnham, Kevin J %A Rowe, Christopher C %A Masters, Colin L %A Kudo, Yukitsuka %A Cappai, Roberto %A Yanai, Kazuhiko %A Villemagne, Victor L %K Alzheimer Disease %K Analysis of Variance %K Aniline Compounds %K Animals %K Autoradiography %K Binding Sites %K Brain %K Female %K Fluorodeoxyglucose F18 %K Humans %K Immunohistochemistry %K Male %K Mice %K Quinolines %K Radiopharmaceuticals %K tau Proteins %X

While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials.

%B Brain %V 134 %P 1089-100 %8 2011 Apr %G eng %N Pt 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21436112?dopt=Abstract %R 10.1093/brain/awr038 %0 Journal Article %J Neuron %D 2011 %T Anti-aβ therapeutics in Alzheimer's disease: the need for a paradigm shift. %A Golde, Todd E %A Schneider, Lon S %A Koo, Edward H %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Biomarkers %K Clinical Trials as Topic %K Disease Progression %K Health Services Needs and Demand %K Humans %K Translational Medical Research %X

Most current Alzheimer's disease (AD) therapies in advanced phases of development target amyloid β-peptide (Aβ) production, aggregation, or accumulation. Translational models suggest that anti-Aβ therapies may be highly effective if tested as agents to prevent or delay development of the disease or as therapies for asymptomatic patients with very early signs of AD pathology. However, anti-Aβ therapeutics are currently being tested in symptomatic patients where they are likely to be much less effective or ineffective. The lack of alignment between human clinical studies and preclinical studies, together with predictions about optimal trial design based on our understanding of the initiating role of Aβ aggregates in AD, has created a treatment versus prevention dilemma. In this perspective, we discuss why it is imperative to resolve this dilemma and suggest ways for moving forward in the hopes of enhancing the development of truly effective AD therapeutics.

%B Neuron %V 69 %P 203-13 %8 2011 Jan 27 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/21262461?dopt=Abstract %R 10.1016/j.neuron.2011.01.002 %0 Journal Article %J Cell %D 2011 %T Astrocyte-neuron lactate transport is required for long-term memory formation. %A Suzuki, Akinobu %A Stern, Sarah A %A Bozdagi, Ozlem %A Huntley, George W %A Walker, Ruth H %A Magistretti, Pierre J %A Alberini, Cristina M %K Animals %K Arabinose %K Astrocytes %K Glycogen %K Hippocampus %K Imino Furanoses %K Lactic Acid %K Memory, Long-Term %K Monocarboxylic Acid Transporters %K Muscle Proteins %K Neurons %K Rats %K Sugar Alcohols %K Symporters %X

We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation.

%B Cell %V 144 %P 810-23 %8 2011 Mar 4 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/21376239?dopt=Abstract %R 10.1016/j.cell.2011.02.018 %0 Journal Article %J Nature %D 2011 %T Caspase signalling controls microglia activation and neurotoxicity. %A Burguillos, Miguel A %A Deierborg, Tomas %A Kavanagh, Edel %A Persson, Annette %A Hajji, Nabil %A Garcia-Quintanilla, Albert %A Cano, Josefina %A Brundin, Patrik %A Englund, Elisabet %A Venero, Jose L %A Joseph, Bertrand %K Alzheimer Disease %K Animals %K Caspase 3 %K Caspase 7 %K Caspase 8 %K Caspase Inhibitors %K Caspases %K Cell Death %K Cells, Cultured %K Dopamine %K Enzyme Activation %K Frontal Lobe %K Gene Knockdown Techniques %K Humans %K Lipopolysaccharides %K Mice %K Microglia %K Neostriatum %K Neurotoxicity Syndromes %K Parkinson Disease %K Protein Kinase C-delta %K Rats %K Signal Transduction %K Substantia Nigra %K Toll-Like Receptor 4 %X

Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.

%B Nature %V 472 %P 319-24 %8 2011 Apr 21 %G eng %N 7343 %1 http://www.ncbi.nlm.nih.gov/pubmed/21389984?dopt=Abstract %R 10.1038/nature09788 %0 Journal Article %J Alzheimers Dement %D 2011 %T The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. %A McKhann, Guy M %A Knopman, David S %A Chertkow, Howard %A Hyman, Bradley T %A Jack, Clifford R %A Kawas, Claudia H %A Klunk, William E %A Koroshetz, Walter J %A Manly, Jennifer J %A Mayeux, Richard %A Mohs, Richard C %A Morris, John C %A Rossor, Martin N %A Scheltens, Philip %A Carrillo, Maria C %A Thies, Bill %A Weintraub, Sandra %A Phelps, Creighton H %K Alzheimer Disease %K Biomarkers %K Diagnosis, Differential %K Diagnostic Imaging %K Disease Progression %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K Societies, Medical %K United States %X

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

%B Alzheimers Dement %V 7 %P 263-9 %8 2011 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21514250?dopt=Abstract %R 10.1016/j.jalz.2011.03.005 %0 Journal Article %J Alzheimers Dement %D 2011 %T The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. %A Albert, Marilyn S %A DeKosky, Steven T %A Dickson, Dennis %A Dubois, Bruno %A Feldman, Howard H %A Fox, Nick C %A Gamst, Anthony %A Holtzman, David M %A Jagust, William J %A Petersen, Ronald C %A Snyder, Peter J %A Carrillo, Maria C %A Thies, Bill %A Phelps, Creighton H %K Alzheimer Disease %K Biomarkers %K Cognition Disorders %K Diagnosis, Differential %K Diagnostic Imaging %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K Societies, Medical %K United States %X

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer's disease (AD), referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.

%B Alzheimers Dement %V 7 %P 270-9 %8 2011 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21514249?dopt=Abstract %R 10.1016/j.jalz.2011.03.008 %0 Journal Article %J Cell %D 2011 %T Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons. %A Qiang, Liang %A Fujita, Ryousuke %A Yamashita, Toru %A Angulo, Sergio %A Rhinn, Herve %A Rhee, David %A Doege, Claudia %A Chau, Lily %A Aubry, Laetitia %A Vanti, William B %A Moreno, Herman %A Abeliovich, Asa %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Cell Transdifferentiation %K Cells, Cultured %K Fibroblasts %K Humans %K Neurons %K Presenilin-1 %K Presenilin-2 %K Regenerative Medicine %K Skin %X

Directed conversion of mature human cells, as from fibroblasts to neurons, is of potential clinical utility for neurological disease modeling as well as cell therapeutics. Here, we describe the efficient generation of human-induced neuronal (hiN) cells from adult skin fibroblasts of unaffected individuals and Alzheimer's patients, using virally transduced transcription regulators and extrinsic support factors. hiN cells from unaffected individuals display morphological, electrophysiological, and gene expression profiles that typify glutamatergic forebrain neurons and are competent to integrate functionally into the rodent CNS. hiN cells from familial Alzheimer disease (FAD) patients with presenilin-1 or -2 mutations exhibit altered processing and localization of amyloid precursor protein (APP) and increased production of Aβ, relative to the source patient fibroblasts or hiN cells from unaffected individuals. Together, our findings demonstrate directed conversion of human fibroblasts to a neuronal phenotype and reveal cell type-selective pathology in hiN cells derived from FAD patients.

%B Cell %V 146 %P 359-71 %8 2011 Aug 5 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21816272?dopt=Abstract %R 10.1016/j.cell.2011.07.007 %0 Journal Article %J Lancet Neurol %D 2011 %T Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. %A Kapogiannis, Dimitrios %A Mattson, Mark P %K Alzheimer Disease %K Animals %K Brain %K Cognition Disorders %K Energy Metabolism %K Humans %K Nerve Net %X

Epidemiological, neuropathological, and functional neuroimaging evidence implicates global and regional disruptions in brain metabolism and energetics in the pathogenesis of cognitive impairment. Nerve cell microcircuits are modified by excitatory and inhibitory synaptic activity and neurotrophic factors. Ageing and Alzheimer's disease cause perturbations in cellular energy metabolism, level of excitation or inhibition, and neurotrophic factor release, which overwhelm compensatory mechanisms and result in dysfunction of neuronal microcircuits and brain networks. A prolonged positive energy balance impairs the ability of neurons to adapt to oxidative and metabolic stress. Results from experimental studies in animals show how disruptions caused by chronic positive energy balance, such as diabetes, lead to accelerated cognitive ageing and Alzheimer's disease. Therapeutic interventions to allay cognitive dysfunction that target energy metabolism and adaptive stress responses (such as neurotrophin signalling) have been effective in animal models and in preliminary studies in humans.

%B Lancet Neurol %V 10 %P 187-98 %8 2011 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/21147038?dopt=Abstract %R 10.1016/S1474-4422(10)70277-5 %0 Journal Article %J Arch Neurol %D 2011 %T Evidence for ordering of Alzheimer disease biomarkers. %A Jack, Clifford R %A Vemuri, Prashanthi %A Wiste, Heather J %A Weigand, Stephen D %A Aisen, Paul S %A Trojanowski, John Q %A Shaw, Leslie M %A Bernstein, Matthew A %A Petersen, Ronald C %A Weiner, Michael W %A Knopman, David S %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Female %K Hippocampus %K Humans %K Longitudinal Studies %K Male %K Mild Cognitive Impairment %K tau Proteins %X

OBJECTIVE: To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner.

DESIGN: Validation sample.

SETTING: Multisite, referral centers.

PARTICIPANTS: A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the Aβ42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) that were abnormal as cognitive impairment worsened. Cut points demarcating normal vs abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples.

MAIN OUTCOME MEASURES: Three AD biomarkers (ie, the CSF Aβ42 level, the CSF total tau level, and the adjusted hippocampal volume).

RESULTS: Within each clinical group of the entire sample (n = 401), the CSF Aβ42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal Aβ42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P = .05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF Aβ42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months.

CONCLUSIONS: A reduction in the CSF Aβ42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level.

%B Arch Neurol %V 68 %P 1526-35 %8 2011 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21825215?dopt=Abstract %R 10.1001/archneurol.2011.183 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2011 %T Exercise training increases size of hippocampus and improves memory. %A Erickson, Kirk I %A Voss, Michelle W %A Prakash, Ruchika Shaurya %A Basak, Chandramallika %A Szabo, Amanda %A Chaddock, Laura %A Kim, Jennifer S %A Heo, Susie %A Alves, Heloisa %A White, Siobhan M %A Wojcicki, Thomas R %A Mailey, Emily %A Vieira, Victoria J %A Martin, Stephen A %A Pence, Brandt D %A Woods, Jeffrey A %A McAuley, Edward %A Kramer, Arthur F %K Aged %K Aging %K Brain-Derived Neurotrophic Factor %K Enzyme-Linked Immunosorbent Assay %K Exercise %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Memory %K Middle Aged %K Organ Size %K Space Perception %X

The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.

%B Proc Natl Acad Sci U S A %V 108 %P 3017-22 %8 2011 Feb 15 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21282661?dopt=Abstract %R 10.1073/pnas.1015950108 %0 Journal Article %J Sci Transl Med %D 2011 %T Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. %A Castellano, Joseph M %A Kim, Jungsu %A Stewart, Floy R %A Jiang, Hong %A DeMattos, Ronald B %A Patterson, Bruce W %A Fagan, Anne M %A Morris, John C %A Mawuenyega, Kwasi G %A Cruchaga, Carlos %A Goate, Alison M %A Bales, Kelly R %A Paul, Steven M %A Bateman, Randall J %A Holtzman, David M %K Adult %K Aged %K Alleles %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Apolipoprotein E4 %K Biomarkers %K Brain %K Female %K Genotype %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microdialysis %K Middle Aged %K Protein Isoforms %X

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ε4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE ε2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Aβ(42) peptide. However, the mechanism by which APOE alleles differentially modulate Aβ accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of Aβ-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aβ deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Aβ synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.

%B Sci Transl Med %V 3 %P 89ra57 %8 2011 Jun 29 %G eng %N 89 %1 http://www.ncbi.nlm.nih.gov/pubmed/21715678?dopt=Abstract %R 10.1126/scitranslmed.3002156 %0 Journal Article %J Nat Neurosci %D 2011 %T Neuronal activity regulates the regional vulnerability to amyloid-β deposition. %A Bero, Adam W %A Yan, Ping %A Roh, Jee Hoon %A Cirrito, John R %A Stewart, Floy R %A Raichle, Marcus E %A Lee, Jin-Moo %A Holtzman, David M %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Cerebral Cortex %K Disease Models, Animal %K Extracellular Fluid %K Female %K Lactic Acid %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microdialysis %K Neurons %K Plaque, Amyloid %K Sensory Deprivation %K Somatosensory Cortex %X

Amyloid-β (Aβ) plaque deposition in specific brain regions is a pathological hallmark of Alzheimer's disease. However, the mechanism underlying the regional vulnerability to Aβ deposition in Alzheimer's disease is unknown. Herein, we provide evidence that endogenous neuronal activity regulates the regional concentration of interstitial fluid (ISF) Aβ, which drives local Aβ aggregation. Using in vivo microdialysis, we show that ISF Aβ concentrations in several brain regions of APP transgenic mice before plaque deposition were commensurate with the degree of subsequent plaque deposition and with the concentration of lactate, a marker of neuronal activity. Furthermore, unilateral vibrissal stimulation increased ISF Aβ, and unilateral vibrissal deprivation decreased ISF Aβ and lactate, in contralateral barrel cortex. Long-term unilateral vibrissal deprivation decreased amyloid plaque formation and growth. Our results suggest a mechanism to account for the vulnerability of specific brain regions to Aβ deposition in Alzheimer's disease.

%B Nat Neurosci %V 14 %P 750-6 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21532579?dopt=Abstract %R 10.1038/nn.2801 %0 Journal Article %J Nature %D 2011 %T Neuronal basis of age-related working memory decline. %A Wang, Min %A Gamo, Nao J %A Yang, Yang %A Jin, Lu E %A Wang, Xiao-Jing %A Laubach, Mark %A Mazer, James A %A Lee, Daeyeol %A Arnsten, Amy F T %K Action Potentials %K Adrenergic alpha-2 Receptor Agonists %K Aging %K Animals %K Biomedical Enhancement %K Cues %K Cyclic AMP %K Cyclic Nucleotide-Gated Cation Channels %K Guanfacine %K Humans %K Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels %K KCNQ Potassium Channels %K Macaca mulatta %K Male %K Memory, Short-Term %K Models, Neurological %K Neural Pathways %K Potassium Channel Blockers %K Potassium Channels %K Prefrontal Cortex %K Receptors, Adrenergic, alpha-2 %K Signal Transduction %K Time Factors %X

Many of the cognitive deficits of normal ageing (forgetfulness, distractibility, inflexibility and impaired executive functions) involve prefrontal cortex (PFC) dysfunction. The PFC guides behaviour and thought using working memory, which are essential functions in the information age. Many PFC neurons hold information in working memory through excitatory networks that can maintain persistent neuronal firing in the absence of external stimulation. This fragile process is highly dependent on the neurochemical environment. For example, elevated cyclic-AMP signalling reduces persistent firing by opening HCN and KCNQ potassium channels. It is not known if molecular changes associated with normal ageing alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings, to our knowledge, from PFC neurons of aged monkeys. Here we characterize the first recordings of this kind, revealing a marked loss of PFC persistent firing with advancing age that can be rescued by restoring an optimal neurochemical environment. Recordings showed an age-related decline in the firing rate of DELAY neurons, whereas the firing of CUE neurons remained unchanged with age. The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels. These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits.

%B Nature %V 476 %P 210-3 %8 2011 Aug 11 %G eng %N 7359 %1 http://www.ncbi.nlm.nih.gov/pubmed/21796118?dopt=Abstract %R 10.1038/nature10243 %0 Journal Article %J Ann Neurol %D 2011 %T Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. %A Jucker, Mathias %A Walker, Lary C %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K DNA-Binding Proteins %K Humans %K Neurodegenerative Diseases %K Prions %K Proteins %K tau Proteins %X

The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism-corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy body disease, Huntington disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders.

%B Ann Neurol %V 70 %P 532-40 %8 2011 Oct %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22028219?dopt=Abstract %R 10.1002/ana.22615 %0 Journal Article %J Neurology %D 2011 %T Report of the task force on designing clinical trials in early (predementia) AD. %A Aisen, P S %A Andrieu, S %A Sampaio, C %A Carrillo, M %A Khachaturian, Z S %A Dubois, B %A Feldman, H H %A Petersen, R C %A Siemers, E %A Doody, R S %A Hendrix, S B %A Grundman, M %A Schneider, L S %A Schindler, R J %A Salmon, E %A Potter, W Z %A Thomas, R G %A Salmon, D %A Donohue, M %A Bednar, M M %A Touchon, J %A Vellas, B %K Advisory Committees %K Alzheimer Disease %K Amyloidogenic Proteins %K Biomarkers %K Clinical Trials as Topic %K Cognition %K Consensus %K Disease Progression %K Drug Industry %K Early Diagnosis %K Europe %K Humans %K Indans %K International Cooperation %K Nootropic Agents %K Outcome Assessment (Health Care) %K Patient Selection %K Piperidines %K Positron-Emission Tomography %K Research Design %K Treatment Outcome %K United States %K United States Food and Drug Administration %K Vitamin E %X

BACKGROUND: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia.

METHOD: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD.

RESULTS: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods.

CONCLUSION: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.

%B Neurology %V 76 %P 280-6 %8 2011 Jan 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21178097?dopt=Abstract %R 10.1212/WNL.0b013e318207b1b9 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2011 %T Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. %A Jin, Ming %A Shepardson, Nina %A Yang, Ting %A Chen, Gang %A Walsh, Dominic %A Selkoe, Dennis J %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Blotting, Western %K Chromatography, Gel %K Dimerization %K Genetic Vectors %K Hippocampus %K Humans %K Immunohistochemistry %K Immunoprecipitation %K In Situ Nick-End Labeling %K Lentivirus %K Microscopy, Confocal %K Microtubules %K Neurites %K Phosphorylation %K Rats %K Rats, Sprague-Dawley %K tau Proteins %X

Alzheimer disease is a major cause of cognitive failure, and a pathogenically related but more subtle process accounts for many cases of mild memory symptoms in older humans. Insoluble fibrillar plaques of amyloid β-proteins (Aβ) and neurofibrillary deposits of hyperphosphorylated tau proteins are the diagnostic lesions of AD, but their temporal mechanistic relationship has long been debated. The recent recognition that small, diffusible oligomers may be the principal bioactive form of Aβ raises the key question of whether these are sufficient to initiate cytoskeletal change and neurite degeneration. A few studies have examined the effects of oligomers of synthetic Aβ peptides of one defined length at supraphysiological concentrations, but the existence of such assemblies in the AD brain is not established. Here, we isolated Aβ dimers, the most abundant form of soluble oligomer detectable in the human brain, from the cortices of typical AD subjects and found that at subnanomolar concentrations, they first induced hyperphosphorylation of tau at AD-relevant epitopes in hippocampal neurons and then disrupted the microtubule cytoskeleton and caused neuritic degeneration, all in the absence of amyloid fibrils. Application of pure, synthetic dimers confirmed the effects of the natural AD dimers, although the former were far less potent. Knocking down endogenous tau fully prevented the neuritic changes, whereas overexpressing human tau accelerated them. Coadministering Aβ N-terminal antibodies neutralized the cytoskeletal disruption. We conclude that natural dimers isolated from the AD brain are sufficient to potently induce AD-type tau phosphorylation and then neuritic dystrophy, but passive immunotherapy mitigates this.

%B Proc Natl Acad Sci U S A %V 108 %P 5819-24 %8 2011 Apr 5 %G eng %N 14 %1 http://www.ncbi.nlm.nih.gov/pubmed/21421841?dopt=Abstract %R 10.1073/pnas.1017033108 %0 Journal Article %J J Neuropathol Exp Neurol %D 2011 %T Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. %A Braak, Heiko %A Thal, Dietmar R %A Ghebremedhin, Estifanos %A Del Tredici, Kelly %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Brain %K Child %K Child, Preschool %K Cohort Studies %K Disease Progression %K Female %K Humans %K Infant %K Male %K Middle Aged %K Neurofibrillary Tangles %K Neurons %K Silver Staining %K Statistics, Nonparametric %K tau Proteins %K Young Adult %X

Two thousand three hundred and thirty two nonselected brains from 1- to 100-year-old individuals were examined using immunocytochemistry (AT8) and Gallyas silver staining for abnormal tau; immunocytochemistry (4G8) and Campbell-Switzer staining were used for the detection ofβ-amyloid. A total of 342 cases was negative in the Gallyas stain but when restaged for AT8 only 10 were immunonegative. Fifty-eight cases had subcortical tau predominantly in the locus coeruleus, but there was no abnormal cortical tau (subcortical Stages a-c). Cortical involvement (abnormal tau in neurites) was identified first in the transentorhinal region (Stage 1a, 38 cases). Transentorhinal pyramidal cells displayed pretangle material (Stage 1b, 236 cases). Pretangles gradually became argyrophilic neurofibrillary tangles (NFTs) that progressed in parallel with NFT Stages I to VI. Pretangles restricted to subcortical sites were seen chiefly at younger ages. Of the total cases, 1,031 (44.2%) had β-amyloid plaques. The first plaques occurred in the neocortex after the onset of tauopathy in the brainstem. Plaques generally developed in the 40s in 4% of all cases, culminating in their tenth decade (75%). β-amyloid plaques and NFTs were significantly correlated (p < 0.0001). These data suggest that tauopathy associated with sporadic Alzheimer disease may begin earlier than previously thought and possibly in the lower brainstem rather than in the transentorhinal region.

%B J Neuropathol Exp Neurol %V 70 %P 960-9 %8 2011 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/22002422?dopt=Abstract %R 10.1097/NEN.0b013e318232a379 %0 Journal Article %J Alzheimers Dement %D 2011 %T Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. %A Sperling, Reisa A %A Aisen, Paul S %A Beckett, Laurel A %A Bennett, David A %A Craft, Suzanne %A Fagan, Anne M %A Iwatsubo, Takeshi %A Jack, Clifford R %A Kaye, Jeffrey %A Montine, Thomas J %A Park, Denise C %A Reiman, Eric M %A Rowe, Christopher C %A Siemers, Eric %A Stern, Yaakov %A Yaffe, Kristine %A Carrillo, Maria C %A Thies, Bill %A Morrison-Bogorad, Marcelle %A Wagster, Molly V %A Phelps, Creighton H %K Alzheimer Disease %K Biomarkers %K Cognition Disorders %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K United States %X

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

%B Alzheimers Dement %V 7 %P 280-92 %8 2011 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21514248?dopt=Abstract %R 10.1016/j.jalz.2011.03.003 %0 Journal Article %J Neurology %D 2011 %T Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. %A Li, J %A Wang, Y J %A Zhang, M %A Xu, Z Q %A Gao, C Y %A Fang, C Q %A Yan, J C %A Zhou, H D %K Aged %K Alzheimer Disease %K Cerebrovascular Disorders %K Cognition Disorders %K Disease Progression %K Female %K Humans %K Incidence %K Longitudinal Studies %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptides %K Regression Analysis %K Residence Characteristics %K Retrospective Studies %K Risk Factors %K Statistics, Nonparametric %X

OBJECTIVE: Growing evidence suggests that vascular risk factors (VRF) contribute to cognitive decline. The aim of this study was to investigate the impact of VRF on the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD) dementia.

METHODS: A total of 837 subjects with MCI were enrolled at baseline and followed up annually for 5 years. The incidence of AD dementia was investigated. A mixed random effects regression model was used to analyze the association between VRF and the progression of MCI assessed with Mini-Mental State Examination and instrumental Activities of Daily Living. Cox proportional hazard models were used to identify the association between VRF and dementia conversion, and to examine whether treatment of VRF can prevent dementia conversion.

RESULTS: At the end of the follow-up, 298 subjects converted to AD dementia, while 352 remained MCI. Subjects with VRF had a faster progression in cognition and function relative to subjects without. VRF including hypertension, diabetes, cerebrovascular diseases, and hypercholesterolemia increased the risk of dementia conversion. Those subjects with MCI in whom all VRF were treated had a lower risk of dementia than those who had some VRF treated. Treatment of individual VRF including hypertension, diabetes, and hypercholesterolemia was associated with the reduced risk of AD conversion.

CONCLUSION: VRF increased the risk of incident AD dementia. Treatment of VRF was associated with a reduced risk of incident AD dementia. Although our findings are observational, they suggest active intervention for VRF might reduce progression in MCI to AD dementia.

%B Neurology %V 76 %P 1485-91 %8 2011 Apr 26 %G eng %N 17 %1 http://www.ncbi.nlm.nih.gov/pubmed/21490316?dopt=Abstract %R 10.1212/WNL.0b013e318217e7a4 %0 Journal Article %J Neurology %D 2010 %T Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization. %A Petersen, R C %A Aisen, P S %A Beckett, L A %A Donohue, M C %A Gamst, A C %A Harvey, D J %A Jack, C R %A Jagust, W J %A Shaw, L M %A Toga, A W %A Trojanowski, J Q %A Weiner, M W %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Cross-Sectional Studies %K Diagnostic Imaging %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Middle Aged %X

BACKGROUND: Neuroimaging measures and chemical biomarkers may be important indices of clinical progression in normal aging and mild cognitive impairment (MCI) and need to be evaluated longitudinally.

OBJECTIVE: To characterize cross-sectionally and longitudinally clinical measures in normal controls, subjects with MCI, and subjects with mild Alzheimer disease (AD) to enable the assessment of the utility of neuroimaging and chemical biomarker measures.

METHODS: A total of 819 subjects (229 cognitively normal, 398 with MCI, and 192 with AD) were enrolled at baseline and followed for 12 months using standard cognitive and functional measures typical of clinical trials.

RESULTS: The subjects with MCI were more memory impaired than the cognitively normal subjects but not as impaired as the subjects with AD. Nonmemory cognitive measures were only minimally impaired in the subjects with MCI. The subjects with MCI progressed to dementia in 12 months at a rate of 16.5% per year. Approximately 50% of the subjects with MCI were on antidementia therapies. There was minimal movement on the Alzheimer's Disease Assessment Scale-Cognitive Subscale for the normal control subjects, slight movement for the subjects with MCI of 1.1, and a modest change for the subjects with AD of 4.3. Baseline CSF measures of Abeta-42 separated the 3 groups as expected and successfully predicted the 12-month change in cognitive measures.

CONCLUSION: The Alzheimer's Disease Neuroimaging Initiative has successfully recruited cohorts of cognitively normal subjects, subjects with mild cognitive impairment (MCI), and subjects with Alzheimer disease with anticipated baseline characteristics. The 12-month progression rate of MCI was as predicted, and the CSF measures heralded progression of clinical measures over 12 months.

%B Neurology %V 74 %P 201-9 %8 2010 Jan 19 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20042704?dopt=Abstract %R 10.1212/WNL.0b013e3181cb3e25 %0 Journal Article %J Ann Neurol %D 2010 %T APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. %A Morris, John C %A Roe, Catherine M %A Xiong, Chengjie %A Fagan, Anne M %A Goate, Alison M %A Holtzman, David M %A Mintun, Mark A %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoprotein E2 %K Apolipoprotein E4 %K Apolipoproteins E %K Brain %K Female %K Follow-Up Studies %K Genotype %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Peptide Fragments %K Phosphorylation %K Plaque, Amyloid %K tau Proteins %K Thiazoles %X

OBJECTIVE: To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging.

METHODS: Two hundred forty-one cognitively normal individuals, aged 45-88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta(42) (Abeta(42)), tau, and phosphorylated tau (ptau(181)). All individuals were genotyped for APOE.

RESULTS: The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45-49 years to 30.3% at 80-88 years. Reduced levels of CSF Abeta(42) appeared to begin earlier (18.2% of those aged 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There was a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Abeta(42) with increased numbers of APOE4 alleles. Individuals with an APOE2 allele had no increase in MCBP with age and had higher CSF Abeta(42) levels than individuals without an APOE2 allele. There was no APOE4 or APOE2 effect on CSF tau or ptau(181).

INTERPRETATION: Increasing cerebral Abeta deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Abeta deposition may first be lowered CSF Abeta(42), followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.

%B Ann Neurol %V 67 %P 122-31 %8 2010 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20186853?dopt=Abstract %R 10.1002/ana.21843 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2010 %T Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways. %A Miller, Jeremy A %A Horvath, Steve %A Geschwind, Daniel H %K Alzheimer Disease %K Animals %K Brain %K Gene Expression Profiling %K Gene Regulatory Networks %K Humans %K Male %K Mice %K Presenilin-1 %K Systems Biology %X

Because mouse models play a crucial role in biomedical research related to the human nervous system, understanding the similarities and differences between mouse and human brain is of fundamental importance. Studies comparing transcription in human and mouse have come to varied conclusions, in part because of their relatively small sample sizes or underpowered methodologies. To better characterize gene expression differences between mouse and human, we took a systems-biology approach by using weighted gene coexpression network analysis on more than 1,000 microarrays from brain. We find that global network properties of the brain transcriptome are highly preserved between species. Furthermore, all modules of highly coexpressed genes identified in mouse were identified in human, with those related to conserved cellular functions showing the strongest between-species preservation. Modules corresponding to glial and neuronal cells were sufficiently preserved between mouse and human to permit identification of cross species cell-class marker genes. We also identify several robust human-specific modules, including one strongly correlated with measures of Alzheimer disease progression across multiple data sets, whose hubs are poorly-characterized genes likely involved in Alzheimer disease. We present multiple lines of evidence suggesting links between neurodegenerative disease and glial cell types in human, including human-specific correlation of presenilin-1 with oligodendrocyte markers, and significant enrichment for known neurodegenerative disease genes in microglial modules. Together, this work identifies convergent and divergent pathways in mouse and human, and provides a systematic framework that will be useful for understanding the applicability of mouse models for human brain disorders.

%B Proc Natl Acad Sci U S A %V 107 %P 12698-703 %8 2010 Jul 13 %G eng %N 28 %1 http://www.ncbi.nlm.nih.gov/pubmed/20616000?dopt=Abstract %R 10.1073/pnas.0914257107 %0 Journal Article %J Nature %D 2010 %T Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. %A He, Gen %A Luo, Wenjie %A Li, Peng %A Remmers, Christine %A Netzer, William J %A Hendrick, Joseph %A Bettayeb, Karima %A Flajolet, Marc %A Gorelick, Fred %A Wennogle, Lawrence P %A Greengard, Paul %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Benzamides %K Cell Line %K Disease Models, Animal %K Gene Knockdown Techniques %K Humans %K Imatinib Mesylate %K Mice %K Peptide Fragments %K Piperazines %K Proteins %K Pyrimidines %K Receptor, Notch1 %K RNA Interference %X

Accumulation of neurotoxic amyloid-beta is a major hallmark of Alzheimer's disease. Formation of amyloid-beta is catalysed by gamma-secretase, a protease with numerous substrates. Little is known about the molecular mechanisms that confer substrate specificity on this potentially promiscuous enzyme. Knowledge of the mechanisms underlying its selectivity is critical for the development of clinically effective gamma-secretase inhibitors that can reduce amyloid-beta formation without impairing cleavage of other gamma-secretase substrates, especially Notch, which is essential for normal biological functions. Here we report the discovery of a novel gamma-secretase activating protein (GSAP) that drastically and selectively increases amyloid-beta production through a mechanism involving its interactions with both gamma-secretase and its substrate, the amyloid precursor protein carboxy-terminal fragment (APP-CTF). GSAP does not interact with Notch, nor does it affect its cleavage. Recombinant GSAP stimulates amyloid-beta production in vitro. Reducing GSAP concentrations in cell lines decreases amyloid-beta concentrations. Knockdown of GSAP in a mouse model of Alzheimer's disease reduces levels of amyloid-beta and plaque development. GSAP represents a type of gamma-secretase regulator that directs enzyme specificity by interacting with a specific substrate. We demonstrate that imatinib, an anticancer drug previously found to inhibit amyloid-beta formation without affecting Notch cleavage, achieves its amyloid-beta-lowering effect by preventing GSAP interaction with the gamma-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-beta-lowering therapeutic target without affecting other key functions of gamma-secretase.

%B Nature %V 467 %P 95-8 %8 2010 Sep 2 %G eng %N 7311 %1 http://www.ncbi.nlm.nih.gov/pubmed/20811458?dopt=Abstract %R 10.1038/nature09325 %0 Journal Article %J PLoS One %D 2010 %T Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. %A Jones, Lesley %A Holmans, Peter A %A Hamshere, Marian L %A Harold, Denise %A Moskvina, Valentina %A Ivanov, Dobril %A Pocklington, Andrew %A Abraham, Richard %A Hollingworth, Paul %A Sims, Rebecca %A Gerrish, Amy %A Pahwa, Jaspreet Singh %A Jones, Nicola %A Stretton, Alexandra %A Morgan, Angharad R %A Lovestone, Simon %A Powell, John %A Proitsi, Petroula %A Lupton, Michelle K %A Brayne, Carol %A Rubinsztein, David C %A Gill, Michael %A Lawlor, Brian %A Lynch, Aoibhinn %A Morgan, Kevin %A Brown, Kristelle S %A Passmore, Peter A %A Craig, David %A McGuinness, Bernadette %A Todd, Stephen %A Holmes, Clive %A Mann, David %A Smith, A David %A Love, Seth %A Kehoe, Patrick G %A Mead, Simon %A Fox, Nick %A Rossor, Martin %A Collinge, John %A Maier, Wolfgang %A Jessen, Frank %A Schürmann, Britta %A Heun, Reinhard %A Kölsch, Heike %A van den Bussche, Hendrik %A Heuser, Isabella %A Peters, Oliver %A Kornhuber, Johannes %A Wiltfang, Jens %A Dichgans, Martin %A Frölich, Lutz %A Hampel, Harald %A Hüll, Michael %A Rujescu, Dan %A Goate, Alison M %A Kauwe, John S K %A Cruchaga, Carlos %A Nowotny, Petra %A Morris, John C %A Mayo, Kevin %A Livingston, Gill %A Bass, Nicholas J %A Gurling, Hugh %A McQuillin, Andrew %A Gwilliam, Rhian %A Deloukas, Panos %A Al-Chalabi, Ammar %A Shaw, Christopher E %A Singleton, Andrew B %A Guerreiro, Rita %A Mühleisen, Thomas W %A Nöthen, Markus M %A Moebus, Susanne %A Jöckel, Karl-Heinz %A Klopp, Norman %A Wichmann, H-Erich %A Rüther, Eckhard %A Carrasquillo, Minerva M %A Pankratz, V Shane %A Younkin, Steven G %A Hardy, John %A O'Donovan, Michael C %A Owen, Michael J %A Williams, Julie %K Alzheimer Disease %K Apolipoproteins E %K Cholesterol %K Chromosome Mapping %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Immune System %K Polymorphism, Single Nucleotide %X

BACKGROUND: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.

METHODOLOGY: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.

PRINCIPAL FINDINGS: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.

SIGNIFICANCE: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

%B PLoS One %V 5 %P e13950 %8 2010 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21085570?dopt=Abstract %R 10.1371/journal.pone.0013950 %0 Journal Article %J J Neurosci %D 2010 %T Memory impairment in transgenic Alzheimer mice requires cellular prion protein. %A Gimbel, David A %A Nygaard, Haakon B %A Coffey, Erin E %A Gunther, Erik C %A Laurén, Juha %A Gimbel, Zachary A %A Strittmatter, Stephen M %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Avoidance Learning %K Brain %K Disease Models, Animal %K Maze Learning %K Memory %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Nerve Degeneration %K Presenilin-1 %K PrPC Proteins %K Random Allocation %K Serotonin %K Survival Analysis %X

Soluble oligomers of the amyloid-beta (Abeta) peptide are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). Recently, we reported that synthetic Abeta oligomers bind to cellular prion protein (PrP(C)) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Abeta peptide. We hypothesized that PrP(C) is essential for the ability of brain-derived Abeta to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1DeltaE9 into Prnp-/- mice to examine the necessity of PrP(C) for AD-related phenotypes. Neither APP expression nor Abeta level is altered by PrP(C) absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrP(C) expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1DeltaE9 transgenic mice. The AD transgenic mice with intact PrP(C) expression exhibit deficits in spatial learning and memory. Mice lacking PrP(C), but containing Abeta plaque derived from APPswe/PSen1DeltaE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrP(C) expression dissociates Abeta accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrP(C).

%B J Neurosci %V 30 %P 6367-74 %8 2010 May 5 %G eng %N 18 %1 http://www.ncbi.nlm.nih.gov/pubmed/20445063?dopt=Abstract %R 10.1523/JNEUROSCI.0395-10.2010 %0 Journal Article %J Ann Intern Med %D 2010 %T National Institutes of Health State-of-the-Science Conference statement: preventing alzheimer disease and cognitive decline. %A Daviglus, Martha L %A Bell, Carl C %A Berrettini, Wade %A Bowen, Phyllis E %A Connolly, E Sander %A Cox, Nancy Jean %A Dunbar-Jacob, Jacqueline M %A Granieri, Evelyn C %A Hunt, Gail %A McGarry, Kathleen %A Patel, Dinesh %A Potosky, Arnold L %A Sanders-Bush, Elaine %A Silberberg, Donald %A Trevisan, Maurizio %K Aged %K Alzheimer Disease %K Cognition Disorders %K Evidence-Based Medicine %K Humans %K Risk Factors %K Risk Reduction Behavior %X

The National Institute on Aging and the Office of Medical Applications of Research of the National Institutes of Health convened a State-of-the-Science Conference on 26-28 April 2010 to assess the available scientific evidence on prevention of cognitive decline and Alzheimer disease. This article provides the panel's assessment of the available evidence.

%B Ann Intern Med %V 153 %P 176-81 %8 2010 Aug 3 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20547888?dopt=Abstract %R 10.7326/0003-4819-153-3-201008030-00260 %0 Journal Article %J J Alzheimers Dis %D 2010 %T Neuroinflammation in Alzheimer's disease and mild cognitive impairment: a field in its infancy. %A McGeer, Edith G %A McGeer, Patrick L %K Alzheimer Disease %K Animals %K Cognition Disorders %K Humans %K Inflammation %K Neurology %X

Neuroinflammation is a prominent feature of Alzheimer disease (AD) and other chronic neurodegenerative disorders. It exacerbates the fundamental pathology by generating a plethora of inflammatory mediators and neurotoxic compounds. Inflammatory cytokines, complement components, and toxic free radicals are among the many species that are generated. Microglia attack the pathological entities and may inadvertently injure host neurons. Recent evidence indicates that microglia can be stimulated to assume an antiinflammatory state rather than a proinflammatory state which may have therapeutic potential. Proinflammatory cytokines include IL-1, IL-6 and TNF, while antiinflammatory cytokines include IL-4 and IL-10. Complement activation is a separate process which causes extensive neuronal damage in AD through assembly of the membrane attack complex. Aggregated amyloid-beta is a potent activator of human complement but not of mouse complement. This is an important difference between AD and transgenic mouse models of AD. Many so far unexplored molecules may contribute to neuroinflammation or act to inhibit it. Stable isotope labeling by amino acids in cell culture (SILAC) analysis identified 174 proteins that were upregulated by two-fold or more, and 189 that were downregulated by 2-fold or more following inflammatory stimulation of microglial-like THP-1 cells. Neurotoxicity may result from any combination of these and further exploration is clearly warranted. In addition, many small molecules may play a significant role. One example is hydrogen sulfide which appears to be an endogenous antiinflammatory agent.

%B J Alzheimers Dis %V 19 %P 355-61 %8 2010 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20061650?dopt=Abstract %R 10.3233/JAD-2010-1219 %0 Journal Article %J Curr Alzheimer Res %D 2010 %T Tau in Alzheimer disease and related tauopathies. %A Iqbal, K %A Liu, F %A Gong, C-X %A Grundke-Iqbal, I %K Alzheimer Disease %K Animals %K Humans %K Phosphorylation %K tau Proteins %K Tauopathies %X

Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phosphoprotein, is regulated by its degree of phosphorylation. Normal adult human brain tau contains 2-3 moles phosphate/mole of tau protein. Hyperphosphorylation of tau depresses this biological activity of tau. In Alzheimer disease (AD) brain tau is ~three to four-fold more hyperphosphorylated than the normal adult brain tau and in this hyperphosphorylated state it is polymerized into paired helical filaments ([PHF) admixed with straight filaments (SF) forming neurofibrillary tangles. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia but not to the same state as in AD brain. The abnormally hyperphosphorylated tau in AD brain is distinguished from transiently hyperphosphorylated tau by its ability (1) to sequester normal tau, MAP1 and MAP2 and disrupt microtubules, and (2) to self-assemble into PHF/SF. The cytosolic abnormally hyperphosphorylated tau, because of oligomerization, unlike normal tau, is sedimentable and on self-assembly into PHF/SF, loses its ability to sequester normal MAPs. Some of the tau in AD brain is truncated which also promotes its self-assembly. Tau mutations found in frontotemporal dementia apparently promote its abnormal hyperphosphorylation. Thus, the AD abnormally hyperphosphorylated tau (1) is distinguishable from both normal and transiently hyperphosphorylated taus, and (2) is inhibitory when in a cytosolic/oligomeric state but not when it is self-assembled into PHF/SF. Inhibition of abnormal hyperphosphorylation of tau offers a promising therapeutic target for AD and related tauopathies.

%B Curr Alzheimer Res %V 7 %P 656-64 %8 2010 Dec %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/20678074?dopt=Abstract